AU2016244220B2 - Human CGRP receptor binding proteins - Google Patents

Abstract

Antigen binding proteins that bind to human CGRP receptor (CGRP R) are provided. Nucleic acids encoding the antigen binding protein, vectors, and cells encoding the same 5 are also provided. The antigen binding proteins can inhibit binding of CGRP R to CGRP, and are useful in a number of CGRP R related disorders, including the treatment and/or prevention of migraine headaches.

Description

(21) Application No: 2016244220 (22) Date of Filing: 2016.10.11 (43) Publication Date: 2016.10.27 (43) Publication Journal Date: 2016.10.27 (44) Accepted Journal Date: 2018.05.17 (62) Divisional of:

2013205271 (71) Applicant(s)

Amgen Inc.

(72) Inventor(s)

Boone, Thomas C.;Brankow, David W.;Gegg, Jr., Colin V.;Hu, Shaw-Fen Sylvia;King, Chadwick T.;Lu, Hsieng Sen;Shi, Licheng;Xu, Cen (74) Agent / Attorney

Shelston IP Pty Ltd., Level 21, 60 Margaret Street, Sydney, NSW, 2000, AU (56) Related Art

US 2005/0282252 A1

TAYLOR, C. et al, Journal of Pharmacology and Experimental Therapeutics, 2006,

319(2), 749-757.

DAVIS, C. et al, Current Topics in Medicinal Chemistry, 2008, 8, 1468-1479.

WO 2007/076336 A1 US 7,288,251 B2 US 2008/0057063 A1 WO 2006/068953 A2 US 7,423,128 B2

2016244220 11 Oct 2016

ABSTRACT

Antigen binding proteins that bind to human CGRP receptor (CGRP R) are provided. Nucleic acids encoding the antigen binding protein, vectors, and cells encoding the same are also provided. The antigen binding proteins can inhibit binding of CGRP R to

CGRP, and are useful in a number of CGRP R related disorders, including the treatment and/or prevention of migraine headaches.

2016244220 11 Oct 2016

HUMAN CGRP RECEPTOR BINDING PROTEINS

The present application is a divisional application of Australian Application No. 2013205271, which is incorporated in its entirety herein by reference.

BACKGROUND

The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 14, 2009, is named A1472PCT.txt, and is 312,447 bytes in size.

The calcitonin superfamily of peptides includes at least five known members: calcitonin, amylin, adrenomedullin, and two calcitonin gene-related peptides (“CGRP”),

CGRP1 (also known as ctCGRP, or CGRP) and CGRP2 (also known as PCGRP). CGRP is a 37 amino acid vasoactive neuropeptide expressed in both the central and peripheral nervous systems, and has been shown to be a potent vasodilator in the periphery, where CGRP-containing neurons are closely associated with blood vessels. CGRP- mediated vasodilatation is also associated with neurogenic inflammation, as part of a cascade of events that results in extravasation of plasma and vasodialation of the microvasculature and is present in migraine. Amylin also has specific binding sites in the CNS and is thought to regulate gastric emptying and have a role in carbohydrate metabolism. Adrenomedullin is a potent vasodilator, adrenomedullin has specific receptors on astrocytes and its messenger RNA is upregulated in CNS tissues that are subject to ischemia. (Zimmermann, et al., Identification of adrenomedullin receptors in cultured rat astrocytes and in neuroblastoma glioma hybrid cells (NG108-15), Brain Res., 724:238245 (1996); Wang et al., Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage, Proc. Natl. Acad. Sci. USA, 92:11480-11484 (1995)).

Calcitonin is involved in the control of bone metabolism and is also active in the central nervous system (CNS). The biological activities of CGRP include the regulation of neuromuscular junctions, of antigen presentation within the immune system, of vascular tone and of sensory neurotransmission. (Poyner, D. R., Calcitonin gene-related peptide: multiple actions, multiple receptors, Pharmacol. Ther., 56:23-51 (1992); Muff et al., Calcitonin, calcitonin gene related peptide, adrenomedullin and amylin: homologous peptides, separate receptors and overlapping biological actions, Eur. J. Endocrinol., 133: 17-20 (1995)). Three calcitonin receptor stimulating peptides (CRSPs) have also been identified in a number of mammalian species; the CRSPs may form a new subfamily in

2016244220 11 Oct 2016 the CGRP family. (Katafuchi, T and Minamino, N, Structure and biological properties of three calcitonin receptor-stimulating peptides, novel members of the calcitonin generelated peptide family, Peptides, 25(11):2039-2045 (2004)). _ la

2016244220 11 Oct 2016

The cidelfonuf superfomfiy peptides act through -esen-iraiisfueoibrune-dotnam G~ protein-uoupfod receptor.- iGECRsl 'The caiettonin receptor v'Cl ”C) K' or' I receptor'5 and VtsER :.·! ρρίο<- ne u pc Π $”tufesy fT’miPt Ks, nhftb lumfo n>· hides other GPCE- th.c rceogm/e regulatory peptide- such a- -ecictin, glucagon urn; \a-oactrie intestinal polypeptide < VIP). 1 he best characterized sph..\ vtrianls of human caicnonm receptor differ depending on fo-e gfC-eoee Dm moth. t ’ Ri 05 Ci E ί no* Ιηουη as CI -. 5 oi .foserec Ebe nuijOf -pin e variant, formerly CTRip er CTKy now known, as CTy) of 16 amina. acids in the first intsakCiiubu loop ckirn ·„ί -J . I -pres-lon of two human skeletal caicitonm receptor ixoforms oloued from a giant ceil turner of boric; the first nth'aeeihthrr domain modulates ligand binding

H) und Mirm. U'<H>oueOo^?i I t. hn hired u bbfok^oo: QoodJIey * d Amy ho i-vcgtois mofocuLu coropoMtiou and phuhnaefoog'., Bioehem v»e, Dan- .. 52 Αό-'ό <2150-1 k Pouter e? al . dfo)?) I he exidene.- of .u u ed two t 1 IRP uveplor -pfitype- hud been proposed horn dilfetenhai untagemu dfinuhes ami agonist potCiivses 01 a \ eons oi m y*.« and ui ubo 'hfos&says, (Beams et aLXGRPfod’fi A calcitonin gcoc-rcbhcd peptide afosgonid rcvealrng calcitonin generated peptide reeepnu hctetogeneifi. ui brain -aid peiiphecy, j. Pharmacol. b\p Ihet . de ^: Idd I ?5 t P^fo 1) tup- et u<. Sniufiue ,»do dy profits of e detfomn gene related peptide in peripheral and brain tissues Peak-nee for multiplicity, J Phan-iiicoi Exp '1 her. 22 I ft I h- ”25 < 15>>S9); Dumont et ai., A potent and seieefo e CGE.P2 agontst, iCy \i ΓΟ?.~ ihi’GRp- eomp.inson in psotoiyp:e<b <'C»R fo ano I'GRPd 01 uh'o assay s„ t an I bTo stoi Phat inaCoI, ~ Go ”! - hi I oo~ μ

I he ¢. i SK Pi receptor subtype two found to he wnsuhe to me antagonist fomm-eth f'GKPifoG~) (Cuba et id , i'aieitomn geii..-i..iat.,d penude receptor antugonsst human ( GRhCG/1 \m. J Physio;,. de-OTEGI Ted? < S'dlhl Dennis ci al (l’>0(o; \fimeauit et al.

( -'snipd disc ufFiiilft·' ami OUgmud·. [sgcueics “1 wnwms fouwm e fo Uoma geue-ielPeO

2? penpda Imgmsufo on e-tDinsnm ^aoc-iekitec peptide rei.„ptois in ο.,υη did pestphesw J

Pharmacol b\p I het , dps- lOV-t. |pop sfoOjp p_}\ eontr.isk the t <«RP> receptor v> us senMtfi·, to iincnr human CORP ihCGRIG analogs, in which thr cysteine residues at positions 2 and ” wete des oah/cd < z g w<ib acetoemmeinedpri |iA-< AGMo jo⁵ ebe Gmtde [Gy μ! G pom ( l IEP fceepio'· wa- oisci-ebye to huemem < GRP<S- ⁱ'i (Demo- et .0 (1 'foOs r}_?._!Si,„_{( et} al ; I mGp Dumont et al 11T5

I n-anei-pet d'selt'. of calcitonin feu.-ptor -aid cakitonut-hk·. teC',.ptor ί 'CE'\ < I R.”o.r “GPt H h depend on the <ο··..-\ press ion of members of a family of a.eessoty protein-, utifodfhe • cecpto? ubsu\ oiodus uig poum-;E \\1i\i i'<», RWIPfanidy ineSodes bnee pmypcpndes < R WIPE R WIPd and RAMP?s that act as receptor modulators four determine the ligand

2016244220 11 Oct 2016

Spcclficdy ofreceptors for the calmlooin Bmiiy members. RA'MPs are type ! fiansmemhrane proteins that share about 50% amino acid sequence idenety and a common predicted topoiogc. v nn short-g tophmnui, C~t rsitnt one truns-inmntnvine 4-'mrtfn ted large ,’srra-e!hf:af V termim nut art sespensihie for the smenkm {.Mel atehsc et al. {Nds) regular: the transport and iigand sp.-ct itchy >u the xMehonin-tveephiraihe rt'ccptor. Nature- 505-533 h‘<Fraser et ai, i I'h'iOj fbe aunno of:receptor aetivhy modifying proteins is a critical demrroi'htmt ofgiyeosylaiton state and lighnd binding of calcitonin rccoptordike mceptmy

Moleeuku Ph-umjcoiom,, 55 rtSM-lbf’U

Io room the CGRP tc-eepmt vas identified as a hetetodmaer compos-., ri of a novel 10 sued transo-ienthr me domam <ί-ο.-Λ\ο% ponet-· reeepto^r aetuoy-iunhus eye pm-s-m 1 <R \MP1!. -aid CRLR (Mei -nelue u at. -amort f io^-lmkmg espettmenis se-gg-,sicd the ( tIRP ν\·'ρΌ! en^?'srt\'d ol <j one-’-wme s---- h'emcmt coiupen cm m CR’ P --nd k \MP' (Ihiaeet et al .ikt 2%, 43132-421 'Rl t2m;1 tt, tn<tre teccm stu-hes nsme smetal rnethodoloeles such a-- BRh I md Bd f mvetded that the nmehomd CORP receptor complex:

1.5 nur- be composed of as\tumenu homo-obgomei off'RI R and nsonm-iei ot'RWIPl iHetonv et< JBG 2S2- eii<l0 MUD<200/'P . . . .·...... J.-\Z pntttiedi Ri R \-tettntnai Jotrsam ti<js been sheen to sne< du'nlh btnd ~ l-CGRP tCkuiih-tn et at. Bmeiierutsi>\ -bh \2 ;200>)b eonittrnmg the important and dtreet ntut'aetion bx’rtwet! the t Ή1 R. ouh CtdfP hg-md hi pt-m- -dar. 1 en 34 and 1 ,-u 3-1 oft Rl R uv bebexCd to eommiute the dm. I nm site of me * 'dermnms l-Tsc-M ot (f d\P {B-snenec m al BMC'

Pharmacol o I unhetmore, Roller et al. thEBS i „-n 531-4-% iph t?f?P2tj obtained evldems th d th.e th-. \-tem-uvil 1 b annuo seal iesidues off Rf R <. otriribiries the -.-. teem e intefaetton with CORP or adrenomedtillin. and inner e> td t Biochemistry 4 h ή f’ 5 ''54 t20tUp μ, λμλ, ;h tt ;he \~t os na- -- n- m - - 1 te-n- tea 3 B rat e⁺\ P1 R necncre assocfd.tioi wnh RAMPl.

stmt tme-iun-mm a nah sts of R '\\1R1 menttfied r-’->i,ines '* I 10 o nhteh ret relate Jo “helis 2 tSimths et al. Btophss .1 °1, 6h2 mm >2000}5, ι·- pot-antalR signukem ut sme-’ tetton uh CRI R- and r, ,nines Typ'd and Ph.3 as potenik-ib mierm. tmg m tih the f tIRP hgand in connection mth its lundmo to the < GRP re-eptoi eoutpiev 1 teand binding studies using a human r<u RAMP I Mumem suggest that the binding she im certain small utoks tde tt-iulmoi-< off i IkP R p. g BlBN40OoBS), is Ιο-, med u dl-os ,-. region e- Inch n-elud-'s ammo acids ho 10? W R RMPI < VtaPcc el-d JBC - U?ri+ t ;2^<ff i20d?rt

CPI.R ha-. 55% ox-a-dl ammo acni -iCipteiice idetnt-s ⁺h i 'PR- although the η'ηηχποηί1·οηί/ domains ate ahno-c 80% idemies! {Mei erttae -t al t pug»; Royuct et ai .

2016244220 11 Oct 2016 inteniuttnunl union of plmn-iutoiogy ΧΝΧΠ The mammalian oukiitcnin gcsic-fdatc-.l peptides. tidrcnomedudm, amyiin and calcitonin receptors, Pharmacol Rev;, 54:233-246 < 300.20.

CRLR,kss been shown to form a high affinity receptor tor CGRRfwhen associated with

RAM PL on to premrentiatly bind adrcnomcduiiin ebon associated with RAMR2 or RAMR3.

<M, i ii’biie ci id < ^!uOSi, Sestets et al, Pc.cpnn i:cts\<L modsiy un pn-tems. ( > ikd <

Signaling. B' ⁷3-h3 LiOOi s. Conner es id , interaction ofc.dchoniri-gene-rehovd peptide with

Bn» ivtiHCd: SoeieO, isansueinu'S OVLtids 451-454 t20C2)) The y!y< ο*-\ t moss state of CRLR ss associated with As pharmacology R \MRs L 2 and 5 franspttfi GR.LR as the pksoiin sur'nbonie aids smut u etncieni tew howe' e? R AMP! presems ( Ri R r- <s nusmnally glyeusvlated, marine gccoptntem and a CGRR t.eeptoi whereas RaMRs2 and * psesent t Ri R >o ci imm-ftitre. tore civ- osy lined idw-non·. dtdiist recepics f'AM'M? AMRMn 'AM reeepuu ii'ras.u et-d i I ooo)} Cauru. ters/atson of the CR,! R, RAMP2 and CR.i R. R AMRA receptors In K0K293T ceils by mdioligand binding L'daidtenontcdohin ;is radioligands.

1.5 iunePems! w-sa·, <c W1P us';aMcm:>?>ii. <st Ιη-'η'Ιιοη-η ,·.! analysis < MA-puiym ty iar-uie get eAettophore'-i-O re\ eated them to be indistinguishable. esen though R \\iPs ? .mg 3 share one R,^s''<. asniiiis aeM s.<i-s -n- c id. d'o .n at P’’s ,,s Phfierene·. - busa bo. n ob- \t, howescr nt the pitanmsconmv bn < Ri R c\po.wed wsth R.AMF 2 \er-us R W1R 5. slosh CORP and CGRVf-32 >.is well a\ ndrenssnu-diiihn and the adrenoincbulbii-derixed peptide AM

2(i 22-M. .ne nets'.< at the RAMI* 5 heteiOdimot, unhealing that this complex nm\ act as b-nh a

CGRPmse an AM sexeptor (Hon it: e> <d , Brush jons-nal of Pharmacology. <40:4 7-4X6 <200$) Mat’ <-t at. Ihpertens Res . 26 ,\>-SS i.2s5tM}) tM-espsessiot'. of human CPI R with rat RAV1RR ,utd Gee ser<a. -,uaccsied that tlx R \MR1 ^pcJcs dekrovned the ph.-esnuiOiogie u et'i caetei i ΟίΟ'. o''itse <'Ri R ΚλΑΗΜ sonspRw w tbt retro t tow\etal »r<i!

nssleetsle CGRP receptor antagonists u.-ted, (Maiice et <d , Receptor Actb sty -Modifying

Rnoem ί deles runi.-<- the <χ\ίοί, v. seem Py oi non-p -pttde < t sR.P r u'oto. <noa .yunos, j Tboi Πκ,ίή 2 A Ko I-Ifo i j epos <20O2^v> I nL->s toeta„d odh a R \MR. ί Ri R t-no* known As bind any endoge-iots- ligand, it is ens?eody the indy <.<P< R thought to helms e tins way <( ο?!ϊί?«·<.ί id.. X hey iol>, tot towsmembstitu. ptolutes Its can nonin taeephu-hLe agonist binding and signaling: tmplLatksns (or ias-ruly R G-pmtcin-coupled receptors. Molec. Rhasrnaeol. 67(! ):20-M 62005 ss.

Calcitonin receptor <fT) has also been demonstrated to form itcterodimeric complexes w sin R, \MPw w inch are snown as ano- ini seceptor-1 \MA ',' ΆΜ V is.” or' \MX feseptot”) cenesalc, Ci RAMPi terepMss irefesred to as ΑΜΥΛ t<- ” XMY IM ha\e high afftntl·, tot

2016244220 11 Oct 2016 sahnun .dkitoniu, angiin ;·,ΐί»1 CgR? and tower aifhdu tot mammalia?i x'uieh\nnin- Ρινί I RAMIM ree/ptct’»MAMY>' or ΆΜΑ 2 '1 and Cl seieptotsr' ? 'or

WIN ?>, a \:il<i: p,ifte.n h man tpalb. xvSe'ted, dthenfoi foe jTni’.x fie ί GRP ;a (oweand n;o eot he Mgrufk-wu at plns-.olngieutk telex utt tkutid eotwenn stiou·» I he pteerO § raceme' phenotx pe is dependent on cell ΐ> pe and CI R sphee \ aram t ί Ί' ,_v or < 1u.»), p e tseni u !\ for R AMR2-getteiuYO atn\ hn n capim \ I ot a\ enpfo, a |W repoiunmi ol ovieeek.o like ».eds repo'-mOR expressed RAMP2, ί TR. and ( RUG but not R \MP| or RAMP* HI g et a: (2UO4i, t GiAopo'dos et ul, Mmopk onx lm te» eptot ao\e tn-m seeepnn aettx its -m-'foG ine ptoixit! attamenett with foee-defoinnt iaeepnn een; pteOuct, Moiaentar

Phe m -,-, Mom ->o ?d t piOOi Mnfi et <d At⁴ anix-m tee» pA;r °\ «ex -uk'e ftdR'v, mg t.eLMijsieetion ofncMeslonin receptor oRb teccpior acOx ny rnoclilying proteins-! or --5,

Fndot t'tneiogy. MO 29?4~3’C’ f p-GOy 8»,.-χΐοη e? .-d. (2001); Lenthauscr et ah. Receptoraeio its-modikmg proi.xm I torms ItetetoduneH with two G-protem-eonpied iX'eeptois to define ligand recognition, Btoehont, A. Ah 1,34‘Άό1 (2000k Giakaratnv et al, Amylin receptor phenotypes derived frosn Itnotrnt eakitomn receptor, RAMP eo-espres-ion exhibit pharmacological difierenees dependent ott nxeptor isnfornt end ho.·»* eeU environment. J. Pirmnaeol L \p (her , 2Α)'·ο I ~~2 t ?000t; Mat- amma et ul , Os*eot ln-»t-hi,e >vds express taccpiot aeuxnx medifome protein 2 application of Mei capone rmciodisseettssn, L Moiee, f'ndneniiol.; 3 » ?^J'M2bi 02002))

Table I, below, sunmiar kes the relafionskip of the receptor components dkevss: d above.

Table I

Receptor Component	CRLR (GL)	CT (cuteitooiri receptor)
RAM Pl	CGRF receptor	AMA I receptor
R.AMP2	AMI receptor	A MA .2 receptor
RAMP3	AM2 receptor	A MAM receptor

Therapemte use·» cd'CGRR atnugonists have been proposed. Noda et al described the Ά uu of ί GRP ot CCRP dia'i\atsxx‘- bn iohfoume pi -aulet aggregation and lot the ireatnixnt ot pre\cn-ton M attorn-sekreMs <>r thi'emt-osis, J'P OAMk Bi) I m et al xhseh-sed tharapentn. uuents that modtd.0,’ th* teftx nx oft' fR, mt lading \ ,-Mt le-eonjoe »*ad pepndes stt-en as eslettoum and b-tmuu of GRP (WOOi MUM M2,1 S 2fo)2 OOfoRMn A;) \ dsoaetjvc CGKP pentiik* antiigonkts ,m»i their ose tn u method tor inhibiting ί tdRP binding to k GRP tecepA'rx

2016244220 11 Oct 2016 n erst disclosed by Smith ct al , such C GRP peptide eikgvui.n· were shciy-u m inhibit CGRP binding to coronary mepy membranes and to relax capsaicin-treated pig coronary arteries. il'S Pat \o i’,.?o\V'4 111;'ahU I S Pai No 0,7'd' ?05 IP'» Pkuctal Cist loses! peptide analogs with CGRP receptor uutagomst ad-s tt\ and then use In a drug for treatment and

- pwh}'h'‘ a \< JCiy o* stoeU's'is lift 19 ’t?o' | ;

CtiRP is a potent wsodbutor ih-n lets hem- unpixah'd m die p-'dnntn s tri'a number of \asomotor symptoms, such all form-» of \ascnlar headache, including migtainas iwith or n nhote an-u asd ekr-tet Va-hi he Dnthatn. Y I'm I J Mu⁵, GO ί 0⁷t-1 ti ’5„2004 Mimam; padiuphy siolom involves the autsaoon of the trigeminal yanghe, ohetx < GPP h

P,t hn ?h/ed <e\| t'GPP \eis siyisd'ic.e:t:\ e., n;ase dir mg a ntg.r one eta s fhfs m tun·, pto notes u.x u! blood \es,e dp.gion .aid nemos. „ sic it Oanruamin and <ns ncto'ou rDoods, G.. Cun. Opm hn.c.-mg Ditn.\\ .1 I de I -I ?OX p?00' tt I'mtlter, the setnin levels ol CORP in the rMesn d juguku vein ere ck-saicd tn p-nients dutetp ongtame headache GsvadOv et al,

Anri Xcurol dm I kb 1Ό0, bum'. ettotts administration of human ci-CGRP induced

I 5 itcade.be and nugom¹'· r- paUsi '*> 'UOCicig buns nujf.uue s'.ui'Oul aria, simps'll mgthe \ ic's that (tIKK hasae;tus tine role m migraine tL<ts,->en ct .ft ί ephahdgia dd Si ><1 ?P0d

Migraine is a totnplex, cosuntitn neurological condition teat is characterized by severe, eptsothc attacks ei headaehs and associated matures, o Inch mm. include nausea, ssnintiue, ocnstte. ns lit bgle, sound ot nun extent In xo.ns’ paifersls the he.id.it he fs pun jden m aevompan co bs an -nt ’ u ncu.k,' e punt r.a\ be seme's and Tas j.ho x' .an. ,\„e'm certain p-dtetits. Migrants' attacks .ns' drituptne to dairi life, hi I. S ansi Wextern Europe, the o\ eta 11 ntesaleiu e -u migt^me '.miencxs i- IP' - of the neueial population «ο*’,, nudes. I s- ί kbf.-mat ot hut th/nnor.·, the toedi tn irequenc'. of macks m an uijo. idti ft o, t _? mount s\ hue there -ire a number of treatfuerrs .isudteds' to r.lisw >ax? o, i eslurs' symptoms, pres enltve therapy is recommended for thoxe patients has mg more th-.at 5-4 attack.'·; of migtaca; per month,

Goii'oby. et .P \ w I mJ j M d Cuxl) np' Some ms era me pa e< nx luxe e vu tic.stcsi y, uh topmumdc, ,.u .etiteoro uriant that Nocks vdiuge-slcpenocm sodmnt channels and - s'tnuu ghn.un.its' rixepiors « WIP-k-k.nn neb potentenes G Ml A-A isveptsn' n> 1 is tfy -uid blocks earbortic anhydrase, fhe relatively recent success of semtonnt 5iΠ-d ri IP anti or .511 Γ30 1 a receptor agentstx, such w sttmutripton, in some pariesix has led resesrehejx to propose a seriUsiUfint. -..itoiog\ os the dfsordci I 'ntbtmnuiGs, '.sink; smtv patients wspotal sscli to tins treumenr. svhets uv rehitisely ο,ν_Ληηη η> us s-ri vis itos-sbl.'r GRP insol',eincw m mimaius· bts l-cuu the basts foi tint des ciopment and Lsime of a numb;; 01 eompotaids that n'thtott >elease ni CORP (e g., sumatuptan}. aniagont/e

2016244220 23 Apr 2018 at the CGRP receptor (e.g., dipeptide derivative BIBN4096BS (Boehringer Ingelheim); CGRP(8-37)), or interact with one or more of receptor-associated proteins, such as, RAMP1. Brain, S. et al., Trends in Pharmacological Sciences 23:51-53, 2002. Alpha-2 adrenoceptor subtypes and adenosine Al receptors also control (inhibit) CGRP release and trigeminal 5 activation (Goadsby et al., Brain 125:1392- 401, 2002). On the other hand, treatment with compounds that exclusively inhibit neurogenic inflammation (e.g., tachykinin NKI receptor antagonists) or trigeminal activation (e.g., 5HT10 receptor agonists) appears to be relatively ineffective as acute treatments for migraine, leading some to question whether inhibiting release of CGRP is the basis of effective anti-migraine treatments. Arulmani et al., Eur. J. Pharmacol.

500:315-330,2004.

Although the precise pathophysiology of migraine is not yet well understood, the therapeutic use of CGRP antagonists and CGRP-targeting aptamers has been proposed for the treatment of migraine and other disorders. (E.g., Olesen et al., Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine, New Engl. J. Med., .5 350:1104-1110 (2004); Perspective: CGRP-receptor antagonists—a fresh approach to migraine,

New Engl. J. Med., 350:1075 (2004); Vater et al., Short bioactive Spiegelmers to migraineassociated calcitonin gene-related peptide rapidly identified by a novel approach: tailoredSELEX, Nuc. Acids Res., 31(21 el30):l-7 (2003); WO 96/03993). Further, a potent smallmolecule CGRP antagonist has been shown to relieve moderate-to-severe migraine attacks, including migraine pain and migraine-associated symptoms, in a recent Phase III clinical trial (Connor, et al. Efficacy and Safety of telcagepant (MK-0974), a Novel Oral CGRP Receptor Antagonist, for Acute Migraine Attacks. Poster, European Headache and Migraine Trust International Congress, London, England, September 2008).

CGRP may also be involved in chronic pain syndromes other than migraine. In rodents, 25 intrathecally delivered CGRP induces severe pain, and CGRP levels are enhanced in a number of pain models. In addition, CGRP antagonists partially block nociception in acute pancreatitis in rodents (Wick, et al., (2006) Surgery, Volume 139, Issue 2, Pages 197-201). Together, these observations imply that a potent and selective CGRP receptor antagonist can be an effective therapeutic for treatment of chronic pain, including migraine.

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

2016244220 23 Apr 2018

Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

SUMMARY

According to a first aspect, the invention provides a recombinant antibody that specifically binds to human calcitonin gene-related peptide (CGRP) receptor comprising a heavy chain and a light chain, wherein the antibody is isolated from a host cell that expresses a heavy chain nucleic acid comprising a sequence selected from SEQ ID NOs: 242-258 and a 0 light chain nucleic acid comprising a sequence selected from SEQ ID NOs: 224-241.

According to a second aspect, the invention provides a pharmaceutical composition comprising the antibody of the invention and a pharmaceutically acceptable excipient.

According to a third aspect, the invention provides use of the antibody of the invention in the manufacture of a medicament for treating a condition associated with CGRP receptor.5 mediated vasodilation or neurogenic inflammation in a patient in need thereof.

According to a fourth aspect, the invention provides a method for treating or preventing headache in a patient in need thereof comprising administering to the patient an effective amount of the antibody of the invention or the pharmaceutical composition of the invention.

According to a fifth aspect, the invention provides a method for treating or preventing 0 migraine in a patient in need thereof comprising administering to the patient an effective amount of the antibody of the invention or the pharmaceutical composition of the invention.

According to a sixth aspect, the invention provides a method of making an antibody that specifically binds to human CGRP receptor comprising:

culturing a host cell comprising a first nucleic acid encoding an antibody heavy chain 25 and a second nucleic acid encoding an antibody light chain under conditions that allow expression of the antibody heavy chain and antibody light chain, wherein the first nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 242-258, and the second nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 224-241; and isolating the antibody formed by the heavy and light chains from the host cell, wherein 30 the antibody specifically binds to the human CGRP receptor.

According to a seventh aspect, the invention provides an antibody when prepared according to the method of the invention.

7a

2016244220 23 Apr 2018

Isolated antibodies, antigen-binding fragments thereof and other isolated antigenbinding proteins that bind CGRP R, particularly primate CGRP R, e.g., human CGRP R, are described herein. Such isolated antigen-binding proteins may selectively inhibit primate CGRP R (as compared with primate AMI, AM2, CT or amylin receptors) and may bind both

7b

2016244220 11 Oct 2016 fise t, Rl R m 1 P VURi mnpme uk of ί GRP R The ί GRP R bmdmg p'viero-, _v\ a-y toursd m nfr'idG. mic* lea v> oh,. ot roodeLoe at Rust one id the b'viogical responses telated ίο ί GRP R, and,as ,sf.ieh. are u.-chii fot myl i-sratme the effects of GGRR Roehiftei ο» bsordeis

Binding of certain amigen-bnidnig ρη items in CORP R caw there fi.ew have one o- more of the hallowing nofivlti.es; mhibifiog, isiterfertng wifib or modulating CORP R, ibhiblthig t a\odid;diof\ decscasutg ncurifgeiue l-dlarometiois, and afiex ititiifg, atneihfiatino, tienting, prex entfitg, or reducing sv mptomc of chronic pain nr migraine.

hr one exemplary aspect, the isolated iintigen-birtdini.’ proteins seleetiveis inhibit itHtnau ί gRV K\epU'j mscom \ucn -writ the nanon \M1, VG2o' as v b, weep hs some i 0 <, tnbodtmi nN, the isolated arstyon boidst-a; n?os ι-i .selecoseh mh<b'is fire Soiw CGRR Ό-,νρην ά uh a seieetw ratio of 50 or more, ?5 or more, i 00 or more, ί 50 or more, 200 or more, 250 or mom, 300 or more, fi0O o? more, filO or mn?e, 750 or snore os 1,000 or snore The begs ee sn M'leGov. muihinou way be determined using aw- suitable method, e g.. nsnnj a eA MP assay as described ηγ the Karoples herein in some embndimenis. the isolated nnugen binding protein

1.5 speeiisealb,· binds to both human CRLR and human RAMI*;, and doe* not speeibeall··, hind to human AM'. human AM2 or a humanamyhn wcepwr te g. AMY! -os AMY?), For example, die ·>ο, e'ed amseen Mp-i'm» pswmn mas sne<dn fix bi'd hum οι CGRP R v, th a R , f uM, ' 100 nM,i0 t’AL or - e nM In spin/ embodiments, the isofated anttg-ot binding. protein opeesh, ad·, binds to human t 'GRP R <\ nh a R,. ίΟΟηΜ, 10 nM, o^r 5 rVf 3« determined using a 1 ACS binding ;ts*ay and analyzed, for esan'ipie, using methods described in

R ithen.cm arm, cr td.. fiw· «οκΡι/; <n <.>' finy/;; My/ ή\ nuft c CowmuncirPiy?,» 55 I ^200.5) 101)4 ί 01 > in soim embodiment;- 4-,- isoiat·, d othgen binding psoiesis h is a !\i of'-100 η vb -10 n\l, >.i n.M, <0,5 nM or g0.1 nM m a CORP binding competition assay, in some ·, mKidimenrs, {'ne isolated aisOm n bmdsm- piots-*i has a ba of' 1 00 nM, '-Ml aM <-20 ΆΙ - ί 0 nM, '-1 nM, '-0 ;- >Λ1 t>< Ό 1 mM m a laibesitbeh ,1 ^!' bCGRP hindum competition ,<-,sa\ to mesid'ss'ies Oom , el is expressing human ί GRR R, for emntpM. the a^say described m Example 5 herein, hi another metrp! ro «cp.a t, the isol Ucd anoeen-bmd og ptofems compete tot bm-hm: to hnmcii'GRR R, e g , the e\tia,el^!u'aj ootnmi 0Π GRP R. oUb ,1 tefesenee nnssbodv ?0 composing a heavy Unno v.uiub'.e region comprising a sequence ^Ucen.d from the gmcp eos-uMiing of S: <g Π * \(> Gh-lMt as«d a light >, hmn xatotbie teeion eiiU-nuxiag <. se.teenee selected from die group coonso-m of bi Q lit SO id ' led in some embodiments, bmdtng < ompentnm is a-sessed using,1 'swum-, .bvits, e e , -is-ng,a isieco.· .maRxis, fia exatopie, d'svieed’ Ivs'jo Mu cm n-on emood' ne'^< -,, 0^ '-o an ,1 a^!i>gea bind „ pnMc is

S

2016244220 11 Oct 2016

- ompete>, for Dudtnc g; human CtjPP R urh ,i rclNem antibody, the refc orc ar i’»i Is etmipteottg Pl ,t ueas_? cbm· wid e o atou composing a sequaioe sePeied front t < ot.p ennsximg of Ss Q ID NCx ri<L Mu, ieb _>inp g s ,md (u'> η 'nfu ih.mt xatia'Pc region vompristng -,-. 'xqueticc selected from the muup eonststntg efSLQ IP \Ps. HO, NN 146, NM and 150. In certain embodiments, the reference antibody comprises ( I; n heavy chain defined by a seCiiiencc sl.eit d from the group eonstDtmj of Μ,ρ H'S 52. N, >5, 5” ami dec and Ο·} a hght Cram defined by n seuuet'ec .-elected from the group eon^-eme of M Q ID NOc id, IS, 2;. 2t ,md 25 hi more -pectf'tc embodiments, die veiesence antibody ..ompttses a frmoy J'at a J ', haht r'am ,Liieee Ps o' >, oltx, ,oi'os\ tec pans ot « acve.-i s^MQIPNO >2 atm SF-'Q IO NO lit <Ε)5ΓρΐΡ\Ο 54 atm >dQ IP \D Ht no_} SEQ IF) NP 35,mdSbQ IP NO 2I; iivi SEQ IP NO- r; and $fiQ m NQ; 25, and (ci SEQ IP NQ- 5U and SEP ID NO’ 35. in one such emiiodimenb die reference antibody comprises a hmo y einfitiefrotprising Sid'd iQ NO; 42 and a light chain comprising SLQ ID NQ· 15. fn another such embodiment, the reference ’nobody -< o-mpii^-s a he.e,\ chant comprising SEQ ID NO, 4 I md a tight chain <,? np'm p nt Q ID NO c la ,.ο η χ* . nbodtm ' t fit, tt 'etc < e a , ' \'s urop >' ^x hemy chain iompristni* SEQ if) NO' )5 and a light chain comprising SEQ IP NQ' 21, In aitoiher such embodiment, the reference antibody composes a hem y chain eomprisnig SEQ IP NO. 5 mid a Sight chain comprising SLQ ID V >' 2⁵· In .mother such embodiment, the o.:t>,.'t'ence antthody composes ·, hems - bam -compt r-mg SEQ IF) NP Ni and a light chain £0 comp; rung SEQ IP NO 25, hi <.ertam embodiments the o.dated miigen omdmg proteins that compete tor bmdmg to hnt^!a.m ( PS.P IS also sCectody mhibn the hnmtm ( uRP t'ceeptoi, c, n Uh , -.Mei tony t«tfo m 100 or more, 2?0 m more, 500 or more, -’>0 or more, 1,000 or more, 2,500 or more, 5,000 or mom or 10,000 or mote, and suelt selectivity may be determined, e.g., using a cAMP assay as described in the Exnmples herein. In related embodiments, the rsolnted attrigembirtdrn» proteins that -. ompete tor binding to hunt nt (.'GRP R specifically bind-· to item.nt t 'GRP R n uh a R;_f I iiM. ? 100 AM, M0 n'4, i?t 25 n.\E e g., as determined using t; S ACS binding assay and analy md, lor evntipk', iishnz methods ucs,i ibcd m Rnthana^oam- et rim, is >,<>;> <?' ίΟή.-ί.’Ρ'Οί tri Gmifiimrii trimfio 544 (2005) 1004 1015. it; related, embodiments the

Isolated antigen binding proteins that gompete mr binding to human ('GRP R Ease a K'i of 100 uM. ' 10 nM, ' 1 nM ΌΑ nM or mt I ttM o; u I 'GRP binding cotupetnimt assay, em a radioiabeled Ί CGRP binding competition assay to membranes from ceils expressing human:

( (iSP R. to- example, the as.,-,y d, ph.-d m 1 \ampl· ΐ he’s.ut

2016244220 11 Oct 2016 hi an> oi the nboYe-numboned embodiments. the isolated antigen-binding piotem that compete-' for nnidose to immau ((u\P K m.o nc, lor example. λ monoclonal .mtfhotfr, a pob, clonal amibod). a rscominnato unnbody, <i human (e.g, fulls humtml anlihiKb. , a honsasd/ed atfobed'.', achimer-e anubtHly, a mtUii-'Specihc .embody. or an antigen buxhng hagmeifr tfereof

Fufrter, the antibody fiugment of the isolated tin dgsp-binding protein that competes for binding ♦o ;mm,m ( t sP P k <. be a I ,,P itagm.t t and' , f ioavueiit, a H lath '5 amen a fragment, n dtuhody or a stogie chai?· antibody moieeuki and may he, tor c.xuropk', a human ironoeka-ai annbotp,,c g,ar Igui- ig<ifo, Igiko* IgcO-ivpe mttfood'' hieera-n embodiments. the isolated antigen binding proteins that compete for binding to human CGRP R f0 uno >’'» neitfitill/tog antigen i’Uid'ng piofems

Inecfinn exemplar aspect- uk isolated antig-. u-bmdmg piofiuns deseiihcd. e.g .

isolated antibodies or fragments thereof, eorupffse (A) oho or more heavy Chain eompiemeutas » defi-rtommg regions ΜΊ )RHs} s.-iei. ted bom the gump consisting, of. 11) a ODRDI :u\lne Pfrfr \G'I a A t to a CUKH? laonm McO ID \O ke.iei M'DRBd

1.5 n, e« nig SI Q ID \D ISn. and option ok <0. t a CDRH oi 1 i), io'> and > tot th,U emu. uns one ot more atnmo aesd -mbMiaPous {.- g, eonsetvutoe m-nnd red ^n'wnotoenss, .lek-fion'i or insertions dee eoUeetlxeiy final no mote fran four ammo acids, (fr? one or mere hgln ebnm complementer·, determining teuton-' ί('DIG si -elected from die group consisting of, Ml a CDRI i selected front the group consisting of SFQ ID \'Osi07, 1 < I and i iS, idle CDRl 2

2b selected front the group consisting co SLQ Mfr, H)X t Id .md 11A uh 5 a CDRI.d selected from the group ettoskhPo of SbQ ID RD- 109, 11d and 1 .lb. and optionally (;O a { DRL of it), t o) <eid igiR tn P s'ontums eno-η naue,c g , one. one, three, font ot nmse, ammo utd supstituifitos (e.g , C’tosenabY,- ammo ac’d <tohsmitoomri, deletions or insertions that colleen·»elv total no mme than foni ammo ,u id< or U 1 one or more heasy cbain ( DRI I- of (Λ 5 and one or more baht chain CDRl.s of RDF

In some embodiments, the ί 'DRIIs further sekebed from Hie group ,om;ixrmg of {i t a CDRH 1 having SEQ IP M Me 1, tut a < DR 112 having SEQ ID NO-152; (iii > a CDRKe ti e.ino Si 0 IO \t t 1 frfr and «ptiou.dfr <s\ 5 a CDRH ot iil, tut and tg-o ih u concern on<- ot more, e.g . «re. two, three, four 01 muse amino acid substitutions (e.g . conservative amnio acid supsimuionsf deletions or m.-eraon.- that collectively toed no more than three amino acids. In ret bed embodnucnis, the ( DR I is ate fmdiet sekx ted bom the suoup <. ensislutg, id'ι i a CDR ill selected from rite group con-oame of frf-,0 ID \0- '0, 100. M!, Me and MS. id > a (DR.II2 selected funn the group i-oi-sisiim·. of SI O ID \D S'k (Of, M2. MB. Me. ;md M'h iin) a ί'DkDe selected itorn the g-'-mp consisting ot SbQ ID NO 'fo, 102, 123 I d'\ and

2016244220 11 Oct 2016

130; and riphonghy (ivj^a CDRH ef (i), In) Arid (iii) driri one Of more, &;g,_s ooo_s hvo, ihtee, touror more amino aud soi>hitiuons (e ^,, eonscr,avoe annuo aesu -nbsmuhous), deL-non- or insettions fh.r. cobecnieiy \ί d ηυ owe than two -antne a· uh hi othc'· -iat,-d ctnbodtments, the (ORihs an.- mrthes -Ohek'd ftotsi du group eonsi-pjm of. (>5 't CDRHi .-><keri'd from dt,.- group eon-kdng of SI Q It) k<) \C Ό, N, s2, be, s\ ‘Y ’*'0 jud IdO; (ii) a (OBJ (2 sekeicd dous the group i-oh’^mine of SI'Q ii) V > “4, ~7, sc, S4, bo ho, ο), 005, ^!'^!h, Id), and 1 ?0 hn} e (J5RH3 ->eiec’','d from die group eon-isring of si q ID \Q γ, Ab 3k S;u, s>7, o(s, ^:5u, qo, icc, 4.5((1 t2 ¢, _ϊ5ι,| optionally ;ο) u f J)Ril of os. (ut and go) dari t onhmis OiK or ipoix, e.g., one, two, Ibree, font or more annuo aeul Mthsimmotts te,g, eou>Cf\ao\,.

<um o ,s d sub-anal ns, < < eat is t m on* m tob-ureR tu‘no no i iimmi m neidk ίη ,sotne embodiment v die CDR) ,s are ivi-her sek-, ten from die croup -. on,oMing of (A a Ci)Ri 1 selected Roni fee pomp . oii,st,s{:ngof SFQ il> kb Rt~, 11 i mnl 1 IY <b > u i'DRI 2 >ekct/d d'om dt. “tot p ^on-oama of si Q d> \(Y ,bY ¹ i md i Cc (uC a f CRl * -ekered

IS port 0 i. porno - ossisiaig o' SFQ ID \t)s Y;d. Yard' and an; on dri {. s m, t DS i ol V\ in i and mil dun, -orsiauis one or more, e g , one, two. three, lour or more ammo add odOmnOn- ,e g , i on,>er\>iri\e enmo .a- -d suboatutiotts), J ’Chous m owe¹ non- In \>ίί, eniboduneuh die annuo eetd -nb-tituuons uea , eon>enau\e annuo aesn vabommori-i, ,denotes or m-ernous colls ·- use!) to: a! no mon th m three ammo a, ids per CF)R? In some embodiments, th; ammo mud suksuuriiom-, deletions or m-eittop- collci.i^!\el\ total no more than too aiinno aeulspc< CPRi . In rji*.-d emhodnruuK die ( OKI s .-re turthet -elected from dis' menu comm-emi. of «< i a ( DR! i seiei led horn die unrip ιοηχιΜνίί» oi'SFQ II) \d\ '<?, b, eke ', o?, <>q, |0J, and S 10. dC a (' DRI 2 seie-u-d from di, group eonostme of M-Q ΙΠ Nils 4b -~2, 55, 5S, e >, ”0, 10-4, ids Π4, fun a t,'l)pf4 sek'Ued homdmtjimp eoUMsung ol b( (,) H) k()s 44,4>5, ?o. 59, ;<4, lof, ,m,l I (ip, and opdonalh cm a < OKI co *i\ in; and (id; rime eonbmn; one m mor>-, e g , one, mo. three, four oi mors- annuo aesd othbimthons o-,n _x,,.onsetsatn., ,-,ηηηο ueid suPsutulmns), deh-uons of insertions th„t >, ode» its eh ioinl no more dutn nso aimno ends <n odmnena! r>,; iUd emhoritmi ni-, rite (ORLs are burinm -eieeied wm rhe group consisting or ill u C'PRl· i ^elected from hie group

3d eonsktine ol bfQ H,> \O-, kb 45, is, 51, e I, ? of, of, um and mb t id a ( i)RL2 eelecmd from di-, gtotep eon^s-nug of Si Q sD \O- -4 b 4m 4¹), 52, 5s, (,p py _ti,y_{s d}

CPRI 3 ,sek\ m<?i fr mt the uronn ^om-tamig of SbQ ft) s,s,u 4r, i' p(„ ?], and ~2. i-ud ontiouady ;k 1 a CORL ol (th (if) and < hi) ritat contains one sir more, i. g , one, hoc, three, tour or mom ammo acid subsumdoms fe,g„ eotusersahve ammo ,u,'id Md-Mhuttons),

2016244220 11 Oct 2016 ilehmons m bi one en'bod.nsvm, the torn! number m «it.iiro <n td oubuuamsus dcLnons of ntserisons ss so more tUm two ammo -.w-cl· per < DK ns another emhodsment she sir?)' <i ae.'i MibsinuPetw _tue os tcj > non subsManors

In nnntbnr embodiments the isolated atiiigcrt^htndmg protein comprises at least one or ? ΐν ο Ci3RII vt m> m the .:><·« < mantoned {Λt and as ien.si one or m0 f DK I of ,„n _u? me dbos e-π-eu Ron cd «Β), in >ct anoiDn enModnmi'uh the odsded auttgen-bmdmg psomin compm-cs put leasi three CURB oDm\ m the ,>bo\e mentmned ίΛ). whefe she thive CDRiri melode CDRIB, a CDKIid and a t 'DRIi \ asu'I su) <a least risree CPRi oi mo of me showmentioned f IB, where th^ thus. ( DKI.s mclndc CPRi Kat DRi e and a ί DRJ d tn additional cmbodmb-Ms, she fsvDted am mm bmdmg prmen‘s dm on bed above comprise a Erst, ammo aud sequence eontprisinu as least one CDRJI and a sceottd amino acid sequence comprising at least one €DR I in one embodiment the first and the second amines acid seno- nt e- are . omieofo bonded So vaen οίην, fn anosiser aspect. she isolated antigen ·Κ<ηη<ηρ proiem inclades a CDRB I, a CDRB?

and a < DRIP In one embodiment. < DRIB usiapiio SI Q ID \O ’K CDRB2 compos.-s 'stp IBM) Ί and CDRIP eompro.es SK? ID\D /? 1st another ensbodur.ernP 'BkDI composes Si'Q IB M?~6, CDRi I? eomprrieo SI 0 IP NO ¹? :mri CDRII3 totnpnscs SK) IB Ms,'R hs another emhodvnust, CBR IB cotunrtscs SK? ID \D'^vo { ΠΚΒ2 comprises >BI ID \< f SO and t 'DEB? eompooes SR? ID SO KI In aasshm’ embodiment, CBR111 ..mnprries \i fit IB \O S2. CBRB2 commas K'V IB \D \?.mJ ( BRBa composes Si Q IB V1 ri* in moth'r embodiment, CURB; eosnprises SK? ID \O:S5,ⁱ 'BKH.? comprises SEQ IB \D D' and t DRI i'< eonmnsea Sl.sp IB \O K? in another embodiment, t'DRII ί comprise* SK? ID NO:bb, ( DKB? comprise·. Sh(? ID \s.)'v's CBRH5 eompr-sC'i SEQ IB \O 90, in another > mhodlmem. CBKIB eompnsesSKQ ID \D R,„ ( DRB2 <. ompmso.s Si t? ID \O 91 ami

1 PR IB composes sj i? IB \O p ie anothet em><>d-.ment. f DRIB tompsssv si Q IB

BQ'92, CDRB? t emprises SK? IB \D 93 and ('DRIB comperies SR? ID NO 9,. anofhv? embodiment, C DR s i i vOipo-es SIR? ID \O o, t '1 )RB2 vOifsprssc , SI Q ID M'« K· and CBR11? 1 vmpri<-ea SFQ ID \O'”K In atsorher emlforimfvrih t 'BRI i I t omprsse'·; SIR? IB \B ?* { DR1I2 eor.pifses s|,p ID RD - e,«| C'DRID cmnpo^s SfQ sp \p On in anothe?

embodsmes'it. CDRHI comprises SEQ ID N'O;97, (' DRM2 comprises SEQ IB MO:dR and <DRB ' eosnpusvs Si's? IB \< s no }_n ^noshv; embodiment, ί DRi 11 comprises SK? IB \D IPO, CDRB? evnsnrt ,es SK? ID \D BB mM CBRBKomprm-, SbQ ID \ρ·|0?

in atsotbet <ipe-1, {he wdaied antigen-brno-ng pmtmu metud, - ,K DRJ I _x,-,pj,-;!,e, a, ( DRJ J se.jiii.nce and a CPU! 3 sequence 1st one coal-eds-ncsst. t 'BRI t eomptsscs Si D ID

2016244220 11 Oct 2016

10:42, CDRi 2 comprises SEQ ID 10:43 and CDRI..3 comprises SEQ ID 10:44. In anoiiier emk'dhoem. IOKI I roiepi^.s* ?d Q IP SO 45 < OKI J vomptisc’- e>LQ IP \D 46 ..nJ { PRi 5 comprise* SEQ IP SO 47 In another embodiment. I DRI i comprise* SEQ IP SOPS, t'ppj 2 ct-mp-u-'Cs M Q ID SQ.4’> and I'PRI 4 tempu-<s si q ip SO,50 In ant’drcr ? ^mbocamcni, ( PR I I compose* SEQ ID SO el, < PRi 2 composes SI Q IP SO e2 md CPR.L I composes SEQ IP Sp.5! hs anoihe· embodiment, CPR.I I composes SEQ IO SOU I ODRE2 ^omprlax SEQ IP S’P;55 and C PRE,? comprises SEQ IP SO;>o In another embodtm.M, OPR! I composes Si Q pa \{> OPR’ 2 composes SI Q ID S(>-s -mJ t'ORi * compo-e* m-Q Ip SO -m |_n mrolhet einbndfineaK I'PRI : sompi'^es SEQ IP i 0 SO o<), CPRI '* composes Si n IP SO '? and CORI 1 comprises 'si Q IP \O ^J'o in ,mp*her ernbodtrnem, CDRi.: comprises SEQ IP NOP*. CORI.2 comprises SEQ IP SO;6| ;md t DRI 4 tempos-.* SEQ IP S<) 4” in anoihet „mbii-hmenE I PR! : tempos * SRQ Ip SO;62, CPRL2 comprises SEQ IP SO:63 and CDRL3 comprises SEQ IP SO:64 in another embodimeiv, EPRi I compose-; SEQ IP 1O;65, EPEE.? comprises SEQ IP 10:55 md i 5 CDRS..5 comprises SEQ IP 10.56. in another embodiment, CORE': composes SEQ ID

SOs.o, f PR! ? vompuscs SEQ JO IO 0' ano ( PRi 3 comprise* SEQ R> SO t S in ancthm emboOm'h m. CDR i : conmr *e* Si Q IO SO O’h CORI 7 ·. mimosas Si Q H' SO 7<J md < 'PRi I comp: >-<* S!.O IP SO,' i in .mother cm bod mu.-nt < 'PRi i comprises SEQ IQ IO oR i PRi comp, xys sj 0 Ip \Q 0 ,mP CPF I ' composes si 17 IP IO 7 in another aspect, the l-mialed antieen-bindine, protein tncimR - a ( PR 1. i -icqncrtce a ( PRI 2 sequence. a CPIUe sequence, a CPROI sequence, a CDEH2 sequence and t CPRii? scipivnce In one emi'odinu.n-, CPRI I cmnp.r-ca SEQ IP SO 47, CORE2 comprises Si O IP ,10:13, (PRL3 compos M Q IP SO 1 1, CPRU I -, empn*-.-s SbQ IP St?- m ( pipf/ composes Si 0 ii/ SQ-74 ami i'PRii 1,oinpitscs SEQ iP SP 5 hi ,moC-ci et--bod·mem,

CPRLi comprises SEQ IP 10.45, CPRI 2 comprise-; SEQ IP 10.4*·, < PRI.3 comprises SEQ ip 141 4”, C OKI i i comprises SEQ IP 10:76, CORI 12. comprise* SEQ IP SO 7? mvi CDRII5 eornpns.-s SI,Q iP SO Ί in another embed-menu ( PRi I eotnptis„x Si 0 JP IO 45 t PRi '^f composes S{ q ip So : \ QpFf 4 e-mipm-mx Si Q IP SO %- CPRPI -„mtsp^*es Si O IP SO 70, < 'PRI !2 , otnpttses SEQ IDS?¹ SO ,md t 'PRi I > eooipnses SI Q IP

St)-s i in another embodiment, I PRE I eotnprlec SEQ JP SIE51, E PRE2 comprise-; SEQ IO SO -7,1'PR! t composes s| Q ip S(» O, CPRH i eompttsc* SEQ IP St) s2, i'PRii 2 comprises SEQ IP SQS? ( PRH5 comprises $EQ IP 1O;S4, in -mother embodiment, ('PRi I eompuscs SEQ IP So Χ < DRi 2 eompt-ses SEQ IP So 55, < PR I ) composes SEQ IP 10:56, OPRIi; tompri^s SEQ IP sn_;s?, i'0Kii2 comprises IRQ iP SO.ht- and

2016244220 11 Oct 2016

CDE'IP < o'n’hes hEf) IP \O h Ir armhet er bo I rem t DR! 1 - o'np' w. χ Nf 0 ID NO 3Έ ( Dki 2 compost SEQ) h> NO c\ ( Dk! 3 compiles Si Q ID NO 3Q < DRDI comp'iscs hi Q ID NO,OQ QDRD? >t>mpn<es SI.Q ID NO so mU CDRII ) totnptt.se» SEQ ID NO.Or In innthvt emhodsmenkCQRi I ct-mptiscs M Q ID NO.tdb I'DRi.2 comprises ShQ § ID NO,55, < DRI 3 comprises SEQ) ID NO,5b, (. DRHI comprises SEQ ID NO a?, CDRU? consprices hf.Q ID NO X6 amt t'DRi 13 i ompttxc» SEQ ID NO--S7. In another embodiment, EDRLI i<sn5pri>ei SEQ) R) NO ±N EOR1 ? comprises SEQ ID NO h), CDR.L3 composes Si Q ID NOs 4 < DRIU composes SI Q ID NO >, <d)RH2 >.empitsex SEQ ID NO.Si and 03RII3 comprises SI. Q ID NO. 7s. ht a nether embodimeng CDEL I comprises SEQ ID

Nt? o t'DRi ~^f composes SI Q ID NO bQ CDS! 3 composes SI Q If) NO eh CDRH!

et-mpo'Cs si Q ID NOON < 'DR! 12 eotnnttses Si Q ID \< ) 93 ,md ί I >kl I? eontposes hkQ) SO NO 94 In aroti'et emtiodotsem t DRI I - om|h sc-'SEQ ID NO 45, ί OR! compos·. SEQ) IO NO ok <'!)Ri t composes M Q ID NO 4 ODRID iompt:»m> SEQ ID Nt) e, CDKil? vomp ,s„s Si Q ID NQ 4s ί DR.H3 ost uises hi Q ID NO '3 is 5 tomes ermoetrter ,

CDRL I comprises SEQ ID NO e5, < PR! 2 eosttposes SEQ sD Nt) 55, < DRI t composes st*) ID NE) m, t DEH' mwas.o SEQ ID NO N? f DRIt certm se* StQ ID No St and ί DRU3 comprises SEQ IDNOS in mother embodiment, Q'DR.i 1 composes NI Q ID NO:42, < DRI 2 compiles Si Q ID NO I k < 'DRI * composes Si.Q ID NO 44, < 'DRt 11 corn prises SEQ) ID NOD3< EDRIli comprises SEQ ID NO. 74 and ί DRIB composes Sf Q ID

Nt) 9<< Ju anolbet -. mbodirrent ( DRi I eompttsv.'i SEQ ID VI't-fg ( DRI 2 composes SEQ) ID NO:07. E'DRl.3 comprises SEQ ID NQQS, CDRH I comprises SEQ) ID NO.9 .\ CORED eo up s, - Si Q) ID NO C are ( Ο ' 11 > un mi ο \! O ID NO Ό ie , an, t erO 'c ra i' CDRU comprises SEQ ID NO :O3. CDRL2 comprises SEE) ID NO:70. CDR.L3 comprises SEQ ID NOOk CDRII! comprises SEQ) ID NOIOO, CDREI2 eompttses SEQ) ID ΝΟ.Ι0! and

CORED comprises Si-.Q) ID NOJ02, In another embodiment CDREI comprises M'Q ID NO m> ) DR! ' - omprm.-s SEq) ID NO ”0, { OR! 3 vemposm SEQ) ID NO QQ i DRiil composes Si.Q) ID Nt⁴ ICO. CDK.II2 comprises hi O ID NO IE I and ( DRIB emppp-es M Q ID NO J 02.

Io ary et rife .vtose-mmmoned seemeree-Ietmcd embodiments ti.e isol.hed .mhgeu?0 boding pfot -m n\e. be. fo>' c\ rapO, a mom-Oonai tnnbed\. a pvRclonQ ant (hub,., tecmnbmam anmmd\, a human tc >' - Ebb, heist -at) amibody, a numam/ed emloeR. a ehm.cttc antibody_Λ d mnlti-speeifte imtibedv,: or an antigen binding fragnteni ifereo E Further,, tite antibody lOgmem of-he Isolated anngen-hmihttg proteins may be a Eat' Impttient. and Fab' harmeng an

Dab') tiagcncm. sr I s fragment, a mabcDy,, o;- _tt single sham antibody mo'- ^.tttc Eos csnmpk.

2016244220 11 Oct 2016 the isolated antigen binding pwtoM wy he a hnfoan. momefoMl Wfoedy, and wy be, e,g„ an LTG.-.foGd Igid o; foG-Gupcarnlodv Itnthcf tic j'.okncJ,mtsecttbsedetg pnvtosnx nun be i',\itf UiaUtg uniig'··, bifi I ' _ protemx hi any of the above-mentioned sequence-defined enthodiotonis, the isolated mfogem ? binding protein may xpveitica! b bind ^;o both human t 'P ϊ p and human K -VIP i tnd no?

specifically bind; to AMI.» .AM2 or a human amylin receptor feg., AMYl), for example, foe ir-oLccd «tumen binding proton; mat speeificalfo fond to human CORP P with a R-. <1 μΜ - 100 ii'vf,' ίΟ uM, -a 5 n\b c g , ax deb.rmmea axing =¾ 1 AC'S hmdmg axon and jm'dy.'ed, for emmpk, iwnu method's dcxertbcd nt Rathamiswusm, »/ a;. fom /u-nfo to and ,Rfo/'Aefo<. a;

fo *.< >·,*'· h / ,;a;;?' , 3)4 jfosOx) 100 I i01 ? fo any ol foe abto e-mcmmmm xcqucncedelfoed enPu\no;tiitx, th; «’av d untieen-Omdum emu-m max ^'eetixeit njiabuhurmm t'Cd<R Rmexii't- io the banian the Λ\t R A\P oi ,Wfo m-, <cp?o”'% yuv’b χΆ grub iatio-u lOfi ot mow, tof-m ujote, ^00 m mote, 750 oi nm<\ 1,000 os f tme, dtooo u. mme, fooOUm mmeot hhOOv of more, where the degree ;o mietoo -. inhibition may be deknohvd uxmg am xinnfole method, e.g,, using a cAMP assay m described in foe Examples herein, in any of the abovementioned sequence’defined embodiments, foe Isolated antigen’binding: protein .may have a Ki Os'- :00 n\h '' 10 «Μ ·-1 too, --{t ^x n\1 m - p I n\t m ,·, t \ dxP bind' \t - empetmon ax\«x e e , in a radiolabeled ¹ bCGRP binding competition asxas to memtoanex from cells expressing hiuu m t 'GRP R. e g , foe uxxax ties, obed m bfonmpto 5 hewm

Another set of embodiment Includes isolated antigen-binding proteins that include one or a combination of GDlfo having the concensus sequent, es described below, and optionally, bind human CgRP P. The eonxenxn- -epneneex are fieri’, ed boot phylogeueficifoy .dated CDR sequences In one asp-.-ei, the CDR.S from the \ arious groups may be mixed and matched n- an> r nto'ul a isolated anum n-to.i-ifug prmem dsn? lands fonn -,u CGRP R to uuomu aspect, foe anti gen binding pro?sin comprises heavy end ii gbt chai n C Dfos that are derived fiem lb-. same pie, log, n- m'-Ufo-tel dee: gomp ofanbhod, clone,·, F\ -mpbn\> CDR em'x, nxux sequences arc as follows;:

KI Consensus

consisting of N and K.

CPH-C XiASSLQS (SEQ ID NO; 1041 wherein Xh ix selected from the group eornaxu ng of A and G.

GDR > I QY\X,\d’\\ I toi Q ID NO ifofo whefem X ix x, leeb'c: oom fo,· group emeaxtato fo I ana N, and X- <x .selectcd bom the mono conxkxung of Y and Γ

2016244220 11 Oct 2016 k 4 ConsetiMts

CDR? vNM X_tK (M Q ID NO tOoh whc-eut Xt ts sjceiesl Oom the etonp eonsfskns, of S ait 1 O χΧΜαχχχμχ

CDR J RASQX_; X>X5X4GX5LX₆ (SEQ 1D NO: I07), wherein X, is selected from the consistin', o^! > attd 4 ί λ, 's seitu ted from the group lOteMsati? of V end X i ts seict led, hem the g^fet p ee-f'stsinm of \ and 1C \? 0 sc'eek-d feo.n rite gtoitp x N1 d k,

X. ts sutee''?O :50m iri? annin consisting ο: X and O, mri X<« 'deen/d nets· the group consisting of T and CO

SO CDR? N,-XSSN;X \i tSf Q if) NOriOX). \shesefii Μ ts sele-efed from the group

Cftkistmc >ri G and V λ' is sele-etcd ftom the eOiei ^oiiMsuug of R uttd I, Y ts v ieeted tioni rite eroup eenvointa <0 and Q, and X\ is seie lee horn the group -, insisting of T md S t OR ) \ QX X X X C\, X- ιΜ O ID NO 0’’}, 'M'esesu X, is s?ie-..t?e ho n t’t? -ίό vor-sisotig of th and I, X, is scketed from rite yroup eensMmg of is and Ν. X, D syleekd from

1.5 thi.· group consisting of X and Ί\ X.? is selected from die ejoup consisting of S. 5' and E. X- is selected Pont the croup consisting Y L and P. N_e f? selected from the group -.ousistmg of C, W and M and X · is selected from rite group consisting ot R and 1'

K? Consensus

CDR i RSNQX1 I CSX g»X X \ ΐ Y XI if) NO i 10i, wherein X, is selecfed ikon the group consisting ot D and Λ. X. is selected front the group consisting of R and R, and X is seWeri non' he utoap - om-isot'eo^h X arm 1

XXxCftriMllOiik

CDRi X SsOM i CSS (ΆΛ,ΥΙ \s<M D IO \n 11 ;< wherem X. ?-> ->ekekd from da gtoap consts^m; ol R and K, \_s js selected riotn Ute gtotm .ouMshtn; oM\ i> and \ X is

2> seXkted hum the utenp tons s'jgg of h , R and K Xt ts sel ,< tec lo-m the otetet i.on-'isuug of N and T, and X-· ts s>-lock'd iron- the group consisting ot D and 5 ,

C'i'tRd X .X SXRXds >SI.Q ID XO;1 ids wherein ,X 15 sOcetcd horn rite gtoup -.oiistsliuie ot I and IX X- ^?s selected from die group consisting ot G and S' ^-utd X? is seieeted h-u-i the oinup < onstsPng 0; \ and i

CDR? MQXXXX .XJ-’X 1 tSEQ ID NO'I EG. >λ herein X= is selected from the uroup eousispng of \ and S, Nw is selc-, fed ftotn the g-oop ufhstskhg ot 1 and 1, Xo\ selected Pont the reoup eottstsfthgoi D end h\ \, is sck-eted from the e oup eonsuemg of 1 are t, -tud X f-> sen I'ted from tits' group i-oustdnu· off and 1

2016244220 11 Oct 2016

CDR? RX X'QRf’S s$f Q ID \O'l i D, Ync’em X s>, 'eeted anni she g<oup conststuvc of \ iind S, .isi 1.2.3 Consensus

C D!\ ΎΑΑΙλΑ\\\ \ <M sd ID XO 115s. mlues X m Aecxd Oom'h„ group consist ing of X and S. X = is selected from the group consi si istg of Y and T. and X«ss selected fro η; she group consisting of S, X and Y.

CUB? X_;XA\d<RS \SK> ID \Q ! to), wherent X isselected from srhe group eon Ahne of D. T and R, X; is selected from she group consisting of X and X, and X: is selected from the group consisting of K and Q.

CDR3 ΧΛ,Χ.ΟΧ.ΥΙ ΧΛό\ <SKQ ID \'O ;Q, whemm X ,s sebeted from she group consisting os <; and A. X' ;s selected frooi she comp consisting of I and \. X< is selected from she group consisting of W and R. X, »s sole» fed from the group consisting of § and D. X-1·---. seemd itom the g'oup consisting of R. and A X_c <s selected from she gtoten i,o'->h-smg of X and Y .md X w selected she croup .,_vi«.immg m' \ .me 1’

LsiAll. .< ΪΙίΜϋ Lb.

C'DRl XY.X .ΧΑ.ΧΆΑΑΑλΥ'ιΛ AhQ ID XAlIXf Ynerem Y is sefrued t'rem fh. gietm consumm; os X mid Q X > i\ ntesem or «bssut, and o p’, «.mt, n. S,\. i\ A -· ted from she gteup von-'fstmg of b and D. ,\._t is prcs/nt or aYem, and is present, ο Y ,Y e.

>e s te 1 so ο A gio ep son* ·, ι γ I I X s st le , d to n m, gr> , « υ <\t\ta , o G and R, X- is selected front the gtoup eon-ustsug of X and 0. As is selected freun the g>oup consisting of X , Ά I-, X< is sehxted front toe group consisting of Y and 1, \Y is selwied front she ‘’simp rosevsSutg m V end A, and Y is setceted hosts the <ponp eu'tsisfuig os S. X and \

CDR2 XA \\ RPx AfQ ID XO.i 19\ oh.-tvtn \ m .e-ecud from dm gro'up sonstsf mg of 1 h U\ 1, and R, X '-elected from the ίΡ'οΐη> consisting of X, |< and S, and X' m selected front the group consisting of K, X and Q t DR 1 \< X X u'JX X X X \Ac\ Al Q ID \O i ?0t, obeoun X, v leered from the at'pHp vOif-ostn^of td, x and A, X' is selected Iron· the gsmap•.eftststmgnf L S and Λ, X's,A< i ts'd frtfm the grs>op ς onAsmg v¹' V< and R X-, h s ’Deled hot'·» the euoep eons’O'ng οί X and D. X< is ses>, >, fed fouti the csonp eot's-seng ol R >utd S. X. ss selected from the motsp consisting of 1 and V X is selected irom the group consXftng ol $ Y and X, Xs n·» selected irons ιΐυ.. etotep consfTint. of 11 anti G, .aid \> ss Aeeted from the gtoup eonsssfing of \ astd L.

2016244220 11 Oct 2016 •KH onsenst.-v

(.'Dili X A ) MX (Si Q ii> \O; 121 5, Mierem X n <t<Jce*.ed trout iiu group consisting of (ί ,tnd D X selected oom die provr consisting-ο D and X

GDR2 Vf IXCPNSGGΊΧΎ XQki O I (SEQ ID \< J ί22k uadcut λ o selected kom the group consisting of N and S,

CDR ( X XAiXX.iXsXAAdiXAsX .Χ,ΛΥΧι-GMDY iSEQ ID \G 12 b. M.etetn

X, is seleiece *ί,·*ϋ the group io/isisitegef D and c, X .select'd from fin; group eon<!sfmg of Q and ¢.=, X-, ts si.deetcd uotn fisc gump consisting oi \1 and 3'. X is seEcted finm the mump eonststtog of i and tE X = ts sekmcd from the go-up consisting of I and 5 . X-, ;s selected itom the pcoup eonsisiun; oi'M and A„ X - is p'csetn o^r ahs-, to. and a pres-.-nf, o; I , Χ_Λ is present or absent. .mJ ii psesent. is K. X> ts setcGed Pont ike cmnp consisting <Ί Y acd i X > is seiccled beto f gietm cema-auiu o'1'etd 5\ X s se'eecd uni' ise so o ^nnsisure -' Γ end n \ is s,'ie=. ied bent ike gtonp consisting ofP and IE and X m present ot absent. and d present, s·Y.

HC2 Con a£ffi>.«S

CDR2 RIKSXiWOGTlWXsAFVKG (SEQ ID NO J 24). wherein X= Is selected from tn gietm eoess-dun; of K mid Γ. and X - is sole- md from ike pump consisting m Ϊ e>-i A ('DR ; X \ X MX-1Si 0 ID \0·I 25). mhe'em X ι,-> λ'^:ιί ied from the group consisting oi I and >, \_; =s sJeGed horn the uouip consisting of S sold Λ, and Xi is selected Isom the group consisting of X aid S ( DR2 XdSX S\AA.xX<XV\nSYMsi,SlQ ID XO 12m. »|=. icm \, is sale, lea from toe group vou-astoig o^?S and .A, X- is sck\f.;d from fh; group vonsDnog of s and G, Xi ΐ- selected ftotti tin. gtonp eonosium of E and G. X ι ts selected ftont ike gump consisting o^s S and G, Xs ;s selected from ike pump consisting of 5' ur=d R. and X,. is selected finnt the group et m s ΐ -a m u o f R and F.

( DRe X ,X ΧΛΛ-,Χ,Λ ID SXA.W A DYk A n\iD\ 0d Q ID XO 12 A uiuient ,X o s d.-ei. d beta t ,c g=et p emmi-aim: oft' .out D X 's -< .ceied i om fhc p'oap c-msu^ngoi G and Q. Xi :s sei<, >. ted bom tbs' pomp consisimg oi \ m=d R, X) is selected ttotn ike pomp

Y) eoosDttrie of x mid h, X- R selected Ifopt the pump consisting ni G .md V. X\, is selected from the mump consisting oi S ami ( ο X- pre-euf m absent, ind if picsem. is 0, \_s is udeefed t-'Otn the gfoap consisting e-i I and X. and \Y ts selected front tkc- croup > otiststnig of $ and G

2016244220 11 Oct 2016 iH 4 CoU\>,'SiVUV

CDR i oXxDdit (Xi-.Q ID SOU28+ whcrohi Xt is selected Ir«m rise group con.vsstsng off and Y

C DR2 s ISX 1X.SX t\X \ \,D5\ ku Qo Q ID XD !»,, oskmei \ - -e-.ckd Peso 5 the group crntMidoig oi F jrd X , \ iv voR-oscd iron': die croup coumvoug ofI and H, X ? i.v .veketed iron! the groop conv;vtr;:g of S and ) , and Xf iv veiei led hotst she r soup couMkong ol

V and A .

( DR i \d?,\ SAA.VSXAsYVXA/A.tVVtiXA. VrSlQIDXn IP5), okmm A- h vdeekd from the group eon.vsvtsng <0 D and I, \> sv selected Pom inc group cou.vsvisne of

Η) I and K, X; sv veXvted ifom she group convivsisig of X and R. \₅ P M’leen'd from the group eei'envisng oi ) .usd V X. so selected i'sesi'i the group eorr-'rs-trsrg of X and 1. X,. 0 veieeted iron's ho iposip KOS'^ot.np <d D οήΙ \R X ‘elect d feus d>. group coavsemo off ,-oD T, \„ vciocied nous the group certvisting oi A and I . X iv video* cd nous Use gsenp eun.vsvtsng <0 11 end Xf \ ., is present or shvens usd tf prewni s.v X , X . ;a ^oh-otol fmm rise troop const-mug ! 5 ok and 1 , \ \ v ,.(.e! ’an the gsuap 1 ou¹- v,u g o* \1 a d ϊ -\d X '*> se ecu J i on *hi gkk p eiS’sesisng 0' \ and I)

ΠCA Cpf Sveness

GDR: λ ,\ \ΛΙ\₄ Al 0 ID XD ik p oisorous X· 0 sclented hunt the mung ; osenvfng of X; :usd S, X,· G selected from the grono consh-tissp of A, V and f, X. us .selected fit P-η s fc ?e? vonvisiusg 01 0. \ . ud t1 ; td X ,-^cet.d : otr*h. s’joap conoer u oi \ and H.

t DR3 λΑ\Λ,ΥΑΛ₍(ΛΛΛΑ<< .X_r\>.\.A MDSFQ ID XD 1 kf>, sksesvin X; ss selected from the group xOtsviMsng <f if A usd X. X - sv v decree from the group utuviviing of k. S and A , is udecteu from rio. gsos.p coneMing of S, <»„ l· and Xf X>, -s prevent os aK.nt and p’ornsesri sv vJcekd tro*n irk green omvivisnu nt k asni I X sv p*es.nt or absent, and if psosetst, iv T, \, 0 veki ted from the group consG trsu; oi D and X. X- o;

-.ideekd frosts dtv group convsvtsno ol'G and 5. X. tv vckued front the group vostvseung ot I, if I. X usd ii, X.' iv vole- sed irons she vsvnp coavivisugin I usd k, X_tl iv voiee’ed η-,on she sroup unoavUng of D insd Y, X> w .vek\ ted Aom Use vrunr ^osjsjvtissp of Y and S, X- e- -Deeh'J frosts tlx g^roup e-'O.vkrisse of 5. Λ and ) _x X -; ;.v .veiciiod t'rotsi sise croup ^ostMMtssg of ?\ and D.

tsssd Xf, 0 veketed fiort: the group ronuevUsb- el P assd S f DRo X X ΧΛΛ \\X XvXiXs X \ Λ X Λ, X X <A_tvX .S Dd Q ID XD 1 ' I), ef ivi'i in \ w sob , ted door tise esos-p ,.ors-s.vtrs.i.· o*'D, \ at.d I. .X' -v veieeted nonthe group cors^'ditsg oi R. D and X' n. voicered irons t,he gsoup consisting of I. R. I.. G end

2016244220 11 Oct 2016

K, X_;. ts si-Iecied ίίΌΠϊ the gutup eonsisiiogiif G, u X, t and R, X- is selected icotn rhe gs oup cottsisinvc ni \ V and ,X, ?<. $s selected trosn th-„ gtoup consisting of x, G. X , Λ and L X- is selected font the gtinip consisting nl I, P. D, ,X and M, \_s n; pt'cssie of absent, and if pn\->en^f, is horn die ^;enp eonsisSine of X and X , X a present os J'scnt. and d present, is .selected trcun the group consisting of W, S and T. Xi, >-. selected front the group xonsisring of 5, t I u’ul (,. \(_f i\ selected horn the rump ciuisisung of S. G, L >ntd 5 , X·; is ptcscufi os absent, use! if present, ts selected from the croup ct>usistntg of U md VS ·, sek\ ted non· she croup consisting of S' .usd I (, X·'s present of absent, and s’ present, is selected ftom th·, gtenp cor ma in. of X and IX \ ' -> .deehd 'tort' (;; ert\ p eonsistipj. of Y. k ,n d k \ is p^% .sent

Η) «η- absent, end it'present, η· Y, X,- is present or absem, and if present, κ S', \_t? is se(c>. ted front the group eonOstirsp of SI .utd I., and X,. is selected front the group consisting ol I) and Λ

HGIX Consensus

COR I iSFQ ID \O I U), u heteui XX is selected dost· the gtonp eo'-.tstntg of X, G, f λ > tod Λ. X- is svieekd Com the group consisting of X b ansi X, X, ts ! 5 selected Con: the gtoup ; ous-stnut ot XX. XX X and G. Xj ts selected fsont the co-tip consisting of M and k. tied V ts selected from the croup ..onststrng of S and H.

C(XR? XXX X ΧΛΛΛΥΧΛ,ΛΧΧιΛΛ,,Χ, Χ,Λ.Ό |Xi 0 ID XD'B5b vritetesn X, is selected dostt the gtonp consisting cd (k \\, Λ, X. >< mid i. X.· ts selected (font the gmup consisting of'K, X, X, XX and Is, \ fs selected from the group censtsung of S. P, G F

2Θ and X , X, ;s present or ab*. ut, and if preset?. o, selected front the gto-jp consisting of k, ( amt R X- is pies.-et '<' absent, vxl d'picsenh \s »elee>?d troir¹ the group eonsoee of I and Y \, ts selected horn the -enmp ·. {insisting of Π, X, IL S end X , X- c-· -elret'..d from the gtonp consisting of tl and X X_s ts selected front the groen constating of G and $, V ts selected trotn tht g.oup consisting of I, C, P, I X, If and X', X-, -s set·, etc·! froo- the group eon'ustuig of I.

X, P. and P, X is selected bout tltc group const-ding of IX X, X and k, ,\r >s selected feeto the group consisting of Y and X X, is '-sleeted non- the gtoap consisting i?i'T, X and X , Y,_} is sc'eet.d it out -'h. group eonsisttov of C and Ο, Xj · ts selected item the vjenp con ostmc of P, k and S, X_{, is scks-'.si t'rotn tus- group xOnsisUnc of V and I-, utd \ is sclet fed from the gsoup Consisting <n k anti G

CGPX X_;X \/XAXS\\ ΧΛΛ,. X· \._?X_{ X -WGW Λ^Υ tSb\) ID XG ' >to, oiler·, tn X. cs sci·, cted lumt the group ions'suug o( D, ii, Ά and 1.. XX is selecied horn the group ..ouetsrhtgof R, G utd D- ^{5 !}> selected from the group ..ouGsiutg o' L Μ, XX Ik I, G ai-cl k, X is scl>, i led fnun the tyonp consisting ¢-1 G. S, I', X, I ancl P., X i- selected i'toiu the group cratsisiutg m· Y, I, G, \ and X, ,\, selected front 'he moup consisting of V (, X , < i, \

2016244220 11 Oct 2016 and T, X - is selected from the group ·. (.mstsuog of 1, M. A. P and D. Ax is present or ul-sem, and it piesent is sel- sted from tac croup eottsjstnty o*S, L and Y, ,\ is puscnt 01 +%¾ mid ifprcsem, is selected firom toe group eonsisiint: of W, R, S and 3', X.,. A seter tod from the mo'W vOU'isin ~οΌ<! n,e.> \ o^cr.djoir'bufAi'Crtii'i'ODi.ciW ; i»md\, ? \, n pre-,cut or -tbsent, md if present is selected from the group gon-dstmg ο* F, Y and \\..

X,! -5 selected fron, the gioup consisting of Y, P, S and t I, X; 1 is tncsem m absent. and if present us selected from the croup -.00515000 of kl'-P o,d ii, X'o 15 scle-ted from fine crouo eon«κίιιΐ^ of λ , k and L X (. i5 'ptesem et absent. and d ptescnt, is 3 , X- <5 pieseni ot absent, and d present, is X' and X- , 55 seieued from die group consistingof M and I

H) fr: any ol the ai«n e-menuoned - omseusus sequence defined embodiments, die isoiamd wuigen~bmd.mg protein may he, thr example, an AVIMER puiy nemide, a .monoclbnaf antibody, a polyclonal antibody, a r.’tomburae annhods, λ b-im.ei <'e g did} human) -aeiKsiv a liumani/ed anodofo, a chimeric antibody, a muSo-speeiOv antibod}, or an antigen binding fragment thereof further. the antibody fragment of die isolmed antigen-binding proteins mm be i 5 <i Fab fragment. mid lab fragment, ,01 i\ah'b fiagenenb an f s fragment. a dntbods. or a smele chain antibody wolenule. For example, the isolated antigen binding pndein.tray he a human mppoeional apbbody, and way he, e,g,, an IgG I~, Ig<32-, IgGah or IgGddypo antibody, Further, the tsobted ectig.-n 'rnndme ptet.-ms mm, tv nentr.diztngantigen bindene protems, b ,n \ » h, ,bin e-e enoo ee 0 ->es si,-,-v p em ne^l ne L m ioa menu m mo a⁽e 1 nufrgon-bindipg protein may speeifrealiy 'bind to both human CRLR and human RAMbl and not spemfie.di} bind to \ \1 I, AM? or ,, human im\ im receptortc g, \\IY 11, m example, ’he isolated aniio-ii bu«tnnj psoiein max specifualK bind m human ( td?P R ο oh -, Km SI μΜ, <i00 nM, pi 0 nM, or <5 nM. e.g., na determined using a f At \\ binding as.-my and analyzed, for example. using methods described in Rathanasuami, < ten , oka A 7^/00/.-07// ZM yfrys/cu/ '·<./; Gmniumfr.otZi'if! 334 (2005) 100-1- 1013. hi an;, offthr sJmse-memioned consensus spqm m e defined embodiments 'he isca ited anigen-binding pmteui ma;. -;Ά'> io efr inhibit human CORP R. sehwoe to dj^ imm,m die All, \M3 ot Λλ’Ί ¹ lees.pto-s,. a , 0eh «, seLeioU\ 0)00 of »OP i(f mor,\ ?50 _n- rnoie, 'bO or mo»e, ’pb or moo , 1 ,ΡρΟ or trote, * '00 m mov, 5,00b or more or >03)00 or more, where fine degree of spleens e mhibiuou may be determined using any ?0 vuteble method, e g, t-ing a eAMp ,ι-,,-,ρ % d.vcnbed tn the I vmqf es her, m in .ui> of the abo\ e-menilom d, eom-i-usns sequence A fmed embodiments, the 00:,tied unWs p,-binding protein may have a Ki ofi£ 100 nM, <i0 nM, bi r»M, <0.5 nM or <0.1 rM in CORP binding competition assay, e.g., m a radiolabeled '^'i-CGRPbinding competition as-ey to nsanbiwicy horn ^e'ds es|'i'cs\j)'g hnmrai <\.RP R, ,- g, the ',sm\ des.'iibed w I \ m-pk ;< hetent

ZS >

2016244220 11 Oct 2016

Soma of the tsoktnd -intigen-bindiug proteins described eompris·,- a beds’- chum s cubic i.vtu'i (X ί ^qtatir^ Jut bus , t „ast 80' <. hM >, utn; 40' i-ei ^i!M > s.qu'.ute ,k',st,t\ with -nt ammo acid sequence seie>. led From the group i.onsisting of SFQ H) \0\ i '0-ΓΥ5, omm of Un isolated antigen-binding proteins described comprise a a Ju chain \artabk legion t Y ? s»,-tjueni.e that Km at least nO”-. 850-, and Oil'k, or -00- -mquvrnc identity v uh m amtno acid seemerec si k'cksi note the pomp consisting m Q R5 \Os { ons 4 Nome of t''-e isohtted anogeo binding. proteins described comprise a \ _{! sequetne frai has at le ist *908501, '*001 oi 95 m scijuencv iile-uitx v- u.h ;'m ;unmo acid sequen, e seh-ei-, d from tm epotep eot-sisting ot Nt 0 ID \Gs 1<n I Ύ and a \ t tha' fas _;g leu--' 500-, n~ *., op-g,_el ηργ, sequence t.ientils w ith an .onino acid sequent e selected from the group xonsisone of NfQ ID \i is, I -t 0 !5e hi some eu-,bodm-,e-ut% the molan-d νη^η-ιΐ'baiding- proteins eotnpuse ίΛ) a heavy chain variable region. (Y₃.t comprising :·, s-..-tinen- e u t s-dected Hom rite group consisting, of SR) iP ’dis I '<N~'i~0, m to) a- defined bs (i 5 and 1 entaUiutg t-ti·. m naue tc g , foe, ten, fifteen or twenty) amino acid stibsottmons ie,g.. eoosenafi’-e ammo m-d substitutions),

5 deletions «Ί ni’-CTtiotis. f B) a \ t emnpiistng a sequence tin) seieenu from the gtonp ,00^--0110 ofN| QH) XOs le mm t-o0tsd bred n in ) ..ontaming om ot mo'eteg, fnc ten,, fifteen or twenty) amino acid stibsti tutions ( e.g ., conservative tttniho acid yubst|titiiotia)_s deletions or inseriions, or t< 0$ \ , of(.\5 and a \ oftLfts In sottsr emt-r-iCliments, th„ isolated iintigen-bmdmg proteins comprise a heavy chain sarmb-c region ί Ynί comprising xt s..>₍pt,tee

2(i scieued hunt the m wip consisting of SLQ IP \< )s ι Ύ- 17b and V et-mpi isittg a sequence selected tnim the eroup consisting oi SbQ ID Y0s 13'· 15c, in one ombodimem, the Isolated, itti dgeit-hin.dip.g protoin oompriyes a heavy chain.

\ artoble region t \ - ) compm-mg ,m men-¹ acid s„-qu,-n^e selected from me croup -„on m-ong of k! SkQ II) NO. 158. iji) ,t sequence that is at least 9150. or 955., identical 10 the soqneuee deist e,l h\ 0t , td {ί,) ,, v\, eree as den tec, b\ t t’t tot kmv tu tm *o ;„η ίτ tm acid siiiwopmons te y touters,tP\c enmo a- id suhsbluticnst, d-'-kkions oi uve’-Pom- in ,-ηοΐη?-embodiment, the isolated ap.itgcn-htnding protein comprises a \ _{- Lonipitmig' an amnio mod sequence selected liom ihe group consisting ol (i 1 Sf'Q if) Υίί 1 59 ·;ι· 5 ,i scuu-cn-. e that is ;e_t least 9ί5*Ν, os 05 -, identical be tin- s-,.-qn-cn>, e defita -,1 h\ (t 1. and f-ti) a sequence as deihteti t-\ it) eontfrinihg up to ten amino acid x^rsbstimitons (tag,,. eonserva.tive amino acid substimtionaX delebon- or niscii-ons In -,noth, 1 eptiioOinienk die n-oLik-d dnbgeu-bmdmu ptoiem eomp-'is,a \ ,eontp{:stug u tmmo mm s-Arumne ,Y. ued from rise e'oup eor-e-mig of ft) M'O H>

V) loO, 11( i a „eqnencc ih 0 is ul i, asi -5()0, -η 05 ', ul, nt-eal ’o tin' -~ηη<, uee dcimed o\ p t, uttd -tu i xi sequeinn as xiefinctl by t if toutajinng up tc ten amino acid substitutions ie,g..

2016244220 11 Oct 2016

-omsesouine sn-nv ted ieicmms o* insertion- In .medic’ *mlo>lms,H. the isolated autigcmbindinu ptotent composes a V _} eomptissut. an an.mo aud sequence selected t'rem is:-. gtenp eonsssimg of g i SfQ ID X» 1 b’· I, f ο i _t. sequence that is u -east 90''.. m A' > identieal to tin. sequence domed h\ g;. .md ίιυ» a -equenci. as defined b\ {j> contamnsg up to e ten . mme a„id seb-mtetio'u, <v a . eonser. .-me ammo aetd •Hib’diumonsb dUeiicm- oi n sest-ons, In unoth-e-'· embodiment the isolated .mt._ttett-bmdmg pmtem comp*mes a Yg. eompm-mg an mtmo aesd sequels, e selected fruits the group umssistrng of (is ShQ ID XO ;'b.\ fiiia sequence that is 0 I>, u-ι AX o: os,, hAmc u to the seqnenet· del med b\ < t·. and i siD a sequeneu as dvfiued lx (si emit.umug up to ten ammo acid sehsiniiismts te g\. cmxcrvume ammo urnd substitutions'», dNetsoos or :melton*· ht another qfnbodsment, the isolated anttgenimtdmg proteut compO-es a Yp eontpi-.sing an ammo aesn sequeim., seXxtcd front the group eonsssm-sc ot'b t Set) ID Xf t DO, idia .-e-qnene. that is.s? DasAiffr m Αχ identiea I to the simm nt e defined b\ is i and not a sequence as denned b\ it'» tentaunng up to ?.-u .morse acel substitutions te i>. eonser-atos„- mttno aem sufi.siimfiomo, deletions or insertions in anodier embodiment, the isolated antigen-bindfitg psomm eons psi «sec a Y_t; comps ising an amino aesd sequence select ;d from die group eon-asune of (s > SbO ID XO IM p< f a sequence that ss at fea-t KhX oi ^lO ’ > Genin al m file sequence defined o> iD and {mf :. s q'-. ft e <f- defined b\ isi containing tsp to ten ammo acid substitutions ie,g„ con<er\at;se emum aetd substitutions), d Aeons es ui*. -'t’on'' In aoofbei >.-mbodune-n the tsoD, o wtsg> r-m.ds'ig poX'm - ompus'--.

a Χ- comprising -.nt ammo aC'.d -xquenee selected from the group eottsisttnn ol -:u SbO ID XO' 165. s in a sequence that => -it leesf or 9yX d-mfiiad to the sequence defined by s D and {ml a suqta'in-e a* d fined U\ o) eonta'uu'-e sip io ten ammo mud mbsnmsiens te g uousesn alive amino add sub-elintiottsb deletions ot insertions in another embodiment, the isolated antigen-binding psotem comprises a Y,_{ comprising an ammo acid sequence si leeUd from the group consisting ol fi) SfiQ ID \O it ·« », {bin ,sCiptcm.c that :-- at feast 9i)’u. or AX idcnlst tl to the sequeme detun'd h\ of. and Dot a s'.-mi.-u- e us d-Tused by if > comuimst, up io ten ammo acid substitutions te g„ con-cn ab\c ammo ..esd 'Uihstitmions), deletion -. oi suseruoi s in «ηοί’Α -. mbodnncm, the isoiat-ed anue-.-o-h-ad-ug profem - omprbrs a Y_{, umsposme an emuo >v. ul sequeu.e seleeitd ftum the gtonn eonMsmsg of pi Sb'Q ID Xt) lo⁷s ?d <n| a sequence that is .,1 l-e?s^T 90' - >'<· <·*>% (Arnica} to tits' s.-t|u,'n_fcc defined b> «ji. and tins a siapi-, ni e a*- defined A tst eont nismg no to ten ammo a. id substitutions p.. g, c«msei\ats\v n it' o v d subsist n es s\ .1 vtos>‘( ns ^f om ! * ot 'es uoios. n >e” . h. vo t u tr nom i'su<iuu profem <. onipt's-cs a Y{ comps :smg an ammo aesd s. quem.e selei ted from the group consisting ottsi fsf'.D ID XO !bf, tni a >i qtvei'c^ dial o at least _t, oi AX identical to the

2016244220 11 Oct 2016 .wqucree defined b\ it) aM ty⁵) < sequoia e <0 tierned ='> tfh'*w* /ntn« up h> ten mnu·» a, id sub-on minus ie e , eon-e.rsetoc amnnt aetd substttnPotts). deletions or insertions. tn another embed sm-nt »he <sol.aed eineembmdme p»oietn c >mp» tses a A p teinpr»smg in aini'»o it id sequence sekued front the group consisting oG E> Si.Q ID NO. io’< in) u sequence that 0 a?

least 90% or 95% identical to the sequence defined by (if and (In) a sequence as defined by (i) umbnmng np to ten ammo acid snbstnntious te g , unisctsafi',e muioo ,v..id substnuttonsi, deletions or insertions tn .ughb-er embodiment, the knjurcd antigen butdtug pmo.-m comprises a \\. comprising an aiumo id sequence -eh-etcd fiotn the group eone-fme of fit SEQ ID NG, 1 tt. t u) u. sequence that 1 -> at least 9i}’,, et AM identical to du sequence defined b< tt t,

H) are tid 1 a sequence ns defined ty pt 10m mung up io ten amino »i> »d substitutions «e g , consenau'.'. mmue aeid substitutions! delei;on*e>t htseifions

In ,ute entbodinu'U die isobded s' t’.gen-bmd'ng nroteni .om-pos.'s a oglu i hair \uri>.ibk' tegfon ί\'t 1 comprising an ammo acid sequence selected fiom tiie g-onp consisting of t i 1SLQ 11 > SG: 13 ?, 1 ii) a sequence fhat is at least _y or 95% identical io the sequence defined ly yr cid on t a sequence as denned b\ »it t oimnnmg tup to ten .rnmio ae»l substn-ations ie g. eouscr ,ιΐ% ammo mid substitutions). deienous ot insertion*. in another embodiment. die isoi uec e t’.uen-hmdmg piotetn composes a A ; e-'-mpnoUig an ammo acid sepust-.c^ seketed front the co-op „ousjs'.mg of 11? b.hU ID XG i %, it? .1 s„qu;ecc that t* at least op'·, _i?5 05 '. 1 deutu al 'si the s.-eti* nt e d -fined ly fit, uni on % sequence as dcEu'd ly <j>

euiiutmng up to tut ammo acid <5ubsumrons te g, emtsemato e .eumo acid substitution* 1.

deletions or Inset nous, in unotbvr embodiment, the isolated anttgeti buidng pOtein computes a \ , comps isim. -,n ammo ce-,d μιΊΟΙ?· s.-let ted fi-'s-t tbs' teonp -. onsisimg td 0) St Q it ‘

NG: 139. id) a -nequeruv that »-> at least 90”„ or AG ideno. al ΐο the ssqnsUse defined ly t» t, and fiii! a sequenc-,. as defined ly in emnamme up to ten mono ,«ul substitutions ic.g , ere Isen, atom minuo ned substitutions i deletions ot insertions In .mofriei embodiment, the tsestt- d tntig·, u-hfndtng ρπΑηι comprises a \ . lOtnpnuntt an amuio acid ,>equene.- tecmd fiom the group eon-ustum of tt) SbQ 1G SO 1 -)fi. tit) u sequence that ;s m k'tni AG» 05 ov'„ identical ΐο the 'eunenee defined ty oi. and tm'» a sequence a.s defined by ίE« -oMaunng up to t.-ii >-,n-»uo aei.1 A'smnt 10=1-, {,< _t-, ,-onsen ;du e atun'o n.td subsptui.onst. detciituts of insertions In another embodiment, the ise-hred sruigeu -binding protein comprises a %.

eotnp?isttiu ΐ',n ammo acid sequence selected itom the pioup consisting ot tit Spy ID \O. tdl, di» i seuticnee that is tt Icaot %r , <v %% tdeufie d to the sequence defined m tit. and <οΡ> a sequence as defined t, i in oniaunng tep to f. n ,-meuo ae».l siGsumito’·»-, io g , t utise» vaue amtuO mod substitutions), deletions 01 insertions In another embtMtmetib the isolated antigen2016244220 11 Oct 2016 bni.h'ig proum- -. emprises <j tomprsim: an ammo .-eid sequence selected note the gmup eoristrimc nl tri M G ID \o I®, f,q a ->- qnm-e., th.n :-- at least 4t}‘ _t, ei identua; to the sequcise defined b> -;s i, and tint a .sequence as defined by (I ? containing up to ten unrino add subshnnion*»e.g, consercatn e ammo acd subsvttuitonsk deletions or insertions In another embodiment, the isolated trntgemhinding protein comprises a V_{ comprising an ammo amd sequence si ieemd stiw Use gfoup consume oi t st Si G it) Yt) I-P pi},-, mipscn<„.' mat e- ui least θο·\, or ov , identical to the sequence defined m. ri) and (ml a scqi«,nec as defined b> u'> eot-bunnis.. up to ten umtno a.t tO substitutions fc e . eon-.,et',<iie,e ammo acid .mbshuifiens), deletions or mseruosts. tn another embodiment, the isolated diitigen-bmdmg protein comprises tit <i \ omprom mmo =-- d seqaeme - ’ eet , Pern fi >\'ottp so's st'ng of.;-) b^rQ ID YO 144, (ii ι a sequence that is at least or op·»,, Identical to the sequence defined by ri), and (iii) oequbiwe us defined by (i) containing up to ten ami® acid aafeafitutiona (e.g_{i S} const I'mitse am-® 11 sub'-ritutioosb deletions m trsett-ms In ^η-un.'i embodiment, the {«Gated antigen hmdmg protein comprises a V- comprising an ammo acid sequence sekeied fiom {' : i-Oui - ousistmg o- r} SI sp ID YG ',-5, to}.-. s-.t-n η 1 e tian's at e.ssi °0’ > tv identical to the sequence defined by Ci). and tnh n sentience as defined by til conmininc up to ten do’·’!·’ a. id snhstuufions · q , eonset< .no.,- ammo acid substitutions), net {tons or insertions. In another embodiment, the isolated antigen-binding protent compress a X _{

- ompi'sn.g an amne '·.· \l sequemc select· d fiom fh-- green consisting o’ tri Sb'Q ID \G '4t<

tn} a sCquetYY that t- at teas; 9fi”. _ut identical to the sequence darinied n\ m, end tori a sequence as ee ®< p, 11 > com un-ng un to ten amuse amd oGstmifiono U g„ .onsets, nue ammo amd «sibritmt oust, deletions or ins-mi-ons. In nnmh-..r embodtmetit. the isolated antigenhinds® pretem comprises a X _{ comprising m ammo acid sequence sfieeted fom the uioup consisting obit} Sb.Q ID YD N. tri»} a s<.qnent.e thin ts at least or '-G'rii ihennea» to tin.

sequence defieed by tit, ,»ud tm} a v qnei^;e„ us d-..fined h, t com omm.· up to ten .umne arid stibstButtons ie g . eonoenaioe -nmno u- id substitutionst, deletions of m«eriions in imoihet embodiment, the isolated antigen-binding proton comprises a Xj comprising un amino acid sequence selected ttom the comp etmststmg-n tft Si'Q ID SO Mb {hi .1 semtcti>,e dial << ai least op»’,, ,}j 05 *,. J/nt-cui S' the s> q®t->, e defile .1 by V s md rio) u sequence as gci'mcn G, i1) emit unntg up fu ten amino acid .substitutions fe.g., eimsereati'. e amino acid subsfimtions), deletion-» or mseruons. In ηιιοΝι,.· embodiment, the f«obted unseen-binding protein comprises;

a X vOmprisit'g to emtn<t >md sequence -ie<'kp irom group enosistutg nt ri} Si G ID \ί'« kN, i ο s a -e-piene-' thO .._s ut I. ast Gfb, -'f °5'. ulenticul to the --qm m .· defined by p t.

end inti a sequence as defined by t ύ eoifiamnig tip 10 kt> .mnno amd substitutions te e ,

2016244220 11 Oct 2016 ; ousesoasne :nmno ted somstisssOonsi. deieoons οι insertions In another embodiment, die trioiatodasrtigen'bindmg protesn comprises a \\ enmpnsisoc an amino aesfi aoquenee veieeted from Si:-..- group e>mss<»fm$; of ρ s Sf.Q ID VJ I pi\ no a oequence that is .rt least ^l>0‘\.«? <D'^f., soesnsea! to ih<„ sequence tkfiued h\ (>λ and Onia sequence -.-.sdefined by Istcontasnnse up to s ten , anno aud vuomtunouv <e e . eonM/n /toe atnsno sent ^ubvtisaoonsl deletion·, or a vesuouv la ariothe*· s'trtbodsssf,m: the ssoRied ,.. m.gen-heid ag psntcm cuaq'a js_v\s <i Yj comprising an ητηηο acid sequoia e veioetod irons the group eouvivung of sis Sf Q ID XD ; ?!. <'ns a .sequence that is rt I, s·’ hf'k o_s ns*',, h-Rmic u so the sc. pie-tea .lesmed b\ < t·. and isn't _4i sequence as defused b\ (si emmursusg up to ten aretao acid sub stums mis te g„ οίκιχιιχ'

H) ammo avid subsf it at uisis I -b-iefions or ne-ertiem· In .moshes mnbori’sneni, she isolated anthxnnsndnig protein ct-mp^-ev a Yf ron-pim-m,. an annuo .a,id veoaeuee μ'ϊοοιο,Ι from ife moup consensu; of i. j SIX) ID Xrt I.Asgfia seqnene. th:a ivat leak 90’ < os ΑΆ identical to tbs' sequ'. m e defined b\ rt i, and tit-i a sequence as denned by <s'> lontaui-ag up to r,m .ornrse ecu! sub'dhueouv ic.g., consenato. v imino stem «iifivofiifionsu deletions or insertions la another

I 5 mnhodnneni, die isolated imugcn-biudmg piosi-m eonsposes a Yj composing ass ammo ucid sequence sheer ;d from the group eon-nmne of (s > SID ID Xt I I be. tjrt a sequence that ss at lea-t'RD., os ^l,s > , ₍densua! io die sequence define:! o> ; D and (m;\ m-. n< e a*, defined by i 5 condoning isp to ton ammo a<„m ms! sutirtsoso sc g . con mis.stive entnto acid substumson.se deletions or ΐηΜ,-rfions in any uf dm abose-snentionod V_L mu! Yp sequence defined ensliodsnserstk the isolated tre'm^n bs ids ^vm psotem mso be, ’or /sample, ,_t mo-tocOiud asmbotb, t nob Jona- arstihodm t teeoa4<in,isn amfisidy, a human te g , full) isum.ui) antshod.y. a iemammed mrtNuR a elmneoc antibody, u multi-specific antibody, or an antigen blading fragment thereof further, the mnboey fiasgmont of the isolated antigen-binding proteins nor. P<, ,-. h.fu baiytsen;. and. b.frf hasgmestt, au

Dab^ *i,mne; <n H a , men < u above, o* a s ng! chain s.,.si m',\ nckane loi eoamp.s, the Isot.rted in-been binding pnrtein mas be a hninari mono, tonal antibody, .me: fi,. ,·> g an k'D; , Igt Id , IcUe . <>t lelD'ispc antiherte ! nsdui, the isolated ..ntsceis hsndnse pseteu's sum ho neiitruI!Dug antigen landing protehis b afM η·, die Dose-s'.eudo' co V a ul \ _{ s, qu. n.e de-uued xusliodsuseuts. he ssokbed anfcigosi-htndsiig protein rwy specifically bind to both htrawt C.RLR and fettnwi B.AMP1 and not spe, ;fi. ..!!<. Ouid io \\I i, \M2 t>r a, hum,us ,im\hn n-eeplot ;e g, \MYI >, ms example, the isola d i.rsogen bie ts_;. ptosem oim sixes^j J ' bum » nus'aa . 11 <R? R ouh a K ' t.M <!00 nM,is) nM, or stM. e g , as detos'miii.„-i! u-smg a 1' \< 0 binding ssssas arsd analyzed, lot ssurnple. using snedsoos deses’s'oed m Rudsarsaswasns, e? ηό. ,r?/on/usf; o/

2016244220 11 Oct 2016

Rme-θ! 5-: omm.me mmsm 'ΧΜΡΟΟ,Μ 100 I - i 0I3 iu am m dm Jiao e-memin'ied \\ ami \ u sequence defined embodiments, the isolated anbgen-bindbg protein may selectively inhibit human ? GRP R, f.a ts-ve to die inenan ?he AMI, AMP of AMh i ree< pm s. e p , euh a selectivity rauo of 100 of men a. 2*0 or rwc, 500 or mote, Ό0 or mote. I .000 or mors, 2X00 or swe, .\H00 ? or mom or 10,000 -'.r more, ohcre me deg-'ee ot selective u-ihibimm may ne determined nsum am suiGhk method, e s-. using u <. AMP assay is descohed ut the I s.m-ples h> min In any of the above mentioned V ;md Y»_{ *emse;a.e dm med >-mbo<hrnems. the isolated aimgcn bmdmg piotem may have a K- of -100 uM, * i0 uM, * I uM, -0 5 nM or 0 I n\-l m a CGRP bmdsnt. eompeiition assay, e.g,, in a radiolabeled binding corngeiition assay: to rnensbtanes f mm , c’b m prox.-nng human t 'GRP R, ? g , die issay des,; shed m Example * hot cm btOif.- ispeei, the ssolaxo amp-vm-bn-dma p-.oients comprise a h.eo, ch.ms s/quarue fh.it has at 1-. a*l SR¹., X'R _cr os seqnom e 'demos v nh m ammo a, id seqnen?

'itdeeh-d ooin the pjour consisting et SI P ID \Os ?°-41 Smne of the isolated .mimeahmdh-u proteins described comprise a bghi chun <ie<juen».^. dm ha,* m least >O'·.. £y_e, 90’b. qt

1.5 05% sequence identity with ats ammo acid sequent? selected from the group lOUsisOng of Sl.'ig

NOsel2-2B. Some of the Isolated antigen-binding proteins comprise a heavy drain see'· 'm ? *bat i,<f* m ieast 50' >< s v\., ep'o, _trr <\S', xeqncne. de'U'ty v Uh an cm 's' -, \1 ’.sipisitet selected front the group cousfstittg of Si.Q IP V Is; 29--41, and a light chain 'icquan.e hat h ο* at least 50', 55'P OOR. m 05 ' - se-pience identity u nit an amino acid sequence sctx'ued ftom the ctnnp tons-sung ot SLQ IPX? Is, 12-2^ la sonx' embodiment*. t^!x' isolated atmgun binding proteins οοηιρη,-,ο iA) a he.oy chain comprising a sequence (i > selected from the eimip ronssstmg ofSFQ IP Mis 20—11, or (a s as dei'uted by t P> and em-iaining one m it'ore (e n , ore, mn, mteen ot tu mays amtno ae-d nibs: mittens u g , < ms,*cv mA- .unino aeid sub*otut'oasI, dGetfOus οι η;*- room. «B? a belli . ham . omptisum a *e.uten< e gn'« seOcled ism ) P'e ^.-oeo consisting <r, M <? IP \O* '2 22, m tu t -,s xefnud iv u'0 co'damme one m mor? te g, foe, ten. fhleen or tv entyl ammo .-a. id subsist adm-s (e e., eomerv alive amino acid oibslimnon-P. deletion-, os insertions, m ;C i a hem v eham of { \ > and a light eham of {IP, In ,*ome embodiments, the isolated antigen-binding prmrnns compose n heavy chain eompri-dns,’ a sequence selected srom the eac-jp consisting ot Sbp H> \Os 2^ί>~41 and a Ιη.-ϋΐ ehum *0 comprising se^twoee xelectd froio Ott m'Oiip con*’s)mgof ^!3 IP \O* |’ m

In one embodimem, 0s? isoGmd ηηΐηρϋ-ΐηϋΐΐ-ϋη piotem ?oinprts?'x <Aj a heavy chant vomp isit'e m ⁴mmo ;d sequence *.>icen,d trem fh, gtoup eonsMme ofpj $bp IP \u ?9, «o'» >·, s<, gntut ,· that s* ,ii Ansi Ot}··,. ^) 05% identical io the s?qif,>n,e di f-ned i'y tsh and tmt a sequence as defined b\ <i> containing up to ten amino acid .sithsiftifiiomi tc g , conservative

2016244220 11 Oct 2016 iitnim» ,a td sybshiutionst, d a ,-uous ns ’itM-rhon*, md {Bi a Istfru eh un composing an ammo acsd seqtieitee seleeisil front the group eonststing of (i} SEQ ID NO. 12, (it) a sequence that b at least '-sfr'c or ^,!5^!,.i identical to the sequence defined by iifr and (lilt a sequeuce as (kilned by (I) conieming up to .fen- amino acid aubstlmEons (e.g,, conservafivc ami.no acid subsfrfrmons), deiefi'ons or insertions, in anotbei ombodament, the isobtu, ri atitmi'is-bmiimg protein comprtv. - t \) a heavs chain conmosmg an antmoaetd sequence seleked from the erotm ..onsiMmgvf (P SEQ IP \O.30, in) a sequence that is .it least¹ *d^;D οι tdeuntea! to the sequence debited by B), and But a sequence as deiinsd b\ os -coidammg up m ten ammo aetd substitutions ie,j, .

i‘d -.O's-eu tisxe arene „ Q st''cste’titiO''Xi lelelams o< mseovtx ami (Bi j. hptt cbaiu con'p'ismp au. annun ,icm -equette' selected from the gn«up consisting id Μ M u tD no | - .;ut a sequence that b ax leak .98% or 95% identical to the sequence defined by (t), and (lit) a 'leqnua. e as .defined by is) continuing, up to ten atnuio ai id suh'dtutuons b„.g, consenati',·? amino acid substimdons?. deletions or insertions.

1.5 bi another embodiment, the isolated amipcn-'blndirm protein t οιηρί'^, - i V> a heavy chair· en’rnnsmg .<u ammo acid scqs^enee selc ted from the erven ^on.-tstntg o? ufrsf Q IP NO 31 in; a sequence butt m m least ο*,Β, or bug. v the sequence debited by *tl a-'ut

Bio a sequence as debited by (tt eontantntg tip to ten ammo aetd substitutions (e.g..

• 0'isersatne amno tu \l st,tf_Otnutt-msi dcieoons ,u mscrUens, a^?ui (B) i hght chain eompi ismg att amnio ,_scid -euuettce selected bon· the ctonp consisting of 0) \i () ID NO, N, in) a seoueree that is u least op' _c or *k% identic d to the sequence detbted D t ii, ano *,hiI >i o up .-ms a as defined t'y ot e-'i't name np to ten «mum m id snmhtmmus >e g , - onset >.,<tiv amtno ?c;d -ubshtunonsh deletions or insertions, in unotbei embodiment, the iso'-an ri anttunu aw.,ute protein i ompi’s· - t \) a Iico s eb.aiu eoittnnsmg _t-,n ammo acid ssqttsitce selected front the gtoim coiwstmg of til M.Q IP NO'?2, ;;fr> a sequence th a is m kaM og'¹, _or oy·’,. ukmteD to the sequence debited by *tl, ami tub a sequence -is delntcd b\ (it vonfrtntntg up to ten amino acid substittifrpns (e.g,.

-, ou.-eiotuw itnmo icnl \g'isligflto’isa rieieiamsm msems't'-, ami (B) x hc-ht chain composing at- ammo acid i-m use sekrted frotn the pump lonsistatg id fit \| tp IP NO t N ,-0 a

3*1 sequence that is u leas* *>9% or ^l'^!?% identical to the sequence defined % iQ and ytnt a '«eipi'.mt e a*- defined r*y tit com umnu no to ten ainom u, ei substitutions g. g, eonscnuti',. amino mid subsbimiottsi. deletions or insertions.

In anothet embodiment, the iseimul ammeu-hmihtu· protein tomprts·. s ? \) j heavy chum composing em ammo aetd seqtt-.uce selected fiotn the gicmp consisting of a 11 Si Q IP oe ,Λ.ι·ρ

2016244220 11 Oct 2016 \Q v, (d) a simacm e foul a- w knsl 90'. ot -denm aim th,’ sequent e defined by ‘ft, and (ίϋ) a sequence ax defined by fit eontthmne up to ten antnto acid substitutions ie.g , eons, rxattxe amom <», id <mhs'imfiontd jak^-ons o~ insertions, at 1t !>i a light - ham - t>'i‘pssrie an amino acid sequence -<keted now tin. etoap consumseofifi SEQ IQ \Q,fi? {tit a sequence that is di least 90% fir 95% i dontifeal io foe sequence defined by (i), and (iii) a sequence as defimed b> u) containing up to ten mnwo acid substitution», te g.,. vw-x'i’v.ttxe anfino acid substitutions), deletions or Insertions,

In junk·! emhodiwen', the isolate»: antigen-binding pjoteuf composes ( \) a he«s\ chant comprising an ammo acid sequence selected from the group consisting of ti? SEQ ID

H) \Q ,?E (ii) a sequence that e- at least 9(}’. w ^;*s%· identic^! to the sequence defined by (i). and «{·{) n s^quesne defined bv p} eontawinc up *e ton amnio .uesd -ubstitutOus te g,

CP'is nx Htxe amm-i «, et subs’!'nt ion?) delcoon- o insert-ws, n»-d t !>t a light bam > mup'Oman aonno acid sequence v.leeted. from the group consisting of (i i SEQ IQ \G 17, (ii) a •>equene„ tlt-rf :,- at least 90% o* 9}% identic,>1 to tits' sequence dciued bx to. and fid? a sequene-e as defined Ex 11'> < eufiunmg icp to ten mwne acQ substitution-, teg,, onset imi-e ammo ten! substitutions, de’etions or msertums fit another enfo-mtunew,, the isolated antigen-binding pros tn eenpr-oes t \) a he«s\ chain comprising an ammo and sequence selected from the group consisting ot fi? SEQ ID \Q;3fo {ti) a sequence that is at least 90¹¹ -, or 95Q tdcmt- al to the sequence defined by ti J. and (iii) a sequence as defines! by fit containing up to ten amnio acid substitutions (e.g., eonsenetix e amino acQ substitutions deletions or insertions; ;md i Bi a light chain, comprising an aonno «.td sequence selected now the gtoup e-tusMouj oftf i SEQ 1!) % i t\ (ot a .sequence that Is _;?τ least 90% fit idemie,n to foe sequence defined by ti?. and fid? a sequencx' as defimed fix 1i) containing up to ten wt-wo acid substitutions (e v., i osmerx utis e aonno aetd substitutions), delations or fosettionx.

Io another enfood:mew. the isolate»! antigen-bunting piovin compiles (At a heaxx chant comprising tm urn mo acid sequence selected from the group consist mg o! fi? SEQ) ID \O ?e. (II) a sequent e that k m Ernst 9()% or 95% identical to die sequence defined by (I i and tin) a sequ»'’i,e ., s defire ! bv , t ooutun tn χ up ό txt ammo aent s.ibsot'.guns o, g , ept',>_vr\alive ammo aefo sub^imtionQ deletions or insertions, ;?nd i Kt t light xhato comprising an aonno a id sequence -keeled ;row fite gtoup consisting? of g i SEQ iQ V ¹ Q\ (ut a sequence font is at least 90% o? 95% idem tea! io the sequence defined bx td, mid .(in) a. sOxtuenee as .kfinedEx 11) tot i,t-nmg up to t. u »m mo .ix't.l substitutions te o ,,oif'-oxom· annuo acid substitutions), 'deletions or mxerfions,

2016244220 11 Oct 2016 hs another embodiment the isvfat- d anngett-buuhng proNan compose- $ Ό a he.e, \ e! urn emttn- ts-ttg ,nt annuo acid ssqiajtt.e sel· ocd tie-u the mot p «.oti -istn’gof t b M Q ID NO ttt'» a sequence tin tt ts ;U least ^lhp>„ _or 9--¹.. flounc'd to the sequence delated by (tb and tub a xequenes as deism, cl b\ Qt vOtdanttng up m ten utmno actd suI-st. notions tern , i,on->en attic amtno a·, id sob-eh m inns), ddcoons or insertions md ribs a light eh.ttn comprising an antit.o aetti s,-iptct4.e seNtled font the t-ioup vot-sisi.ng ol tb hi t? ID NO, 20, oba seu'uenee ibut is $t ;e,:-e m>% or 9?'\, identical to the sequence denned bp tb and tpti t n -ftpivtit e a*- dcftn.-d n\ is) com omne no to ten ammo u. id suh-mtutsous g e,, cons.-nato,. ammo aetd vubsftrution.s'> dciettou'- or insertions.

it) l·· another embodiment, th ’ isoum o unffgen-btntitus. protein tempt's-.¹ t -V a he eg shut on ),is ng ,u ·. n tsoaesi -e.g ute ul..v tin n t κ met n „o sasiir^o* t '' Μ O D NO 3' itt * a,sequence that ts >n !„.,-a ov’, ot 9^χ-\ oi nutesd to the seqtteue ’ defined b> <tI ami <iii) a sequence as defined by {tit i..oiUants.ny up to ten attune acid suh-stHuttons (e u .. conservative amino uOd substitutions t, deletions or insertions and (B) o light chain comprising

1.5 un amino acid sequettee selected ftom the group consisting of b) St.i) ID NO 21, rib u sentience that is t* leti-a ’·><)-·,- or ^t}?⁰n identical tit the sequence defined b\ t tb and inti a seen, ri? defined ts) e-mtmnng no to ten «re no acd simsmntfon·* t. p., xonse^.nn ammo retd -'ttbstirnfionsb dciettou-ot insertions, hi another embodiment the isolati d >tntit;en-I»nd<og protein compos»,--1 -b) a he,e, t ehuto composing .nt ttmun, aetd ssqu-.ure sel- acti fo-tn the utot.p ^ou-tstutg of tri Μ O ID \0'36, mid sequence mit is „ hast oy ’, or 9» , <d„-m.e:-I ti- the sequence detin,J by <ri md 11:t) a sequence 'is deih-e.l b\ (it .oubutung up to ten attnno -,ctd substitutions te e .

„οηsen attic s-mmo u-- id sitb-uimtionsh deletions or Insertions, and t B) a light chain comprising at- amino «eld -».qtistici- selected ftont the c-toup cooststittg oi ri) tii.Q ID NO,22, itt) a sequence that ts at least 'Ht'bi or (denttea! to Ihe sequence debited b\ (ib and t tit) u sent·¹ oi, e a- debited ·ρ, t s) e-mt otong im to ten «none m. id substitution·» -, g , consci- ate, antnto aetd -ubstirntiesns), deletion- or insertions.

In aeoihe? embodiment, the isolated antigen-bustilng protein compose¹ t -V a he.og.

-. hat''¹ etui-pi η-mg tm sut-nso acid sequence selected titan the croup .O’asfstnu· of (i) SI Q ID

Nt)-3,- !ti$,t sequence that Is ,a ti-a-o 00’.<or 9s-¹.. ₅Jenhe.·1⁴o the sequencedetined by ftt md Itu) a sequence as defined eg to .otthminu· up, m ten amnto a>, td substhubons (e c . vo'^enatise mmo subohtintO'ish deletions ·'·* insertions md (Eh - tight ek,un eompnsna at amua, .ano ~ qn> nee sen t fed fuun the on,up iot sist.ngoi hi 4 Q ID NO 2b rt)a sequence Ihat is al tiu-d 9tb',- or^u<)., id-..uncut to the sequence denned by t Π. and t tit) u

2016244220 11 Oct 2016 sequence ts definad by <J> t'Otuaintng up to fen utnno ae\! wb-nbunons (e g . -on*~;.-rx'ni\e awao acid substitutions), deletions oj nisei items.

In unoftwr eu-hod-metr the isolated anttgen-hindtng pro·-.-hi eonipooes (Λ) a herox chaw vomprismg an urnino uud sequencs' selected from the group consisting w nj Ship q}

NO:5b, tu'> π satjumvc that G at least VO’,> ot VGA· tdenwai ro the sequence defined by tit, and < ίn'> u sequewe us defined bv -is contuunng up to tsii annuo acid snbsunwuns te.g , cnns-u'xaitxe ammo acd -whewnt ion-A deletions' or insertions, and i Kt a light vhatn eotnprGmg an utrnno aetd sequence -Gecred srow fise group consisting o{\s t ShQ IP \< ),25, |-s) a sequence that κat least 9t)-,. ><s- ny¹., identical to the sequeiix-C defined b\ tit, und nut a sequene · is nefin at by «A tewum-ng on to fen menu w \1 sobstnuuo w <e e -on* su>e amino acid .substitutions), deb-ttons or insertions, bt eno-her ctnUodunco',. the isolated utntgen-dundtng pros in eontpmros t \) a h-e-ox xham -otnpitsuhj mt tnnmoui'td sequence seteevd oom bi-· group consisting <n tA Sidy fit \f) 53, tut a s,uite;we that I*- -b least WJA, or vyy identical to th,- sequence Uefined b> o' h end < nt) a sequen- e u*< defined by r-1 coWuitnng up to t>, t. annuo acid -uhstitottotn-' te g , eo’tset'xatrsx tmm_v <-c-j -u rommo-A del-won-*or insertions, and tKt t light vhaut totnprwme an utrnno ot senueoee -, looted imm fiv group eonoewtg of-j t Si Q fi) \O ?4, <ul a ’,>,tpKtu.e that i--o, least 90-,-. _t\$ identical to Ute sequence denned w nt, tnidtwt a .sequence is defined by (it containing up to ten amino aetd substitutions (e g., conservative ammo .tod substitutions), deletions oj nisei news, bt another embodiment the is-.'lated antigen binding pro* ein compm-es (A.) -t heaxy chan; ,otnpttsiu-f m ammo mud scqncnc- sele-Aod trout th-· group consisting os td Sldg ip \O:5^<(, tilt a sequence that I* at least ”0% pi 0e‘\- tdemixal te the sequence defined by <K, swd <nt) u sequeo-e «*< defined by - it etiniutmng up so wo annuo acid Mthxrrtsiiton* (e.g, cottscf xatix'- -aumo ae>d suhstimtioosj deletions ot insertions. and t,Ki a light chant compitsroe an utntno _u id sequence s-Ceeied trout the group consistingol'tt t fif'Q IP \{ .),25, {at a -«.qttenee hint n- at least 90-.. <<; oyy identical to W<, sequence defined by tit, and tid 5 a vsoquene ’ as eefinwi by yAtomam-ngno to fen -euroo ,n \| sobstnuiions te e -on*.; ro ntxe atmno acid substitutions), deletions ot ηκοιΐιοικ,

In another embodiment- the isolated antigen-binding protein comprises fAG a heavy chant composing an ammo acid sequence selected Oom the group consisting of tit SEQ fid

NOQO, {fit a sequence that is at least 90% 95% tdemftai to the sequence defines! by ti h and «iu> u sequc’i-e a*< defused by >o consumm·-, up to t-1- arnttn» -seal -nbsuwtiou- u g , eottserxatix'. ,ati-uo aeul suh-mtufiou'd deletions ot insertions, -tr-d tRt a ItJtt chant comprising

2016244220 11 Oct 2016 at «ΊίΐΊΗΐΚ .(ii' c se 11 le I^v ism Jv c o ip losmoan y idg j M tp if) \O A, ; ,1 _ti sequence that is leu-d ^fHs% <,= uyq, jtK'ijucui tn the *equettei, detnied b\ syfi. and (.nfi a sequence a* defined h\ is) eontnnsng up in ten «msno a, id *ubv,ni ns so: :,* ·,. e., Ciinsei^cuv-amhao uetd ^sm but s rn nous k deletion* or ttt^eroosts,

In mod-set entboointenh the i*ei.ikd autieen-binding protein eomprtse< i A? a beam

-. bam comp: ssutg, an u't'Hso aesd scqiausee seketeri frosts the gsvssep i ois*s*s me of id SI Q ID NO 1I, ni s a scdue’iee thus Is ,u lea*t 9o’„ or 9qN. idesmed us she sequence denned by p s snd isu) a sequence >.·„χ >lelhsed by {n ,ontamsiig up to ten jsiiiiso a> id sub*tstutvm\ (e sy . eon-set vat tv e a nt mo acid seo-nstumms), deletions s.-r maul ion a. ..-.n-d iBsa heist elsmu comprising ci’s mimo aesd mu η· e senes te-.I -nmi the croup eon-voiing gt tsl SFsl II) NO-?'⁷ -sss a sequence that is „e ka-d 90% or 94% sdeistteai to the setjuestec defined by t 11. and s sis) a seen in e us defined % ist e-.'sunssmg up to ten «m n-ι and snhsmsilsos.s < g, xsssssewuto amino ssend 'snbststunos'.s), dele-ion* or uiseruons.

In aWher entbodimenf the isolated antigen-binding protein comprises (A) a heavy

1.5 .chain compfising an amino acid acqncnce.selected from. the group consisting of (i) SEQ IB NO; If jsint sequence that is at Lu-a <\ΐ^:ι·< or 04% sd/niieal m the sequence defined by (i's usd sds) si *eqsienee sm defined by (it eontaisisru,· up so less asmsso .acid sub*issuiussss se.ie, con*-.!vatsve. mute a-ud sub'.titutn-sts), deletions >e m-sud-nM. and sBs a heist eitstsn comprising an amum aesd aesnuai, e seh-<. te-d fiom she group consisting t>f Sil tsFQ 111 N0'?>M -ol a sequence shat is m ka.-a ^Jhs% os '’mb, snout scut to she sequence defined b\ syfi. assd > ns) a seunenee a* defined by ti) eon* ustmg up *o ten amuse suhsitinitotv·, A g„ -„onsefxau\e ams-io aeui «sibstitntsosss'i, deiefiots'tos msereons

In ip> e? she ,sbo\ .- mentioned hubs and he tv> - ham sequence desisted unbodnnems.

*1 i sol.Ued >... trge’i-l 'mbm notes', t' s. comps - she *m< 'fie 11 i^s\ ,esd os ef , etuns' sequence, but wstls a dsffiaent -somd peptide os with ue Ovisui peptide its ,-ns\ of the abovemenfioiied I split and heavy eh.sus s-aiuo·:-, e det Is :-..-d esni'-oduu- ss'-s, fist' cohued usPuets-bu’idmg protem may he. tor example.;; monoclonal sustiB.sdy a poh clonal antibody, a reeosrtbstAot jftii'ob, i bum,iii le g , tssR Immas.} eesAnA, -s msmanf/en mums.,.!? a chnnen- ant'Csils, < ms J a-specs A. .mhhody„ omm antigen biisdssiu fragment theseof I nstlscs. Ik ,-eUsbodv hmysssentof ?>) the coleiC'd antigen hmdme ororems m.e, be a lush nngnt.rn and f ?b’ t’.ignsvm, an hab’) fsagm-. nt. ass I c fsagso-. id, a JiaF-mE, os a suigk- i Isam esinhodv mok-esda Ϊ ot csausple, the ssvko d , nngen binding psosesi' ns n he a bent ss* utostoclots i asuthodv, m d m, \ be, ° e, <ss. ΐι,ΰ , iy(let lb, o. Ie< 14~t\p, as.tih-idv f ns si-, i, the col Ued coins n t'lsab’ty ppn- a-s max he siessnahenty asitsgesi ksudsssg proteins

2016244220 11 Oct 2016 hi an> m Ov cbcoe-fnennoned hght ami heavy eham sequence defmen embodiments, the i/oluted antigen-binding protein mas speentcatls hum m both human (RI Rand human RAMP! and not spe-..i Ikaliy hmd io AM I, AM? nr a human ami hn re·, eptnr ί e g., A M3 i), for example, the Related antigen binding protent rna> -ipccuftealls hum to human CORP R o uh u e Ko ' e\i, ' JM nM, 10 uM or e ΎΙ e a , <-s de^-.umned menu >· I 3si S bmmne tssm md at-aKeed, lot eemspue. u-mp memo is etes,ttbed m Ramarusy-atm m _t/ &,<>, _tp -,00 j^&ieiOT& GmkkmmArMiA .334 (2005) 1004-1013, In atty of the aboveementiobed light ano heats ,ba-n s-ctuiem c -ielhi d emt'omm.mt-. the i-soiat-,3 .intmen-lmidme psotetn mas -.decks el-> tihibP hut tan C t IK 1' R, nJ ease to the human the AML \M2 ο \'si3 ₍ee, ptom, ', g worn a .select;\ nA takoof ^;00 m tiw, MO m mate, eOOormoru *”Wm mom, hOOo o<

trims, 2,500 or tnoie, h,000 or more or 10/300 or more, sshue the degics oi zdeefiss inhibition may he detenhied tsdiig asy sthOtble method, c,g<_¥ uMtiga eAMP assay as described id die Examples herein. In an> of the abose-rnensloncd light and hetos- chain sequence-defined embodiments, the isolated antigembinding protein may bas e « R',i of y l00 nM. <10 n\1, M n\h ri0,5 uM ot' y-0 I «Μ in a f GRP binding, eompeHtion am-as, e.g, in a tudmlabeled '' l~i GRP binding -<.<unnethion mmy to membranes from veils expressing hum,mi ('GRP R, e.g , the tsoo dest t ecu m I „irmk - ’ tern in a kn'tbcs u-gesk .wo piowLct me isolated t\>e\'e a„id nolynuel.chides dad encode any of the GGRP R mhgcn-bmdmg pfotesti-s -utum ·Μ.-\Ό chose In one embodiment 0-e isolated polynuelci'ttde compose,- a sequence -deeted trotn th; gtoup consisting 01 >1 Q ID KQs-l·'?, I R\ I'm I '0 ID1 181. Iff, IS? 1D<, 18'. lb*. I so pit, 192, P« PM pas, I Op, 107, 2150, 201,202. 20 204, 205, 200. 207, 208, 20< and 2!0 In uttmimt embodiment, the wo^!ated po'snneieonde comprises t .eqnenes, seRs ted mmi the ermm < o'e-isi mg οΜΜ-γΐ ID \Ds 2?9-25s iwanoihei embodiment, tb- ,sokn 3 noKten lemide _xonm· ises a sequent e capable of hybridizing under-iruigent hsbikneation conditions with c sequence sekcled from ihe croup i oust om>g of RF D IF) M)_a 32-1-358 h, a?iomo embo-hmem, Oh- .so: it d pots tike lemfiR-comprises λ''.quenuu Huu t- about 80'' 1 he’1-,‘MY 0 ^<JM <os moi utende,-/ to a sequence ‘ek'ett d from tn,- gromo consoling of si Q O') \1> Y* 1-2 D- In some u stunt os, the i-mutod nucleic aeM molecules ate op-,, raids-huked to ,-,, O’Utol sequence. in related emlvMsmarm;, fit,.’ isobovd poo nucleotides am incorporated mio ,ut expression vector,

Mso included ate cel; hues Wm-dormed wsth esptes-ion \,ctW\ eotuinfsnig isolated pe.snuelesmde- , s dwcriKd >d'n-,e in a r.ltt.’d aspect, .0,0 pootded are w.m msion seeiom and host cells nansfbinied or transfected unit the esnmssion secksisdfai vompo/t. dis'

2016244220 11 Oct 2016 jfoemcnritmed isitlateti no·. tom arid mold uses tliat encode i'GRP R asmgen-bmdmg pnuems described abox e

In another aspect, also provided is -, method ;u prepao'iu.· die ant seers-binding protects that includes the step of preparing the antsgee binding psotetu from a host ceil that secretes the antigen-binding protein, in some embodimen s, the antigen binding protein is generated using an tmmunouen comprising soluble CGRP seeepiot. in some embodiments, such soluble CORP receptor is obtained by eo-expressing and purifying an N-terminal cximeeihtlisr domain (ECDt ol human CP. I R anti an I C Ό of iuinaus KAtoPi, e g. m i < D ct human CRLR cusnpn.susg SI..Q ID \O b u,d a i^! ( Pe»f R Wild uomposmg bi Q =P NO^- f, tor cxaume, as deseohed sr, i samples t ana hen-m in x a .utodter aspect, a phattaaetntiCdl eomjtosittoo is provided composing at lead ot, of the anhgun-binding protons otmnns' ί/ed abox e and -·, pharsnai. estsieiuiy acceptable m, spient in one otnbodime-ts, the pisaimaeeuite d eontposumn may compose an additional active agent thm ts ->ekcied from tin.- group coo^Fftinu of a radioisotope, radionucbde, a toxin, or a

1.5 themjicutie and a ehito tosberape· itsc group..

In one ,η-peei, toe coined ant,gen brndmc protein w cllcetiv e io sn’idni visodiah-tion and οι dei re tse neurogenic mtfimm.mou n hen odt-mtisiewd io a p nsesu In one embed·?'· rto the isolated antigen umdine pten, m ts efisGtve to seduce the fteenetsev and or se\ etro' of h„ad,i,bes I'm ex nnp'> , ungnm-e i cab tehes Γοι e\ -.mole the ,mligen bmdmg mote-n may- t'e

2(t nseo is an 'tent; to .us'teu* ot n -ui. me, ane ct ,t> a η on'·'. lactic be itm„nt to ptotont os tostoee dse frequenev s nd m -o, ,env of symptoms. pa rt-, nieriv p.nn symptoms, a-,sOe-neo vxnh a migraine attack f liber top.-ets umber pro\ sde methods tor treating or prex ennug s condition essvx sited o uh t 'GRP R tn a pattetn, comprising 'administering Io a psihe;;? an eficetixe amount of a? least one isolated ,mttii„r>-hmdnig ptoteut summ nseed above in ssste embodsmenh the condition κ a he>via, he, tor example,., migraine be idu, he oi ciueto, upad.i- bo m anotb. r txn. -n pam, - g , .· chtonic pant, nt anutbes emhootmeoi it ts d>,ibetes me!bins to,pc II), m another ernbodtsu.-nt it ts htftnui'n.sttou. pa-lit ukriy lu-iuOgcne ιηΙΙηι-κυαίιηη; nt another embodiment 4 is a eardioxaseubir di-aifder. ns nooihef embodiment it ts a hemodynamic detanyemen? .tssoi sated noth e-udotoxemus and seprity In another embodiment it ix. vasodiaktion.

in imo'ihe· aspect, also psovir cd w a method of inhibiting binding oi'CGRP to human

CORP R, e.g,, the exbwellnlar ports-m o* f 'GRP R, in a patient coniprtsiag admhhstesdng an efTeedvs amount of at least one aniigeo-biods'ng protein provided heroin and/or summarised above.

U

2016244220 11 Oct 2016

I'hesc .wd other -expects wfb he Jex, rfoed in greamr dc'eoi hewm Faeh of the .expects provided: can encompass various embodimenta provided hemim It is therefore anticipated that e -,-1 of fh embod unvote m\ oO mg one elens. ns o; · onitom turns m ,-:00-, sU< ns n ’ -neiud\i us meh expect described, and ad such eomoutniionx oi the above aspects and embodiments arc expressly considered. Ohm tei'ures obieeis and advantages of fix (mention .ire appwrem $n she detailed dexenptuto that loitow.x.

BRIEF DESCRIPTION GF THE DRAWINGS

Fig. 1 xhow-ao -digusucfst e? RAMP-1 sequences foam huina-'·,. \ uomoigu- monkey and rat,

10: fog ? shows g: ahgomerU su CR1 R <-eqnence-< t'rem husnatg eynesnolgex memkey and rat,

F;-gs 3 A and SB show phyl-^genetically-based s·, o-ience alignments of light cham GDRs from th'„ indteaten und-CGRP teeepios antibody clones has mg kappa light ehastex, and vertam eowexpondma consensus xcduemes

Kg, 4 shows phyfogenefeanyda&sed sequence alignments of light chain. CDfi.x itas the indicated ano f 1SRP -e.eptoi .tnnbod' clones nm, mg I imbda light chains, anti o-rtdin co? responding consensus ovqnonces toes ? A, 5B 5G, 5D and 5b show phyhsgenetseaih -based sequence alignments oi' hx’uv, elsum tf DRs ikon th-e indicated anti-A GRP re- eptor antibody , tones. and certain cosrreapotidmg eonsert&us ssqne.8 ces.

Etg ?i- xhowv, consensus sequenc/x of exemplary ano-CGRR receptor antibody heavy char i ' K,s disclosed herein ; w. tits 5 plet'd d.q$ tnuw two experiment? show tug percent mbib-ttou fo SabcDd hg,g.d binding to t'GRR R bv BK2 anti-A GRP R t’vhndomi oipemfoafox foninioadx· and »'N negytk e control stipernaumts (squares v

F;g-< '’V-Dshow ew'-npiax ,A\1R tx-e, 1C?0 J,nu from e ’Us csp-essim hf'GRR .receptor ii in. 7ARhAM’ (b'tg ⁷B;, h WI2 (log. TO and human amybn receptors (E-g, ~(>j for three indicated anii-CGRE R m-Anx

K> ίχ shows nil example of 'l-GtlRP hmdmg dtoa such us may be used to tiet.urmne 30 the Ri of nsAbs to l-uot.in ('GRR receptor

Fig- 0 VD show fhacore coinpotiOon dtoa lot selected atmbodtes tii-cioxed hetetn

Fig. 10 shows a b ACS Rd dgtcrnnu.mon of mAh 12GR, = w ΐ I shows ,-,η abgnm>, to of < yiinmolgns, Inm-an. human eh-ws ra-<, 1 d, and I'hcxnx

RA.MP.1 sequences.

2016244220 11 Oct 2016

Res i 2 A-B show an alignment ol'humnn, cynomoigm-, rhesus, rat human drueem and consensus CRLR sequences;.

Figs i? : O' snow repres» , TAt n da' ;. <n riittej.’tU ehmtene CGRP reeeptofs binding, to anti-CGRP R antibodies.,

Re I 1 -hev χ peptide map- decked i*<w \xp\ dm/shoo- ted i.»RP R aien.· «eni'imatosnau· \) and h«s\ dmextom o^! <. eonnoi sample , om oon.g t 'GRP P monoeduud annbnds 1 ?Gb ututt'i.ii'n B'<

tog 1 χ -hows Asp\ digestions of CGRP P nt the presence of different concentrations of t % IRP R nents uh, tug antibody.

'' g lOshe'ox ^λ'Μ'\ duteseunxol < tip P P ι i the p exeneeeRb ietent e«leentnnton

CGRP R ncutreh/nog mthbodv, 4V.4,

I'm 1 ~ sfiow- mt nnnobtx'Ct hem: cry -', numg unemuy of» cits -spre-mn χ at mux reeeptp; compoucmx with ammod', MIR

DPTAit.PD DESCRIPTION

1.5 The section: headings used het ein cue for orgamzu-ionat purposes only and ate not to he construed m- Imtbmc the subicet matter described l 'niesx others f-e detined >u t»nn, -eiennfie ηη»Ι teehnkal setmx us- d m t onn».x non v. .th the ptcsent apphc?tji«n xhail have the ioeanntgx that are e<>ntntonl> understood bu fno-eof mdutuy -kb; in the art further, unlexs mhctxM-e requited b> contest, xmgulur ietmx xhult nxtude plcuahts.s and plural tertn- .-hah tneludc the -angular

Gencmlh. nomcml nuom u.-ed in e>>nneetton n itb and Rehriques of, eeh and Itx-ue eutt'ce, moks m a Rohm'', re inmok>g\, nueiposn-'gx, gg uctu ·- and p.okm ami nt.ekne ..cul vhem.istty and hyRidBaOoo described herein not those 'acP known cud eeroninnk used in the art. I he tnethodx »md techniques oi the present application ar»: generally pe· lor med according to eoro enoonai methods well known nt the art and as described in sarums generul and more so»-eilk reference- that ateeu».-d ami -.Psenxxed thmutdtout the rnv-enf spot oksnion usde-s other wi-e indicated 5»v t.g , Mutbrool »v ,d , Molecules ( lonetg Λ ϊ abotatory Manual. kd /d < ok! Sptine Harbor 1 aheram χ Pies'-, i elxi Spring Hmbm, \ 4 MOOf) \nxub>;f ,7 ( furent Psot'-cois m Moieeui e Biologo, Green». Puhbxtmm Ax«t»sues t HE}, uud Hafoxv ami

I nne Mthbodies: A Labor,dors Mamed Colei Sprint* Harbor Liberators Press, Void Spring Harbor. \ 4 t rt^J1'^!0}, which am lixoipooUed fie,».in in mf/reuiv I'n/ytnatre tern. Rot's md purification technique- are performed according to nmuuUxturer’s xpe», ifie.dton<, as commonly accomplished nr the art m ax bcx. tibe»i lu tern i fo eonnuologg used m ιοηη» rt.on w uh. aid the Ul<o.utot\ piOecdmesand L-ekmquesot, anakfoal ebernrxtrv. x'-othaPe oremne chemtstrs.

2016244220 11 Oct 2016 and medicinal a nd pharmacem leal cdemistry described herein arc these wed known and commonly used in the are Standard teehmques can fee used for chemical syethese», chemical analxres, nhanndceuiical prep.oanoti, fmmnfenton. and deux cry, and tree me? e* patients.

It A redd be trndet-m-od that tins nreeneori are I united w the partictuarmethodmet. >.

protocols, and reagents, etc,, dvscrilwd herein and n-> meh may v-try I he terminology used hereon ;s 1m the purpov. ot desei ;bl tty pytltenltit embodon. nt-oiiN, and -s not mtc-tric-.l to btnP the ---op. rerihe present mxetiitnn x'lmb is defined s-me'y by the -Grew

Other than nt the opereuing examples, m χχ-hefe ofnewxws indicated, al! nutnbefs expressing miamlmm of ingredients or reaction conditions used herein stiotiid be intdeismod as modified in all instances by the icon ''abort; ’’ The term ' abom” xxnt n used nt rem>‘-t non with percentages means ±1%.

Μ&ΐίΜ fhe term “pol·,nucleotide ' ot ''nacree acid'' reeiudes both stogie-stranded at.-l doWdcsfiundc-d tnictcotfiL· pofe mens I tie nucleotide’-· . otnptts$ng the poly utideotide can fee

IS rmoneelcettdes or de-wy rtremoree-wde- or a modified form of etthc'' txpc of trend .-obdc $ red fodiin.atm-'s reel',!? ea-<. s\o fefirutso's sa,' re- b'ot'aret if, me mosaic ,k treats, - f -''s, modifte-tnotw meh ,re 2',5 -dideovreibow, and intermn kottde linkage modifications such as pho-p' modt'o ee ph,re xnottneimoat-, 'ft-repP m-'seleome., pi osplto'o-h -ehutoate pho'iphotoantiod'noatc, phoA aw utadate and phospla reoureedaic .30 The tern; “ofeosntueleottde'’ mentis a poly nut lentide emuprls'rea 300 or fewer nucleotide, p; mme embodiments, obremicGoitdes are- io to oh bases nt length. In et iter -, infeoditrents, mtgotsi'deonde¹ are 13, if !!, IS, to. 1 re, reh m-?d to-id miGentide-in length t dt-;otsti>. k'otjihs may b-„ -angle sounded or double sa nuk'd, i re, tor ns., n,i the construction o*'a mutant i.--nc Obgcnnvlceesd--- rnay be sens;.- or atm-cu.-e oltgorenJeottdes \n ohgonih'k'mf.ic cm; utelud-. a label, welndre.g -, lad-Abeb a fitiorese-. m hd-O. a iiaprem m w a man - I re * d. csfio is- xs t,t uonoekotdes re χ be ns_vj k> c\ nip i, ,o »N k p>- wets, eigmp.v pronets or ny bi id- '«non pretbe-,

An “t-aikued tt-tciere acul mmeude' means u B\ \ m RN \ ot re tanme mRNA, eO'NN, or -y ntltcisc orig-n or some combination theteot xxntelt is not asset sated 'xuh all or a portion Ά pels oneicottd; nt Audi trie isolated nolvnueleottde ss found nt oatuse w - baked to a polvnw, lenndo re< which it ts not linked in nature, for purpose.-; of this disclosure, it should t'c uud-tMuod that “a 'iucGiC acre moici tde ιοιηρπΜΚ a preticnkn rue'- nmN se-jnenc- doenet --reompas.- nxutei chromosomes red ned nucleic aen.1 moicethe- ''comprising' specified nucleic acid sequences may ntehnk*. in addition to the specified sequences, coding .sequences

2016244220 11 Oct 2016 for up io hm m e\ on up to tva'ti-i other protoms or porumis thereof, or tna> iiKiude operabh hi?s„d tcgniutoss sequences that control e'press-on oi the eod=ne tcgion oi tl·; routed hudest add sequences, and or ary m, hide xeetot seqneneeCmcss specified othetwisc, the left hand end of any Mite k· sounded poivnudeotidc ? sequence discussed heron n- the ?' end, fiw left hand direction cd double -Handed pmvnueleolide sequence- is «eleoed to as the '< dire, tn<n fhe dm ci.on of 5' to ” addition of n iseent P.\ t tmnsenms \s referred kt as the h, inscription direction, sequence regions on die Π\ \ '-fraud h,o> nig the same -eip-.m,e as the R\.\ turns, npl foul are τ k> the 5' end of die PAA tcunsctipt ujc wfio.ed to as upstream sequences, sequence ?eg=ons on the D\A siia-.J home the - nr-e sequence as the P\'\ troi-enpt that ,ue V to foe Vend of tn- R\A lian-eopt art reSctred 10as \lvxji stream -eqncnea-

The term eontrs?: se-on.-n· e refers to s poly nut iswf'de sequence that e.m affect the expioss'on and ntoees-mp of coding sequences <o 0 io, h n is heat, d The wihne ot such control sequences mu -, depend upon the host opg intsnn hi peritcubr embodiments, e-mmw

1.5 seqnesie-es hit poiki-uyotes may include it promoter. a rd'-osooi'd binding site, and a tianss-riptioii termiratton sequence b-.-i ewmiple, control sequences for ettk u votes may include promoters comprising one or a phiraihy of recognition sues tor tranxeriptfon faetom, transcription etthortecr -cqucnecs, and tran-eription termination sequence Control sequences⁵' can include kia-der siain·;.-·-.es and or fusion partner v-q-i'entes

The tcirrs eetor means any molecule or cnti - 0 nucleic uetd, ptttsmtd.

bacteriophage or virus) used to transfer protd»boding information into a host, coll

I he toon ’espres-fou \ eetot” or expies-een eo-'isom i.-tios m <i sc. tot tn -,t is odHabie let nonsfornatton ot a nosr ceil ano com.-in- muiek two sc«tu.necs du-t duwr mJ or -..ontrul ij?t eoniunebon w Ub the host cell} Csptes-ion ot one m more hekuoivijous <„otht;e tegunts operatively I inked thereto. An expression construct may include, but =- not htnited to, —e,, < i\ es the affe> = of eemrol trjHseidption, irtm-dtmun, and, ii unions are present, affect PAA. spnetne ofa coding tegton opemhb tniked thesetiAs used herein, operably linked'' rneare· thai the eomponenix to which die term bappbed ute ί'ι a 'AmooVtnpfont afowv- mem to eaty, ote ?' ei inhowm umebous unde?

suitable conditions For example, a control sequence in ,·> vector that =- ’’operably linked” to a protein coding sequence is hunted thereto so that expicssion of the prolent coding sequence is achieved under conditions eompidmic with the transcriptional aetis ity ofthe control sequemeex.

The term ' ho-= eelf' means a gd 1 dun ha-; bee?t trati.sfbi nied. or is capable of being tmnsrorrned, 0 uh u -.itidC'C acid sequence and thereby cxpies-es a gene o^? intct.-ei I he Serin

3b

2016244220 11 Oct 2016 hu halos the ptog my e·' the parent cell, whether or not ^Tbe p'Ogeny ss identical so morphology or tn genet'C make-up to the ssogun-d parent cdk so lone the gone of imetest ss psesent rheto'-n· U- msdtttcon' means the t- mMerot genes Horn one ba.t -otun to <methe? usually by bacteriophage ' 1 mnsduction also refers to the acqmssiion ami transfer of p uAaryone vebuiar seqnemes by repbeaoon ddcc'lu setrovni-cs ’ L ^fe m' tta 'si i t op' ; wets t > .iptahe o*'Rucmr m cow tso'.s |)\ \ lw a ee L an< a edl has beeneirawfected” when the exogenous DNA has been: mtrodneed hwde the cell. inenfPs'uto Λ un.isbw of trans*cotton ti. htnques ate wed Known tn the „n t and me disclosed beretn, hoe, <,g . Chahant <. > al, ! R~3, t ύ-igogr 32:-156: Sambmok et a/, 2*Μi. Mokxulaa

Cloning; A, LahotWny Maneal, vnyw; Davis: gr M., I.936. Sos to Afei&oiA / n AffilbcgRw

Atu/,>g', hlsm set, Chti rial, DM, Gcoo B PC Snclt technnines can bcuscdto nstrodaCv. one os more exogenous DV\ moieties Into ssihable host eelk

Ute icon 't-anstbrtnatson” refets to a change m a cell's genette eharaetettsties, and a cell ban been transformed when ii ban been modified to comum new DNA or RN A, Cor

1.5 example,: a cell is tmnnfertned where .it is genedeally modified fmm its native stare by mfiodosutg r._ve eet'eti., nt nert.tl we mtnsf;e'e<nt, noesdneoun, or ethos NJuuutsw. I chewing tr.msfeedon or trnwdtsiOmn the transforming DN A may recomomc wnb that of the cell by physically· integrating tnto a chnunosome of the cell, or may be maintained transiently as an P's'Uoa' ¹ e item ou'Otst beny x’d _e,ei ot r a_? -epm ,-, mcepencent!_? as ,, p'as? no \ celt ts eons'detee it- kaxC 1«, ar- staop, mmsimmed ski' the uatisfottrnm. DN \ is tc phe ned with the division of the cell, t he icons ' pulypcp-ide'' ot psotest'’' me uw d mn u isungeahly Μ n tn to teles *o a polymer of amino mud residues. I he terms also apply m ammo acid polymers tn which emo or nuex' amnio aesu tcsnhuw is an analog m ostmeue of ,5 >. tm> spending ram ub omtmrsw' amino acid, as well aato naturally occurring amino acid poly mem. The terms oats also erteomp -,ss tmmo acid po’ytueis th>n b ive been snodoted, e g , ny the addition of i nhohydmie re-isdue-s to form ghcoprutmns, m phosphors luted Polypeptides and protents cats be posdneed by a namrahy-oecnsrhig and non-recombinant cell, ot it ss produced by a genciicaliyoiig.lncered os recombinant cell, and comprise molecules having the antino acid torp.icnce of-be n m\ pmtesn, or molecules has ine deletions from <sddumns io, and or O.tbstmtfion-> of one or snore amino acids of the nath -,. sequence, The terms 'polypeptide'' and protein'' specifically vtteompas.-» antigen binding proteins, e.g,, CORP R antigen-binding protects, CORP R binding proteins, .mtihodiu'., oi sequence that Isas e deletions bom, additions to, and ot «tihstdtdtotss of one ot more ammo aettNof ,-.n anttgrtt-l'inding psowiw I he term 'poRpeptsde Imgment'

2016244220 11 Oct 2016 ' feu to n mny peptide i'mit has ,ut ammo-tern seal f \,un. . , at bow'-tern usd f. Gun and/or an internal deiebors. as compared -with the .fall· length, protein, .bitch fragments- may also conbiin modified ammo acids compared with the fuddengih protein. bi certain embodiments. tragmems are about fir e to 500 amino acids long. lor example, Iragntents may

Pc at least s, o, g, 10. I b 20,50. fr h)0. 110, ld0, 200, 250, 5()0, 350, R)0, or -GQ amino acids fom, I sj,d nob pent.>1? tmemew.s u.Gik1c nnwinfutes i. t|i\ ten, 'met-ί uagmc'Cs ol antibodies, including binding domains. In the ease ol a (GRP R -binding antibody, useful haon-ents tin lade mn ,ne mu homed to a ( DK rceion, a ' .liiab-e ifemai.u oi a he e«y o: twin chant, j pottton mart .tmihods chain ot pea u- \ unable ooiumn including two (ORv and the like The'X'GRP recs-ptor''. or ''(.'GRP R'g understood to t emprise RAMP; and C.Rl.R i he tetir· “isolated p,ou.in tc e . isoGLd .mimes, bntdntg pixtemb isolated polypeptide or ''isolated antibody” means that, a subject ptmein, polypeptide os antibody (I t is bee oi at lesst -mm other paoien-s w sib wIn. h U voted notmaby he fomat. (2t o. essenhalb free ol other protems from the ,mm·.- source, e.g., mom the .mme specie-., (3) is expressed by e cell .from a different species, .(4) has been. separated, from, at feast about 50 percent, of polynucleotides. lipids, carbohydrates, or other materials, wbfr which it is aesoeiaied: m neture, s' '> is ops'taEb, associated thy ,o\«lew ot noneosaL-ia mfei«etiont vnh a ρο-y peptide v oh v inch tt ts not associated m nature, m' go not occur m natitic I > pieath. an ' is,dated protein, isolated poly pepmb os Ί5θΙ<οο·ί aniibody ' - oosomtes ,m bak ab-out ?% leao about lO-.,, at least about 25%, or at least about 50% of a given sample. Genomic 1>\ A.

eI5\ \. mR\ \ ot oi'het RA oiGymhetiCoitgip.ot any eemhwmton thereof m.y encode.,'.,eh an isolated pson.m Picfemhly, the isolated pioicm polypept·.!' ot antibody is substantially free from other proteins or other polypeptides or other contaminants that arc found in its natural environment that would mierfete v tilt its iberapesme, dUguostic, pmphy Incite. iesea-cit

2.5 or other use.

\ Ά aoant' of a nob, poowfr to e , m antigen bmd'ng pOicm, of an antibody >

comprises an amino acid sequence wherein one or .more amino acid residues are inserted into., • Hee-tl from -m,t ot suhoiuited into the ammo .« id seoue'W rel stn? G anothe¹ pop- pcptnie sequence. Valiants mchute fusion pro tents ' d υ\ no ’ ol, ro'vpeet.d _ss , po speptt;»' o < m ar men nt <w „ ptm. η ο» .monody) that has Oven chemically nimbi led m -omc tnaanei tb-miict font, insertion, detenon, oi snbsttRuion v id,cuts, cy. -m eooiugation to another ehenned motor,

-W

2016244220 11 Oct 2016

The term naturally otci *nng as m-ed thromdiom the spceRte.-UiOu in ιοηι-οι mm with binli-gudt mautMts such as nob t\nodes, nueieis' aesds. ho-τ echs, and the die. retem to muieriaG which are Ibnnd in nature.

An ''anoueu binding pOfrtn ' a-' used hetetn tneans a ptoietn that spccdkalo binds a 5 specified target antigen, .such as CORP R, partietuarb. pmn r'e, =, g„ human f 'GRP R \ (' GRP

R antigen binding proiem ,-q'e<. oRjIty binds itts- human < (TIP reteptoi

An audg-.n binding pre-min -, ud tn speeifte.tiiv bmd n.- tareei when the dmsosi nton eoiro.HU t R.d is * 10'' Μ I he anidrods spect f, ad\ lands tits' tai get arty-. n s', Uh Gm h aftutdx ' s' hen the K ts t s 10 ' M In one embedtrnem, the .mtibod'es aid brod tn GuRR R, ip tn b'-uian t t-RP R \s Uh ,$ R. As lo , ή .moth e embodim-rot ?< autibod ., - w-P h nd w-di a R A IP . sn another embodnueut the atti»bodjes wdl bmd w uh a & > A 10 \ tn -eimhcr eiiibedurtx’tit tits' uttfbvib-'s w ill hmd uh t k_p Αχ ί 0 \ in another embodiment tbs' antibodies s', dt bmd s', uh -, R 5 - s\ id , tn mmhet embodiment tR antmod^s wd: bmd w-h- si ha>I x ; it ’: in another embodiment rite anutAies will bmd with a hro A-x to ^!'i m another

1.5 embodiment the antibodies ndi bmd onb a K;_;< e t,s 10

An amsbody, unity., n binding fragment thereof or tmiigen bmJmg protein selectively

U'htbpG a -mcedo u, cram », bttfso to othm r -- eptots w hen the R At ₀{ .jnttbodx, .nmgen btndmg nagotstti thewr-1 or ηηιη.ί.η biUsdne tvotem nt an inhibition assav ofthe specific receptor u· tn least eO-ioU lower than rise R 4p _;ii as imubiimn assay m another tv n-ren.c” teeeptoi, 1 hs' seieetw u\ tarn» is the K '5ft of the reterenec- tec eptot do ids d ty K Ά ot' th*, speettk tee.mtot An antibods, antigen biroire fragment thereof or tnng.-n binding protein sGecnw-R ufiotuts <R. human < tsRP teeeproi -fthe B'50 ofthe antibods. anty-xti binding fragment thereof ot antigen hrodmu protein in a eAMP ass,tv, e e , i he e \MP inhibition assay a¹- described ,n I * ample 4 heiens, at least .Arnold iowet than the R A m pud sunn· antibody antigen bntdtug fragment thereof or antigen btrnhng protein tt> an in''nbroon assay of the human \\t i, AM.'or ,ut ,im\ lm re.eplor te g , AM\ :) PR o.y pfnondmmuig marnnk’ if die IC50 u’a -cede a, t, ί > jRP R mitd'oea m a e\Mp<, ->\a\ ot tR'GRP R s „ a , Ki-sestt 0 ί »R mid Rt t.M, and th,- tt 5b of th,- same unitbod} m « - AMP <osas t«t the h \\i R h AM? or tinman \M\ I iccepfot is lOPPnMot t'.oie P-at amtbo.b, -adecMeR »>dnbus itit· ?'< GRP seeqUot ?0 \n antieen b.ndmg orotetn mat sCeettteR inh'lnm ., speed·. ro».\Ptor i.- also tmdeioiood to be a tientrab/ith' s-amg.-u bunting -not., m o nh te--pe<. t to that tee·, one ' Guigen hmOutg rveiotf' means a protein. <>r a ροΗοπ of a protein, dttu stxetl'Rads binds a specified antigen. ; or es.atnple. that po.rdon of an antigen hindu-i.· protein that eorstams the amino acid residues that internet with an antigen and center on the antigen binding protein

2016244220 11 Oct 2016 s{\ sr», ciίλ'ΐty au-l atbmty Yr ihe U'Wg.-n t\ tet'erred io as 'awi-wo Dmhng reg.uat,'' An antigen binding region typically includes one or more ''complementary binding regions tCDRs).

{ eii'iin ardfgun eindirg r yso; <> akom, hie-e one o- moo tr in.cwos L '⁵ emeu-, X '\'DR ' n an ammo acid sequence that cotdt ihutca to antigen bindum spccifmuy and dfsmtv, r< 'bi',tme'·>Λ ' regions e m ud m tn tmtummg th.- pieper con in» mahon o’th,. ( DKs »o pmmote binding between the aufigen binding -'..soon and an antigen.

In certain aspects- recombinant -tnogen binding protein-, that bind f GRR R protein, or htiroa' CGRP R. arc proylded. tn this context. a 'recombinant poncin'' is a protein made n-ong .vcni' ι ·’' edit .p,<~' <. , htongb luv^ioso ot meeithu >’w v-.,,. a„id a-d„ wi md it) hen, oi Method¹ and techniques 10» the production of o- omV'mmt twh ms me \sei* known m the art.

Tin' term ^v embody' teters to an iwa,i nninnnogiobishn cd any emiyne. ot ,et antigen bnuimv ifagm..nt met-. oi that e.et s-on-p.-te n ith W-, uttatatitibod, tor specific bn.1dn.1g to th-,. target antigen, and inektdes. for instance, chimeric, immaumed. tally human, and hispeelfie at tibod'Cs V. antibub' .w stab is , so iteso»„u cimyeu b.nd eg ρ^τοη·' M, .mat i arm body generally will comprise at lecst tree full-length heavy chains and two Rh I-length light chains, but in some lustaucca may incl ude fewer chains such as emlbodies naturally occurring in ca.rnd.id--' which rnas comprise only homy chains, Antibodies may be derived solely from a o-npfte source, nr may u;·- -'ehnnert»',' that «* di'lm no portions of the antibody nay he doused it-nn two .hif.xent .wtihoetcs as de-ci tl·. d nnihet 'oe-'ov- rite amigot, hindiog ptoL-ms, antibodies, or binding fragments ntay be produced in hybndonxts. by t'ccombinant DNA technup,- s, ot by enzymatic w chemical cleavage of mta, t auliboehcs I nless oth.-rwiss' indie-tke, the term ''anttbodri' mGudes, in addition to .whbedies comprising wo fidi length heavy chains and two full-'' ngtti hyhi ehams, densutsvs, su'iatfts. lim-W'-nt*·. ,nd mutations thereof, examples of w hich arc described betow,

Thelen-: hdn chum'' niciudes a tpheength itgbt chain arul fragments tb-..reof h-tv dig wittc-ent \unable ivemn sequence to outAt btndinc spveineity mil-length light Giant includes ,-t variable region iinmaiti, V., and a convcno tegum doniam, G; Fh>.- > at Dole region domain of the light eh un ts nt rite amlno-ten mnus of tbs' polypeptide. Light chains include

Lapp t chains and lambda shams lbs' tc-m 'hs'siyy chauf’ includes fidi-dengdi heavy chain and fragments rhcreoF having sufficient variable region sequence io. confer binding spocibcity, A ftri-b length heavy <. I aw un hides a y utiable legion dom -on X . and rice, cnnWini ivyiot» -io-n ,ms, <M⁵, C ,2. mid (ijd I he Yn domum is at the arnmo-tet mums ul the polypeptide, and the domains are at

2016244220 11 Oct 2016 dm carboesi-mrinunm mth the C»? being closest to she uslwybes'msnus -m the pob.peptide Heavy νίηπΏ'. may be of any i'W\ p<.. meindme IgG (including k<J i, lyGd, IgGe and IgCG soirtypA, IgA tindndmg ;g \ I and IgA'’ Ay' -s, igM and Igl he term signal sequence”, leudi.t sequence' ot 'signal peptide teters to a short <3p A amnio acids long) p.-pride , ham th n dm,ets h · transport of a pretem Xigm-i txpttdes may also be called targeting signals, signal sequences, transit peptides, or localization, signals,

Rome signal peptides are cleaved trims the protest! h> signal peptidase after she proteins arc is unspoiled, -meh that the t’h'iogi·. alk ac0\e hum of the protem te g , <m antsgen binding protein us described herein) is the clem cd. shiner form. Accordingly, terms such as 'antibody eO-upi'i-ang a heavy elnuu ”, ''antibod) composing λ IseM chnsn, ”, etc , nhere the antibody is eharacterized as htu s< t hem s and ot hetu eham u sth a particular identified sequence, arc andeisioifd *e meitsde it <. dies ha-, mg dm spa, on 'deioifted ^fc 'em n Vs, embodies Ku mg the specific idenvfsed sequen.es ev. ept d-at the signal -runon-. e-< ate repiac-, d to OoiefetU signal sequences, as well as antibodies hnvsug the identified sequences, minus any signal

1.5 -sequences

I he term anricen binding fmgmem' lor fimpiy ”fnigmeni'“t of an antibody or imrnimogbhsiM chain (heavy or light chain}, as used herein, comprises a portion: (regardless of how that portion is obtained or suithestzedt of an untibod'. that lack- at least -osue of the ammo u-ids pies· t** m a bib-length ebam t'stt whu h is capable of sp.-t itiemty Hndmc to <sn

2(f ummer xu<.t> « no tet.m i„'m >,« J\ jync n to o t tey be d si-„_v to dm tarn't antigen and can. compete - wi<h other antigen binding proteins, including intact antibodies, for -,Ί,ί. it,e bt 'dt 'v to a j' ms ep ’m· I ι>τ.ό \i? s\>' a hay us. m v. t sckn at least -me f DR present in the .full- length light or heavy chain, and in -ome embodiments o ill comprise a single Ucm y chasn ami ot baht ebum o*· portion thereof 1b- >-c biologically autoc S'mgmcms omy be

2e rsoGa„ed 'v r,combat tot D\ \ techniques, o: ;-u\ b„ psoe.ccd l<> . cunix >n , be-mval cleavage of antigen binding proteins, including intact antibodies. Imnmnohagie.-db tunerioqa! tmntnnoelobtshst Augments tnehnk, but ase tsof bmikd to, t-al-, i-'ah', t-fabd , I-', donums antibodies and ri-igle-cbaisi antibodies, and may be derived from a-n. mamm.Unm so.h.w sin ludu-g but nut burned to tnmun, mouse, tat, camelsd or nibbit it c- {.oistempkted 1 -isthe:

?>) that a fbmtton ri portion ot {be antigen binding protems disclosed Aem, :h* Aeropie, one or mot..' CDIfo, could he covalently bound m a -eemtd pioiem ot to a -amd⁵ molecule m esc ne a iherapeuuv agent disemed to t parttertbm target m the bod', noAsMtm brAmel»mm diemp/ntte psopcstst.·, or luoiii: a p-olo-tged --einsu hali-isii.

2016244220 11 Oct 2016

An I no ftagtnem'' is compr-wd 0 one Yoe oit tin and (he C- 1 <md \art-tbi· reemns of one beaky dune ι he h.aky cYmi ofa fee mob vale eatmot term a dtsuiride bond w th another boasy chain molecule

An 'Ye'’ region contains two beak \ ehmu fragments comprising the (Yl and V i?2 5 domains of an antibody. Ϊ he tw 0 hew, y chain I ragrrtenY are held together by mo or more hsnhblc bonds anti by hy ΥορΡοΥχ miotau.ons of d,- ί 4 dom nn·\n c<-e frngme'd - options one kt>h' ri w.n me a pmpon of one h > w\ chain ih 0 donums rise Y>( donum and tY. i':₍i donum and aRo the union between the (_it i and Cp2 doi u to s>.eh ι > mt rk’ca 1 e, nHscc ho d ear v fotcaer Ywr p c oko hea'i canso*

H) t\\n hat? Ymmenw io form an t'Yb’)> mobs pk' \n '⁵ pm)- Itcmnust eotke.ns two tight ehams _t-n,I two bc<o\ dun's eenu mm. a portion ofihe constant region Ροΐν < p die f Y 1 tnd C_n? domains, sm h that nt tnierot«nn disulfide hone: 0 homed between the oso 11--.:0} elums \ 1 't ah'?.- ftagtnent thus is composed of two V.ih freemews die t are hold together b\ a disulfide bond between the iw 0 ;v,o -, ehmr-s

The 'Ύ Tcgfon c-wtps ses t\>. xas 1 Yle tegmns oom both the heax \ -,od tight thauis.

but lacks ihe constant regions,.

'Yingle-chain antibodies'' arc Fv mole-, tiles in \\hteh the heavy and light -, iiain variable regions have been connected bs a ftextl-ie hnkpr to fottn xt stngk poivpopr.de chain, which ferns -in vmg ’'i-h-o.hng te-,ροη \ini;k' -,hupi e-tibook's are dis; ip-sod m det id nt hneniuttonn't Patent Application Publication No. “O 55 Oto-b·⁵ and {’tided bnoes patent No 1,9 to/YN :md No b,Y,ft 20?, tlu dis-josmes pf which are incorporated by. rete^rcnee

Λ Ylo-mam antiho-ls’' is an untminoiogtenib- Fnneticmal nuriiinmgdobnlnf fragment eooiairtirig only tite variable region of a 'heavy chain or ihe variable region of a light chain, bi some n*tinn os, two ta mote \ oopops are ctw den Gy lomed with a p-, pride timet rp pe a,- _ti msa et. d.oT.ue anrihods 1' e *wo \ 1 '» gams ι-t ,- 'nsalent dt-'ti. to at tioods n e> tinges 'he Mine br d i f Te rent anti gens \ bo :d;m tndtgen Inndmo protein' or Ysakm atitibodv ' ei-tnpt'i-es two antigen i'm-ht.g sues Υ seme itUdiu es, the two ti nd ng s tiw h,t\O 'ho s,nn anno n sp a tii„m. s Bnu-et, ,mt pen I w.hng p-ote as m-l I -a\ * amtim-im*. ppr Y 'nspe, Y , ₍i, a-;?,/

A Yeeltispeclfic antigen: binding protein’' of 'xneltispeeifie antibody’’ is. one that targets more titan one antigen et epitope.

\ 'bistxenb..'' 'died speetn/'or biiim-umiiah' mrigen bmdmg ptotem or antibody abkbrid antigen binding protein or antibody, respeerixoiy, basing two ροΎνιιι antigen binding s,us 3)spevrie wtrinen I eklm. Ptutep'.s at J ,n nn-kris's at r a sooitos »>: nm i,sp„eriw auri^er

2016244220 11 Oct 2016 binding protein or mu hi spec site antibody ami may be product d bv .·, mttek of methods including, but not bruited to tnstou of hcbttdotnas o; linking ol fab’ bagnKuu ng, Stingsivilat atid Laehmstiti, 199(1, OM Xbyr fin&titnei 79:315-321; KoHeltiyO mb, 199201 j 4s ' η P-150 3 be mo hntdno. -tics of a bopecdK antu/cti hind.ng ptotytn ot e arm mJ\ -t tb bine ti¹ too diOtev ep'.t mes, s nt, n may se-’d. on tb, same or dtlfcmm ptotetn targets.

The derm “neutral tzing antigen binding prototb” orOetifcdmngantibody”refers io an ant m t, binding pioiesn ot ennbod). « esrvep\ ely, that btnOs to e 1st.and, pie\.η- Intidetug of ttie h-L'.nd io o- hndtug pannet ano mtertupt- Ibe biological response tlv.t udierv-ise n-ottid ts-utb it) twt the hganti b u-.bug to iu I tndmg partite¹” hs tso’xstng th- binding m.Bpe· oiem of m ttutt gen binding protei n, e.,§;, an antibody or tmniunolngleal ly functional and gen binding fragment thereof) an antibody Or ftagmeat will stibstandnily inhibit binding of a ligand to ip binding putim t o hen an - o ess td amus'd-. tenuse- foe tut min» td busdusg pattne' bound to the ligand by- et Last ehout 29%, 30“.·. -19%, 5O'b>, OOP, ?'0%. SOP., b5%>, 9(1%. 95%. 4/-%

P oo'> ,,){ ntott {ts n i«sms.>; th <it , ?·;-< cor eu hove b.ne.ttg w-sa·, I b'*k case ο⁴'t PGRP R binding protein, snob a neutralizing molecule will dimmish the ability of CGRP R io bind.

{ GRP.

the term eoi-npcGP when tt-ed tn the eont<.\t of antigen bnnime proteins that treo fund the „iio fegatnt on a Gtgci .mtigeu, nt an· tompeti'nm beiveen ant-g ’u bmdmg p oteusx ts d'Jesmtti'.d b\ an assay m n, Deb the anthers binding ptotetn ρ g , antibody or hrnmtttoksgPalo. iorsmtona! antigen binding Pigment thereof? under test presents or inhibits sp.ei.tlk' binding of _u sele-euce antigen binding pttuetn *>\g . a bea-airi. om reletettec nntlboiiyl to a common antigen to ?., ('GP P R or an antigen binding fragment thereof) Λ to of a min’dpr te lompC'-Ptie b·tid>tig as- q s <„<,ts be toed ot exu'up'e soh.l phase Ί-.. ₁1 to t- dm m otdivirmnuneassas tΚ1Λ\ solid phu-s'Ottee⁴ of mibrcct eue-tne tinmuns\tsM\ Π ΙΛι. sandwich eooipef'm-r jar t- > 4 N-y-p ?,,9, ίΟΝ», H<5» /, ·?- / ·?-','??% o 2 l?Ps lg sid'd phase direct biotins', trim 11Λ is·.. cec Kirkland >.e _{</„ |9sb, M,pG'.ti'd -b.PRH sobd pm*- doom hibe'ea assay, sohj phase ,b’> t f label' d samOs i> a assay G e, < o Ha ton anti Latte, lobS, BoG·?/·'<·>, J G/i-o<P>n <'old Sin lug H nbpj press), st<hd phase dreP Gyp p: \ mine 1 ?e h e %-><·? .. y \b‘rel umP '9hS, Η·Α, tiyom -/ ?e 'e?_x stfhd phase dtneet biotin-ay uho I I \ me _t g, ( Itenttg. e/'.-.d , iO>»{g t ·<;<' j..7o 540-552), and direct labeled. RIA (Moldenhaner er nf, 1990, Seun/f <X bwuwf 32.:77-52). Such an u-sa-. niuy insulye the use ol puntied antigen hound to a solid -untie, o*· cells beatmg either»'!

th'*se, an tmlabelied test tnuiucn binding nrots'in and a labeled rePrenee antigen htndtog

2016244220 11 Oct 2016 pm *’1» ί ompee^'xe tnbfo'lton 'nay π„'_Ρ-,;ι’ >d 1 y dot. ?’!)'n ?g fi< an.onr* ο·'^: ,·Ί bo mJ the solid surface ot cells m th; piCsenee of ον? test atwgen buichne protent Antigen binding proteins fo.-w-fte-l b> compel t -m assay t> map ting ntogen holdout proteins! mehi-lo anog-. r binding proteins bsttcung ro the same epitope as the relerenec trnngen binding ptotetn,- and antigen binding ptotems binding, to: an adjacent epitope suffieiendy proximal fo foe epitope houwi by the fctc-vm, e antigen bw-tnig protein bn stetatc hmdiauce to ολίρ ΐ Isiudly, ofo _{! a competing antigen binding protein: is present: in excess, it will inhibit : specific binding of a releienex antigen binding protein to a etnutuou antigen by o least 40%, 3% ., -?(i%, ss‘% >:fo%, 653·», 70% or 75%. In some instance, btndotg i- inhibited be a* Re n So%, -\f<%, ’fo ’.», %%, or

97% or mote. Competitive inhibition may <?Ao be mea.si-n d by atitnobibdug a ?>. -brewe antigen wodwg ponem to a -nbstiate, e g , a sen-os idnp espinone awwcn ott the -ubstiate vie binding fo foe reference aniibody, and assaying whether a diffitrent anttgen binding protein <a 4 ompciuig antigen bitubtn.' rrotem'> can uklttionaih bmd to the antigen An example of the hour eompvt'.me binding -ssay .'innlovsa Gwcoc analysts t td is fomcrfoed nt 1 sample herein.

The term antigenor ''immunogen' refers to a molecule or a portion of amoleefoe e„p foie -a g '«ο bound by >; -lectixe bat'd up agent, s'·- b is set anw en bmd'ng p'-oten ( including, e.g., an antibody or jmrriunoiogieai funelionat antigen binding fragment thereof!, and additionally capable of being u,_Sed In an animal to produce ans<bods>„-s capable of binding to that antigen. An antigen may possess one or more epitopes that: are capable of intcraeffog with dttVewni binding pnn,dm, ey, we bod io the icon 'epOopc s- th. [wstiun of a moleenh* that n bonne ny a.u antn on binding protein (lor example, an antibody?. The term includes wiy dvtemnnmt capable of spemtkully binding to ui awu - n bwdwg piotem, sued as a»? wtobtaiv or to a '1 -ci 11 leeeptm V? -, pitope can be contiguous or non-eontignous (e,g,, (t) fo a singiewhfon poly peptide, atnino acid residues dt.it ue no? cwnfoowis to eno mom-, r m the polypeptide sequen.ebm hia? o uhm m contest of the molecule are bound by the antigen binding protetu, ot οι) in - muitimwie receptor, e.g., CGRP R, comprising two or mom individual components, e g R-Albt and CRLR, amino acid sesidius prewnit on two os more of the in-to ab-ial components, but that tviihtn the context ol the muhsmeric receptor are bound by the unmet· bntdut.g protein) In eeoam cnibodnuows. rpuopes w -e, be non-etic w dun they compii-w a fwee dimensional structure that Is simil-u to an epnnpe Used to generate the antigen binding protein yet comprise ti-tr-e ii- ouA some ol the ammo at id ?es'dncs toi.wl , that epitope a- ol to gsWxtuie the at tigerbjftdntg pioiem Most often, ep? topes- re-ode on proiems, but nt some instances wav reside on

2016244220 11 Oct 2016 otb'-r kinds of meh t uk's, <-nch as nw leu ;·,> u1*< f pttopx' delsmuroanis way in- hide t henu· ally aGtxe sunaee gio->pwe- of' molecules suds η> imroo acid-, sneat xid: eltatus phospit-'rx I to sulfonyl groups, and. nuy haxe specific three tlitnensioual sh net. urn! ehnnugerGlie*;, and/or specific chaoce t. he; act.u {sties, Gctsccalix, antibodies sp/ctbr tot a pastiudas t,ug„t .robgcit ? \xsM preferentiaily reeugwr-γ an epitope oo die meet mitgen ir a eomp^!e\ mtsinrc of proteins are, o' 't'.u or oh<- -des

I he tern· 'bdenbod' refers io a i-elaitunsfup hetxxeen the sequences of two or mitre po:x peptide molecules ot too ot wim $iu- ten at t,1 itteicenk s. as deieinnred bv alromne and comparing th- sequences Ikucent uknmy' weans ihe pet cent of identical residues between the erwo acid¹· o⁵ nut leondcs tn the compared mohs uk's nnn ts . ak ul.ii.-d based or w>,> st/e o·' the swad. 4ot dtu ) tole-ales ben -computed I ot these vukn utu-'ts, cap*· tn a ig; '.rents < p my) must h, idd-'essxdbx a purnookr ntarhemaiual model or computer ptopr an p> < , m Git ondftn) Method^ that e.-at he used to , uPtOute the trienoo of iG, -digued rue* te a. ids ot polxpeptides include those described tn Coen 71/0/.-07% .PG.Yx. s'/cn iY-o/ogt’, <1 esk, A. M , ed i,

1.5 I'iXS, \'cw 5 ork (tsdbid 5 aiixeistty fifes*- Bioeon:putnse luioioiaiics ano Gknonu biotceis (Smith. k>. W„ ed. u I dot, Neve d ork; Academic Press; Computer Artaly si-- et Sequence Data, Part k ftruffn A M and G-ffifm. II G ed*< ; pG-i x\ k'isey : biot.ats Pu w, x-w I k'fuje G., 19X7. Sequence .Analysis tn Molecular Biology. New York: Aeaeiettne Press, Sequence K tao s's P' itv iGr χχοχ,Μ atdGe--^fe x 1 ed* >, ’99! Y w Soil M Bto--mu P ws, and Canilo -7 % P-Rd, AVJ l/o G'yeY.x/ YG/Λ 4SjtG3 hi oalculudt „ p. cent identity, th/ sequences hero,a competed are aligned tn a way that gtses otc 1 ages'- ta-n , ts-twcee die seea-ees Pa em-ipu'-c' pugg eu ese-l to J.-tetf uee percent identity ts the GCG program package χχInch includes GAP tDexeretrs vGnY b/h i, \>r / J-1 i >G χ ί 2 G7, Genetics { ompuk'f Group, 1 wxeistiy id Wts, on-ro. M-adson. VYh pits' computer -ugordhm G \P ts u-ed to align the two pnlxpepttdes ot poiytiuckx'fnies rot

Much tits' petcent s-wustne sdenitfx ts to he determined Γη·, seqoeui.es are then·ί! foropimsul «bitching of their respective ttmioo acid or nucleotide (the “watched spank as determined by the ,ih:on{bm) ί gap opeun.g penalty {xGn* % ts eak':d.«-\i as ?s {be axetege dn-genak xx haient {'ne ' axe-rage -Ρ-ιροη-ΐΓ ts the axefsige oMhc Otagon-n sp'ote eompanson maittx Pena ?d used, the Ύη,,οοη.Ί'' is the acoro o rtttmbe’. otgned to e tch perfect ammo acd tn o, h b\ die petlu tear -. eiiiparuaut tn-nnsi and a, gap extension penalty txUnch ts u*nahy 1 Id 1 iw>, * {he g.en opening penalty}, as xx-ell as a comparison ntatr-.x such as PAM 250 ttr 3L0SPM «2 are used fix eomu''u'ta>u sxUh the ah osol-os hi sSti-no enibodt-nems, a oatniatii eompnu ,sxm m„*trt G-t, l7-tG ο^Λ st oG'9 r, IG.o ,e G.W w M-iNx , - mW on e< Go 2 a P xC h« h,l’\A120

2016244220 11 Oct 2016

- ompat'son m Memko·'!', ,j,’ IRC Ρ/,ρ \<m a a.' < /',$ » So 10 B G·Rtio _fRBI OSl Μ '‘·2 eompartsou mains? is aRo u*cd b\ the* .ilgmitlim

Re commended paimnctcrs iqr determining per? ent identify for polypcnn-l ’so·' nudeomk sequences using the GAP proemm -.no the ioiloonte'

Algorithm Xeedxnnm mo/ U>>' And -ΒΉΤίΑ

Comparison 'tktttix Ri PM \i r<2 horn ikntlodl ,n₍;, lm?R m? or Gap Penalty: 13 thm '-Gth no pemdiy for end gaps}

Gap I '..uglli Penally · 4 I hreshoid of Similarity: 0

H) i'erl lid ahgnm,-m m nemos lor aligning eno ammo acid oequcne-. '* may resuh m matching υί only a short region of Ute wo sequences, and this small aligned legion may have vmy h-gh sequeno, ideums >,\cn 'hough ther. u> no s'emtk mt reiaPontimp b io enPr-twc fmi-1 nPk sequences Λ>. i osdmn iy, rise sc⁵ ι te I alignment metiiotl A1 \P peon; mu can I»' adjypfcd o' «ο dc^red m refill m an alignment that spans at least 50 nontiguous amino acids of

1.5 i i r«target polypeptide,

A* used herein. sub-mmt.aik pure' means dr t 4u„- described *reeies of molecule is me predotninafii spe>. ies present, dint is. on a mylar pits'* ti is more nbiuidant than any other rndss ideal -.pcctcs m the smne mixture, tn certain embodiments, a scbsiantiulB pate rnoteenie i* e '(.imposition v, h' mm Pie elycR spi\ : ->* eompos· * <p least yp», _{ίί5Π 4}, oiokn basis'» of di ma. iomoleeuiar spec.es present In other embodiments, a sub^mmiB pure compo*si50o mil compose at least 1¾ x?%, 4tv ,.. <>?-,., or PR << ot ail rnaer 'moiecular species present m me composition In odiet embodiments, the objeu speeds is nunfted io essential homogeneity nne’C mnt «meat ng messes *,mro’ »\Ά*ι'd n *' s utws ιό'* b\ com cm oral deteeuon methods and thus the composition consists id a \ingk- detetdahk ni isromoieenhn speeies;

The lent: fm-atlng'' refetx to any indicia cP success so the me.mnent or amelioration ot an injury, pathology or condition, haduding any objective or .wbfective parameter anch. as: abatent* up n-mission, dmt-mxhutg of symptom,* ο<- making the mjm'y, pathology o^r i omnium mote tokrabie Its Pie p-meuu sloe, mg in ihe rale of de;tenettPtou or decline, making the final poi nt of d egeneration leas debilitati ng: Improving a. patient a physical tir mental weitifeelng.

The Iteatmenl or mnchotut'on of symptoms >, an he based on olne·. use or sithjeetise perarneG-r*. meladutg the result-» ot a physical c.santinaoot', ncurcpxseiuatrte ex mis- and ot a s\ ( mtt'i, „ ^a'aa.iie’ Io „\amph' c Pout me hoos pte*$ t ue he » usut.csslt! . e-ai nusp-ae.e headaches cube! proplr. lacnc/Jiv ot ,»-> an aside Pcatm-id, deetc wry lit- hcqucncx

4b

2016244220 11 Oct 2016 ui'migmme headaches. deco-using theseceniy oGnigmit-e headache.-, and or anchor tf-ng -. symptom .ixxv:ust;a e, uh nngw»nc txadaehes \n elR·· H\c amount'' is general·; -n amount sntYte»·..n- io redtue she severity and or frcquoucv oi'.symptmn.s, aksrnrsntc the ssinpionos and et' umktlvuin cause, present the ot.cdrxnce o*'symptom·, and or thou underiy mg, ause. ao-j or smpro. e or remediate the d enuqe that oomis bom ot \s assocum .1 noth nugmtre headache Its some embosh munis, the edectoe amount »o a therapetmeaiU vt'Dem, ,· uxouoi of a prophybgite.dU etYeeo',.: amount Λ 'the· co one eR ofl· t Poe anu-eM'' ts ,m amount sutYu -„nt to t.-me-.R a oi.seu.se state t, p rmgmnte hetuhtche} or symmoms. parisenUriy a state or symptotos associated wtih the disease .erne. or other's »se pxxem h-adeo febo J or r,-\, ;\e the progression o- the disease state o* any outer unde oral de symptom associated vGth the ds.-eux ut rate oto ohatsoevet Λ ''p’ophyiaefu'aily eU'cettse amount is an -nnoimi of a pharmaemattcal composition that, when adomn.su, oat to a suhteef, oth base the intended p-opt'. Rone effect, ·, g, picveumsg ot d-i y mg thv onsu tor xocem'reneej of nugranx head who, or reducing the likehhood. o' the

H ons.-.to too, eur.i. ee. s o'·' turn'.me hcuma be o t ng a te' ead uhe symptoms l'e I d therapeutic or prophyUetii. efieci does not necessarily occur by administration of one dose, and ma; ο» t nr only afiet adtnmtstr toon oG» χ>π,._Ν oGtos·. <· Thn.s< t -hempenm ally ot ptpphc'iuciicehiy etYecove anttrnnt mac he admnth'temd m one «r snore admimsfratiostri.

“ Vmno acid'' sm. hides its normal meaning m the an ϊ lie twenty n.uurdtly-occurring ammo aetd·. and fitsτ abhrecuitton-, follow comeniumaj usag; .xe, Itrnnuttoh-gy·,Y Smiths s;s, 2nd bd'tiom if o Gohth and P P, Green edsj, Sutaiter Wox ties sunderkuxk Mas< '^<r , xu po at ett. e tl· te.ex x> ο» , t pi Xtcisoiso ir sr D-ammo a test of'the twenty souvent'-erttd amino acid·,, unnatural antmo· <teids such ns «••jt-dtsubsntuted amino -u. ids. X-alkyl ammo aetds, and other uiiconseniimiat amino acids may aiso he suitable components rnr pgl\ peptides and are nxiuded tti the phrase annuo aetd. Examples of unconventional ammo acids meiudc' 4-hydro\vprpiin·.'. . -eathoxy glutamate sA.X.N·· ifimUhy hsstne. <. 'X-ucetcIRMix, G-phosphOsermc. -aeeiy iscrine. X-fe-tn'tyht'iCthtontne, dtneihy ihtsbdme, >-hydro\y Ιν,-,ίπο. >~A-mmhyd;ugtnme. nud other similar ammo acids and nmno acids O.g, d-hyd'-osApirrhu.·). In its. poly peputR notation us,.d herem. ilu. ieb-hnttd direction the amino xnum d direction and the right -hand direction Is the carboxyl-terminal dueenott, ot a, cordum e v. tut xm.kiid usage no! eouxeutton

Antigen-binding portents th 0 hold < GRP R, protein. including hutu,m t GRP R thi t 1RP R) uetsmi see me' ,.Ld hcic n 1 he . nt.yen huid m. melems ptos med m.

2016244220 11 Oct 2016 pnlypepfides inh) which one or mdw? complementary determining: regions (CDRs), ns described herein. arc embedded and/or joined. hi some antigen binding protents, the CDR- are embedded mm a ' fo.oicvvoi G temon, which orients die < DRpst such that rite proye¹ antigen bmdmg piopcrttes td the CPRt-t ts achieved. In cettend. antigen binding protents diet no;

provided can intcrlcrc n Ith. Mode rudttve or modulate tbs' internet:©» between CGRP and ( GRP k.

Cenam antigen bmdmg proteins described herein .>rv amibod'-es or are derivedfrom animori;·, *·> hi, count embodiments, rite poly pepinf. site, tnre td the anOeen brnding ptoteuis t* νΑ ^f >vt ojtd.Ji e I mo η n „e ^ft< motovlt t ^f v, „s nspCv ' <. _t nt booths

H) munhori’es gsovnam .uUtbed’es, ,>y nine,u embodo's (xoo.cwn-. < tmetred to hem-u <·\ ” etubotb, nomeuM'?, Gmneoc annbo»iie-. humanized wtUtbodu's, onmatt antibodies antihods lustons * son:·,.time⁴ referred to herein a-< Gmiboriy iO5nugates'\ and Ifapnietus dteient The vadOitS .structures ate further described herein below the antigen brdb'u proteins provided herein base been demon·>mated to bind to ('GRP

1.5 k, o pasticahn human CGP.P R \s jesetuvu fmriict e Ge e'aotp es b 'ow, e.».m antigen binding proteins xere t/sied and found nt bind to epitopes dtOerertt trom those t-.-imd by a number of other mhfcodlos directed spinst one or the other of fhb ebritponents of CGRP R.

Phe antigen bmdmg proteins that ate pro\tried compete w?,k e.GRP and dterebv prevent < 'GRP bent bmdmg *' us j< eptot a umsequen, e nm arm · r bmdmg pio,<ns uutv'd’d hewn at-' capable nJ itd'nbitmg· ('GRP R .write ttv in partiutiai, antigen binding pmtems bmdmg to the.-e ep.topes eun h tve on.- or moi.- of dm fodow inc act-vines, mbib-trng, -> /or .,/-./ mdueooti of CGRP R signal irsnsducEon pathways, inhibiting. vuxodiMatlon, causing vnsoeonsirfetton, decreasing mPa mutation, ,- g , netu'ogente tnll.nnma.oon, ,md other physiological el feels todnot.! by t. GRP R upon < GP.P binding h„ atPteer 'indine pt ot„ m- dim ne dmtrios, .1t eicm, n.oe a v _5lj- t, o, utumes Sow,, of lit'/ arnigsu binding proteins, for instance, arc useful in speeds binding assays affinity put me mon of ( GRP l\. e, 1 .ck.ni u hi v JRR R o. its bvetid - <wd n sc e.tn. u nssev s to identify' ofner antagonists of CGRP R aeliv riy. Some of die ttntigcu-bbtding proteins are useful for inhibiting binding of ('GRP to (GRP R

The anfige-n- binding proteins eun be used in a v anew of trenmiem appl oat ions, as e\pl -atved heien, I 01 example, e<, riant fGRP R anifgeu-bsnrino ptotcilts ur us>, nd tm ire nine conditions n->sowakd w ith GGPP R medinted signaling, seen n,- redits ion, ailev fating, or tt.-alnit the frequenty ,·.»{ or -.eve’dy e, mtgwutc h.xntacnc, eu-nnn , adcxiatuig or heatntg duster headache, reducing, ailev n-gtag, or ire.dtng enroute pmn. alic-v tatnw or to, atntg

SO

2016244220 11 Oct 2016 diabetes medtoG (type· J])_s seducing» alieGaiing, or WeM-ing. esfoioYgseubr disorderes and. eeae ur, t let tat.ne, ot ueating 'temovo uvree oetaug-.t, erw oxeuau d wf end-no xctc a and, sepsis in >.; patient. Other uses for the anti-mn bmdmg pi'oieiuo include, for example, diagnosis o* t1 IRE R as-oeiDcd ti >;„>·.·- m eordujnnx e,<1 <? ,011, a -.sx.o χ ίο dc’crrr ire fee -rexenec or absence 0'«· vRR R, Some of fix antigen binding proteins described her.,m are useful in framing oonxettueneiw sy mploms, anti ta the pathology >im«. utetii st iih «. < il\P R a. tix ify These inelnde_$ but tire not 'limited io, various typos of migraine headaches.

id'j.E.B...R.iGsl.TG.

t he antigen binding proteins tiisefoxed herein fond to CGRP R. nt particular human 10 CoRP R CGRP R is a nmlthnef that >tit hides both CFG R <nsd R ΑΜΡί The nnei< raids' sequence of human CRLR in provided herein ax: SEQ ID 'NGT, The amino acid sequence of htnna-'i CR( R is pros uh d he-'c-u as SI Q ID Mb? flic no-. Cm.do sequent 0 oi human RAMP I 1- piovided herein as SLQ ID M⁴ > Phe annuo a. id se jeenc of hem m RAMP! is pi - mdheicf ehVQDNOt Ito ⁴ Gc*' u di p o⁺en χ <'ese’i w , e^! i id me

1.5 extraoe hut ar portion of CGRP R, Which comprises the eycaneihtiar portions of CRLR anti RA\i'0i An .'\empia*y /stra-Mlui u domain ('Ή P''C«* human CR1 R '-encoded m P.„ nut leotide semic-nee pres-.-toed is Sf Q ID NO 5, and ίι-,χ the arsine .λ- td seoaotne pre-onrex! 0 SI 0 ID Nt M< 1 'as s.qut’ue etomdex .1 s.et.a. oeomk. ,..;i e.sensp.a.,·, tram,. >m.nus th.

.-gmfi peond-’’ ί PI P 11 D has the amm-’ <, > ί x-’quen» c p esemeti <-χ M Q ID Μb Id An ewioplatn 1 (.'Dot human RAMP; u; encoded oy the nuekovdo,··><., qn«.iiu picxcnteti as $i-,Q ID NO ' and im- the amino tom sequence pr.-sented as SFQ ID NO a ih*-> sequence meind/s a signal peptsd-., an exemplary m/ttuie «minus me -agnat peped.o R MIPl I CD has the amm-’ acid ->e-qnene..' presented a« SEQ ID Nt,t I i As described bdew, (.'GRR R prmwns may also include itia.manUx As used hetem, tin. terms a«e used mieteh-ntgeabiy to mean a reeepiot, m ptoitcuhit. unless otherwise speeded, a human mccpto? that lands speeifiealti. u» < MRP

The tent; t GRP R .dsn m„ hides pesMt msDifonaa rnudtift mono of fine CGRP R ammo acid ^gtixnsa, for commC, possible Moused gl eeosx Gum sites fihn-. the «mug. n btndine ροη.-ηη may i’lidiiwii a, getter nod non' pom, ms gly , osy lale-d <u mr ot more e⁴'the positions.

\ ··> a« wiy ofixeto'lrxe -ending ng-.nt- useful lot regnbUing G-,. achx tty of CGRP R am provided, fhese agenu include, for instance. antigen bintime protents thut contain an antigen mi dme do u.ui'« \e . srnvle 1 ham antibodies, ,h»n«m aultbodtes. 'mmuroedhoxOtf-, tnd polypeptides with, an antigen binding region) and speeifteally bind to CGRP R, in particular

2016244220 11 Oct 2016 hsun ·,« 1 GRP R >omc ot the ,gv»G lot ., sample are ih: fid m mbd-ttmg toe bmdusg ,4' CGRP to CGRP R. and can thus be used to mhthn, «nericre with or modulate one or mote aenvtues as->pet,iiee wuh ί GRP R signaling

In general, the antigen tontout, proteins that ate prox ided ivnieatlv comprise one or p more ( URs j-> d.-sertxd herem u g .. I, ?, 5. b a or ol hi some instances, the antigen otodirw pjotem complexes po a polypeptide spoenue and (ho one ot mote CDRs that ate warted U4o and o joined to the polyp.-ptole struetore I he pol\ «eptide structure can t.4,.- a x unep, of dtlfetet.it fmnis Pot example. 4. e..m be. ei compose. the fr.oneo ork of a uatutallx ocemting antmod·,, oi f.agtnei'U or sariant thereon rr mac Pe completely synthetic nt nature i samples itoxarsoip polyp- pinto xtnictow⁴' am fm'tn., r 4ysi nhee mrion

In cerium embodnnents, the polvpeptsde strnetute ο» the antigen landing protents :- an antibody or G derived feto an antibody, «winding, but not limited to, nwttoetotob antibodies, btspertlk untsboibe--·. mitoboritos, domain 'ahtibodir*. synthetic antibodies ;sometimes referred ίο he?em as ''iwhbodx rmnwiseCto chimeric ants bodies hnrnanized itnrihxiiey antibody

1.5 Ifisto» toomemmes mh-tu .1 to rs \mtd oris iotswg.«esl atto potmms-'i h ugt e»G o*'cai h.

respeetn eb in seme ;n-ri,«wcs. the ato.gen hmtong proletn w an nnmuttologfe ti fragment of m <ii4tood\ V 4 , a 1' t!\ a I λΡ , a h(ah 1 or a I s 1 The s a nous Ottwnnes are furdwa descstoed and ,'ktmed heist»,

Cott.on of the' antigen hmdmg piowm.·, a*» provided harem epe> ific-dly h.n.i to hunuot ((IR P Is hi a specific -. mboibment, the antigen binding proient spsCitiealty binds to human s1SRP R ponem comprising human ( R.LR having the imino said .sequence of Sty) ID YO.2 and human R WI PI has mg toe annuo at id seemer-ee of Slid if* \i^{5 4} in emhvriiroertC « here ihe antigen binding ptotew is ust,b lor towapeuRe tppi >„et:ons. at- antig·, n binding ptoteut e m inhibit, mtorfetc xs uh or motototto one or mine btoRtgieal aMtsdies oft {IRR R. in (hts cu-e, mt anot.-. it binding protem binds spt.mticnity ami or sitosiusitsailx inhibits «mriing of human CliEP Is to CGRPxvhen art e<eess of :n4-body reduces the quantity of hum.,» < Gisi’ Is G-und to CGRP, or ι-n’ hx ;,· least ubout 20%, 50-, 40%, 5(ι* <, i-O'', 70^!'<·. x0%, 05 % ’^!0% 95%, toy·,. ,·>_; ηχοίν ifor example hy meusiintig P-iadhig m an ’u wro.· eompet-tw, binding assay }.

Rome ot toe atxrigen hindine proteins that me provided base the -tmetme tx pi-raity uxsocistod with oatitridly ooctirrmb tmfibodtox. The sintetors! 'units of these tathihadtes typti adx compos,' one oi mme ietiamets, ea,'? < on.pnseri ot too ntoom al t onpiets ot gob pegs ,L cyans· ttowgl son e spe. s. ·, o* ot immtrs a·;» rroduee iwisbodte. hax i >e tv,x u

2016244220 11 Oct 2016

Angie box y chain bi a typical antibody. each pair or couniei includes om- fris-length Might' chain (fo certain embodiment about 25 kDa) and one foiWength “heavy* chain (in certain embediroesifo aboui 50-M) bDab Each mdiv sdna; nnuiunogiobiiiin eh bn is xuiuposed of -.evetai ' smmnnodohulin domain-'', each censistmg oi remghlv A to 110 annn« ,u ids and expressing a chameforistie folding pattern, These domains are the basic units of which atmhody pel-peptides are composed, Ute aiinnu-leimiwu portion m cadi chan· tynmuliy mehidvx a ' arable domain that is responsible for antigen recognition. The carboxyeerminai portion isnsoic conscivexi evoinooifinils than th» other en.lot rise emott and :- lefet-'cn mas tlie ''constant tegfosf' or fo' region i lurnan light chains genemily are classified as kappa and

H) frn'bda fight. harw, ,nι>I each e^T' these eec'aius o*ie vatnibie desna n and one -, oust on domam I teas s chairs ate t, pieadc c asstitfo o mm deha. cui tri u aloha, oi cpMtee chan· ·>, atm C esc define me antibody x woly pc is igM, IgD, IgG. h k und igk-expeeuv A ig.G has \cveial .-ubtypes, mekidmg. but nm Inimed to, kj.G 1, igG2. hjG Y and igG4 tg\1 χη'οΐνρ» s mJnvk' fg.M ano foMc I gA subtypes mchfoc In AI end ieA2. hi human- the kA and igD iv'Typc.15 eonfimt four heavy chains ami tour I gin e'-ants; the IgG and kb isetypa- eont-un two heavy chains and two light chains; and the IcM nmfvpe connhc- five heavy chants and fixe Ifok chains. The heavy chain C region typically comprises one or more domafos that, may he responsible foi efieemi function i h< number oi heavy chain constant ivgion dornants w di >1 ’pond er hie iso'ype k,G heavy cfonns. S'»' , sample, e.;.i h eon'* on Hue· i « ’gtou donnons

2(t knoxvt as k ,i, <2 2 ,mxl k ^Λ I fie anmoTex that aic now ided -ar 'tav' arts ot tucx„ tsotspes it id subtypes lr certain embodiments, the CORP It antibody is of die IgG 1 igG2, or IgG-i subtype, io foil fougtb ifofo and. heavy eham-, the van ibic me; wm-t.mt regions are joined by a ' Γ legion ,;if al'On· tv else oi finite .mt.no a, ids, w nh the heaxy ch-un J’-o including α Ί>“ iCgn-n xft about ten mom amnartieids foe. e e,. rendamem.d immunology, 2nd ed th ⁷ ibml, \V , ed i i -fo'^! Yen York' Raven Press thereby mem penned by reference m us entirety for all purposes}, I he variable tegmns of each hehfhenvy chain pair typuabv form the amigeo I'bi'h’ig shx'

Gne exampfe <if ,ui hfiG heavy ,ou-taut d«rn-ntol mcvcntpiaiy kt IRE R nmnoeiouat antibody has the ammo >,-id sequence:

ySiKGPSVhPI. MVSkSTSi'S'i \ \i tiki YkDYfPbPYTYSWSSG \! Tfofx IlffP

AYLQSSGL YSbSSvA I YESSM'OTOTYTCM DHRPSN 1KVDR iAbRKkTA'hi'PprpAP

PY \GPbv I 1 1 EPKPKHi i Miokl PI Y'ft A Y\ t)\ SHI DRIA fT'kAA YiXA I ΥΗΥΛΚ fk

PRttkQENS ITP, YYSV L'IA Y HOD A L NGKEYkCR VSNRG i,P API Ifo 1 ISK'i kt folRR 13>Q\

2016244220 11 Oct 2016 \ Π PPsRTbM ΓΚΝΟΥSI TCI \ KCTYPED] u i'A ί S\BQPfW\ κττρρχπ !WFX,sm > SKLi YUkbRWQQGNYI S(>Y\ii JkAi.i IMG FOkSi.Si.KRGk (the last mWue*of ihe *. qu ·· . e shown as RfQ If) \G.29i.

(hn. exMispk oi a kappa light Constant domain of an exemplary (.'GBP R monoclonal p errmody h is dt.· ammo ic'd s/ou mee

R i'\ YYRSYl U'RRSDl Qi RSGIYSYYt I I NNI'Vppj \K\ QV< K\ i'>N \l QSGNSq bW liQDNkPWWi xSlLG bkHk\ \ KTVIHQGi WR\ RG1C che

Iasi 107 ie.*id-.u.s olthe *enueuec shewn as Si'Q II) NO Id)

Yi rtah'e ice;«!!s of innv mK'ghmahn chan x ..cneulo .-siebr, f,». same οόι,'.Ι ip -md · o up of p u kd s, ' t or-ww >. I^T amewo s i, g on¹ i > Ki )e m d b\ fo” e hspetxariuhk ιοριοηχ. mom idien called 'Yompknucuiaoiv deternhumy regions'' or (13P,s. The CBR.S from (he two chains of each heavy ehsinfoghi chain pair mentioned· above typically aie aligned by the framewesk legion* to sosm a xhnemse iha? bind* *pc,ificu.sk wen a sneedw epitope on she nonet p.okw w. „>, <3 d<'R Ri F root N teuton, I so ( nxnvu ί rnmnuiv·· oectirtfog light and heavy: chain variable regions; both. typically conform. With the: foliowing orderos these elements^- F R k v '1)R I, F R 2, <'1 )R2. FRY v '1 IR? and FR ; \ numbering ,*vMem has been devised for assigning o embers fo amino acids that occupy positions In each ofthese domains. I his numbering sy Mem is defined m Rabat Sequences of Proteins of hniuunofogiea! Interest {IfoD and 1991.19111, fkihesda, MDro; Chodua & I Cst, 19X7,./. Ifo/ #/>>/. lofi-901

91 ~; <‘hotlttu or a/., 19X9. Yowro ,M2.R?f -bX.Y the venous heavy «-bum and hgm eham variable regions provided herein are depleted in Table 3. Each of these variable regions may be attached to foe above heavy and light chain -on-must regions m form a eemplec .uvibodv he svy and light chain, rexpeem, jy Pnrthvi', •z&eh o^; {he so generated Coavy and hgln -..hum sequences may he combined to form a (.simple·, aimhodv snucmm I; should be umV.istood rh«n tit; heaw chain and bebt eh.dn nubia region', piovded berem e.m else be «mubed ίο οιΙ\ - oum nu domains liming differed' sequences than the exemplary sequences listed above.

Spe> use e',unpies of wmiu of din full length hgbl are hem y - hams of dm ano'boib ·* foul am psovided and then eouesnonding amino acid xeetuencox am xuminiuf/cd m I'aiis.-s 2 \ and IB. Tabic 2A shows exemplary light chain sequences, and Whin 2B shows exemplary heavy eham sequences.

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Table 2Λ ~ Cswmpian Antibody Light Chain Λοηπο Add Sequences

SEQ ID	Design ebon	Contained In Ci one	Sequence
12	LI	01 Ell LC	«BRVpAQLLGLLLLWLRGARCGWLTGPl· $V\; APGQKWISC SGSSSNiGNNYVSWYQGLPGTAPKLLiYDNNKRPSGiPDPFSGS KSG‘iSATtGn-aQTGDE.ADYYCGPA'D$RLSAWiGGGTKLTVl GOPKAHPWTLFPPSSEELQAHKAKVCLISDFVPGAvTyAWKAD GSPVKAGV&HKPSKQSNNKYAASSyiSi.TPEQWKSHRSYSGQ VTHEGSTVEKTVAPTECS
13	L2	01H7LG	MDMRVPAQLLGLLLLWLRGARCQSVLTQPPSASG7PGQRVTISC SGSSSHiGSRYWWYQQLPGAAPRLLIFRSNQRPSGVPDRFSGS KSGTSASLAISGLRSEDEADYYCAAWDDSLSGWGGGTKLTVL GGPKANP7VTL FPP5SEELQAHKATLVCIISDF YRGAYTVAvVKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEOWKSHRSYSGO VTHEGSTVEKTVAPTECS
14	13	0267 LC	MDMRVPAQLLGLLLL WIRGARCD1GMTQSPSSL SASVGDRV7 IT CPASGGiRNDLGWFGGKPGKAPKRLiYAASSLQSGVPSRFSGS GSGTEFTLTISSLQPEDlATYYClQYNiYPWTFGQGTKVEiXRTVA APGVFIFPPSOEOL KSGTASVVGLL NNFYPREAKVGWKVDNALG SGNSQESYTEQDGKDSTYSLSSTLTLSKADYEKLiKVYACEVTLIQ GLSSPVTKSFNRGEC
Ί IS:.........	L4	03BBLC	MDMRVPAOLLGtLLLWLRGAReSSELTQORWSVALGQTVKITC™' QGDSLPSFYASWYQQKPGQAPVLVFYGKHRRPSGiPDRPSGSS SGNTASLTiTCiAQAPiiEADYYCNSROSSVYHLVLGGGTKLTVLG QRiCANPTVTLFRPSSEEL/GANKATLVCLSDEYPGAVrVAWKADG SRVKAGVEnKPSKGSRNKYMSSYLSLTPEQWKSHRSYSCQV THEGSTVEKTVAPTECS
w	LS	03CSLC	MDMRVFAGLLGLLLLWLRGARCDIILAGTPLSLSVTPGGPASISG KSSQSLl.HSAGKTYi YWYLQKPGQPPOi 1.1 YE VSNR1SGVPCRI· SGSGSGTDFTLKISRVEAEDVGiYYCMGSFPLRLTPGGGTKVEiK RWAAPSVFiPPPSOEQLKSGTASVVaLNMFYPREAKWKVD NALQSGHSQESVTEODSKDSTYSISSTLTLSXAQYEKHKVYACE Vi HQGLSSPVTKSF NRGL C
17	LS	04B4LC	MDMRVRAQLLGLLLLWLRGARCGGYLTGPPSVSAAPGGKVnSG

S3

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			SGSSSNJGRNYVSWYGGLPGTAPKLUYONNKRPSGiPDRFSGS KSGTSTTLGLrGLQTGDE.AOYYCGIWOSf'iLSAVVF'GGGTKlJVL GQPKAHPTVTLFP?SSE£.LQANKATLVCliSDFYPGAV'TVAWKAD GSPVKAGVEnKPSKQSNNKYAASSYLSITPEQWKSHRSYSCQ VTHEGSTVEKTVAPTECS
IS	LZ	04H6LC	MbMRVPAQLLGatLWlRGARCDIVMTQSPLStPVTPeePASISC'' RSSQStLHSFGYNYlDWYLQKPGGSPQLLiYLGSNRASGVPDRF SGSGSGfiOFGLKBPAEAEQVGVYYGMQALQlPFTFGPGTKvDS KRTVAAPSVF9FPPSDEQLKSGWYVGLLHNFYPREAKVGWKV ONALQSGNSOESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC
19	18	«EC	MDMRVPAQLLGLLLLWLRGARCOliLTGTPLSLSVYPGGPASiSC KSSQsSLLHSDGKTYLYWYLQKPGQPPQLLIYEVSNRFSGEPDKF SGSGSGTORLKISRVEAEDVGTYYCMQSFPLPLTPGGGTKVEIK RTVMRSVPIFPPs$DEGLKSGTASWCLLNNFYPREAKVQWKVD RALGSGPSQESWEGOSKDSTYSLSSTLTL3KADYEKROYACE VTRQGLSSPVTKSFHRGEC
20	1..9	09D4LC	MDMRVPAQLLGLLLtWLRGARCQSVLIQPPSVSAAPGQKVTISC SGSSSNiGRNYVSWYQGFPGTAPKLLiYDNNKRPSGIRDRFSGS KSG'TSATtGn'aQTGD&A(5YYGGIW0$HLSAWiGGGTKLTVl GQPKAF4PTVILFPPSS£ELQARKATLVCLiSDFYPGAV7VAWK.AD GSPVKAGVETTKPSKOSNNKYAASSYLStTPEQWKSHRSYSGQ VIFiEGSTYEKWAPTECS
21	110	09F5 LC :................................i	MDMRVPAGLLGtLLLVVLPGARCQSVLTGSPSASGTPGQRVYiSC SGSSSN iGSNYVY WYQOLPGAAPKLIILRMHGRPSGVPDRESGS KSGTSASLTISGLRSEDEADY'YCAAVVODSLSGWyRGGGTKUVL GQPKANHVTLFPPSSEE LQANKAF LVCBSOFYPGAVIVAWKAD WVKAGVEnKPSKQSHNKYAASSYLSLTPEQWKSHRSYSCq VTHIGS1VEKTVARECS ........................................................;;.........;...........;...;........................55......;;.......;.......55.
22	tn	10BLC:	MDMRVPAGLLGlLLLWtRGAPCGSVlJQPPSASGTPGQRYTtSC SGSSSNiGSNTVNvWQGLPGIAPKLliYTHNQRPSGVPDRFSGS KSGTSASLAiSGLQSEDFAORYCAARDESLNGVVFGGGTKLTVL GQPXAHPTVTLFPPSSEELQANKAT L VCLiSDEYPGAV TVAVVKAD GSPVKAGVETTKPSKQSNN.KYAASSYLStTPEQWKSHRSYSCOi

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			VTHEGSTVEKTVAPTEC8
23	L12	11011 HL. t i n e LC	mdmrvfagllgllllwlrgarcggvltgppsasgypgqrvtisc SGSGSNiGSNYYWYGQLPGAAFKLiJFRHRGRFSGVPORFSGS KxSGTSASLAISGLRSEDEAPYyCAAWDDSLSGWVFGGGTKLTVL GQPKANPTV'RPPPS8EELQANKAR.YCLLSOEYPGAVTVAWKAO GSPVKAGVEnkP$KQ$NNKYMSSYLSlTPEQWKSHRSYW: VTHEGSTVEOVAFTEGS
24	in	12E8 LC	MDMRVPAGLLGLLLLWLRGARCOITLIQTPLSLSVSPGGPASiSG KxfeSCSLLHSDGPRYLYVVyLQKRGQPPQLUYB/SNRPSGLRDRF SGSGSGTOFTLkiSRYEAEDVGlYYCAIQSFPLFLTFGGGTKVEiK RTVMrWiFRPSCEOLKSGTASWCLLNNF^RREAKVOWKVO HALQ.SGRSQESWEQDSKOSTYSLSSIIILGKAOYFRHKVYACE yiHGGLSSPVTKSFNRGEC
25	L14	iSGfeHL	MDMRVPAaLLGLLLLWLRGARCQSVLT(iPPSVSAAPGGKVRSC SGSSSNiGNNYVSWYQGLRGTAPRLGYDNNKRPSGiPDPFSGS KSGTSATLGni3L.GrGDEA0YYCGTWD$RLSAWFGGGTRi;P/t GQPKANPRRLFPFSSEELQANKATLVCLiSDFYFGAVIVAWBO GSFVRAGYErTKPSKGSRRKYAAGSYLSLTPEGWKSHRSYGGQ VTHEGSTVEKTVAPTECS
26	Life	13H.2LC	MDMRVPAQLLGLLLLWLRGARCDIGMTGSPSSLSASVGDRVTIT CRASQGIRKDLGWYGOKPGKAPRRLIYGASSLGSGVPSRFSGS G$GTEFTLTISSLQPEOFATYYCLGYNSFPWTFGOGTOEiKRTV AAPSVFiFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVONAL G'SGRSGESyTEGDSKDS3A'SLSSTLTLSKADYPKHKVYACEVTH GGLSSPVTRSFHRGEG
27	Life	32H7 LC	METPAQLLFLt 1. LWLPOTTGEiVL Ϊ QSPGR SL SPGERATLSCRA SQSVSSGYLWQQKPGQAPRLLIYGASSPATGiPDRFSGSGSG TOFTLTISRtEPEDFAVYYCQQYGNSLCRFGQGTKLEiKRTVAAP SyPrPRRSDEOLKSGTASVVCLLNNPYRREAKVGyVKVONALOSG NSQESYTEQ0SKDSTYSL5SRRSKADYEKHKVYACEYTKQ6L SSPVTKSFNRGEC
23	LI?	32H7CSLC	METPAQLLaLLLWLPPKGEiVLTOSPGTlSLSPGERATLSCRA. SQSVSSGYLTWYQQKFGGAPFL L iYGASSRATGIPORFSGSGSG TOFTLTlSRLEFEDFAWYCGGYGNSLSRFGGGTKLEsKRVVAAP

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SVFIPPPSDEGLKSGTASyvCLlNNFYPREAKVQW^/DNALOSG NSQFSVTEQOSKDSTYSLSSKKSKAOYEXHKVYACEVTHQGL SSPVTKSFNRGEC

Table 2B Exemplary AoObndy Heavy Chafe Arfeno Add Sequences

»10 MO:	Design alw	Confessed hi Clone	Sequence
29	Hl	01 Eli HC 04E4 HC 0904 HC	MOMR^AQaeaUWUWCQV^tWSGGGWQPGRSLRU CAASGFTFSSFGMHYG/ROAPGKGLEVVVA.ViSFOGSIRYSVDSVK GRF‘nSROHSKN'n.FLQMN$LMDTAVYYCARDRLNYYDSSGY YHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSEST AALGClVKOYFPFTY/TVSWRSGAtTSGVHTFPAVlOSSGLYSLS SM7TVPSSHFGTOTYTCNVOHKPSNTKVDKTVERKCCVECPPCP APPVAGPSVPLPPPKPKOTLMISRTPgincVVyOVSHPDPeVGFN WYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHODWLNGKEY KGKySNKGLPAPIEKHSKTKGQPREPQVYTLPPSREEMTKNQyS nClVKGFYPSDIAVEvVESMGQPENNYKHPPMlDSDGSFFLYS KLTYOKSRWQQGOFSCSVMHPAtHMHYTCKSLSLSRGK
30	H2	01H? HC	MCMRVPAQtLGLtLLWLRGARCEVCtVESGGGLVRPGGSLRLG GMSGFTFxSNAWMSW^QAPGKGLE^VGRiKSTTDGGTTOYAA PVKGRFT1SRDOSKNTIYLOMNGLKTEOTAVYYGTTDRTGYSI8W SSYYYYYGMDVWGQGTWVSxSASTKGPSVPPtAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAyLQSSGLYGL SSWTVPSSMFGTQTYTGHVOHMPSMTKVDKiVERKCCVECPPC PAPPYAGPSVFLFPPKPKDTtyBRTPEWCWVDVSHEOPEVQF NVWOGVEVHRMIKRREE^HSTFRWSVLWVHODWLNfc. YKCKVSNKGLPAPIEKTISKTKGGPREPOWLPPSREEMTKNQV SiTCLVKGFYPSDIAVEWESMGGPEHMYKHPPMLDSOGSFFLY SKtTVDKSRWQQGNVFSGSVMHEAlHHHYTQKSLSLSPGK
31	H3	02BHC	MOMRVPAOtLGLLLLWtRGARCEVOtLESGGGLVQPGESLRtS CAASGFTFSSYAMSWVRGAPGKGLEYvVSAISGSGGRTYYADSV KGRRiSRONSKNTLYLQMNSLRA.£OTAWYCAKOQREyGPYSS GWYDYYYGMi5VWGQGnVTVSSAOT KGPSYFPLAPCSRS TSE S taalgclvroyppepvtvswnsgaltsgvhtppavlqssglysl

S3

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			SSVVTVPSSNEGTGTYTCNVDHRPSNTKVDKTVERKGCVECPPC PAPPyAGPSVFLFPPKPKDTLMISRIPEVTCWVDVSHEOPEVQF HWYVOGyEVHHARTKPREEQFHSTFRWSVLTWHQDWLHGKE: YKCKVSNKGLPAPIEKTISKTKGQPREPQVYTtPPSREEMIKNQV SLTGLVKGRIASOJAVEWESNaQPENHYKTTPPytDxCDSSFPLY SKtTVDKSRWQQGNVFSCSVMHEAlHNHVlQKStStSPGK
32	B4	«HC	yOMFWACMGLLliMRGARCGyOLVQSGAEVKKPGAGyKVS GKASGYTFTGYYyHvWRGAPGQGlEvWGWINPNSGGTHYAGK FQGRVTMTRDTSISTAYMELSRLRSDQTAYYFCAROQMShMtRG VFPPYyYGyD¥WGQGnVW3SASTRGPx$VEPLARCSRSTSEST AAEGGLVKDYFPEFVTVSWHSGALTSGVHTFRAVLQSSGLYStS SVVTYRSSNFGI'GTY'TCNVDHKPSHTKVOKWERKCCVECPPCP APPVAGPSYFLFPPKPKDTlMiSPTPEVTCWVDVSHEDPEVQFN WYVDGVEVHHAKTKPREEQFNSTFRVVSVLTVVHGOP/LHGKEY KCKVSNKGlPAPIEKTISKTKGQPREPQVnLPPSREEMTKNOVS LTCLVKGEYPSDIAVEWESNGQPEHNYKTTPPMLDSDGSFFLYS KLT^KSRWOQGN^SCSVMHeALHNHYraKSLSLSPGK
33	Ηδ	03C3 HC 05F5 HC 12E3HC	MDMRVPAGLLGLLLLWLRGARCGVGLYESGGGWGPGRSLRtS CAASGFTFSSYGMHWYRQAPGKGLEWVAVISYDGSKESYAOSV KGRFTiSROISKNTLYLQyNSLRAEDMVv'YECARERKRVTMSTL'Y WFYYGMDVWGGG’iTVIVSSASTK.^sVFPLAPCSRSTSESTAA LGCLyKDYFPEPVTv’SWNSGALTSGVHTFPAVLQSSGLYSLSSV W5SSHFGTQTYTCNVOHKPSNrKVi5KIVERKCCVF:CPPCPAP PVAGPSVPLPPPKPKOTLMiSPTPEVlCVVVDVSHEDF'EVQERRY YVDGVEVHNAKTKPREEOFNSTFRVVSVLTVYHQiMlNGKFYK CKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSt TCiVKGFYPSOIAVEWESNGQPERNYKT'i PPMI. DSDGSFF1. YSK LWDKSRYYQQGNVPSCSVMHEALHNHYTGKSISLSPGK
34	Ηδ	Q4H6 HC	yDMRVPAQLLGLtLLVVLRGARCEVQLVESGGGLVKPGPSLRLS CTASGFTFGOYAMWRGAPGKGLEWlGFIRSRAYGGTPFYAAS VKGRFTkSRODSKTiAYLGyNSLKTEDTAYYFCARGPGiAARWDY' WGQGTLVTVSSASTKGPSyPPLAPCSRSTSESTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV'/rvPSSNFG IQTYTCNVOHKPSNTKVDKTVERKCCVECPPCPAPPyAGPSVFL

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			FPPKPKDTLyiSRTFEVTCWYDVSHEDPFVQFNWYVDGVPVHN AKTKPREEQFNSTFPVVSMTWHQOWtNGKEYKCKVSNKGlPA PIEKTiSKTKGOPREPGVYriPPSREEMTKJlGVSLTCLVKGFYPS OiA VE WOSNGQPENNYR'n PPMLOSDGSFF L YSKLTVOKSRWG QSWFSCSYMHEALHHHYTQKSLSLxOFGK
35	H7	09P5HC	yDyRVPAQLLGLLLLWLRGARCPYOLYESGGGLVKPGGSLRLS CAASGFTFGNAWMSvWRQAPGKGlEWyGRiKSKTOGGTTOYTA PVKGRniSRDDxSKNTLYLQMNSLK^DTAVYYGTTPRTGYStpW SSYYYYYGMDVVYGGGirYTVSSAS'TKGPSVFPlAPCSRSTSES TAMGCLVKDYFPEPVTVSWHSGALTSGVHTFPAVLGSSWSL. SSWTVPSSNFGIQTYTCNVDHKPSNTKVDKP7ERKCCVECPPC PAPPVAGPSVFLPPPKPKDTlMISRTPEVTCVVVDVSHBPEVQF NWYVOGVEVHEIAECrKPRlHEGENSTFRYVSvYJVYbtODWLNGKE YKCKVSNKGLPAPIEKTISKTKGGPREPQVYTLPPSREEMTKNOV 'SLYCLVKGFYPSDiAVEWESNGOPENNYKTTPPMlDSOGSPPLY SKLTVDKSRWQGGHVFSCSWHEALHHRYTGKSLBOSPGX
36	HO	1004 KC	y(}yRVPAGLLGLLiLWLRGARCGVGi.VG0GAPVKKPGA3VKVS CKASGYYFTDYYyYWVRGAPGQGLRWyGWiSPHSGGIHYAGK FQGHVTMTFiDISiSTAYMELSRI.RSI)OTAVYYCVRGGYSGYAGL YSHYYGyDVWGGGTIVTVSS.ASTKGPSVFPLAPCSPSTSESTA ALGCLVKOYFPEPVIVSWNSGALTSGVHIFPAVtQSSGLYSLSS VVTVPSSNPGTGrYTCNVDHKPSNTKVOKTVERKCCV£CPPCPA PPVAGPSVRPPPKPKOIlMiSRTPEViCWVOVSHEDPEVQFN WVDGVEVRNAKTKPFEEGFNSTFFVVSVLTWHGDWLNGKEY KCKVSNKGLPAPiEKTISK7KGQPREPQVYILPPSREEMTKNOVS LIGLVKGFYPSDfAVEWPSNGQPPNNYKTTPPyLDSDGSFPLYS KL;ryi>RSRWi>OGNVi'$CSV-yHEYv:.HNHYTGKSLSfBPGK
37	H9	11011 HC	MDM.RVPAQUGUttWLRGARC£VaVE.SGGGLVKP(^SLRl8 CAASGFTFGHAWMSWYRGAPGKGLEWGRiKSKTDGGHDYA APVKGRFTiSREIDSKNTLYLQMNSLKTEOrAVYFCnORTGYSIS WSSYYYYYGMOVWGQGTT/PvSSASTKGPSWPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGAlTSGVHTFPAVtQSSGLYS LSSVVTVPxSSNFGTGTYTCNVDHKPSNTKVOKTVERKCCVFCPP CPAPPVAGPSVFIPPPKFKOTIMISRTPE'/TCWVOVSHEDPEVQ

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			FRWYVDGVEVHNAKTKPREEGFNSTPRWSVLTWHGDWLHGK EYKCKVSNKGLPAPieKTISKTKGQPR&PQVYTLPPSREEMIKNQ VSLTGlv'KGFYPSDIAVEWSSNGQPENNYKrTPPMLOSDGSFFL VSKl IVDKSRWQQGHVFSCSVMHfc ALHNHY TQKSISLSPGK
38	H10	11H8HC	MOyRVPAGtLGLLLLWLRGARCEVQLVFGGGGLVKPGGSLRLS CA^SGFTFGNAWMSWVROAPGKGLEWVGRiKSKTFjGGTTOYA APVKGRFIlSRDDSKNTLYlQMNSLKTEOTAVYYCTTDR-TGYSiS WSSYYYYYGMDVWGQGTTVTVxSSASTKGPSVFPLAPCSRSKSE STAAtGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVIQSSGLYS LSSVVWPSSNFGTQTYTCNVDHKPSNTKVOKTVERKCCVECPP CPAPPVAGPSVFLFPPKPK0'U33iSPTPEVTCVVV0VSHEDPEYQ FrAWD0VEVHHAK7KPR£EQFNSrFRWSVLTVVHGOWLNGK
EYKCKYSbmGtPAPlEKTiSRJKGQPFtEPG^TLRPSREEMTRNQ VSLTCLVKGFYPSD!AVEWE8NGQPENNYKTTPPMLDS.DGSPFL YSKLTVOKSRWQQGNVFSCSVMHEALHNKYTQKSLSLSPGK
3δ	Hit	12G8HC	MDfimVPAQLLGLLLLWLPGARCGVQLVESGGGVVQRGRSLRLS ' CAASGFTFSSFGMHWVRQAPGKGLE'AA/AViSFDGSIKYSVOSVK GRFTISRDNSKNTLFLGMNSLRAEDTAYYYCARDRLNYYOSSGY YHYKYYGtAVWGOGnVIVSSASTKGPSVEPLAPCSRSTSES'TA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLGSSGLYSLSS WlWSSHPGrQIYTCNyDHKPSNTKVQKlVERKCCVECPPCPA PPVAGPSYFLFPPKPKDTLMISPTPE^GWVDVSHEDPEVGFN WYYDGYE VHNAK'T KPRE EOFNSTFR WSVLIVVHQD WL NGKEY KCKVSHKGLPAPIEKTISKTKGGPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWE$NGQPFNNYKTTPPMIJ3SO63FFLY$ KLTVGKSRWQGGNVFSCSVMHEALHNHYTQKSLSLSPGK
40	HI 2	13H2HC	MOMRVPAGLLGLLLLWLRGARCEVQtVESGGGLVKPGGSLRLS CAASGYTF3TYSMNVWRGAPGKGLEWVGSISSSSGYRYYADSV KGRR1SRDNAKNSLYLQMSSLRAE0IAOTCAREGVSGSSPYSI SWYDYYYGMDVY^GQGTWiVSSASTKGPSVFPLAPCSRSTSES TAALGCLVK.OYEPEPVTVSWNSGALTSGYHTFRAVLQSSGLYSL SSVVTyRSSNFGTGTYTCNVOHKPSNIKVDKTVERKCCVECPPC PAPPVAGPSVELFPPKPKDTLMISRTPEYTCVVVDVSHEDPEVQF NWYVOGbEVblNAK'TKPPJ£FQFNSTPRyVS\0.TVVHGOWLNGKE

6!

2016244220 11 Oct 2016

			YKCKYSNKGLF.APIEKIiSKTKGQPREPQWTLFPSRFEMTKNQV SVTGlVKGFYFSDlAVeWNWENNYKTTPPUDSD^FFLY SKLTVDKGRWQGGbfdFSGRVMHEALHRHYTGKSLSLSPGK
41	ΗΪ3	32H? HG	MOMRVRAGLLGLLILWLRGARCGVOLVFSGGGWOPGRSLRLS CAASGFIF’SSVGMH WVRQAPGKGLEWVAVIWVDGSNKYYAOS VKGRFHSRDKSKNTLVLGMNSLRA&DTAVWCARAGGIAAAGLY YYYGM0W*iGQ6TrYTVSSASIKGP$VFPlAPCSR$ISE$TAAL iSGLvKOYFPEPVTVSWNSGAtTSGVHTFPAVLQSSGLYSLSSVV rdPSSNFGTQTYTCNVOHKPSNTKVDKrYERKCCVECPPCPAPP VAGPSy^LFPPKPRDTLMISRTPEyTCVWDVB.HEDPE.VQFHm VDGyEYHHARlKPREFQFHSTFRWSVLTVYHGOWLNGixEYKC ^SNKGLPAPIEFTiSKTKGQPREPQ.VYTLFPSRFEMTKNGVSL'I CLVK^YPSOIAVEW'ESHGOPEHNYKTTPR^tDSOGSFFLYSKt WDKSRWGGGNVFSCSvhMHEALHNHYrQKSLSLSPGK

(he fb'-a ?? amino ae«ds of etch of the hghi chair- sequences ΐο i -ble 2 Λ. except h'di' _tn-d >21 P ( S. ο a \-rr<>«i sequence hi the i ao.· of $2H7 are PH ? 'S, the s>gmd sequence is 20 air-ino uuids Ssrmhmv, die test 22 ammo ac-.ds of meh »>l the hem v eham ->< .junto m e 1 abb Ή is a signal s-’tjiieuce fh ? - it nui peptides m*q. bo eh.mg,.'! m sign d peptide* hax mg diffmem sequences. e g„ for nt<ne optimal expression in s orient bom ceils it w ill be tbeietore be understood thai the tnxcntio't also m Judes antibodies ha* mg the light md οι heavy chain sequences a* specified m hikes 2Λ and 2K, ho wnh <bfhoust signal ssqnemrs

Again each of the e.xemptare heavy ->oams iHl, H2. He etc > listed in Bible 2B can lie combined νχΐ?Ιί any ot ihe exemphuy light chums slmoo in Tabic 2Λ io ibrtn ats antibody Examplesuf *ueh vombmumms include HI compiled onh mq. of ΐ i iborngh I 112 unidmied with air, of 1 « ftnxmgh 1 H > combm-,d oilh -ay ol ί I thiongb 1 P, ,md soon in some instances, the antibodies nxiud; at hast one beam eivmt and one hem chant from those listed m fable,* ,md ?R hi miiiu- msian-'o-, the mblssb--s comprise two duTeo-m heass ebano* and oxo dilletent bght chums listed tu lakes 2Λ .md 2R, in other instances, the antibodies contain too identical mpt chain* imd tue «dontic.d he.oq. chains A.* <m exaucple. at-antibody m nnmnnoiogteuliy btnctiowd ieanuiii mm mclntiv too til heavy Jiumsand oxo LI hghi «.bants. or tv.o H? heax\ eh.un* and oxo 1 2 light «.hams, m io·? lid heaxy ebrnns and too 1 * halt!. ..hams ..md othet stnuiat -..mnkuulmns ot p -m* id bghi chains anti pans of heav e char > a* '«sled .n ^! bias ? k <md 2B

2016244220 11 Oct 2016 am g- 'ibmdmg psoieus-. Y.w cieprovved <-tc v em-nts ot antihodvs mimed Y combination of the heavy and light chains .shown in Tables 2A and 2B and comprise 'fight and ot heavy chains that each hnv ·... ,n. least “')?,», 7s'',,, 50%, 8v0., 900., Ύ0, 070, yr '*90. idesnstv to the amino acid sequences ot these chums. In some instances, such antda-rik-, include ai least one hem. y ·„ham and om. light ch.un. wherons tn other irwianves Ye v arum bums contain too identical light ehaut ,md two kenne d heavy chums VanuhkDs^^

XRo pros id-, d me a-'.beew I-tikhug ptolems that com on an antibody heavy knam v vubk tcgjnn selected item tits' group eovo-oug of \ n k X ,2, \ ?, 0 X -A. YnA \ -ti, X t, 0

Η) V-ih. X'00 V;-.lif Yj:11, Y-.-J ?, .aid Υ;? I 0 nm1 or .m .moti-siy light chain sarsabie region sek'eted from the croup vousistitu ot X I, X? 2, X 3. Y 4, XX 5, X : e, Yi 0 X' 5, X : 0 Yi Kt,

Y, i 0 V. 0?< X; I 0 X. 14, Y| I ΐ Vj to, .uid X j I, os shown in Table 3 below, :ni-d imnmnologieahv Amotione! tragmvWs, onto abv. s, matsum a?-d var-abRet these tight ctunn and heavy chain variable regions,

1.5 Sequence ehgtntsc'tis of ?h vunons he e,v n.-d ht nt en ,iu -,an' tile s-yuows, respectively. are provided ;n figs ι λ and IB.

Antigen Yu.hug protects of b ty pe - an gene¹ dk iv designated by the fonnuiu X j \ X V,” whstc ”s corresponds to the ournhet ot heuw chant vanahk seasons -.ci-d '0''

-. onvspond⁴- to she numbei ofthe light -, ham variable reg-ouv lahlo 3: Exemplary X q and XT Chain Ymhte Yen! Noqnences

Contained in Clone	Designation	SEQ© HQ.	Amino Acid Sequence
1F11	'0.1	137	□oVUQPPSYSPAPGGKVTISCSGSSSNIGNNYYSWYQOLP GTAPKLLIYDNNKRPSGIPORFSGSKSGTSATLGITGIQIGOE APVVGGTWOSRLSAWFGGGIXUVI.
IH?	V I £.	138	QSYLTQPPSASGTPWWTISCSGSSSNIGSHYYYWYQGLP fMAPKaiFRSHQRPSGYPORFSGSKSGTSASLAISGLRSEQ E^VYCMWDOSLSGWVFGGGTKLTVL
21.7	0.3	139	DiQMTQSPSSI.SASYGQRVTI T CPASOGiPNDi.GWFQGKPG KAPKRtlYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPBDLA Ί'γΥΕίΟΥΝτ/ΡΑΐΡοαοτκνεικ

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2016244220 11 Oct 2016

Contained In Clone	Designation	NO,	Amino Acid Sequence
386	Vl4	MO	SStLTGDFTVSVALGQ'TVKITCQGOSLRSFYASWYGQKPGG AFVLVFYGKRNPPSG4PDRFSGSSSGNTASLTITGAOA6DEA DYYCNSRDSSVYHLVLGGGTKllVL
3CS	VlS	Ml	DiilAQTRLSlSVTFGQPASISCKSSGSlLHSAGRTYLYWYLQ KPGGPPQ1. L i YE VSNR6SGVPDRF SGSGSGTDF 1Ί..Κ iSRVEA EDVGIYYCMOSFPLPLTFGGGTKVEIK
<4	o	142	GSVtTGPPSV8AAPGQKV7ISCSGSSSNIG.NNYVSWYGGiF GIApKLLiYDNNKRPSGiPORFSGSKSGISHLGITGLaiGOE ADYYCG7WDSRLSAVVFGGGTKL7Y1
4HS	%?	M3	DiVMTQSPLSLPVTPGEPASISCRSSGSlLHSFGYNYLDWYL GKPGOSPQl.LiYi.GSHRASGVPDRFSGSGSG'r(}F'riKiSfb/i:; AEDVGVYYCMQAlQTPFTFGPGTKVDiK
5F6	:SW;	144	DiSL7OTFLSLSV7PGQFASiSCXS8GSLLHSDGK7YLYV7YLQ KPGQPPGI.LIYEV$NRPSGEPDRFSGSGSGlDRLKiSPVEA EDVGTYYGyGSPPLPLTFGGGTKVEIR
904	VlB	MS	QSVLTQPPSVSAAPGQKVTiSCSGSSSNIGNNYVSWYGGPP GTAFKILJYDNNKFPSGIFORFSGSKSGTSATL GHGLQ7G0E ADYYGGTWDSRLSAMVFGGGTKL TVL
O	v,w	146	OSVUOSPSASGTPGQRVTiSCSGSSSNiGSNWYvVYQQLP GAAPKLLiLRNNGRPSGVPDRFSGSKSGTSASLTlSGLRSED EAOYYCAAWDDSLSGWVFGGGTKLTVI.
1064	wii	MY	QSVLTQPPSASG'iPGGRVDSCSGSSSNIGSNIVNWYGGLP GTAFKtLIYTNNGFPSGVPOFFSGSKSGTSASLAISGLGSED E ADFYCAARDE SLNGWFGGG'T KLTVL
11 Dll MHO	WI24	146	GSVi. TOPPSASGTPGQRVI iSCSGSSSNiGSNYVYWYQQLP -GAAPKLLIFRNNGRPSGVFDRFSGSKSGTSAStAiSGLRSED FADYYCAAVVDDSLSGWVFGGGIKLTVl

2016244220 11 Oct 2016

Contained In Cteno	Designation	S8Q10 NO,	Amino Add Sequence
TO	vds	149	ΐ5ΓΤΠθΤΡί818Υ8ΡΘαΡΑ5180Β808ΐΧΗΒ0ΟΚΝ¥Πνννί QKPGfd^FOLLJYEVSNRFSGLPDRFSGSGSGTOFTLKtSRVE AFDYGlYYCMGSFPLFlTFGGGTKVFiK
12G3	Vtl4	150	QSVLTGPPSVSAAPGQKVTiSCSGSSSNiGHNYVSWYOGLR GTAPKii M'NMKRPSGl'PORPSGSKSGTaATtGnGlQTGOE: ADYYOeT'ADSRLSAWFGGGTKlWL
13H2	VdS	151	DIQMTOPSSLSASVGORVTITGRASQGiRKOLGWYQQKPG KAPKf?LIYGASStQSGYPSiiF8GSG.SG1‘FP11..‘riSSi.()PE[}FA TYYCLOYNSFPWTFGGGTKVEIK
32H7	7d6	152	EmQSRGTLSLSPGERATtSCRASQSySSGYLWGQKP GGAPRLi.IYGAS$RAiGiPDRFSGSGSGTDFTLTISRi.EPcDf: AVYYCQGYGNSLCRFGGGTKLEIK
32H? CO	VdT	153	EIVLTGSPGTLSLSPGERATLSCRASQSVSSGYITWYQQKP GQAPRLUYGASSRATGIPORFSGSGSGTDFTLTISRLEPEDF AVYYeGOYGNSLSRFGGGTKLEiK
S2HS	7S.W	154	D;VMYGSPDSLAVSLG£RAT1NCXSSGSILDSSNNDNYLAWY OQKPGQPPKLt lYWASTRESGVPDRFSGSGSGTDF TtTISSl QAEDVAVYYCQGYYNTPFTFGPGTKYDiK
3385	Vd9	155	DIQMTQSPSSLSASVOTWCRASQGiRNEJLGWYGGKPG KAPKRLIYVASSLQSGyPSRFSGSGSGTEFTLTiSSLQPEDFA TYYCl.GYNTYPL.'iT:Gi5GTKYFdK
33B4	J jWx	: 15S	EIVMTGSPAHSVSPGERATLSCRMQSVRSNLAWYQQKPG QAPRLLiHDASPRTAGlPARFSGSGSGTEFTLTiNSlQSEDFA YYYGGGYNYW'i P1TFGQGϊRLE IK
3483	ναι	157	GSV1. TOPPSMSAAPGOKVTiSCSGSSSNIGNNYVSY/YQQLP GTAPKlLlYDNNKRPSGiPDRFSGSKSGTSATLGiTGLQTGDE ANYCCGPAGIGLSYWVFGGG'TKLTVL

2016244220 11 Oct 2016

Contained In Clone	Designation	SEQ ID NO,	Amino Acid Sequence
4E4 904 11611	Vh1	158	GVQLVESGGGVVQPGRSlRtSCAASGF'iFSSFGMHWVRGA PGKGLEVWAViSPDGSIKYSVOSVXGRPTiSRONSKNTtFlQ MNSIRAED'TAVYYCARDRLNYYDSSGYYRYKYYGMAVVVGG GTTVTVSS
1H7	Vh2	1S9	EVOLVE SGGGLVKPGG&RLSCAASGFT ESNAWMSWVRQA PGKGLEWVGRIKST7DGGTTDYAAPVKGRFT!SRDOSKNTLY LQMNSLKTEi5TAVYYCTTDRTGYSiSWSSYYYYYGMn'AVG □GTTVTVSS
2E7	Vw	180	EVQLLESGGGLVGPGESLRLSCAASGFTP3SYAMSWVRGA PGKGLEWVSAISGSGGRTYYADSVKGRFTiSRDNSKNTLYL QMNSLRAEDTAVYYCAKDQREVGPYSSGWYOYYYGMQW GQGT1VTVSS
	Vh4	181	GVQtVGSGAEVKKPGASVKVSCKASGl ’ RGYYMKWVRQA PGQGLEWMGWINPNSGGTNYAQKPQGRVTMTRDTSiSTAY melsrlrsdotavyfcardgmshmlrgvfppyyygmdvwg GGTTVTVSS
3C8 12E8 5F5	W5	O	QVQLVESGGGVVQPGRSL.RLSCAA8GFTFSSYGMHWVRQA pGXGtEWVAVISYDGSHESYAOSVKGRFWROISKNTLYEQ MNSLRAPDTAVYFCARERKRVTMSTLYYYPYYGMOWGQG TTVTVSS
4HS	VwS	163:	evqlvesggglvrpgrslrlsctasgptpgdyamswfrqa PGKGi. EWIGF1RSPAYGG TPE YAASVKGRE TISRDDSKTIAYL GMNSlKTEDTAVYFCARGRGLAARVVDYWGOGTLVTVSS
SF5	W	164	EVGLVESGGGlVKPGGStRLSCAASGPTFSNAWMSWVRGA PGkGtFWVGRiKSKTOGGTOYTAPVKGRFTISRDDSKNHY LQMNSLKAEDTAyYYCTTDRTGYSISWSSYYYYYGMDVWG QGTTVTVSS

Ac

2016244220 11 Oct 2016

Contained In Owe	Designation	NO,	Amino Acid Sequencs
10E4	V,:8	165	QVQtVQSGAEVKKPGASVKVSCKASGYTFTOYYMYWVROA PGGGLEWMGWtSPNSGGTNYAGKFQGRVTMTRDTSiSTAY MElSRLRSDDTAVYYCVRGGYSGYAGLYSHYYGMDVWGQ GTTVTVSS
ii Dii	Vh9	166	E VOL VE SGGGL VKPGGSLRLSCAASGR f: GN AWMS WVRGA PGKGLEWVGRIKSKTDGGTTDYAAPVKGRETiSRDDSKNTLY LQMNSLKTEDTAVYFCTTD.RTOYSISWSSWYVYGMOVWG GGTTvTVSS
11®	VMO	167	EVQLVESGG®VKRGGSLRLSCAASGRFGNAWMSWVRGA PGKGI.I· WVGRIKSKTOGG TTD YAAPVKGRT TISRDDSKNT LY LQMNSLKTEDTAVYYGKDRTCYSISWSSYOYYGMDVWG QGTTVTVSS
12®	70	168	GVQlVESGGGVVQPGRSIRLSCAASGRPSSPGMHWVRQA PGKGlEvWAViSPDGSIKYSVDSVXGRFTISRDNSKNTLFtG MNSLR.AEDTAVYYCARDRINYYDSSGYYHYKYYGIAV'vVGQ GTTVTVSS
13112	Vh12	169	EVOLVESGGGLYKPGGSlRLSGAASOTFSTYSMNWVRQA PGKGtEWVSSsSSSSSYRYYADSVKGRRISRDNAKNSlYtG MSSLRAEDTAVYYCAREGVSGSSPYSISWYDYYYGMDVWG QGTTVTVSS
32H7	VMS	170	QVQLVSSGGGWGPGRSLRLSCAASGFTFSSYGMHWVRQA PGKG1.EWVAVIWYDGSNKYYADSVKGRFIISRDKSKNTI.YLO MNSlRAEDTAVYYCARAGGIAAAGLYYYYGMDVWGQGTTV tvss
32H8	VO	171	QVOi. VGSGAEVKKRGASVKVSCkASGYTFTAYYt K WVRGA PGOGLEWMGWiNPHSGGTNYAGKFGGRVTMTRDTSISTAY ME L SRI. RSDOTAVEYC ARGRQWI. GED YWGOGTI. VTVSS

2016244220 11 Oct 2016

33EE <54 SC'S

Vh17 ί 79 : ί A.

173

GVQtQQWGAGLbKPGETLSLSCAYYGGSFGGYYWSVYiRGP

PGKGLEWIGEIIMHSGGTKYHRSLKSRYTISVDTSRNGPSLKL

SSVTAADTAVYFGARGOWGFFOYWGQGTtYWSS

GVGLVQSGAEYKKSGASVKVSCKASGYTFTGYYMHWVRQA

PGQGtEVVMGYvfMPNSGGTNYVQKFQGRVTMTRDiSISTAY

MELSRLPSDOTAm'GARHEYSSAWPLGYWGQGTLYWSS

GiTLKESGPTLVKPTQTLILTGTFSGFSLS'FSGX'GVAYiiRGPF

GKA-t£:WlALjYWWBKRY$PSfKSfn,Ti'iKLriSRNGVVLRMT

14MDFLD7ATYFCAHRFGGWFDRWGGGTLXTYSS

Fsu h of tb he o y ( haw \<n mRIc regions, f._oie-1 in Fable 3 iwiy o comi’m. 3 wnh wo, of ,be gl\ u>iaji v fi'a'Me ,e>x -» mown n \de > to an »wi»'„en mn ιιμ«,·νΐι f saifsrR'sv sb o'nb'na, Uns s', into X ; 1 emoi s e v, s h wo ot X · X fo Y_{ * X > X >

Vi6, \R fo XR3, Xyfo \R 1.0, Vs II. XR i2, AR 13, YR 14, VJ5. A'Jfoor VRJ7; V_H2 combined with -or. of V i. X 2, V. 3, V ΐ XR 5, XXί-, X - / V,h. X fo X ίϋ V, I R XR 1 ? V. I R X > 1 1,

X 15, X 16, οι V, 17, X >, * -. embused w uh any of V. R X 2, X t R V, 4, X > fo X _t X . 7, X, S,

X fo YR 10, X'[ 1 R XR 12 XR ifo X 11 I, X’· ifo X · 16, or XX I fo and so on hi some -iisi.rtiei s, the amn.-w boidm-' pfotem ineh«i>, - at Exist one heavy chaw s wiable region and or one he in chan; \,n sable region Roni tboac Si-ted m fable * hi some nisi υιόν-, ihc aisiigen fondmg review inehide,- a? Seas? two dd'E-rom heavy , h mt variable ;„eio, > are o, Fein chan saoal 'e s».e'ott\ ^p o.m tbo-c a-ud os ^! able ? V, C'.aj tgk of su„h aantigen bisidmg protein comprise- fa)one Xfod, and (b) oneofVif?, V_i;3, XR3. XR3,. YfoO, YR_S7, X aX, X scX XX: fob XX 1 fo \\ 12, o: X .>1 > Anodic: e-ampk· composes fon one XR;2, and ibson.· ofX'nRX 3.. XX.. 1 X n> X : ο, Χ'ϋ X X - X, Vufo X ; 10, X iJ R X'n IA or X - 13 Again another example composes foo one XR;3, and lb? one oi v _t, 1, XR:2. Xfofo XRt.fo X - b, Xfofo X’nfo XRtfo VgKR Vid I, XfolS, or Vp 13, Ge, Again another example of -such an antigen binding protein -ompfises ias one V ‘, md t h? one of XX 2, X-X, 3, XR 4, V·. 5, XR 6, V; 7, XR 3, YR fo XX 10, YR : ί,

V-12 X . RR X - Ifo V- I h, X t lo, or X : 17, v, rr \ , |u y, %!, <si XX 21, Agwu anoine? „\umpk of stub ssi .mopeo brndmi; nreiem , oremise^ la's one X < ?, and tb* one <tt X ; R X , R X' 1.. X ; 5,

VfoR Vifo. YRJfo Vgfo VjylG, Vj,l L, Vi,12_? VQfo V_tM V_t.!5₅ V_tM Vj-F V, IF,XRJfo VR20, or XA.21, Again another example of aoeb an nnbgob binding protein eornprss·, -i ,A one Xfofo,

2016244220 11 Oct 2016 and tb) one id' V₍ 1, V_; ?. V, I. V_e 5, V· rt Y_; “ \ , bk V;A Y_t 10. V₍ 11, i 2 Y i 3, V_; 14, \ 15, v ={., \ ; 1 γ V, ih, \ , p. Yjgo, 05 \ di, ue.

The lariou- eontbinattom· of heavy ch.-no mrlable re-gams may he combined rehh any of me ianon- eoathm.dson- rel Iteht eham luttahte tegum- re- ss apparent to one id Adi m the art h uf-ct maat i e\, the .-.t-geu b Thug |>-m- re- < re tret -- .wo . fens-. d Isgat char, retrt.'ble regions und'or two identical heavy chain variable regions As an e-ample, the antigen btndtuo ptotem may he .m a unhod', ot iminunoiosue.>.hy tuoetsrereji tremore-w that m-. hide- two Ught eham -. unable tegtott- and neo hem i eham iactable region- nt eornbittatton- ret pan- of it) t >ht ha \ , sal e egom <mj naw χ ⁵ ,re\ a,or -> t 2A region- λ-, t-tee res I , ie 7

Some amtgen binding protests.-that are provided comprise a hea vy chain variable • domain comprising a sequence of amino acids that differs from she sequence of a heavy chain .aoid'le oomnm v re-cfed ttom \ I, Y>}2- 5 - k 3 i 4. 3 >?. 3 tA, Υ-· Υ;Έ 3 ri. 3 a lm Yu I\ .(i 2. and V J 5 at only I 2. e. k 5 o. 7. re ^l'^! 10, I i, i 2. 13. I I or 13 ammo acre! residues, w h.'em each-ueP-e ptene, dd'e- i> * is w.k pcu.leutts esthc- a dried.>- n.-eitsrenot

-nhstouiton o| one motto aetd. with the deletions. in-rentons and or substitutions scstdtmg in no more dw 15 amino acid elwgereretofve io the lore going vbrihfefe dororih sequences. The tree- > elsam -aoabte reason us -erne antigen hmdmg protents -ostipts-es.. ,-equenee of ammo ai id- th it ha- ,·.ΐ least ⁷t)%, Τ-Ά, sgre, op⁴',., 05--,., 07 -,, seqtteti-. e kti.mtty to she ammo aetd -equeoee- ot th; he.rev eham -. artah-e teuton o| V_i5i, Y, 2, Υ,ρ. 3 ; 4, 3'% Y- re 3k.7. RA. 3 _;ri. wtlb Ynl I. YuIA -usd 3 _tfB

t. etta-u mtajen bmdmg p:ot> tu- . outpo-e a ugnt chum la-nO-h eomusn composing . sequence of utnt.no acids that differs from the sequence of a light chain variable domain set- vied -rim- Y_: 1, Y_t 2, v, k Y, 4, Y 5. 3 .re γ_{ ’ \ 3 o. y. )m y. t i. \ J 2. Y ⁴ k 3 14.

3 , ire Y to, m I at ot^!O L 2. 3.4, 5. -:-, , s, >>„ If;. 11, 12, 13, 14 or 15 ammo sesd residues, wherein each such -eiptenee dtlferenee A independently either a deletion, inset non or mb.-ltmttott ofretc etmno amd. unit thi, del.tmst-, m-e-non- and ot -tth.-tidittott- tv-tdtmg >n to more that: A ,uwrso .tent change- re-kno - to -he tore-gome, i r-reble ere'trem sequences The heist <. ham -;u iaike «τχηι ut -ome amire n bmdme pi mews comprise* a -equonee of annuo acids that ha< at iea.o '0 k>, ?%. 8?%, v?¹'c, 0 ’’ < or -Hb·, .-equenee tden-my to the atmtei ac'd ctuten-e- of the tight eham -.tutahh. region ref V, t, V_; 2. Y_t k V, a, \ - 5, Yj o, \k 7, \ re V, ire \ 11. Y 12. % ;3, \ ’ l 7 Vi 15, \_{ to or Y_; 17.

In adekorereat mst-ttiee-, emgeo hmdmg protein-comprise thr.· forirew mg paumg-of helit ehatu and la,; ii ehtuts i .triable domains, \ IJ with YIIL Y I. a with YIL2 Y L3 o dh \ Ikk

6b

2016244220 11 Oct 2016

VI 4 w iih VIM, VI 5 w iih Vi 15, VI 6 w uh Vi 11, \ 1 w uh Vi 0\ VLb with VH \ U 0 w ith \ Hi. VI 10 with VH VI it wsth. H\ VI. i 2 with \ tlfo \ t 12 with \ II10, VI 15 with YH5, VI,14 with Ylll I. VI 15 with Yin 2, \ 1 iOwtih VI11 λ and YLI 7 with VI It 3 In some instances, the antigen hunhng proteins sn the above pimancx au\ comprise attune aud .-><s,:eeneex th<u base V s0^;>,. G, ’Xi%, O5’b. or 00^Λ·< sequence kiewtv wkh the snecified sawable domains.

Suit other mPs.cn btndmg proiem% e.g mnbodw- or irntninsoh'-gieatls ttmemmal iummenis, mebide \atium. toms- of a xatiar; bcasx eh'-eu aid a inswap injbt cham as pest described.,

CDRs the anti,vest binding postcius disclosed herein are polypeptides into which mae or more t DRs as.· arciled, uiseaed and ot osn- d Au anngeu busdun; pfote-u ,,m bare l< ? 3, 4, - m 6 C'DRs \n antigen hwhae niotem Ida- .an hare, On example, one 'sonsy >. tsaist ( DR I C'CDRH t Ύ and br one heavy chain CDR2 ('X DRH'2'Ί. und er one hens y chain ί DRd «'< DRHd'd, and ns mie limn cham CDR! f (OR I 1”t. and <n one light chins’ CDR2

V'f DR1 2 i, ,md or one bent eh.un 0 DR5 I'Y'f d<s v) Seme antigen brnmiye prote-ns ία. lode both x { DRII? md d'DRIS. .specsin iu-axy uni higheham ί Diss ev'denofiied m Fables 4Λ uts.l ΊΒ, te-peetisels

Ceuiplen-eniariiy detemun-ng region- tCDR-} and firamexxorl >egin$is (FRj of a ids on uimho.lx mus p.> idenefied uxmg tlu ss-teir· .Iesewhed t \ Rabat et al m sequences ni Pteteniof hnsrsttnn.ingienl Interest, 5th Ed , DS D-.-ρΐ of Hcabh and Human Services, EHS. MH, MH Puhmatson no fo-w-C, ΝΉ < euam atmoodies mo roe disclosed hetem comps ixe micor more mnit’e idd stmueneex diet are identic si or base sutist mmil -eqaenec identity to the aminoacid seqsienees oibmc or mm-., of tlu t DRs presented m Ί ublc 4,\ H DRHm and 1 able 4R (CDR.Ls).

Tahk-4t: Exemplars Ilmny Chain ( DR Amsmi AekI Sespseneex

AUNnm ;	SEQ ID	Corhawd m Reference	Designation	Sequence
42	n	1EHHCDR1 OHCDR1 QG4HCDR1 1OHCDR1	CORK 1-d	SGMH

2016244220 11 Oct 2016

Ah Mum	SEQ ID NO:	(Watoed to Reference	Mgnsifen	Sequence
43	71	1H7HC0R1 8F6HCDR1 11D11HCDR1 11H8HCDR1	CORK 1 -2	HAWYS
44	79	2E7HCOR.1	CORK 1-3	SYAMS
45	82	388HCDR1	CORK 1-4	GYYMR
46	B	3C8HCDR1 5F5HCDR1 12E8KCDR1	ChRHl·®	SYGMR
Γ w '	SS	4H5HCDR1	CDRR 46	OYAMS
48	82	WE4RCDR1	CDRR 1-7	YGYYMY
48	87	13H2HCDR1	CDRR1-8	: TYSMN
50	189	32H7HCDR1	CORK 1-8	SYGMR
51	74	1E11HCDR2 4E4HCDR2 9D4HCDR2 12GSHCDR2	CORK 2-1	ViSFDGSiKYSVDSVKG
52	77	1H7HCDR2	CORK 2-2	RIKSTiDG(5TiDYAAPVKG
53	88	2E7HODR2	CORK 2-3	ABGSGGRTYYADSWG
54	83	3B6HCDR2	CORK 2-4	WiNPNGGGTRYAQKFGG
	as	3C8HCDR2 5F5HCDR2 T2E8HCDR2	CDRR 2-5	ViSYOGSHtSYADSVKG
86	89	4H6HCDR2	CDRR 2-6	FIRSRAYGGTFEYAASVKG
57	81	9F5HCDR2	CDRR 2-7	RIKSKTDGGTTDYT.APVKG
58	83	10E4HCDR2	CDRR 2-8	WiSPNSGGTNYAGKFOG

2016244220 11 Oct 2016

Ah Hw	S£Q ID NO.:	Con to med in fefemtw	Oesignshon
50	95	11DMHCDR2 11H9HCDR2	CORK 2-9	RiKSKTDeeTOYAAPVKG
50	95	13H2HCDR2	CORK 2· 10	SiSSSSSYRYYADSVKG
51	101	32H7HCDR2	GDRH 241	ViWYDGSHKYYADSYKG
	75	1611HCDR3 4E4RCDR3 9D4HC0R3	CORK 3-1	ORLNYyDSSGYYHYKYYGMAy
58	75	1H7HCDR3 SF5HC0R3 110MHCDR3 11H9HCDR3	CORK 3-2	DRTGYSiSWSSYYYYYGMDV
54	81	2E7HCDR3	CDRH 3-3	DORRVGPYSSGWYDYYYGMDV
S5	84	3B6HCDR3	CDRH 3-4	DQySOyLRGVFPRYYYGMDV
56	87	3C8HGDR3 5F5HGDR3 12E8HC0R3	GDRH 3-5	ERKRVYySTLYYYPYYGMDV
57	90	4H6HCDR3	CORK 3-6	GRGSAARWDY
58	04	WH4HCDR3	CDRH 3 ?	GGYSGYAGLYSHYYGMOV
59	90	1S8HCDR3	GDRH 3-8.	DRLNYYDSSGYYHYpYGLAY
70	95	13B2HCOR3	GDRH 3-9	eGVSGSSPYGiSWYDYYYGyDV
?i	102	32H7HGDR3	CDRH 3-10	AGGiAAAGLYYYYGyDV

2016244220 11 Oct 2016

Table 4iS: Riempbn Ughi Chain COR GUI Sequent

Ah Hum	SEQB BO:	Confined in Reference	Designetfen	Sequence
72	42	1E11LCD1 4E4LCO1 9041.001 12G8LC01	CORL 1-1	SGSSSRORWS
73	45	1HZLCD1 SF5LCD1 1W11LC1 11H9LCO1	CDRL 1-2	CGSSSBIGSNYVY
'74	48	.2071001	: CORL 1-3	RASGGRBDLG
75	51	3B5LCO1	‘ CDRL 1-4	GGOSLRSFYAG
75	54	3CSLGB1	CDRL 1-3	KSSQSLLHSAGKTYLY
77	57	4H6LCO1	CDRL 1-3	RSSOSLLHSFGYNYLD
75	50	SR51CD1	CORL 1-7	KSSQSILHSDGKTYLY
79	62	10E4LCD1	CORL 1-3	MGSSWGSRTVN
69	65	12E8LCD1	CORL 1-8	KSSGSLLHSDGRHYLY
[ M	66	13H2LCO1	CORL 1-10	RASCCRKDLC
62	50	32H7LCD1 32H7m LODI	CDRL 1-11	RASOSVSSGYLT
83	43	1RCL0D2 4E4LCO2 9O4LCD2 I2G8LCO2	CORL 2-4	DNKRRS
84	a	1H7LCD2	CDRL 2-2	RSBORPS
88	<	2E4.CO2	CDRL2-3	AASSIQS
§3	52	335LCO2	CDRL 2-4	GKBBRPS

2016244220 11 Oct 2016

Ah Hom	SEQ ID NQ:	Confeined « Reference		8^«
87		3C8LCD2 5F8LC02 12D8LCD2	CDRL 2-5	FVSNRFS
	58	4H6LCD2	CDRL2-6	LGSNRAS
80	61	9F5LCD2 11(3111(12 T1H9LCD2	CDRL 2-7	RHNQRRS
| 90	63	10E4LCD2	CDRL 2-6	TNHQRFS
	67	13H2LCD2	CDRL 2-3	GASSLQS
92	73	S2H71CD2 32H7niLCD2	CDRL 2-10	GASSRAT
93		1 Eli LCDS 4E4LCO3 0D4LCD3 12G3L.GD3	CDRL 3-1	GTWDSRLSAW
94	47	1H7LCO3 9F51CD3 11D11LC3 1lH9tet>3	CDRL 3-2	AAWDOSLSGWV
95	§0	2E7LCQ3	CDRL 3-3	LGYHIYRWT
»	S3	38SLCO3	CDRL 3-4	NSRDSSVYHL7
97		3C6LCD3 5F5LCD3 12ESLCD3	CDRL 3-5	: MQSFPLPLT
98	63	4H6LCD3	CDRL 3-5	MQALQTPFT
99	64	1084(. CDS	CDRL 3-7	AARD( YLHGVV
100	e	13H2LQQS:	CDRL 3-8	LQYHSFPWT

2016244220 11 Oct 2016

Ait Bum	SEQ SD HO:	CsshlaM in Refwaee		Sequoca
101	71	32H7I..CO3	CORL 3k	COGHSLeR
1Q2	72	32H7m LCDS	CDRL3-W	QOyGNSLSR.

fls»' sunetme and ptopeiftcx ef'GDRs wulnn » ttaimulls oecurriug antjbicis ha-, hires: described. MA'a Briefly, m a iradiuenui antibody, the CDRs ere embedded within a trameworl, in the heavy and Sigh- chain vaoubie region wh-ci'·.- they con^ms-te she regions respuUMide for asmpeti binding and mcogmta-n Λ variable region comp* ews at least disce heavy or fight enon t DRs me, m/m? ikr.n rt ,r m, Nvi, X(/'.aia >,a oz'Pc.-0/>0 >;' Λ».<η>,<λ·.>Λ>·4 h'kx w, PtiblK Health Sun see VS.H., Bethesda, .'HD; ό also I hothm and I esf. i*BV Dm d‘m, 19η-ορ1 -B \ C hothia. * a/. 1989, AGrex >♦? s-;.vxsl within A ftatnewotk legion «designatvil Itamewotk regions s -k 1 R k 1 R2, 1 KG and VP, 4. by k,»b n > 1 id o K'/r.e „kn f h-mua .end 1 os'.,, Hb ' <.>/>,>„'} (heVBRsp_L« id-d he?e n, however, may not only be used to define the antigen binding domain of a traditional antibody struemm, but muv bo embedded m a variety of othet pokpeptidc sttueturex ns dosenhv-d herein, in one aspect, the < ORs nio tried me ta'> u ( DRH s;ieetod horn the uttxtp vOttsistma ol ti t a CORD I selected worn fhe group consisting of\f\' If) RO ~'x Ή, h7, *5, ks, Ά A, and 100, s i) ι a COB 112 seketed from the gtotip coaxxntgot SI'Q ϊθ λΟ'Ή, Ά Sit, be, Ko,

Ά or 9R rt?, ‘R lot end ; ?c>, <0= j ,>. f DRHd selected oom the group consisting ·,·ι SVO SO SO ~x ~S, b ί, 84, e”. 'h) o»\ 90, 103, and 1 2 >, and uv} a Gt 1RI1 of 01, tjt t and {ml dart contains one or more, e,g.. one, two, dwoe, four or more .nnino acid subsmuttons sex,.

-..onset veuve ,ctnno >»C’,1 substitution,,), deletions o-· n-sertmus ot uo tnme dnm i've, four, t'mee. two. ot one irtouto uuds >»$t 4 GORI -eieeu .1 horn fix group eonst-mm oi «υ a ( DIB I selected from die runup egnsiehng ot Si's) R) SO 42, 4\ 7 j <S, 5-7 0?, r>5, nt» a-xl -Ό ).?'» a f OlH,2 selected (wttt the ,-Γοηρ constsinte of St Q 10 \(> 4b -In, -hb Ά he, 5 k ok *0, PR »jud '9, » I DRi 1 ‘elected from the gtoun eonsi-Png of bid) 10 SO Ά 4 R 50, Ru 5·'·, ri ng, pyg 71 7g, _;.q,| 1 4 COPS. ot tx, (nt and mt) that eounnus one v»r mme. e g , one, two. three four or mom amine· aetd substitutions te g„ costserv auve .unino acid subst tnu son*», dclenot! or utsed-ons nt no mere than fue. tour, deue, too, os one annuo seats utnmo »eidin another aspect, an antigen binding protein includes I. 2. 3, 4, 7 or 0 variant forms co the t ORs hoed m Iab^!> ¹ 4 X and >B, 1 <Α having at »e »,9 89'», bA °0’. (Arts s'Oit u- e :30 tfktrtttv to .»GDR sequene». isste»» m Sables4,\ and 4S1 dome antigen btndttsg proteins aielude 75

2016244220 11 Oct 2016

1,2 Y 4, 5, >n MAihe VDR\ hmed in I'aVles 4 \ and 4B e ι·.η ddlefing by nomoreihan 1,2. ,Y -I nr 5 aninit! acids from Ihc CDRw Owed iu these lablev

In t' i eiother tspeet, th - ί DR\ di\ foxed hewm m. hide conxetwiix sequences I -need from gfoupx ol raDtaci nion-wionG atiOboibe* As described herein, a Υοο*ν.π'ΌΧ w-quanee' ? rafow to .nmno ,uid sequences has mg eetwen ad untnte. aeics common nntone >* ntursber of seciucrees and wen-foie .-eu'-no ,« Q* that \ai\ nothin a given «ιη-οο a, -d xeqnene, * rise t DR consuls sequences tw ;ded include ('DID. corresponding to e.uh of f DR HL ('DRD2 CDRI I.Y ( DRi 1,( DRI 2 and ( DRI I in soil another aspect, an antigen binding protein includes the following axxochtbo.os of i0 CDRi LCDRI 2 .-aid CDRI Y SEQ ID MR- 42, LY and 4-Y SI Q ID MR 4 Y do and 4;

MtflLKfo 4h,o9 awibO S:-Q ID MR bl.M and 5,Y Si Q ID MK b4,;o ended. 51 Q ID MR 57. 5S, and 59; SEQ ID M'K 60, 55, and 5A SEQ ID M'K 45, M, and 4?; SEQ ID MK o2, ο Y and b4, St Q ID Mr 6Y 5\ and 50. SK) II) MR bo, X, and Ox, St-γ) ID M is M, 70. and 71;and SEQ ID MO.< 6‘Y Q\ and Q

In an addttfomi aspect,. an antigen feiitdiug protein .tochtdes tbs following: associations of (DRHI, CDRH.2 and (' DRHY SEQ ID M'R YY 7 Y and 75; SLQ ID MR 76, 9, and 'S, SI'Q ID MK 7‘\ XO, md Xj, SEQ ID MR Μ, M „nd S4. SVQ ID MK x? Xb. and XY SEQ ID NO*; SY YY and 90. SEQ ID MK: M 91. and M SLQ ID MR 92. M, and o..p μ-q id NO,s' 7o. 94 and ?X; SEQ ID W.K' 3, ⁷4, and 9<v, SEQ ID MX. 9?, ox, snd 99; _<nQ SEQ ID

MX .100, 10Land 102..

lit another ,>creeE an ttfogu' hntding protein include¹· the follow. mg association^ of CDRi L CDRi 2 and CDRi i with CDRE11, CDRI 12 and CDRII3; SEQ ID MR; 42. 43. and D wfoSi Q ID M?K ,Y ’!„ fod *,tQR)\Q^ m, K, end 1 - vnh SEQ IO Mr MX ano ~b X; Q ID MR 4X, W ,nd 50 wifo Si Q ID MR ⁷ Y X0. mid XK Si Q ID MK 51, M, and be wdh M Q ID Mr S2. x.Y ,t-td 54. SEQ ID Mk sa, my and be with SI Q ID MK. 5,\ xb, and x~, SI Q ID \<R 5 7, 65, and ^7<i w '0 Si Q ID \(R XX. fot ,_1}ί| ''Ό, xi Q ID M'R b0, 5b, and, .% with M Q ID MX SY So, and YY SLQ ID .MK -15, M. and 4? wdh SEQ ID MK D.O end K M'OIDMK · Y M end b < w Ύ SEQ ID M.R 9? η,,,Μ Q,XH?IDMK 45. 61, and 4⁷ with SLY) ID MR 76. ‘45, and M, SLQ ID MR 65, 55, and 56 with SEQ ID ?0 MR X: So, and E , XrQ ID MR 12, 4 Y md Id with SEQ ID MX ' Y Y .mJ ^<7Y XI Q ED MK o6, b~, and bS wdh XI Q ID SD* o\ o,y ,,.q qq SI J ? sD Sfo* b'Y ”0. mid ⁷i wn'h Sid? ID SQs; 100, I0L and *02, and SEQ ID N'Qs t-9 0. and 72 with SEQ ID MR: 100. iOL and E02.

2016244220 11 Oct 2016

Consensus sequences were dotermiuefr usin g standard, phyiogenip analyses of the CDBs cm responding w th; \ ·. and 'W ofatsn-CGRP R aiutboibe- 'Πιο roasen-a-' -eqaenc/s een, denen-ined by keeping the { DRs enmigunns v innn the sam·..- s--qsxP.ee -. orw-pondmg n? a V» or Vj,

As illustrated in Rigs. 5A. -B, b 3A, 3B, ?C, 3D and 5E, lineage analysis of s variety »n iheat-ngen Gnune· proteins pto\ vied he'em tesalted i*> eto-ap- ofichued sequence-, designs led as baht chum I DR group- k k kA Kd. end Re t 3 \ und 3B). bgln Uwe¹ DDR groups t I, t 2. 1 3. and I 4 ti nj 4 s. an·.! buoy eh-iin CDR guuipx HCl (big, ,5At, H€2 (fig.

5B s, IB' > t l· ig. ?< ) IK 4 i b\„ D '·, j Ii '> j*'$e 5D) and IK o D in >5·}, Some of the afro e proap-w, re used to genera:- aeditsona’ - om-ee-te- '-eqnene- s, as blu-moed m I ig- b-λ 3B, 4, and elb to v eld liglu chain CDR groups k 1,4 t E;g 3Ak kdD Bug. 53). .1.. 1,2,3 Dag. Ή, ami I 0- II i I ig 4 k and be:e, y t bain CDR groups I R A and1ICB ; Dp. %' i.

he eom<, nsu\ -eqnenee.s of the various CDR region groups are provided below: kiLs2toB.ID.RS

1.5 CDR I R XXQGiRXiDl G (St.Q ID \O BGk wherem X; i- selected from thegtoup consisting of X and K..

( DIM Χ- XSSI Q< tSPQ ID Xt t 104i, wm-rem X '- seb < led, iron, th-' group eou-t-ong of 4 and G

CDR a HYtS'XjSdAS Ϊ iSFQ ID X'G-10 D. wbetem X is-electee bom me group consisting oi : ami s, ,mcs X is -ekeied front the ero.ip eou-tsttug ί·Π and E,

B:iX.otoBnsus

CDR5 QD'vGSSLXiR (SEQ ID XO.Rlhi. whereat X_t is selected from the group lon-bintg of S and C

K. I. .4 Consensus

CDR 1 R XSQ.S X XDdGXo X, iSi Q ID XGiKCk whctcut Xi is selected from the giot'p χθη-s-tu'g of ^v .aid Cs X ts -clean'd boat die group etut-t-'ou> of \ and b X s--macted boot the group ecut astute of S and R. X; is set-rued bon: the group uon-tsttng ol S x ^td k.

X i-- seieu.-J from tue group ,οη-b-tlug of 4 nn-t D and X'„ e- -eM ted from the group -.ousixtetg of I and G

CD!'? X 4S>X ΧΆ, ist-t HD \O I(iSk obetetn \ w .-elected from the groep eon-Bhug of is mid Λ, X; is selected bom the etonp consisting <o R and l„ X -.s selected frem the ygoup constsfing’d X md Q, and X-, i- wleewd fiorn tlw group e>n-i<hug ol I md X

CDR > X Q4 X, X', X _tX' X X (SI G IG XD KG}, λ la, rem X' is selected tiom the gienn consisting >4 Q ,-md I, X' is -JcGed bom the mono censi-ong D G and X, X. t- sebeted fiont

2016244220 11 Oct 2016 dm group wnvdsni! ot X cd I X_; m s·. 'ced'd mm die group eonsisOng ot S, 3 a’>d Γ, κ selected ftont the croup conststiitg of f and P, X_c >s selected fimu the group c-on-wong of ('. \\ and x. end X ts selected I'uun the uronp consisting rd'R and Γ.

H) dm group consisting oils and K, X m sole, ted from the gtvt n xOttsO tun: os'F Dat'd X X to sek'tted from the croup couMsthte of Y, Is and K, Xj ss selected from the group con-u ante of X tnd Γ, and X- is selected trom die group eons'-sting oi D and 5 , ( DIC X'\ XXRXa <M (J ID XO 1 Ι?Λ vheteui \ is selected uom dsn gsoup vo-,tstirtg of I and r X - w se'ected from the eroar consists c of m and V, md X; is selected

I 5 irons the group consisting os A and F,

eoronduic af Λ md S< X' is sale- vd from we < I’-wp . onsistuig ro I e,d \ X is sale- ten Poet the group consisting ol R) .wd R, ,\. m •wfretut ftoiu that group eonswnw of t and 1,, and X nt selected t'rotn die group consisting of F and I .

( DR? R\ XQRRS iOtsD ID XO,111\ oisro;nt \ is seketed from shegroup consisting; of X and S

XOlogffias

CDR i S<iS\SXB LXA'X_s\ X «XFQ II) XD 11 sp wn-. om· X -s selected from the group consisting ot X and S X' is selected front the group cousjstntg of Y and I, ami ?<> is selected from the group consisting of S, X and 3 ( Died X \ X\ Rd's »\1 D ID XO 1 X g oik'.eet Y '« _ve .d dom di. group > oicsisong of D, t and R X- ^?s sele> ted oom die group consisting ot X and S. -rod X, is selected from the group consisting of R. and Qi

Ml CDR3 ,Χ;ΧΛ ΟΧ,.Χ.Ι Χ,Λ Y\ tSFQ ID XO : > Ό, vhe-e-n X o selected from the group < orousimg o*'G and ,X m si lech-d oom she group convOwu ol 1' and ,Xi is •selected from the group consisting' of W and Ifr AG fs selected front the group .consisting of S and D. X< is selected front tint ι,ιοηρ consmtunt of R and X. X. is selected from the group consisting of 5 and X, ami ,X- is selected irons the group consisting' oi A, ,_U-_K| q

2016244220 11 Oct 2016

Ab Consensus

CDRI X_;G,\ λΧΧ-Λ Χλ’ΧΛ,ΧκΧ. (SLQiDV* to. toc-ww X fssekeied lictii g et. i <,onss?a..m ο \ ,iiQ X ts > e.s,.nt or <Λ ’ nip s' i ® it. is X. A.. is sckt.n. tom rite vienp c<w«tst ng o*X nod D. X-, is ^resent or βρόΒ. and ri weseot. ts \ is .selected from the group consisting of I ,md ϊ, X. x selc'tcd from the group < eusisitng ot Q and Ik X· t- selected from rise gtoup eou-astuie of X ,wd S. X>, is sdecteel tom Ihe cumin consisting of X ,md k X.'ts sek-vtcd from she group von-astmg idV one k Y_f, ts selected from the ι ’.imp eons'sPng >>f V ,md Λ. and Xj is setcekd now tii,· yionn consisting ot S, X and \

H?K2 XiX XXdsPS >XkQ ID XO;I 19), wherein X; is selected from the group - o'enstrng ot D, <u T and R X 's s >ected how the ri.-onp O'i’\hni>a! X k .md \ and X» w selecied from the eroup consisting of k, X mid Q

CDRd ΧΑΛ ΟΧΛ-ΛΛ ΧΛΑ -,XI 0 ID XQ 13o), wberem X ts selected horn dm group consisting of G, X and, A. X; is selected fioni the group consisting of f, S ;md A. Xi k selected from the group consisting of Wand R, X?. is selected tom the group consisting of S at-ti D X' ;s ss. I>,t te i tow die monp t ons'si.ng of P, .aid k X, ts sale· 'ed Isom the group cpostsfine oft and V X- is s/lected Pom the gtoup consisting ot \ h end X, γ n, selected from the group cimsistnig of A, H and Cl and .¾ w Mdbcfed. from the group coosktmg of V and k,

Π( Ί konscnsns

CDRd. X > 5 MX {X| 1) H> XO; 121 ?, wherem X ts sdeeied isom th; gmup consisting of G and I \ X · is selc-.tcd t'tom the croup consisting of II nod > ,

C'DIk? V IX'PXSQGI'XYXQkrQG tSkQd Π> XO.122). w herein X_s is selected from the group consisting oi X and 3.

CDPM X \X SXtoXkvA.GXkM.X VAY.VbW tSI'Q ID XU 121). wkvtetn X ts setotcu tom me etot.p ,οη-ostmg ot'D one G, X w selected oom di. gsoup consume of 0 and <», X»ts sale,'ted tow die group cwisisung ot M and 5 , X, is seiet ted tom the mono conssstmg of 1 and 0,λ, is selected tom the group consisting pt t mid 5 . X, is selected Irom ♦he oap c n's's^,'!got M ' d A, X ts p csent w .to t mid fptes m 'sIQ, s wesem -u absent, and ti'psesew. ;s k, XX is selected tom the mono v onsssimg of \ end I . X-, is selected Irom to g'Onp consisting of if mid Y, X,_; is selected tom the croup consisting to P .md X. X< is sole* ted h<w the gtoup - ensmlBip ul P mid th and X -w rtesciu w absent. and ri present, o Y.

2016244220 11 Oct 2016

H( 3 Consensus

CDR2 KlkSX.IDQGTrOYX/APYKG (XkQ ID AOJ2U, wherein X₅ is selected irom h:-. group eonsminn; of R and T, and A- t\ selected From the group consisting yf T and A;

H£%£ldisensus ('Dk I A \X \1X« tSFQ ID AD I 35h wherom X m selected freto the group urostsiuip, of f and S. X,- is scie>, led hom the group eot'S-shng id 5 anti \, and XX ts selected iroro ik_v group eonsAtitte «>’ A .rod $

CDk? \JSX.SX A'-.XA, 5 X'ADSYku (SI'Q *«* AO ^>t. «hetero A, A sekxied fiom the uenp eow-ustuig' of 51 and \- ts seleefrd fiotn the group consisting m x and D. X.

Η) X- selected fiotn the group eo*isro>n$; of X ntd G, X , ts seks ted intro fee eroup > onstsiittg m'S attu G. X' is seioeled trout the group eeusxsteig <1 X spd R.. and X <\ sek eied *i>it« die viroip constMing of R and T.

t. DR) A- X X Λ Xs\, VID X\sX A\ 5 DV X 5 tAHb «Xi Q ID AD I2), u ne-c '., A.

Adeen d from the group eroisAtme oi h and D X. A seioeled fiom the group consisting nt G

1.5 atsi tfi. X - is st. kt io I from the group lensis'roig of X ami R. X_t ts sAwd Pont ihe group eonsAfine of x ,>nJ I-. \<t A selected fiom the group consisting pi C .rod V, A., is seketed from 'hs' <:ro,tp »ot v.-e, up ot X ,r\1 η, X w pte-e' o absent, ,etd O'presem, to e X_s's s Awd ; roe the group consisting id' I and S. ansi As ss selected from tits' group consisting- of S and G.

Co Consensus

CDR i SAXiMD iXkQ IG AO: I28i, wherein Xi ts selected item ihe group consisting of F and Y, ('Dis? VISA d'R ISA AY A.,X }DSv'kG «,81 :Q ID NO 1 29), w herero .\= ,s w. I acted from the group consisting ·Υ I- and X , \ > * -cleeied from the eroup eous.isi'ug of I and; I, X ? ts seketed Iron- dis' group consisting of S and X , and A, is sele>. ied horn ihe group consisting id

V and A.

UXIV A'PAA AA-A,SA-\A\XA _t xfDuXA. YtSf'QiD AD 1 .fit» e.fi.nem X is-«.leeros 'to n <tu ets'eo vonstsiip. «ΐ 3 aid I X e sJcsfre iron I'e gu-i. > _u< sedate of I ,-ubt R, X-, «s seR'cvd non- 'he group eonsis't u> ro A and R, \₁ k select,-a Oetn t:u group consistent, ot'X and s’, \, Is seketed from the gtot.p ,oiro-ansg of X' and 1, A,, is «.elected from dis' eroup serro-mnu of D rod M, A A selected from the group consisting of S and T._; Xx ts selectei! uotti die group consisting oi st amt I . X ts seicelesi Pont ihe group consisting «η 11 see X’, A , is present ot ihsetu rod <f press.ru, ts X , A m set etc A from dis' croup eom>is^Kug ot k and kA-, ts sek eied from the group esnsMsiiro of M a*ni I , md X m -eks'lt d from d«t group constating or A, and D.

2016244220 11 Oct 2016

DC A ..Corr'Crtcm

(.'Dili X-.X'.X M\j ί Si Q ID XO. HD, w herein Xi =-- -elected Dorn the group oon-fst m, of \ \’i,i fo \, j- >.e.le_sg.cc tr-om the group >„o'»Mst rt;, A, V «:<' 1 X-, w s 'eck'd item the mono coriMstmg ο* Ά , \ and G, and X, - selected, Don't the gomp consisting ol S and H<

CDR2 Xri\;.\-.X;.\ .X.iiX'X-WX-AuXi.X HX A'KG sXt CglD ΧΌ Hfgohesen X, ts selected from the group consisting ui R, A and Y, X> is sckxred frun? the uroun eon-.s-ring of K, S and \Y, ,X. is selected from the group -. ousisluig <n 5. < I, Γ and \ . X , is pre tern -.-s absent, end if present is selected from the gtutn) eon-wntg of X end I, X, is present it) or nhsnm, and if present, r- k -s -Reeled oom -he group consisting off) and S X is selected front the group consisting (it?ϊ end >, X. is -elected from the group eonwstmg of I, k. I. X ,md I I, X k selcxt.-d uom the group con-m-ong of T .mJ K, X_{ rs sek\t. d ftom fhe gionp eou-n-lme of D end Y„ X;; :-. -.elected doth foe group eonstsluig of V and S, Xde is selected from the ueup eon-nsimg u* { A and \ , X- -w -.elected from rite group ecm-nmne of A mid f) and X:: i- -elected Dorn the group cons-Ouigof l·' and S, t, DIH X X-\ X-X X, X-\ Χ.Χ,,Χ \.Λ -X X_tA-_t\ GX,-X VRbQb) \O H'g vHeier X sek\X'o-'rom the pr-ino ousiste'g o* D A trO Γ, X --.elect doom the group consisting ¢.-1 11, Q and G. X -, .ts selected ft uni the group eous-sung of b 11,1 , G ,md X X w s> X'eted non', die po'-np eonwstmg -u G =” X, 1 ,-np R, X. :- s 'eeied notu the gtoup consisf-ne ol \ V utkl \, X, :- --.elected notn th. group eonsi-tsng ofx. G, h , Λ .md b X- is selected from the nr-eup consisting of I, IX D, \ mid Μ. X, k present of nk-mf. and tfpreocm, is selected born the group ..ousisting of S turd V', X-: i- psc-senr ot rd-sent. and -f present- ts -exeted iron's she group eonoMing of W, X and '1', Xu- i-> -elected from she group sonshnlng of S, G ami 1,. X ., is s,-te>. led bom die pump >. ouso’ ng id S, G, L mid Y X - is m.-s-eul or absent, mid it present ,s set- cted from the mono „oii-istsug of Y ,-nrd Y, X- = -,\ set- cted from the group eoswr-rm., of λ an ID X, ₅ is present or nb.-nt, and u m.-senf, f-> select’d from t··. gtotm eon-ustmc of λ -md D, X :·> --.sleeted fiorn she group consomng of Y, k end ?·, ss present om-hs >' \ and o' p?' <- cut, η Y, V i is'vesent owd's ” s, one ' <-cm, ΗΛ, is s,-te> ted ts-nu the- group eonsimuigol'M and 1., :md Xp is sole, led horn the gmnp consisting of D ami \

H£>Consensus ( Dkl X- XfoXX.Xs tSEQ ID XO ; M), * itetstn X, ts selected horti ilk' sunup so^-nstutg of X, G, 1), S tstd A. X- k '-eicekd horn the group emiskhoe nf A r and \ , X, ssc’ei'ted fi'inu ths' group t-oiiM-nogof W- Y, λ md G. XX is selected Dorn the gi-onp cotisislmg nt \1 mid 1, and ts selected ftom ths' gioun -eou-rstnu of S η?Ή 11

2016244220 11 Oct 2016

1.5

2.5 ('DR? X t\ v\,\ k X ΚΛ.ΛΛ λ,Λ λ ΎΛΛ -GtStYJIOXo AM ά herein \, s- -eieeu.d from th*. group eon-si/tom of K, Μ, \ , 3 and t·, X - is seieeted from die group eem-mume, of k. V S, \V and R, ’<. is Ss-ieetod fiom the g?uttp eonsistingiat' X, P< u. I and MX-1-' pre-em ot absent. mid if ptesctii. ts selected horn the gioup eomusttug ofk, 1 and P, X G prowni or tMeot, md fi' present, is sGeeted oom the group consisting oi Γ nnd Λ._: X,_:, t- srDet>„d fiom tbs g,toup> eon-usimg of D, V Π. 3 and Y, XX is sek\ tod lioni the romp consisting ot'G ,md S, X,- is selected from ilk' group con-dsbng of (i and Μ X·, is seleeigd from the semip t'emwong ol i. G, R, k k. II and Y. k-- m -<>. look'd sunn fi«e gtoup omi\tomv a; |\ k R and P, X is sekued fiom the gtoup consisting of D. \, \ and S, kt > is ejected item the pro > onsisiir ; «o'5 ano s X \Ο'> Α'Άόό tbo group i eno,<'p eH < \ ed \ X , u selected front the pro-ιρ consisting <^5f A 0 mid D \o is sedeeted fonn the c mtm consisting nt P, R mid S. X_!t, is selected from the group consisting of V and P, and X_; is v k'eted Pom Hie oionp ,o'iMstim_ o*'K and Q

CDR3 k,V\A₍\ S\,XΧΛ k X, \ \,Λ',\ M,G\ kA (kHAp kt ^! 1 fig, A- it m \ -a seim tot fiom the oiontq , onwring of 1>, G, A toad l· k - ;\ sekt tod from the group consisting of R, 0 and Q. M, is Aeeted Irom fix group consisting of'f, kt Y, R, I , G and k, X, is selected from the group „ oust stint.· of to 3 Γ, k, 1 and R, k- is selected from the mono eomwonr of d , I, G, \ anti \, X,- is seketeu from the co-up con-astntg <o S, 1 \ G, k nnd T, X sⁱ- eject., d fiem the gtoup co wwtmg off Μ, X, P .mJ f), X is pi -sent oi absent mid if present, is seh „ted front the mono conststnia of S, i and \ , ?k is pu/cut ot absent mid if present, ;s selected fsom the group consisting of V, P, X and f. k_;, is selected from the gtotop eonsisptn of S. m out’ i , k is selected tioni m, g?oup vOtisistmg o^! 3, \ t,

G ;md Y, X,_? is picsent or absent, and of present, is selected iron· the group consisting <' f, Y and W, X. is Aeeiml irom the group cons-Gmg of 1 , P, k and i 1, X ₅ 5s present ot absent, and tf pio-seng is selected iron) the gfoun consisting ol S P, D and Ik X·- is sclcck\i horn the group xonsisting of 3 , k and P, Xg, is ptesem or apsem. and d present, is Y X; is pieseni or absent, end fi pr; Kin, is 5', mid Xi t- -eteeted fiom die moitp emis^n;^ of \f _Λη<ί I., l·'! some ea-es the .mtigen !nndmg profem eomnrtses ai least one hews > ham ( OR g (DR2, m < DR ^; has uig one of the aho\ e <, mtsowns sequences in ‘-mmc eases, the antigen binding protein comprises at Das? one light Utam GDR1, ('DR.2, or GDR3 having one of the a.bo\ e -, onsensns sequences In ofig-r eases, the emmet; binding ptoiem composes at least m o h.ep.··> chain ί DRs .le-.ordirm to fin ehcoc eons.-tii-us .soqig-rmes, and <»r u leasi u\o figin eh on GDPs ai-eofdtng to ihc above consensus sequences In soil other casus, die antigen binding

2016244220 11 Oct 2016 pmiuin cnntprises at least three heavy chain CDRs according io the above eonsensus sequences, and/or at bast three light chain CD Rs according to the above consensus sequences,

Xceotdtug to one aspect, pso.tded -> an :«riesed utmeen-bindinu ptoiem that bind-»

CORP P enntpristna t 'D one os more hems chain eomptem.-mary determining r-.-eion< ( DR! Bs vriected isow rise group eonststt’.g o! r l -, ϊ Ί SRDI ss‘eeD.1 now rhe gaoup eonsbhnv ofSbQ ID \O b Ά D a.\ 33, s>- 93, 9'\ and 106' tli) _x! CDRH2 selected iron! the sg.wtp i-on.s-.simg ol SbQ ID \O 4. p). So, o|, ·?>, O\ o\, I*)l. „naS I fob not=.-, < 'PRlle selected front th. gtoup eonswtwg of M w ID XO '5, >, s , h-h S \ R>. ‘u , on, s{;~, <md I 33; ,ntd t <\ > a CORP, of Ok to t and yb) the coniwn-, one <w more, c g , one two, three.

Run· or snore amino acid substitutions, deletions or insert on - ol no more than live, ionr, three, four, r.iP or ot:-.- nswno acids, t fit one or mow beta eli:>su eomph.-meni:o-\ duermming regions (CORLs) seiCsted bout She g-onp -..oo.sisStng ot, ti) a CDRLI -elected S'tow tit-,, group connstmg of 5FQ ID \t t-43, 15 1g, s|, S t, >?, iC (fo, np, and i»9; yri a CDRI,? selc, ted

1.5 from S'<, group -. os costingot SFO ID XO'4b 4e, 49, 52, 55, 58« 61,63, 67, and XI n.is a ί DK1 ? ^elected from the group consi-rtine o-'SI-Q ID SO 11, -1 ’, 56 ?b 5^l! ol, oS, I, mo ” ', ,wd S ο I a V DPI of y s, -;-1'> and t nri dnn tout wss one or mote e o , one. tv.n, tDe>,. font or more ammo u-„id sue-Citutsoms. deletion- ot insertions of no -note than five, fonr, ht-ec, trim two or one umtiio <n ids, os t<''»one or more heavy bum CDRlXofi \ t and one os more heist cl,w' t Owl s «4 IBt bt\,-’ motu,-i cmhodnn,-m, the t nhrtod mi-gen bmdetg pom.-sr mm comprises Ό i DPR! I seleemd oom She gsoup consisting of y 5 =-, < '1 Hill I ‘-eieeted, ftom *he group cowi-lmo

ano : 23, t its a CDRI sole- ten worn tv wwtp - ose-wmsg oi ;ri v ( PR! ί -elected ftom fin-

.-el t ted from site git»op {.onMstnig of^l Q IS') a >, 4o, |o, 53. 5?\ ^JD, o k o⁵< _t>~ m-l f>.

os, , .md or R'l one or mow- Ka\y eh,>m f DRIP of i \ ? and one vr more 1 iebt chain CDRI s ot t B) ft ow. enihpdm.ivi!'. She i-eDted euStgen-btndtng psotem m e, tnehide t A) a

2016244220 11 Oct 2016 m .. and <<9, a f DRi ? tit SFQ ID NO 4? -b, 49, % 5\ ® fit o5, %, and '’m and a ( DID I ot SEQ ID NO-44,4% %t, >?, ?p, 59, »'<4, Oh, ”1, and 2 tn another enibsriniu.in. the heavy ehaf'n variable region 1 V_i:) has at least “Tr’n, 611%. Ν5%, 90”,., ’>5%, 97% or 99% -equene- tdctthty with an armno arid sequence selected from the group xowustnig u^f’ SEQ ip \Q 1 .% I 0. under the V, hn<,;dkasi Ο”,·. '5% x0'S>. χ%·<, 90%. **'%, 9' m t)% v ι-ηα.-, ,- aV-tittty wph an atmno aud seqceneo selected aunt the group consisting of $LQ ID NO: 13 · 153 In a rnnhei embodiment, the is selected from the etonp - o'!-i,\ting,ot Si Q ll ϊ Nt⁴ 1 'S-mO, and tn the \ ts sek\ ted u<»m the tjonp . onsist-ng of SEQ ID \D. 137-153.

in another asport, also provided is an isolated antigen bmdmg protein that specifically bntds ni a,5 epdop- lormccl of ant-tie uctd te-odino. item both th.- ( Rl R and R.\MPi components ofthe CGP.P R

Io \er .motiiei embodiment, rhe (sol g.-d „,schocn bn.rin.tg protein desetid', d hvrem eiose comprises a te ammo acid sequence .comprising ar least one of the. CURB consensus

I sequences th-elused herein, and i sc-ottd anutte ucnl *<: qtietn, ,- umiptwrog at least on-. of the ( DRL con-ettsu*, swat-axes disclosed netem In one e*>pe„r, the fnv emut·? aeri -cqurttse composes nt lea-f mo of the t DRH ennserssis sequen,es. and or the se,ond anunt» acid ’u.ip,\hc- CiOiptf-es at i.-ast t\-e ot the < DID conseusas wdvxnees.

hi certain oinbodmsents, the hr,a and the second ammo aetd sequent e are eox -dentb.

2Θ bonded to each, other lit a ktrthei embodiment, the first mwno arid sequence of die isolated antigen bntdotg prot.-m unhides the C'DRim of M Q ID NO ’5, -Sril.Mri'’ 00, 9o, oa, 102, and 123, CORK? o? SEQ ii) \o Ί, ' O3%5 so. 39, ^UR 9% ^1>N Idt,-md 129, and VDRHl-o'

Nl Q ID NO ~k ~f>, Ί, \2, be. %, 'C, <-% and 100. and o* the second aitttno ,« »d sequetad of the isolated anogers binding ptotem compose*, the ί OKI 3 of SER) lO NO ad, 47, so, >5, go, so, n4, oS, ~ 1, and ~2, Ci )R I 5 of Si Q ID \Q- 45, *b>, 49, %, 55, ?S, p 1, 0 R o~. and 70, and CDRLI of SEQ ID NO 45. -1.5, 4s, 5 1, 5a, 57. tri. be, ob. and od.

In 1 thrthiT emhodioii,to, the umtgen boridwe protein comprise»* at hstst txxo CDRlt sequences of heus y chain sequences ill, 112, ID, 114. H 5, i IP, ΕΓ. HN t P, 11 IO, 111 k Η12, or

3») 11:5, a<* ^hown in I able 4Λ in ac.nn a fuuher embod-roem. the antigen binding protent compose-* at least twoCDKI ^etuiem a*·of itsDP einun, seqncmcs I >. I 5.1 R I 4, 1 R 1 b, I %

Lb, I ”, I in, 111,1 17. I 13,1 El, I ie, 1 Η», or 1 1 , as shown ro kihk- ?B bt scam a furthet mi tn at new ,h, a \ go, et \h o p o,est eonp.s,* ts ,~u<a »wo t DRU s, qu, mes ot ua, , eLtro sequences Hl, D2. H3.D4, H5, Π0.112 I IN 1|9,1110, Di I, ItC.oi 1115, .is shown ttt

2016244220 11 Oct 2016

Talk 54 , aid at R'.uti twit ('DRI s of I n’lt' ekon sequen.es I R 1 R 1 5. I 4, I - I o, 1 ) 4 LA t in. 1 i R LI 2.1.. 15. I, 14,1.15. 1.16. or I I / as shou n in Table 5 8.

In iiatn nnniber enthodtnKni. the antigen lending protein tcmprHe*· the CQ811R ('DRII2, and ('DRIB sequences of heavy ehatu sequences HR H2 lie H4, 115. Ho, IB, IB,

IB, HIO, Hl I. Hi.?, or Hie. as shnun tn Fable 54 In \e> another embodiment, the antigen binding protein eoitsprtses ihe (DPI. I. ( DP I 3. etui DDRL3 sequences ;g tight chant sequences LR L2„ U. td. LB. 1,6, 1,7, IX I »> I 10, HR LI?, 1.15. 1.1 R L15, Lin, or L1 ?, ,«s .stem ti tit Table 5 IT.

ti· »et Otinhei e in hod intent., -'he ^fttieen lond.ng pi«nuu u-itipiises all sj\ t 'PE- of I I and HR or 1,2. and 112, or 1,.1 and I l.R or 1,4 and 114, o< I 5 and Π5, ο¹’ I b nt id HR or I ? and H6, or Lb nnd H5, or 1,9 and .Η 1, or 1.. 10 and H ?, of L11 and ΐ IS, ot I,12 and H9, or 1,12 and H IO, or id 3 and HS, or 1.14 and Hi I, or I, IS and II12, orLIeeetd HRRortl/ nndHId.as damn in fables 5Λ and Mi

Table SA - Hew plan Heap (bain Arnmn Add Sequence Regions

o	o > Jp $x *** 23 1 £ u o	>r a s ύ«ά : 1 s £ 8S	49, sx ££ 2S 'SX O ¢0 £ ax m O ί „ sx §5 ® 1 1	Rt 0 'ϊΤ > S3 ,B O‘ m IM as CO O e f 1	0 0 0 na ϋ o 0	0 s O m 0 3ε 0 0	0 s O' UJ w &£ 0 0
LE11	: HI	29	%f	158	73	74	75
1H7	H2	30	Vn2	139	70	77	73
2E7	H3	31	VnS	0 <0	79	SQ	81
388	K4	32	Vu4	101	32	83	84
3C8	HS	33	VhS	102	85	80	87
4E4	HL	29	Vnl	153	73	74
4H6	HO	34	Vq6	163	08	I ®r	dO
5FS	HS	33	Vi,5	102	86	88	87
904	Hl	29	VhI	ISO	73	74	75
9F5	H7	35	VRR R	164	70	91	78
10E4	H8	30	Vh8	165	92	93	94

2016244220 11 Oct 2016

S3 «> <3$ £>£	CS O §2 40 sx **· X Ή S ti- O	CCS XX o >> o *$ ΊΣ tS - o £	S c ex $3 s£ O	Jg 1 i a «§ 0 x eo *s ,S «1 xs w <s ”fc -XroC XoX-	o ?jwd o O' tu « H o o	o a I o o	o s Q O
non	R0	37	VuS	166	76	05	78
11H9	H10	38	7,00	167	78	95	78
125:8	RS	33	Vt-d	162	85	86	87
i?G8	R11	39	Vdl	188	73	/4	98
13H2	R12	40	Vi-02	160	07	08	09
32H7	H13	41	VMS	170	WO	10T	102
32H7 CS	H13	41	7,03	170	100	101	102
32H8			Vh1.4	171
33B8			:'%B·	172
33E4			7-16	173
34E3			7.-:17	174

Table SB -- LxwKphtn Light Chain Askss Add Sequence Beghins

1 <3? 45	ex XX U .-*M( XX „.i X 2xs si O	’ex XX 2 o ix O «S — x: O s£ IH	X o ISs x x KjS UT XX X Λ iX S 1 I u > o	X ’3) 1 si g 5 i a '§ o 1 1 i	o o o tu w> »*** .X ££ O O	o *ej»: a o tu o 3 o o	o **3»: <sS3 a o w ο xs .X ££ O O
tin	Li	12	VlI	137	42	43	44 *T*t
4H7	L2	13	V\2	138	48	46	47
2£7	L3	14	V=3	130	48	49	50
386	L4	15	Vi4	14Q	51	.52	53
3C8	IS	16	V=.5	141	64 \y?	55	56

8b

2016244220 11 Oct 2016

	g o 77 gg £X S5S: £> s2 δ	g 'S 2 O Ή S U, £»	» (g $§f δ i I § s ,S? ys ,¾ ™r > O	1 f § « Έ S 3s, § a > «5	O o a na Si Si £3 tt	s gg*f ο «3 Tj	a jgg gs a s? rv «a si o o
4B	Lb	17	VǤ	142	42	43	44
4H6	L7	16	V«7	143	57	58	59
6F5	1.8	19	V«3	144	80	55	56
904	L9	20	Yl9	146	42	43	44
9FS	L10	21	V«1Q	148	46	61	47
10E4	LH	22	V,1i	147	a	63	64
11011	112	23	VJ2	148	45	51	47
11H9	1,.12	23	V:12	148	45	81	47
12E8	L13	24	V«13	149	88	55	68
12G8	U4	25	V«.14	'V	42	45	44
13H2	115	26	64.15	'01	56	57	88
W	Lie	2?	W	152	89	70	71
82H7CS	LIT	28		156	69	70	72
32H8			Yds	154
33B5			V:19	155
33E4			7,20	158
34E3			Vl21	157

to one u'ipeei. the woktcd antigen-binding pn'neuts pwoukd herein etet be a «nonoehm.il antibody, a pe'selona! antibody, a oxombhiant antibody, «> human antibody, a 'iif'd’u .1 >r,nhoes a ,a ,un ..ut'bod, a t».ih en . fs. ,rh'w k o ar , to iu iv art uer button»* fruunxm that eot

2016244220 11 Oct 2016 in another embodiment. the antibody fragment of the isolated anti gen-bindi ng protents pi'ovided: herd» can tea Fai? fragment, a Fab’ fragment, .an F(·sb% fragment, an W fragment a, dt.ibtftly, or a -nude ahaiu antibody molecule

In a turth/r embodiment,me isolated antieen hmdme p-meta provided harem vs» human 5 antibodv and v-ut be of the iuG 1 ·, IgGN IgG?· or teG-f fypc hi another embodiment the antigen binding protein consists of a just a hght or a heavy chain polypeptide a·, set forth m 1 wbles > A 5B hi some uvibodinivnis, the anneen binding ptoieuf consists tu η *tl a h-ns chum v.nnhie ot he -e,v eh on v '-.rtahh· domain Mich as fiso-, hd.-d in Tables 5 AM B, Suda antigen bmdmg ptotgins can he pegy fated with one or more PEG !0 molecules.

in -, el .ntudk'i top*. a. the i-aUat- d .uttigen-nindme protein p-tovtded harem, east be coupled to u labeling group and t in -, ompete for binding to the eAtaeeHuinr portion oi'lmman i GRP R with an antigen btndunj protein of one of the isolated antigen-binding proteins prov tded beteirt. fit one embodiment, the isolated antigen binding protein pre-, hied herein can reduce monocyte eiiemomsfe,. inhibit monocyte migration into tumors on Inhibit accmainlabon and function of tumor associated: macrophage in a tumor when administered to a patient.

As. will be appreciated by those in die art, fer any antigen binding protein with mote than one < OR from the depleted sequence-'·,, any cooibiniUionoiCORa independently selected bent the rii-pn t.-J ' mw'¹- es is oswid 1 hns, antigen bmrimt. protons wuh m<„\ two >b ee lout, five or m\ of tadependent;', selected < DIG tan ne generated Howe'er, as will b?

ipmeeiated hv tnos.- m the ar„ spe-Jtie emood wenm u/'v-raib atthee vombtnanuns ol GPRs that arc non-iepetitive, eg., antigen binding proteins are generally not made with two CI3RH2 regions, etc.

Sonic oM-tc antigen binding pjotents powided are dt-etisst-d nt more defat* below ~5 AsMd*...Bi.tidi.t:uyifrpi.e.tns \ttd Bmditm. Epitopes apd Bmdmg tMtnams \\ hen <m wiPgen h-orim-e mutem i-> wed to bwd m .-pUope, sit·,-;: ts one o¹ bods vontpotu.ds ot r * jRP is, o; dw estnue'.h. dot ta n oft >'jAP is, ;o: ee.utsp e, wa e »s means ts that the antigen hmdofg profotn speeitu tliy binds to << specified portion of CGRP R, which may be on < 'Ri R, RAMER ot spun pm dons of bods CPJ.R mid R vMP I te ea-es vefrete the antigen binding protein binds only GA1 R Rmd nor R \MP1}, the unugvn binding protein would not be expected t<»' <.< m, P- bind ( <IRP R boe.iuso < Ri R *- -ft -u-, ri, ,o,n,- -ten, wuh Mi 1 awl

AM i receptors ri n Jut y m < aw*- 'hew? the antigen etndiny protem mnris only RAMPl tend not l ri-M R j, tl _t .ottuyos* binding 'w-W-nt* noted M't Cspect.-d to Ά, no A h nd GtoP.P P beeau-e RAMP; n; mui'*. d, uttet aln-., with ΑΛ5ΥΙ feeeptor. In Cuses whetethe .mtigcn hmrimi.

8R

2016244220 11 Oct 2016 p«o -- m ticn-eio w ith boY ί RI R ., id R XMR the <i!^,!i;er bn-tiny pto'em s eweefeti bind testtiues or sequene*, s id residues, es semens m boils (RI.R and R -XMP: In tu>sie of the foregoing embodo-:01¼ ts ,m antigen binding ptoiem m peeted io eonmet -. ι·;;ϊ residue w sthut f'RLR or RAXIRi Similarly, not every -.00100 acid substsmit-iis nr deletion wdnin < RI.R

RAMP I or the extracellular domains thereof is expected to OgmficuHtiy affect bitiditig affini ty ,

XIei ·η Is oetuneti e g 1 I \a»rp e ' “, may I e -ts.-o -o as- os 0 AU eg u\s n' tmtidmefic meeptots., snob as GOR.P R, may be involved tn binding to selected antigen binding: ptoteuts bAWgiiita.Ani.igcn.Binding pttgejns

In auothet <isn-o 1, ammon Priding psotesu*- are poo ttie.1 Ysi cotnne-'x- wnb <me of die escinpHded, os ''reierenee' mit-bodrss or tutieut-siai isagniwt'-bti-dii-g uo the cpnone dews shed above I-,'! spo, ?fie bnutim to CtsRA R Sneh «nnpeu btnd'ng mote:·» 0 <sy nko On-i to Y, same epitope as one ofthe herons exemplified antigen binding ptoiem.x, or an oxcrhsppmg epitope. Antigen binding protema and fragments that compete utY or hind to the same epitope as the exompitfed or reference antigen tedding proteins ate expected to show similar functional, properties. The exemplified antigen binding proteins and fragments include those with te- oe.iry and tsghl ehasw, v ante-te regOs? doo-ams \ k\- 1“ md V₍:l· X A anti GIRO tneh-akti tst iables 2Λ, 2B. 3. AN. -113, 5,X and 5B. thus, as a specific «.sample. bhe an'tgcsi teii-isnp proteins fh n .«o’ prowled m-ehtec those dial compete wsY .-at ,-ηΐΟοΑ basmg «a s ail 0 of die f'DRs issted fot an antibody Ikud tn Ί nbles 3Λ end ,>B. tbi a X',_t and a X', se'.e> ted bom X I X , 1 ',- id \'i I X 05 end feted tor an entibodv 'swd -n fed-, s \ ,;₅d TA ot sc) two light t'hauts and ’wu ti-, a-y chains a.-- '-pe-. -tied hu at- at-itbo.ly hated in fabies ·’ X anti ?B Other examples o^x'suitable teterenee antibodies meh tie Yose that have a heavy knits variable region basing a sequence . otregumteng its any ofthe sequences identified as Q ID

Ni) If-N-1 ⁷U ,utd a heist chasn -.arsabuc teinett hav tug a wquettee t-otte'-ponding to any ofthe sem·¹ tn es -demoted a-< St Q ΙΠ NO 5 0] sy sAndnu. eoo'ei-j.uos' me e x e-sCs „.d, fet csaum,-., tosne a bts'S'-.ur as-av s s, eh a- the Ιμ<«.ογ v 1 <· ϊ co, I, or < « ow Ο n t ox ηρ ν ’ ί d>oO es I ee> be’o wen.: tested against each te m\ ' referen-.e antibodies — five nestnah/mg ntmfiodies sj ΐ Ol 1, 3i3fe ti 1 Os tnd * <1- o j a nd one non neutral' .'mg ant tin Os OOI 30 The assay tesulte, sho·- n in k-. he I \ indicate t!\,t a I ofek teste I tientmN ' w aut-b-sl e«II O J11 \?b 'jBo„fes-A'-h ΙΗο,ΟΥΟΟΤΟΟ,ΜΙ' 5011,0 0010 b. I ?Gfe I Ml? aiO 320'1 i'nst tti vsst utadb, the same region of < GRP R, otiii, h ,,, OiMinct ftsno the legion td t 'GRP R, tn,U s-bound bv the ison-ttetmOi/me inihbodtes tested (3205, 33B5,33E4 and .Mho). Bitted on these

2016244220 11 Oct 2016 data, any of the mmti.iti/mg anulmdim· would mate evemplary n.-fereoen antigen bunting proteins nt a competition ussm, particularly any of the neutralizing antibodies that vv/re immobilized m the tssay d.-serdvO m ksampl· 7 — I I ί> 11, efiw 41 R>, I A l\ and 9Γ' 'he »r men υ di e ptok'rs h ¹ me» ded »< twe non c v> f ! ft bodies 1 n m d to CGRP R. Monoeional antibodies nu\ he produced using any rechmque known u ihe ad, e.g ., by hnmordbzing spleen celU harvested from the ti'>in.*genh; mmui she’' completion of the imr.mnv u-on cchctieie 1 he *gti,en »ells can re immveti.ibze»'! using any let hmm, known m the «rti e <;, b\ fuun^, them we'h .nselnn,, cells to pu<dnee heet'demac \b dome cells Sos use in hybridoma-probe» mg tuGon pto * dimes preferably are tion*,muho>iy~proJucmn., nave high fusion efficiency and ·. nzv me dm „ e e-e*. that tendet them «neapahk of growing nt certain selective, media which sagpoti the gro wth of only the desired (bsed col ly (hybridofw;) , Example* of smtahie eel; hues tot use in mots** fu-aotis in-, hole Ορ-20, P >-\ot Xp\ p >-Xo V Vgh omk \\I i Ac 1 1, s_r? |ti \_u| t, ft ), \RO I , MIX 1 k MPC 11Λ le G I'G I, ? end

SP.M'5X\O Link examples of call tines used in rat fusions include R2 ^;0 P.CS k Yd-An I 2 A IR'-’kei ..id IR?10 Ornes cef hue-» awtid for cell Os.on* am I. 2eo. k-MleOd GRG2,1 ICR 1 OVHMy? and I ( .y,» ~>_x>, οχροη y method of prepsong monot hmai antiho»ti.’* r, dexer-oed nt I xample 2. eeioo, hi sonic uisi.ine-,Λ, ,j hybridoma cell tine Is produced by immunizing an animal (e,g , a transgenic anmnd hax mg human nnnumogiobuhn sequences! ο-th a CGRP R immunogen, hatvestmg ,*pk\-n cells frotn the tttumumecd annual, fuxmg the harx vied spleen cells to a inv'biina e>, ti tine, theieby w neurone by rndmna e«. tis, ».ssabn*hmg hybrnloma cell lines from the hybridoma cells, and identify mg a nybrtdema eed hnc that produces att antibody that binds ( t »RP I* i. ,g , a* des< t'lhed m I xamph-c 1 - k below ) Sn>. h 'm hodotms cel- bus's. and mti25 ( GRP R monoclonal antibodies meduccd by them, me aspects ot the pscsent application

Mono» Iona? antibodies seeiefed by λ hyO'idoma - eh Hue *an be purified u*mg any technique known m the art 1 hzbitdoma*. or m Ve* may be further screened to identity mAbs xv itti parti» tiO. ptope r>, v voh is iht Vnti'y \> hum t elk* >, '.pmvam» t GPP eetiuv to I k\ k m mtisfe.e the banding· of the CGRP l-_t mdoi CGRP,»- peptide, ui rtte aluhC to finsemuniPy ?d block the re-.emoi e u using a e.\MR ,.-»sav> e g . a- desvabed hetiwy .ίΐ11Μ2α2.4Ι.1.ί.Ι:1ϊί.Ρ'4ίΐ .4Antibodies

Chlmeoe md htiniuuh'Cci antibodies based upon the foregoing sequences art also piovtded Moimeloual antibodies for use as therapenth. agem* may be modified in various xvay.s prior to use. One example is u chimeric antibody, winch is an antibody composed of

2016244220 11 Oct 2016 gem. segmenbi from different antibodies that arc covalently joined. fo protiiw ftwenoi»<j.1 immum<gh-buhu toiu o- heavy ehams or immuiOloeieadly bmeoowfi pontons foueof ikrseraliy, n portion of the Heavy chain an J or !η:ηΐ eh,tin is ifotmeai w-tii or homologous to a vorrespondfog sequence· m antibodies dersv eti from a pameular specie,'·; or belonging io a ?< is-mecDi antibody J tss or sub.,lass, while the i roairtiei of t te eh,-m(si is ue identic si v 'tb ot h-ww-foigoe-, m a cmicspot mi y u artfio i *- iV-ov,-e bo n «notin', specm-et belonging to another aimbodv das-, <n -ubeia-s I ot methods r dating -e ehnnene -on fo, tot „-.->, v _t, foi evareph , i riled Suites Patvul No 4,Slm'ti~, -,n-l vloirison w to,, ί tit-5, Pro,?. YM ό a / Ow . 5 ? to idol ιλ5^λ. winch are aerebv nicr-rnoraud by 'cleience v DR giaiimg ', i(t -b-er-md fm m-ample nfo nneti Slates P item No b.ISfod^O, No Yem ΥΎ-,Ν No Υ·'··Μ ?<.!_v No. .\5fo\0fofo and No ffodti. Itii

1' jcneiaiiv, die go η o·' orfoing a ·. lumen- nntibo-.b. is io > reau- a chmteux tit which the number of atmno at id-, ftom tin, mt,.n,i-„d, patient xpoe-.χ is tnasninred One example is die ί '1 iRwrufieti'' amfootiy m which the antibody comprises one or mom eomplemenmrhv

1.5 dem-mmimg rt moux tCDR-j foots a puiltenUi spin les m belonging to a purtii ul--a antibody ehe-xe-s wibelu-o. while ''he remainder of the antibody ebampst is am identiu’i v- 'tb or homofogous to a corresponding sequence in antibodies derived trom. another species or balmwnw to another uultbod'-. eki-,χ or subclass, rot u-e m tinmans, -he variable legion or .wo eied ί'DRs ftom ,-. rodent embody often ate gmtieti mto ., hum -n ammo,·/, repi -.cun: the mmimllv -oeearrmg variable region-, or C 'DRs of the human antibody.

One useful b,pe of .ntrneuc a ufoed) t- a ’uur.atueed antibody Gene'- til'·,, a hutnam, ,.ti anntimb :-· produced ftom ·, monoclonal antibody mixed h-tiiulSv in a non-human animal ί ertam ammo acid residue- in tlu-; monoclonal antibody, typically from non-antigen efouiu/mg pomoitsoi the mmbetiy. -ex. modified to be homologous to eonesiiotulitig luxidu&r nt a bum,m antibody of ecu responding u-oippc Humani/aitr-n can In performed, lor ew-.ntpD, u-tittg vauoa-; methods by substituting at lets! a portion ol a witieni vert,tide iegmn tin the voricxpondmg tenons ,4 s human antibody gu. e.g 1 'ruled Males P.nem No. .'..NAib-i, and No 5,0 D,⁷o?, Jones , · 4 i4Xo to:-*', jj, 5''-'’? Y Riee'^}uvnnn < /to, DK to?. toY?~, ve'hoey.-.,7o', ifofo.

In one aspect, foe ( DRs of th.„ light and heav y eh,tin y oi.fole melons or the antibodies provided hemirt Gee, fable 4} _;ue eiafled lo ti-miewofo legions {ΓΒ-t fomi antibodies born the same, or a different. phylogenetic species I'or example, the CDRs of the heavy and light chain vntnmle region^ \'_Hi, Y--.2, Y|;d, Υ,Η, V jf'- 5 -fo- Ytw V:jK, \ fob \hjlti, Yfo i, Yfoto. and v sid, and or Y I, \ _{d, v Y Y -I, V, 5, v m Y, , V, 5, \ ·. fo V, 10, \ , 11, v . i2. Y to, \ · id.

2016244220 11 Oct 2016

V« I5, Y: I b. and V, I ex, ba grafted to conwtMh human F'Fl· I'o exmc romxnso·., 1,uniats 1 it·-, bHs horn -xx- ml human bens, chant <« debt chain unnro acid sequences max be aligned to «damns a consensus ,-,«nmo actj sequence hi otoet embodiments. the F 11·· of t m-av, ehiin or light chain disclosed herein are replaced ouh the I Fl· fiom a d tin. ten I haaxx chant os light team. to one ,nqx\u rare amino ;«mds in the kte of she bvaxy and light chains of autif GRP R antibody are are replaced, while the icst of ihe IR ammo acids are replaced. Λ 'hare amino acid is a. specific amino acid that is in a position In which this particular amino acid is not usually touud m «n t'R Ahetnatixely, Ihe gsafied s unable regions from die one heavy m light, eham mas he u--»„d odh a concern region mas dtikiuu stout too constant reemn <n {»,,«

Kt p rfseei a bans \ m right ; bam as dx- 'os>. d bexw b« vibe . mbodmxms, toe _; r.dtod sar ab«a regions arc part of a .single eham Iv antibods·.

In · at mi s« embodimentx aerv mt legion- t'rmn sp , ms ehiv than unman x'nt ba used along o tilt the hun-aii ,,u t tola ieg imps? x prodsta·,. hx brid antibodies BdiYlkRUarLAnimodjes

1.5 « ntlx inuiu*' a«mhodics ,na also pioxided Methods ,n,a ι«χ,η!α1·χ io? making lull·, bum in utrimodtes spee«fu tm a given arrtgen xsifbont esrovt-c bt«man hemes to the anngm fWliy tertian antibodies’'). One specific tnecna presided for teplemenfing die production of fulls human antibodies ?-> the '‘homant/aiton’' of the mouse humoral Immune wtoem. Inmsdnebon o'hum ut uvmmoglobt'b «tig's ha i uno mice «η >\h\h tin,- endogenous lc genes have been maefivated is one means of producing fully human monoetonai antibodies (oiAhs) in mo»<x, an <m;m,«i dial can be immumced xsito any desirable antigen, FRing fully human ar i io I -ia rirr < t, r ttao^en .use ahxgie msponxs ri,at « χί>ι, owes a, v a-v to. adminiOeimg mouse or moose derived p'«-\bs to human-, ,r- tbempenite agents.

I mix bum,r« ato-bodies a n« ba puxhned «v «mmnm,· sug- iiansgeme ummalx (usually mice) tow are capable of producing a repertoee of human anfibodies in the absence ol erdogcrou-, ii'intunocRsb'-hn piodtu non Avti. e <, bn tots οηιρο,χ ixpteabx Ko a six ot mom contiguous ammo acids, and optionally toe conjugated to a carrier, such as a hapten, ,s-v _t ,y., jnkobevus :2,W93, Pr.i< Yam -her Me i'.Y-t tot ,M51 -25? Y Xiksibov ns .7 m.. 190.1. :Ypii.'.’'i np2-,25.5-258. and Bmggerm-nui c/u/, 199a, terImmunol. 7 53. In one example of ?0 SUM. t method iruux.pxia antotaks ,na produced to mcapw,.· taring tbs' auifeeamats rro,t,x tmm«tnoglobubn Io, an, odu«g tri, mouse ha ov and right nmiinnogtoteini chants therein, and irs time in* the ro ,e eero.re knee ri.igm Ά of bum r: e,neng OSA co tri wine I xs ’h.o •.unde human rieavx and «rmt team pioteoi' Paitjalys modsfte I annual·, win, n have less than the full eomplemcnt of humais immunoglobulin ioei,,are then cross-bmd to obtain an

2016244220 11 Oct 2016 aromat hammi dl tn'the d· wm-d immune -o sten. modi beat iwro When adnnms-c-eo an immtmogcm these trausgeni e unbinds produce' antibodies that are inirnnnospeeific for the imrt.tnoqer bat base human - ith ' *,h.m routine .curoo a td sequewes wennhea -he s cm-Ee region'·, i or hinder details of such methods, --. e, for erorotpla, < No 5 Γ fo .,-md

WO9WG26G2, Additional methods relating fo transgenic mice for waking human antibodies ait -esetibe-fou I tme-i States A ;e tt No ·<Α4^>0, \o o.”' bo'b. \o tvXANn,

No, 6,102,963; No, 5,545,80?: No. 6.300,129, \o w?5;· fob No :<>/ ,M/; Xo ?A 74.290 and No. 5,545.306, in PCI publications WOP I iO4t, WYH0 9 Id fo, and in I'P 54H5YM31 and £F 540073AI.

7'be tramgetn-. mice dosen'Ud above. rel'ere-d to herein as ΗηΜ,ιΕ' rotce. contain ,.

hutintu itirntanoglohuh.n gene mini locus shat encodes nnreaoratgcd human heavy (instil and igammnji and jkapp.ii hghi chain mnrgrooglob.ibrs sequences, together wbh targeted miitaifons that inactivate tin,- endogenous iron] and |kappa] chain loci (1 tmbeig. eted . i’’94, 20,16.0s--.n ; op Cod’ el' I .niu',' ib t w, „ed Wt’iwio efoi,v C-d ot fo ιρη P me ro response to nnronro/atsuo -,nd the umoihe ed hem -at luav sod dght chain tratiM’enes undergo class switching and somatic munition to .generate high afnnity humiui IgG [kappa] monoclonal antibodies i I otiborg < 7 o/, snyrou; 1 nnherg mid llns/ar, i095, .61/.777, Age. Erowroo,'', B 05 Ab t hadrog and Losthem, fo-fo, ,p,^, \ ) p,,·,/ 5,·, 2gd5.fo-Mp}, I he p<ep eaiio'i i»« Ib-Mab ,r e ss d< ro fb>, d in <’< uni m Mt-, Io ite-' ^!Aw Λ. , . roh /tewwifo 20:6237-6293. p n._C{, _{l7 ίί;}ί, οο,ρ /suvwumroo? brown?, Auge g 6-7''~ό5ο;, 'tXahfou et nA 1994. J, htiiimnid, 152:2912-2926: JLonberg ermA 1994, ΛΡθο<. ΝΑΑ56··859: Lemberg, 1994, /foffforoohofr&p· Ahip'pidwfogy 112:99-1 OI; Tayiorwsh, 1994, At/rowrfrwZ Prowws\sgu’O.5’^;<i-50l; 1 onforgand Ihsszar. 1995, b??e,;?, fo-n. /mmuno/ 13:65-93; Harding, and Lonbetg, fou-g ,1,.,7. \ } j <; 7 A >' AM ή fo-54o, ΡιΠι^ρ,Ι, HA V-,

7A<m. - foeroro’ 22 R45-S51, the foregoing tefr-renees are hereby· incorporated by reference in iheir etusr, u, Os a U purpose-, A, I'ltidie; Armed States ban-ut No 5,5-*\SOe No ,\5-’9,b?\ \o %'2'J2t\Xc 5 6%.42m \o s 730,6-0 \_o s,k,fo , \o moobOlo, No .\bfo,MA No 5,374,209; judXo. 5A⁷G,429; as vvoil as Aroted Slates Patem No 5.5-45,307; International IbibOcatio'· No·- W(i -P. 122, WO'E Enfo. mid Att’M U'folS. tn-. dis, Asm- ol ail ol

0 inch me herobv r-eO'pw, ted h> ufrtenee ro th..i . ntireti fro al' pu noros b\’ 0-,-0-0.7utihzed h.; producing human -embodies in these u.wseewe uuec dis, losed J-o ro 35 0 .'h-o-O.Aand Meodce eAb 100?, \ AMrom - i? 116- I5o vlwh arc hereby sneerpos ded by 0 fricwe i'oi esa-npie, the Hi o” n.d JR'o-2 ts msgeme twc<, suamsem- be

2016244220 11 Oct 2016 used A> gem') ate iiitbt GRP R .·, ηΡκοκ- Furihe⁴ xlcu.Ps tegatdmg dm ptodm bon of human antibodies u^nu mmsgrmc «nee ate ptrotdcd m the examples below dig hybridnnu technology, uptigeu-speciiK humors in Ah- w. Oh the desired spectfs;.ity can be produced and -ek-eted from the transeetne mtec such as those dc-'cribed above. Such amthod-cs nuy be Joned red e\prc<-ed using a suiiuhie < ector and host re il, or the antibodies < <.u bx-1 uneA'd w i i, m i\$ ash menu·, .eli*

Fully huinsn anti bodies e m ri-o be derived from phage-displuy librnrieu ins disclosed tn I iooswtfbooc .red, i-)*':.,,¹ Vo/ &>><' 22 *M, md \latksre <7. 1^1, ^! If / 7”>*

222~5>-1 ι Phage chspho techniques mmne immune selection through the display rP antdiody re-p·. noues on thr surfac.' ot nhunemou-· b.n ieriophuoo, and subsequent selection of phage by tbvtr binding Io mi antigen of cliotcre <>ne -uGi technique ts nose- sire d in PCI Publication Ao. \\P ii y pre betxtre t ofo π .,, s ire, re -1 ’ q.re ^! r.s 1κ ι-χ·> ioto^f i all hup, and functional agonfstie antibodies fot MPI - and ntsK-rei.eptots using siu.it an approach.

BispeeifieCfr.Bibmedmnd.AnuuerijiiAidii^.^iidni⁴

The andgen binding proteins that are provUlcd also include btspeeide cud biftn 1.00.- n ti'ouo I the. 'c'nPe cue o- mo- ( BRs o- encm no-e\.undue regre-s isPe-re bed above Λ PrepeufK' or bounetion.il antibo.h, in some instances ss un artificial hvbrtd unttbodv has me two ihffi-u'ui h \i\) hgh: iham putts and two difforeu* h-n-.hue --res Brep, i dh nushudire- tn,re bx' produced bv a larteo of methods uwludmg, but not tunned to, fusion of hv-hndomas or linking of TW ftagmentei., Sen, ng;SongsivtUi and Caehnnuny 1090, .fb, /win-wf ’d Vi5M21, kosK'bo rem. SW,7 14d 15a7-k%

VdrWsOlh^^

Some 0* Uk arm <. n bu-dtnu ptoiems that are pto<. -led ate v c sunt hums »n the annger

2o binding ptoLins disclosed above ό g , those hw, nm me s<. quettces It-ted m I .Poles 2-A, l or nisi nice, some ot toe <usWku bmdmre wetems h.o one os mow eonsetv<·ΐη>- menu acid nibstnutiou- ni oue nr more of toe lureo 1 or light chawre reumi-ie rumens m CGRs listed m Tables .2-5,

Natiionly-o. eus one ammo ,u uk mas h> eh reded imo >, las^ ,x Orecu on O’Pii'mii s-dx' chain properties.:

I} hydrophobic; noth, tu me. \b {, Ala, Val. Leu, lie;

?t neutral hvdropluke f Bcr. I hr, Asp, Gun 5 i .Kidie; .Asps, Glu;

4i basic; Bis, Lys, Arg;

2016244220 11 Oct 2016 s residues that u-lbienc-..’clu-.iu oriennniow Gly, Pro, and oi urotntto-c: ‘Trp, 1yr, Phe

Cons-.-rx s’be asoino acid -obsiitn’itins may involve e\,h,utge of a mewfe io on of these vias-es w tft another member of the same eia-s Couwivative amino netd imbstimifes snay encompaas non-naturally oeemring amino mid residues, winch am typicaliy muorpomted hy· chemical peptide synthesis rather than by -ynthcsis in l-tologteal systems. These inclurle peptidomrmeiiev and other reversed or inverted ferns of amino aeid moieti es,

Noii-eottscr-ato, -.. sn’ostOutions m-ty nnube*he exchange of a menfe? of on.· ofth.· abo\ „ <. asses {ot a mcmbci now mu-thei claw sfe· sal st need u. femes may ^He wtiodiued b,t into iepuins ,>t rho embody that am ho’ee!o< ons <v»,h uiiriau arobod. -, o< nvo die nonhomologous regions of the molecule, in making such change- aceosvbug to cerium ewho-kweni,- die by drop tohe mdes of amino acids may-· he considered. The bydropattuc profile of a protein is cakiuetcd by as-m.-nn-g each amino acid a numerical value C'hydmpmky lodes _;aiu then mpetrnv cly ,o /ravine these

Viduex along the peptide chain:. Each amino acid has bsen assigned a hydropathie index on the o s-sor v by'dwmneb.edv w'd fegve dt mwier-mw 1 he- . *, n>oku„ ne i - ' -a urn i ' + ” s, 1 n- me t · 5 S ?. pb/rsy hduum g ”* 5 1 xy.-tenw c) son », ' 5 u we-i'Onme t ί ^l’h ahuuuc k I hl, Jycufe-Od). threonmcidl.'), sentu. s -0,3'». tryptophan 1-0,9): tyrosine t-1,5), proiin-.’t* I ORksOdU'e s-' ?1 ghttamat-..- (-¾ 5» giuiamme i~ 5) aspartate (-¾ 5 r asparagine t20 'M e, sire t e'0, a»d .uui'-me ί -t 7?

I he impownwe td the hydropathic profile in comcrrmp mtcr.wttvc biological tunenon ou u prinein is nnd--.rstood in the art fee, e.g.. Kyte wo/, 1032,,/. .)/)7. //.7.7) .1.57 105- 14I ·. it I- known that artim ammo acids may be -ubstimted tor other ammo feds hav mg a similar liyd-mpathic mdC', m -eo·-..- and still letaui a simdai Ιηοίονηί',υ aemfity In waking changes based upon the hvdropkhle index, in certain embodiments, the .substitution of amino acids whose hymepuihu snbic-c- ate willin' to is mo>ud-'d In some e-pc> % those which are wUhin

I ere w„ hided, and in other uspects, those w ttbut 10 7 -,uc included.

b r-also nudes-too,! m th ' an that the Mihsitfuf-en of'd.e umno i-eub t m ^f’ n„-k

-, th. et'sep, ou tit- basis of hydtopbiliesiy, paitienlutiy whole she bmloy ieally lumtionai ptuiew ?0 or peptide theteby erected s-> tmended for use m nnmueolotm d embodiment-, a- w the pte-eut ease, in certain embodiments,. the greatest local avenge by drophd-edy of a psotom. as uo'cmcdby the Ifere-fewem of tn- 'diac/uf muuo sod >, cone' tes w 0' tts immunogen un-, ai d ,w‘uge?i-i'nidnb m immunogene rt-, that is, w-tl- a l.io-oeietii mopert- ot 'bcpioteiu

2016244220 11 Oct 2016 ί he hnkm uig ip, ,lj ophth> u\ \ diiic\ have been nssagned to these -anmo ;·,« -d residues 'VI ,\M'C1 R) isoa_t.*„‘ ' 0< It „lt, , »{«· ( Ri ilVI'Ct d'i s\!ii>tk' ( ^rd * K gbitjmt''\' i 0 ?gA, me;()'» iB oem o-O-ss piohne'-d? Π, alanm,’ (-0 O, htviidme i 0 5h evstem. < -1 Oi med'ummk y-1 di satnu t -1,5b leeente t - Lhs, isbLuetne (? 1 Η, n resme t \u pnemUlnntne t λ?ΐ and nvpTophun i 5 is In tn i\m_b chance*- bawd upon smuGr hvdiopbfe ns it- eeittno .-tnhodnne-'iis, dm sulMdutfun td anntm aeuis whom h\drophbe··'·, t antes are wabn τ2 A nieb-bd, m ether ensbo<imsenis. rhe<e w Itsvh >u ,· withtn ' I a-'e <n, leded. and tn etU other embodiments, iho-e o ubm ts ^ς< am meleded Os smile nssiauees. one mm also uk tint). epnopes trera piininiy ammo ae-.d i-eciueueea on the kw* ef b d'ophd:- U\ Tli, se rentons am <dso mtened io ns 'epimpi> core regions ' \entpiuv tenses \ utn e nnnno aeidi stshstUaiiOn*' are s< t brut m I al de «’

Table 0; Comorvfeive Audrw .Acid Subsihubook

Origins! Residue	Exemplary Substitutions
Ab	Ser
Arg	Lys
Asn	Cfi.fi, Hr·?
Asp»	Gb
Cys	Ser
Gin	Asti
Gin	Asp
Gly	Ρ-Ό
!>.	Asn, Gb
He	Leu. Val
Leu	He, Val
Lys	Ary, Gin, Glu
Me	Leu, 1b
Phe	Met. Leu, Tyr
Ser	Thr
Thr	Ser

9b

2016244220 11 Oct 2016

Orlgirml Residue	E»rapl«-J SrtMHosiens
w	Tyr
Tyr	'11 p„ Phe
Yin	lie. Leu

A skdied etosan w «ji be to determine settable \au'.irtts n{ pub peptides as set I'oitb herein using wen-known techniques One skilled m the an may identoy stnl.thh’ ,uea- of the .roLxme that mas be eh mye.i wtthei.* eesuovtfe .mto us tw t.gyem'g teutons nm bJ-es' J to be impenam for activity The skilled -wm-mn also will be tible to identity residues uid portions of the tpolet toes tliut me eons-. rsi d among sunnas polypeptides hi imthei enibednnents, e\ et· are ts thut ntav be important for biological n-< to tty or lor strucmm m t> b.’ <ubu,et to uriset vativu .rnnwo tie· J sii'istitutto-w w Urnne lesitoy tn ; ts biAum J a, os tty m w tt-iout adversely affecting the polypeptide stmcture.

Id \edfitP ι iy,one «sf le 1 n 11 at' ,nn tev'ew soutu m*l ortso t-iwlnw mer'shr ¹ rexducs in sttntiat polypeptides that ate important lot activity ot struciere, In view of Mteh - omparsoo, o m t a*' pm b t *be ..mportance ol am.,no λ,,,,.Ι residues ,n »* pio'cm 'be.»ermpo \1 m amnio .sold tesidwe- tmpotuint for aohv tty or '.itn>. lute ns simdtH ptotot's Otto skbled m the tri mis opt ler eh/miaul ly smnhrmmmonub sid'simmons fersucb predicted nuportan; ammo acul testdues

One skilled in the art can also analyse the Amhtnenslortdl structure and atnt.no acid oenuene · tn n kttson to that so step m m » aid m pe» pepnees In \,., w <n on- u mimmeiseo, .we skt'l.-J i the utt tr.e, meuset me ahcmr/ut ot uty-ino uud tcs'dncs ot mt mid t,.iv wph tesp.ei io ns dire dnmuvtn.i tl \*iiu tme One sealed m the <nt may eitoos not-o ot.A tub. at changes to ammo netd re-nuies predicted to be on the -mrtace of the proieni, sines such residues may be involved in important interactions w id· other molecules. Moreover, one skilled in the art may generate teat ^;varianq eojitairtmg a single ammo acid gubbthutimi at each desired ammo .utd sestdue fhe-e v aunts ea-i then oe screened usmg assays tor t \«R? R m-msabeuin aciisn'y, to c esaniplus below t thus uehbne tnlbonatfoii tegardtng winch annno d? aCitls can be changed mid whteb. must not be dimmed itt other word-, based on irtiurnunion gathered moot Mieh routine experiments. one shilled tn the .-.rt e;m readily determine the amino ucid positions w here inriber substuvutoes -hotdd he avoided cither alone or in combination with other mtnudens.

0-7

2016244220 11 Oct 2016

Λ -mfiilH-r of scientific ρΐιΙιΠν.ιΐϊοη'* nave been devoted to the prediction ofscennhuiy stvuetme dtt.Mnuk. DM' -: m- {>>< Λ; /Λ<»λ,7< yddd 43, ( hou .:-o . 1974,

K.323-745 Cb.mm?.A, |o~4, ip?II-322, ChmaPo/, H7\ 4,4P,A\7m' A/mA ZkoA 4 /.45-145: Chou cmd,. P>⁷A .{#>?, A\ v. ///000001. 4 7,351-5 276; Mid. Chots u ,ιό 1979, BbytAys, X 36:367084. Moreover, computer progrants arc eio-e-:0y -e,aihibic to assist with predicting secomhuy stiuchtfe. One method ofpiedtctnig seconder·, struetme ts based upon horno'ogv modeling her example, two poo peptides or proteins the;- have a sequence identity of greatei than 30%, or snn-hsils g· cates than 40% can ha v o similar xiti.se lurid topologies. The recent giowth of the protein structural database : PDIM hes pros ided enhanced pw-dkiai'inis of secondary strut hue, including the pofontia! number of Inks άιιΑ a n-'Npe'b.L w« p oietN stj.etate Mr. Holm 0 7, 5», <’ i Ad ? ;.ί,^Λ e~ h'i\bo” » ip-este 11 li’Cte', ί 1),-5-,-,-1 B_tt-l to M 6 >

that these are a homed nwohes of trdd* in a given polypeptide or protein and that once a i, ritual number of structures have been re* weed, structural prediction will become dramatically mow ue-. node.

Additional methods ol prcdMmg secoiulnrx onteture m-Jude ''th;\admg Gooes, 199 i'arc <’p?a 7??’-<* 7.,,) K^v’~~dX~', Xipr4 _t ? m , |'U6,>„ 4 15-⁵9>, ’ p.'obl ’ analysis ' tbo'v ie e?o.’,. o*9t. Awe s?253 lo4-;7(.i, < triklos A,A, i*^liΌ, l/crd A??e”,o BG l-K-B’i, (oibssos . i o’ -- A,/Ms ’for * o</ 7 ; \i 4H5..555A'} and' evohftiooufy 1ml age’ sAx.

l lolrn, I'foA -eo-m and Btetmer, TG7, we-m) bt some embodiments, ammo ac'd enbstimtdom; are made that; (I) reduce .susceptibility to ptd to lysis, (2) redone spaeeprihilrty to oxidation, 0) alter bind mg afdnity for fbtpting pre-min complexes, i l> ,dmr bg.md m antigen binding afunitto, and or {4» confer or mo„hp. other p!!\s-„o>, heimcei of imiehonai psopeshes on such polypeptides. lor example, single oils multiple amino acid substitmiohs (in -cemin embodiments, eouservative amino aeid std’stit'.foon*) may he made m the uabo nly-o, cmimg sequence Subslimtions can be made m that pmiion <4'th. autieodo that hes out-file the domains si toimmu ottArnoleenier coma.is 5. bi meh et ibod'meni.», cons, native emmo a, id xuhcnnmonx - ,-n be u-ed that do not suh’-tautiedtv eh ewe the -tmstmid 1 isaiuetriisoes ol die p mm? s.-queo.e 0 ; , one or mose replacement amino acids that do not disrupt the secondary structure that ehareetenres ihe gamut et uatf',·, eeingeu bindingpson.mj I sample*ofatt-oxoiinf/ed polypeptide see-imbuy and iciiiary sneemscs arc described m hrotems. Structure* and Molecular Principles M (Cightoii, 1 <!.), 19X4, A II, \,-w Soil, I fccm.w ,nd Cun-nat-x. Introducl.on k> Frigem

2016244220 11 Oct 2016 vtmerm · (Bnmden η id Tvo'c c<R ! RG Sosk Gcr'am⁵ iAibfobma ami ; immo-i ,, m’., I'Wl, YrtmvnSHOk which s?c each ukoi-pmated he-cm h- leibronec.

Additional preferred aubhodv vath-aus include cysteme variants whereat one or more ..e-^kine residues in the parent or native amino acid sequence are deleted from or snb-4ifoled wah mmhet ammo amd te e , serine* ( ysteme v tnaut- are u-cb.d, Am when minbodies must be sehbdcd into a bioiogicaliy active cimtormatiois. Gy-teine variants ratty hie- e fewer cysteine residues than the native antibody, and typically have an even number fo miuirmze trtenh t on- sc-alte e fro t . np< nodι v \}>n- eI he heavy und light chains, variable regions domains and DDRs that ate dr-do-cd can ί’ a-., d to pi pate pel· pepnde- fo,’^! , oamm an atu-qc-n G-Mmy tegtoa th V > an sp t ig, .rib bsnd to t Gel·’ R, i'or esample, one m more ot the t DRs hv.ed nt I abk- n and 3 -an be incnrporafgd into a moleenlc (gyp, a poiypcpbde) covalently o? noncovnlendy to tnahe an inntmnoa.lhe.-ion \i- niinmncrtdhe-ion nm\ atempotate the i'PRm ,w natt ot a ;,uge? poypepvde cham may eova:cwy Imkthe GGRi 3 fo trni'oroolv p efide J\nn et m \

1.5 iAeo.tpo«rfo the CDR(s) noneovdetrby., The CDR(V) enablo the immunoedhesion. to bind spectikuMv to a pertwoho .mnacu co nnes-va w t, , k uRP P or epitope dt -rem) \bmeo,s n y , ''peptnb mimetic- er pepisdonnmeo, V'; based upon P.· -enable region domain- and CDR- that ate de-enbed herein arc el-o pro- ided. These analogs can be peptide-, non-peptide¹· or eombin.-aiom- ofpepnde and no-'i-pcptide regions. Rauchere. ; 9X6,

GY /ν-,<> tw- he,2°, Yehct .md I icnbiib-r, Ifo-A ,7\<n ITA and! -nn-m v, l^ua',7 tfo/ G'Am 3d I '.A?·¹, which are incorporated herein by reforcoce for any purpose. Peptide irutn-fos d-at ate -nucmmlw sttnOa*’ to thempeoneMA u-efir pepndes tnnv be used fo piodnee a amniar fhempetittc or prophylactic effect Such -. oinp«.ntnds ire often d.w doped w nn the mb ot eompatenyed mokimlaj modeling. G.-nemik, pcptoknuitnehes nm ptolems that arc srruetuiml- stnuhtt io an aiusbocb dispiav atg a desired Guiog-ea! aetiv ny, -uch as hete the abihi> to speeidealb. bind C GRR R.htn Ko e one of mor·- peptfdv nnhage- optionally replaced lw a linkage--elected lienn Gli-XD , t I l-b , -GD' -GH. -CHA II ms and iraii-b GtRIG. -O hOI I sGi i -. and ~G> 1 -SG~₍ by methods w eli knewn In the a: t System me -nhsninhon of one or mme ammo a. ids of -, eon^m-ns sequence with a D-tunno .m-d of the -- one Rp. r g ,

D-ivame in place of G-lvsinef nutv be used in certain embodiments fo geuemte more stable proteins, in addition, eou-naiavd peptides comprising -, consensus sequence o· a sub-ttnUtailv ideinieai consensus sequence variation may be generated bv methods known in the an i'P.igo uild Gierasch, 194?.» · -^;nn ,Άί- Zbm At-m. pi:.IS7), ineorpomied herein by reforeaees, for

2016244220 11 Oct 2016 e-suinple b_? «.Ming Pion d cysteine -estdaes ear u«le ot IXnung niu-aitsoieeni ir dtsnlbd.' bridges winch cyclic the peptide.:

Detm ttf\es Adie .mtie.-i; b'.ndmg pioieins that are deser-U -J herem me also pun ided 'fee deti\atszcd atutgen binding proteins can comprise any molecule or suh.-tfunee that imparts r< a deseed pmperiy to fe umibo<R or fragment, .-meh ,n inetv tsed half hie in a particular use The doiisnniz'.ed antigen binding protein can comprise, fm example, a deteeitthle {or labeling) moiety {ey t raJtoacnu, cokmmeiric, aungAe or cncy malic moleeu-c, a deieetehA head i'-atek as a magnetic os deetrodeusc te g., gold) bead), m it tnoleenie that binds to another rnoleetdc {ο.ν,, biotin or siiepunodut5f a the* ape tine or diagnostic motetv tc g , a radioactive,

H) cyioto ;e< or phunnacent Lally arrive ntosetyp or a inolceine dint increase*·· the ,->utt<febiy of the antigen nmdmg pttfiem lot a parti, alas use R o . ddianttisifatiotj to a stdeect, seeb us a human subfebor ofer Zo my? or Zp fey? uses)., Examples of rfidlecufe that ew bo us«d io doriyatfe an antigen binding protein meh-de albumin tc.y, human -on mi uihnnuiit and poly eim. Seise glwo! tPKR, Albumin·linked and Ph'GG.ued dcmaioes of antigen binding proteins can be

1.5 piep-ncri using techniques well hnoon in tiic ait. ί ettaiti -ntf-gen bmdmg piotems inekide a regy filed single chain potvpepiidc as described herein, in one embodiment, fe antigen bmdmg piotein .s eonpig tied os nfetu'oe linked no n mistily t etin t1 Tx) or a FTP < <n t.utf I he 1') R nr f I'R ν,ϊ,οΐιηΙ cait be chctnieallv modified with, tor example, a chentieai Meetcd from die g oisp consisting of >b-\iran, poly «η-v tm> I py rrohdonot, poly efe'lene giycoR pioprvpy lone glycol hotnopolytneis, pnRpropy lens' OMde’ctfn:cne oxide co-pohmets, poi\twyethylated po'yo's mopey η' fame ο

Other doixebscs sm led. < toaiem, m aggiegatixo -oimtgntcs <e% GisR R binding proG-irw n db edict piviems or poly peptides, such as by expression o) recombinant fusion i'ioicujs lomprisnig hot·,, π «logons polypepiftlm fused to die N-ti.tminus oi C-tOiinnins of a

2> ( GRI' R I Odum p-vlei't ’-o e\un. pie. me eoo.ueatyd. oeptioe m.o K a betetoh-gogs -'uiel tot I adet 1 pofecp'fd·. < o , the ye*·»' alph.i-i.n *ot 1 adci, o¹ a n. pude meh as an ’Pitope iag CGRP antigen binding piotent containing fusion psmem- can sompnso peptstks added to faediiine puritleaiion or idemtikmum of ihe CGRP R 'randmg pro.vm g g , poR-11-.-0 s ( GRP P binding p-’oteni also can be imkad h> the 11 \t - pent.Ή as eles. nbe-l m Hoop < > m,

IbbS, ffeAbfeio/o®? b; 1204; and United States Pafeof No, 5,01 I ,9)2, The FLAG peptide is InghH anti-geme and pios toes -,o epitope te\ emti-'U. hound o\ i spot ilte monos Iona', .mm'-Gs on Ab). enabling rapid assay and frefe purifiestion oIAxptvssed recombinant protein Reagents usAl tor piep.unts·. fusion protein- tn u Inch the I'l \G p>, pitde i- feed u> e gtSs'n polypeptide arc commercially available (Sigma, $$, Louis. MO),

109

2016244220 11 Oct 2016

Oforometx ro η .onktin <'w ot »»w t, DRR R -«rohro. protems ot q be ’ropkqed us ( GIG* R aroagomsts t)hvotue:s mam b< et the form of eos'd/mlronikcd ot eon eosulentlv finked tinners bmt,m* or lugger oheetocbs. Dln’omets composing twoo; root* ( i.-RPR binding piotems am cnnteanplated for us„ writ one «sample being a bomodirnet', Other oligomers Inehfee heierodunero, homotrnnem, hefcroirimers, bomotetrnmetx hetcrotets'nmcrs, cm.

One vtuboduTient n directed to< oligomers eompiroug mtdttpt. < GRPR bmdrou po-\pepfides jmtfed i>,< e-unkte m non-e-.wafem mtetnctOtisRfiv en pcpmfe mroebes lusen to the V GRP R binding proteins. Such peptides mas be peptide imkets (spaeetsi, or peptides

H) that ha\ tn ¹ pryp>. riy of promoting oltgomeriyairon. I eucme zippers mid cenmn polypeptides derived iron; antibodies sue anting the peptides ibat can promote oligomerization off GRP R binding pfotenm ait u bed ther Io, as dost tmed m mote detab below fit pmiteukr embodiments, foe oligomers comprise from two to font f'GRP R fending ptoi ,-tn* Ihe CGRP R binding tnotero moieties of tlx obuonu nt.o be »n m> -d the t'-'-rois

1:5 described above, g.g:,. variants Or ffegmccfe. Preferably, the oligomers comprise CORP R bbtdfeg proteins that have CGRP R binding activity,.

br one embodiment, an oligomer is ptepnred using ooh peptides -Icroed from immnnoglobulins, Ptepmwtion ot firoon proteins eemprisine cedant luterofogous polvpeptides fused ty \ arsons portions of antibody-derived pobpeptides tiro hiding ihe F> domain} 1 as been described, e,g,, by Ashkenazi et ok, 1991 , Croc, Mri/. rieufe Sci GS.i 66:10535; Byrii et 0/., t’f-tb, fec.ro 5 H'·'-·'¹, and lloitenbaugh m' , fox? otroruettoe of immiisb-gl-feubn fusion Protein*’, m ( uoen· Protocols sss Immunology, Ruppl m pages 10 l‘> 1 -1 (t io 1 line embodiment is directed to a dimer comprising two (nsion proteins created by fusing .-. CGRP R fendmg protein to the I e teuton of an antibody The dunm can be made by, hu «s.irnole msettnic .· gen« ro*nm ereodum the tesOtt ptoiero tmo an app-.opr ate evpiess-on sector, es pressing die erne fusion m hero tell·- oarisiortned wnb the ?e> ombmant -esps'sronon \eetoc and allow mg the depressed fusion protein to assemble much like antibody molecule's, whereupon Interchain di*nlbde bond'* tfimi between Ihe I c moiebcs to yield the’ dimer.

Fisc trim ' 5 e poh peptide'' as used hetero includes naltse «ml tmib.ro lornis of rely pert: do* de; A cd from the he region of an anuboeb 1 runeroed torois of ,*neh poh peptides eommmrro the binge region Run promotes dimerization also arc inchubul bustou proieros comprising I'm moieties bmd oligomers formed therefrom) oiler the >gh enrage of taeilc pnrith .coon by affinity eh-'Omatogmphx o*ei Proiem \ ot Iholem G toburoi*

2016244220 11 Oct 2016

One *-mlablc fc polypeptide, described in PCT -Application WO to tOtsf and Gnited State-·; Patent, No. 5.426,048 and No, 5.262.522, is a single chum polypeptide cstending irom the N-',- rmmal hmge region to to.- native C-',.-rw»nn· of 'die he tegton o: .1 humvo antibody Auotbef useful F e polypeptide is the be mutein desciibed to 1 rated Mates Patent

No 5.45/,035. and in Boom et ii/,, 190-4, £5///(5,5 jj:39^2-4001 The amino acid sequence to bus mule»· ts i-icnt-cul to that of the native i -.: sequence piv-entcd at W<) 95 I OI 5 I except rib? amino acid 19 has been changed from Leu to sht. amino acid 20 bad been changed ton-. Lets to Gio, and; ammo a„id 22 lias bee» changed now <ds M Ma Phe nuium eVu'wts rcda.ed a ton; ty for be receptors.

it) in otbet v mbodimeius. {be variable portion of foe hcoxy and or light chain* oka CGRP

R buiibup protect -.«eh a-* disclosed hetetti mac Ik substituted im the var-ahle portion ot an antibody heavy and/or light chain.

Mier» at · els. the obpom. is a fovwi p-oi'-m conet»fO»g mull-pic t < IkP R bsoraor pi» n* v d oi e'To tt wnsec ·,···· ··.,_ pern d o vo® 1 x *»w to pepiu^{v >} hikers are those described in (.«tied States Patent. No. 4.751, i K0 and No 4,955.235.

Another method for preparing, oligomeric CGRP R binding protein derivatives involy as- ot' — leBxme mppet' 1 eawne .'upper domain,- a»· peptides that promote obgome- t/atto’i -, u the | twins n..aeti tee·· .«c ..o„.a,... Leucine ...spinis oiminaJx .to n ned m w-, „ a DNA-bmdmg p-oicins <1 antoehub e< fo, i9Xs, fo ., a. o 2-H- I ’59j, ui-1 have since bee» found

2(1 m a vuricw to diflerem proteins \mwig the Know o Icuene wpp<. r.- are tiatuudly occurring peptide¹ and derivatives theretothe; dintervc os trnn-.-ri;e bsamplcs » leucine trippes domains sorae-le sot pioductng soluble oiigomet-c proteins am -tescidn'd in K'T application WO 91 )O?0-x and the kiuinc /ripper eeso ,-d from lung oarr'ict.mt protein I) (3RD) described in Hoppe;? u/. 1’t‘A / /.7/,4 / cm >44 i^i.lietebv louer-wat/. J b- ick-msec 19-. usi ot a modified h. ucme zippei that allow s for '•tul-le timiet teattmi of a haietoogon·. protein fused thereto is described in Fanslov, <ta/, i’t'M, oavi’<? bvm.vj .,·/ 6 26ΎΎ In on-.-approach, meoi lb·,» e-t o -,-ei pioteuts comp ‘smg a t v >i<P R b ml m„ Pioteai f-aenmat o den> atsxe fused »i a mue-nr /;ppc^r peptide ,nc e-p⁵'- ^l-sed m swt-ibl.’ ho*-t cel's, and the soluble oligomer» < GRP P 1-mdma protein i'ruements nt ikovauxcs Tut two- aie reco>c;e-.· t-wu ihe cainne sdpcrwwmt, hi certain embodiments, the anime» binding protein has a kt> fe.'pubbtuitu binding affinity ι of less than 1 pXt iO ρΜ, ϊ 00 pVk 1 n\l, 2 »M. 5 n\t, 10 nM, 25 »M or 50 oM

Anoihet aspect pros ides an aniineu-bindiiig ρ-otei» hoy'»;g a 'ualt'-tue of at lea-t one day »< too,; or w rfo; fog., when administered to a human subjects bi one embodiment, me

102

2016244220 11 Oct 2016 antigen binding protein has a half-life of ai leasi three days, hi another embodiment, the autibo.h oi pomon theseol h-ts ahail-hf„ ot font daw o: lomaci In at'olhci embodiment, the anobosk o^r po-ion fh.-w of has t halt-bn-ot'entin e.tys or longee hi mothef ombed-meni. h;,. antibody or antigen-binding pomon theseot s det'oaheed oi modified -meh that it ha, a ioiu-er half bfe as compared to the nnderivatieed or unmodified antibody, in another embodiment, fho amngen kudme protein contains point mutations to meio&sc scrum half life, such us described sn V O od tnifod, published Feb .? D 300b, incorporated h\ reference

I Kton he anticen-bjndmg piotcm Out base .¾ gl\ce\> lation pattern dint is different or altered fhipi that found m th-’ oafs\e spe, i.-s As is know<t m rim >ut ghcos} htPvn panelm t an denei'd on both bx sequence ol the protem <',·- the presence m absence ot paineular akeos;, kmoo ammo a, id nd-t -s dtst msed k-kw s, oi the best ceh -u mg, eusm m ob'-eh the piokan is pioduecJ PaibcstUt espiesJoo ^vstenu are -ksems-ed below

GhsOig lotion of pop, peptides is o,pwalh either \ -linked or O-linked Vbnked refers n> die attu. hment of the uukOv, .hate moien, to th- side chan- o- „n ,-.spa'ag.nc levdtte ¹ hc in-peptide sequence- asparaeme-.k-serme and asparagtne-X-ihreoninc, where X is ,m\ an-moae?d e-,e, pi pioluie, 'c- the lec-ymiPoo s- oitet^ es tor enc;, maim attachment of the embolo .hate moiet? to the ast\nau„ne -,\b chant, 1 has. Hie presence co esehei of’h/se in peptide sequences in a polypeptide creates a potential glyeosyladou site, O-bnked

2P J>u-s\ khon feie-s to the a:ta„rm ent of one ot m„ s.v; -> k ,c„f > u d< eiosammc, ga'aetosc. o xylose, lo a hvdivcyimmo aem, most ^ommonty .-enne or ihteomne, althot eh ? lo dtossptubite οι 'dsvhoxs Issmc tu«_? JAi. used

Addition of gb eosyi ifton sites to me antigen bin,tine protem is coweni/ntx accomplished t'y idtcrnn- the amino turn! seqnenct. such that it contains one oi more of the abo$e desetthedrn-pepudc s„qu;pecs (tot k-lmked ei\co-station s-tc-d Ihc .dtetnnon m,o aUo he mane b\ the addition ol of snhstmmoe b\, on.- ot mote s nue of dneonme rewdr.es io the staling. sequCfiee tfoi (‘-linked elseos\lat-on sites}. ease, the antigen 1-m.lmg ptofent ammo nod seqnc me mac ho nPe*en -hroagh - bam:r<- at the I'fkA lose!, partu uksdy b> rmfianng the Dk \ euct,ditty the tai get polypeptide at pis selected bases .such that codons are generated that o ill mtnshife mto the de-sred amino aesd-, knofhei means of mere is- tg die nnmhet el emboii,, .hate moietms on the until -. n hindina protein is A ehemse-d or eiv'.mutm coupling o’ e’veosides to the pmiem ihese pjoeeduics an ch.-jit&geons m that fk \ do not mqiui. ptodu. lion ol the prok-tn sn a host t eh that has gh, cosviafiott capabilities, tot X- ,-.nd D-tinks'd alyeo-o iamm. Depending on tbe

2016244220 11 Oct 2016 coupling mode tued, the sugaris) may be attnehud to i a) arginine- and hiriidiue, fb) free earbo.syd vt'Otips, tet tree suiihvdtv I wunps such as these id' essteme, t,H Itei hydtoxyl groups sn· n t\ those w -w 10,-. threown.' or by Jrosy ptohu,-, ·,οί tromatte iv«dsseo such <A tbo«,- of phertvlakwatte, tvrostne, or n\ ptopitmi, os u't the amide gtottp of glutannuc Ihese tneUmds ate dvsenlxd in V- O $’'05530 published Sep i I. k^!S'\ and in \plin and Wristow Hte j f,\’C <’>>/ #m fi v<-, pp, 25°Π06,

Removal oikarbohycimte ntoicite?- pre,-cut on the starting antigen binding protein may ba accomplished chcnneatis w anz-m meahy ('h’.?Wa>„al d^giycosylaiion τοηηη>, ·- mposme of tbeptotqin to the qompouad bifiuot'omethmtesoktbote aetd, or an equivalent compound, Thia

It) treatment results in the , Ravage ot most or ah sugars a'.ept the 1 wkmg sugar {Xte .web Igluvosiunotc os Vaeeiv IgaDuoMminek while leas ,ng the poR-pepti.'lc ntteet Chemical degjyvasy :,otoo is Jest ttbed ay ’bAsmuddm -1 ,d , ΤΆ s_(< /?-, , /\;η ,9 ,-g - . ?yp rp _ίΛυ;{ by I dge t / at, 1‘frk ,Μιί/ itkki Λο-ίϊΐ IH Hi bmyutato ckasage oikalhohy d,raie mesiettes ott poly pc phdes can be achieved be tbs' use of a variety of endo- ,md evo-dveoodsses nv described by Thotekte'a m of _? 1987, 3/eril fri?zwte£ 1.38::3.50,. Giyeosylaiioo. at potential glyeosylatton sees m,e, be prevented by the use ol the compound humanly cm <ts described by Diisl m c: η/ Hvy g 3<; p-v~ i pyy Πμη,,'πην am blocks the ibimafson of oroteotA glveowdc huhug;->

Hen - , asp -· is welt-i ’ gkeesy iauou veti.tnt* o'the at-ugen nn.dtng protews wk tern ’he e, whet md, ot 0 pe o’, Reo-v wmn sjtet ,ιό, Ken alts'- 3 eempmeo .0 tb m.vte ae ,1 sequences of rue parent roly peptide. In eertaw embodiments, antibody protein v ari.inn. comprise a greater or adesser : number of X-iteked glgeosydaftou vires than the native eetibody. An Yltnked ghvoyriation site is characterized by the sequence; -'wn-S-Ser or AsnXlhv w h.aem the ammo ui id residue .l-w-nated 0 \ ma> be any emuo >icui tesidiic cm apt poTu,

2*> I .est Ps'iVjtto 0 armnoauP es lees u<create fit's , tp e> u ^rttos.des t Potential new s >„ |,u ihs' t'ddit'iin ol an Vbnhe.i t a-bohym ae ham \h- ru.oweh, sub-ertfitoos that ehnnnata or alter this seqnenet, w tit pt cut addition of an Vlinked sarholtvdiate- chain present us the nmric polypeptide for es-itupie, ihe niyaosy hnion >..;m be reduced ny the doleoon of an A.\u or by suhsutsttniu the Ase with adofetent amino acid, hiotbei etnboditnents, oneoroiore new bklmlted site.-» are -. re a ted fouteodics ty pteally have a N--linked glycodylaticn site in the Fe region

Labels and Effector Groups hi ,soiua enibodinieuis, fim >utrigenrintubus: eompi ises one ot wore labels The term 'abeotiv uowp' ot ΊΗν' weans any dte.eeiab:c Loci 1 samples oi -u u-ble label-sq. motets

2016244220 11 Oct 2016

ΚΙ

3.0 unhide Mn m rot to the iollowmg rmhe⁵\ok>p>¹ o^? radio ns, l«d‘ h< g,, 11 Y\

S.'A A'k. ’ In, '1 '”ji, II· loresecM groups i zee, t-isC, Ihodatrutte,iandimnde phos >beo >, en/y mane groups p g , hvoe\,dtsh p rosida-,, I’-galn. tosnlase, la, oem-m, alkiduK ph'WpduuKP ckoihurou’ieseent groups, b>oiinvl group-got prcdcterntiued pok peptide cpinipes recognized by u secondary reportei toy., leucine zipper pair sequences, Gudina sues fot s,'eo'id,i!> .ernbeihes, mead birding dom on-, epitop.. tuns) In some embodimc'the h p„ug group m „o.ip'cd :-¹ the antigen pi: du.u protein i<u .-pis' ί mis ot various lengths to reduce potenii-ti sietu hnnDanee V?,irons method- tin i.ibeimg proteins are known nt the an and may be twed us is seen it

The etm eftbetm gnuip means me. ηοιηρ -.oopled so <m mtdgen binding prut, m s' ,,i ads ,_;s _Λ esmto.sic «acU I \antp:es |<n -eiu;dd„ .-deetot gemps „re fmati'i-otopes o nm.ou, id m< g, 1' <1 S -v, 1\ 1, it tbheistd.il· group-'nt h ee ne.ms, foetapeuKc gsonps, or eheroortrctapeiUie group- 1 'samples o’ suitable groups include c«h>, hwtrmehn uunsiatsit,- geldanamyein md m tytartstne, in some embodupems, the effvetor group is coup led to the anti gen binding proton) cur spacer arms of various longtbs to_: reduce potential steric bfodraoee.

b> gen.-ral, luln-k ltd; uuo a sanely til eluso. depending on the a-sac In w hieh dies ate to ΐ\' detected, a) i-otoptc lubeX, which aiav he lachoactiv a or kc,iv v .isotopes, b) nsanmusc labels o. g , m ignetie paritehs}, et redos active niofeUes, ,1? opimel dyes en.wn'atn gi'onps tzee hotsetadtsb peros-.d^se. p-e.de.eto-ida-e, luctiertse. allahne pho-phan-e}. et btnprsv sated groups ano ri pseddetpttned nolvp.-prole epitopes ><'.<>,-meed b> ... secondare lepmurr g t,, leucine sripper pa& sequence^, binding sbsn for yeeonriagy unubodisn, uietui, binding deenuins, epitope tags, ete t, in some einboibtnenis, the labeling group is couoled so die antigen binding ptoicm spa,arm-ol vat sou- lengrosu» ledu.e poSeuPwi -ten» Innd.anee \ -,'sons ipctsio.ls tr>: hhchiro ptolents arc known m die art.

Speciin labels inelnd·-optical dye.- including, Inn not iimued to, ehromopnms.,-, phi'Sp', οι-«ml lino vpUnes w,f, the'aite P-u v spcc-bc ,o u ato tustai,c«» IIt.o op: <n.-. can he euher ''sum!! mole, ale*' lluores or protein,-loroo- ilw.By 'TliiOrescont t-abef' -s meant mn moke uie ih.u may be detected via its inherent fluorescent properties Suitable fluorescent labeU include, bin are not limned to, fiuomoeitp rhoriemu:e. n.'i,unetlo hhrokunroe, coon,. nthro-m. eoutnatm. ns thy;-, oumasuis, pyiem. Maisen.-green,s'dlbeii/, l.nctfe* Yellow,!' tsetde Blue,’, k\a- Red. lAHbWS, VOWS, BOPIRY I'i , I (' Red Odd, ( y 5, C> 5 5. 1 V Red Al·’, Ptegon gis'un, the Alc-a-I'Inoi gws trile\a I loot .Ash Aleva I luot tert. Ye\u i krordus \ri\a rnmr.'-de, \L-\a I tuo: bob. Ak-\a

105

2016244220 11 Oct 2016 loo. Alex,* Pinos t 7) Ak*^a 1 dot fi{“ Ah xa ^r<uor060, \i \a Pipoi ChUL I .wCul· Bloc, CAscade Yrilev and R-phyeoei-ilnm (Pi 1 (Molecules Probe·*, Ragene Did, I I Π', Rhod<nnnx\ and Tt«<n Red {Piero-,, Poeksosd, ii ), (\ \ r ~ ί \ i Anu t darn I ne S> moee, Piltxhagh, PA'» hummi- ορικηί decs, memduig Onoroplnxios. ate described -,n Mdt ί > Vi \t

Pbe'-u Ή \\⁵«⁴- (>κ % R^ka'.d P H«ug: inch hctem ’\pressi> m> orpomt-'d by 'eferuxe

Smlal 'e pouets.uc tnt\ dnoscxcew I Ρ» A also i’k hide, bv no) iim-md to, g.ecn tluoresecm protein inehidmg a Panda, Pidos-ncns, or Gnmorvx ssvete·* o^rQFP iCh,>lfi,e e? >F, rood, \ „ , , do > k02-N0'R>. I d: P A loe.e-1 I uhs , De , Cerhur'-v A. eaxsvu-Num't i l 55”Ρ2), him. nnoroeent protein iBl'P, Quantum Bioteeimoiogtes, hx„ Quebec, Canada;

1.5 No. 577707% No 56043X2 No. 914 No 5Χ2νΜ5, No .'ΑΡΡ'ΝΜ

Nut'lew icfitx linn encode for the nnfigen binding ρ?οιαη,* described her-, or o^;' porrioo.i ihereoi. ,kc aGo provided. including nudeie acids encoding mte et Poth chains of an atsnbodx, or a fmgru>,-m, perkanx-e, ?nutem, or van no thereof pob.nueh'oodes encoding y eh uu satiable regions ot onb, CDRs, potynueh.oitdes sufficient fot use as hybrdie.oton piobce, PCB primers or sequencing prinxir Hu ukritBuig unuivzrog, nuiHdsn.g or amplifrine a poGundeotfrie emodtre a pop* peptide, anti-s-.-us-e on-, rise acids io? mil-biting e\ptesvo?t of a p-ηχ nucleotide, tnd complementary sequences of die foregoirm the nucleic acids con h.> un\ length Fhey can he, fi» pxampky 2 IP, a-, 20. 2R 91 IR 40, 42 Ό, 72 too, 125 Do, CR

200. 250, Rh}, 550, 400 450, %_{ρ- %o, 1,000, ),500 or m.nr, uurieotiiks ni length, and or can compose one o; more Qdrionui sequences, fi> example, regal,lUmv sequences, ami or u- pan of i lamer i\,d-.e ,esd, hu -xainp'e, e x-.-io; lb- me. e,c a.'d·* e.et be *meL sOamkd m denote si? ,n,;e I and e.et ικι-ψην kN \ are ?n DNA m - 'em A, _% and atfkr*i x arums tn of ie.g . peptide naekte ands) '1 able shows exemplary nucleic add sequences encoding ,>u IgG2 heavy chain constant segton, a kappa itghi eia-ati constant region y»j.l a knnhdu nr ί-i tight chain eonsta.m region Any xanuble muton poo ded herein may he aim-.hed m thev constant regions H- firm <, ?>mpb\o Guvx and held chant seqaemes ikmev.·, ti shoni.i 0-' mt-le-siood that iha-e

Cf'-isnnu revmns sequences are prov tiled as specific examples only --- one ot skill in the tut max

2016244220 11 Oct 2016 ,-mp'.ov oibes re gto w, π,, bidmg by Ή 'n’<⁵'> -bar? iet>'!\ b’CC ot igtsd heavy eham eon-dimt teutons, ans of the seven lambda hght chain eon-wmt regions, including hi l-!,h( I ~lb nCt -v and hCt -7, uvnM.nn regions th » have been modsbed fm improved shsbuitv, esptesumt manager luiti no es othu ecsned vbauste,tst,es. me the ni,e H som,.

embodiments, the variable region sequences ne joined to other constant region sequences that am ί>u i\\i at th,. ait l-v.-mphey ttneiete aetd sequ.-it.es encoding hews .md hoist eltiutvariable «egions ere provided m table X table 7: Fxemplan tk-nxy Assri light Chain Constant Region Audck* Acid Sugncnccs

Type	Nucleic Acid Sequence/SEG ID HO,
lgG2 heavy chair»	gciagGaccaav}ggGOG§lcggicitGCGcetggGgcccigctc®ggagcaGcicGgagagGacagcggcc cigggcigtxiggtca3gg8ri.acitccccgaa-xgg?ggcggigicgigga3ctcaggcgcicig3rxagcgg GgtgcacacctiCGcagGt-gfcciacagtcctcaggactclacicccicagGagcgtggfgaGcgk>xefccagG aacticggv^cc^gacctscacdgcaacgiagaiGacasgtxi^gcaacatxaaggtggaraasacagt igagcgcaaatgitglgMagk]cccacggtgGGcagcaccaccfgtg<}caggafX$)icagtctlcctctxece txaaaacccaaggac<iCcd.txvlgai.ci.ccGggacqxjlgaggicacgtgGgiggiggiggao-gtgag(X3C· gaagaxGcgavjgicGagitGsacfggiacgtggaq^gGglggaggtgeataatgGqaagacaaagccacg ggaggagcagbatacagcacQliocgtgtggiatycgic.ctcaccgttgtgcaccaggactggctgaaeggc saggagtacaagtgcaaggiqccaaGaaaggcctcccagcccacaicgags^aaaccatetecaaaaccaa agggcagc'X;cgagaafxacaggigt8Gac0ctgccixcal<xcgggaggagatgaoc<tfig3g{xaggtc agccigaccigoctgghtaaaggcltciatxccagttgncdd^cqitggagigggagagcaaigggdngccg gagaacaactscaaijaccaeacdcccaigctggactccgacggctccficttGCtcfecagcaagcics^ecgt §gacaagagi:aggtggcagt^ggggaaGgicdctcatg(..lct>gfgalgcatgaggcictg<Ga®accacia0 acgcagaagagcctGtxGtglcccgggtaaatga ISEQ ID NO:2§9i
igG? Mw light chain	cgfecggtggcfeca^atcigtcttealdteccgceafetgaigagcagttgaaa&tggaaGlgGctGtgtlgtgt giXigctgaataaisticlatcccagagaggccaaagGcagiggaaggtgga^acgciXiccaaicgggtea ctGGGaggagagtgiGacagagcag^cagcaaggacagca'Gctacagxtcagcsgeacectgacgctg agcaaagcagacbtfteagaaacitcaaiKfichvegixtgcgaagxtacccatcngggGctgagGtcgcccgt cacaaagagchiwcaggggagagtgttag iSEQiPNOiWt
igG2 lambda hCL- 1 light chain	ggtegGCGaaggccaacsaeaGtgtcactc^ncGcgGGaiGctctgaggagcfeeaagccaaGaaggcGa cacfagfgigtqg3tcagigacii.ct3Gccgggagcigtg:3cttgtggcciggaaggettgaiggcag*W:gtc «sQuiS'dS^S^SsgaGcaccaaacGciccasacagagcaacaaGaagtacgqjgGcagcagciaGGtg agcclgaGgcGcgagcagiggaagtccatcagaagctacagctgccaggicacgcaigaagggagsga^jgt ggagaagakagiggcccGlacagaafghcatag ISEQ ID NG:2S1]

107

2016244220 11 Oct 2016 fable o shows cscnnVan nuclei; ac;d s. qixnees encoding he,e<y cknn and huh? chant \usbhie regions, in which id·.. sunou*· CDRI 1, C Old ? and CDR? 3. or VDRIH, CDRH? and CDR HA sequences at'»; embedded.

Table 8: Exemplary tight unci Heaxy C hub V anabie Region A'udek Add Sequences

Reference	SEQ ID NO.	Nucleic Acid Sequence
2E7V,	176	gaCidixaQtnigtgdxagiciccatecfcfxigtideeatagleggt'igaithgagtefcDPcadl gccgggcsagt^ggg^nagaaaigattfeggctggidcagcagaaac^gggsaacscc (Mm gee tgaimigctgcaicesgilgcqhsgbgggfcceaiceaggiicegcggcagfg gstegggaesgaBcaetcfeaea^ tctacvsg^^^latttacxcgtggacgUcggc^agggacxaaggtQg^^aicaaa
13H2V,	176	gacalceagetgecccagiciccatcclct'xigtclgcaicigteggagacagagicfiecfdcecit ge^ggcaagicagggcetiagaaaggsttleggctggtelcagcagaasceagggaaagcc cctaagcgcdgetctatggageatcceghigceeegtggggieccaicaagghcaQcggcagi ggatctgggacagaadcacicicacaa'Xagcagccigcagccigaagatttigcaactia'uacl giciacagiafnaiagdiccegigga^hcggcceagggecceeggiggaaahsjee
3385 V:	177	aggtgcegdgglgcegicigggghfgaggtgaageagleiggggixtGagtgaaggtetedgc aaggcdctggaiacaccttcaccggc’isclafetgcaclggglgcgacaggcccciggacaagg gchgegtggetgggqtggateaaepctaaeagiggiggcaeaaacteDiacegasgiheegg gaagggica^i^gagcegggig'UAtgiCiiatetgeecagccfaetdggngcigageaggelg ggalctga^acacggccgtgtaUadgigcgagaaatgagtaiagcagtgcciggcoaHggg gfetiggggccagggaecccigglcaccglclctagi
4H6 V-	178	gabUglgatgaclcagtciccaiAclccdgcccglca^cctgyagagciggccIccalciccig eaggtctsgtcag8.gectcd9C8tagtDg9giaca8ct3tiiggahggtacHgcaga»agccag ggcagicicca<;^gGfcc-getcdttfgggri<;iaaU;gggceiceggggtce<,igaceggifcagi 9gea9tg9a^ggeacagaBacactga8aatcagceg»agig9aggDga99atgUgggg hlattacigeaigesagcteia®aa3ctec3lteact&ggc(xigqgaeDhisgtqgabic.aaa

lot

2016244220 11 Oct 2016

Reference	SEQ 10 NO.	NuAfc Acid Seqaence
SCO,	ns	caagtGtagtcagagcctccigcacagtgGtggaaagaGGtatKgtattggiacGtgGagaagx agg(:i;agGGtGGaGagGt{XigalGl.atgaagUk;«)acxgUGiGU)gagtgGcagalaggtte agtggcagGgggicagggacagathcacactgaaaaicagccgggtggaggGfgaggatgte] ggaUlafeGlgcaigcaaaghUGcgGUcGgcl^G^GggGggagggaxaaggiggagatc aaa
SFSVt	180	galalt3ttaigac0aagaGtGcaGltfcteigtecgteacc'Xlggacaga;ggcacGatctccigc aagtetagtGaqagcctCGtgcacagtgatggaaagaXtetSgtaUgglacGigGagaagGCG ggcGagcctGcacagciccigatGtaigaagttiGcaacGggttQQggagagccagai'aggitGa giggGagGgggiGagggacagaittcacactgaaaatGagccggglggaggctgaggatgtigg gacUalfeitgcatgcaaagllkecgebcegcfcacHtGggGggagggaccaaggtggagaika 38
1WW	181	gataUacaitgaGPGsgactGG^ctttcnkgtccgtctGGcciggacagccggcGtGGaiGicGtg GaagtGtagixgagcGtelgGaGaglgaiggaaggaactalclgtaFgglactegcagaagGC ^c^^wg^gc^c^aagtgtecaa^ghfetfetgge^g^gataggfic sgiggcagcgggtGagggaGagatltcacactgaaaalxgGcgggtggaggctgaggatgFg ggatttettaclgcatgGaaagiiOccgctlcGgclcaQitcggGggagggaccaagglggagatc aaa
0J-*/ 'Λ	182	gaaaUgtgkgaGgcagictGcaggcaccctgietUgMccaggggaaagageqaecddxt gcagggccagtGagagigiiagcagcggciacitaacGtggtac'GagcagaaacGtggccagg ctctx:aggck',Gt{tetkaiggtg?teta.ag-;aggg-'Ga-Giggcat!>GcagaGa@gtica§tggG ^IT-OSSiGOSSISGagactlcaGiGiGaccaicagGagaGtggagcctgaagattstgcagfgiatt aQgkiagcagtalggtaaG-GactglgcaggtUggcGaggggaGcaagGtggagatcaaa
32H7 CS W	183	gaaakgtgkgaGgitegtGtxaggcaxGtgtcttlgfctaggggaaagagecacedetel gcagggc^gtcagagfgUagcagGggciacttagoGtggtacGagcagaaaGGtggccagg ctexagaciqctcatctglggtgcatccagGagggccsGiggcaixcagacaggttcag^gc agtgggicigggaGggaGdcaGlGlGacGateagGagactggagCGtgaagattftgcagtglatt acIgtcagcagtatggtaaGtGactgagGaggittggxaggggaxaagctggagafcaaa

HQ

2016244220 11 Oct 2016

Reference	SEQ ID NO.	ftadefc Add Sequence
33E4 Vi	184	gaaabgfgafga^^gideGagxaxdgtctgigtemggggaaagagccaecddc dgiagggccsglcagagigUegcagcasftiagcdggiaGcagcagaaacdggccaggdc GcaggGkctcattcsigatgcafcccccaggacGgdggiaicccagixaggncagtggutgtg gatdgggacagaatfcacfcfcaccateaacagcctgcagidgaagatnigGagiitahsdgiG agcaglataatiadggackxgaicacdicggGcaagggacacgaclggagaUaaa
3»M.	188	gacalcgsgalgacGGagtdcxgaGtGVdggclgfgtGtefgggcgagagggecaeGdcaa cigcaaglccagccagagtahliagacagctccaacaatgaiaadadtagdigglaccagca g3aaxagg8cagcdcda88d.qdcah.fadgggcaidaxcggga»ia>ggggtecd.g accgattcagiggGagcgggfcigggacagafttcaclctcacc^RiagGasjCdgcaggdgaa gafglggcagtifatiadqicagcaala^algalackca^cacUfcggccctgggaecaaagtg gaislcaaa
1E71 VL	186	cagidglgUgacgcagcGgccdcaghiidgagigGCGcaggacagaaggicaGcstctcdg dctggaagcagatacaartadgggaafaaliatgfetcdggtaixagcagcteCEaggaaeag cccccaaadcGlGaUlalgacaaiaafeagGgaccdeagggattGCtgaccgattGldggctc xagidggcacglcagcdtGqdgggqaiqaxggadqGggadgggigacgaggccgalfat tadgcggaaGatggga^gGcgGdgagtgdgiggitttGggcggagggaceaagdgaGcgt cda
4BVt.	18?	cagidgighgacgeagccgccdcagigictgcggcoaGaggacagsqggfGaccaidcctg dclggaagcagetecaacat'igggaataaHatgdtcetggtafvagGagdfxraggaacag cvcccaaadcdcathatgaGaafacVaag'SgacccfG'igggaSteclgsecgaHddggd.c caagtdggcacglGaaccaccdgggcaicaccggadccaqactggggacgaggccgatiat tacigcggaac^ggafaggGggctgagidgiggmicggrggagggaccaagdgaccgf acta
904 V:	188	GagiGgtgUgaegcagGegceGtGagigtGtgGggfAXGaggaGagaaggdacGaiGcdg cccGaaaGt<xk;atttaigacaat83taagcgaccctGagggahcGlgaccgaHciciggGtcc aagtdggcacgfcagccacGdggt^caieaecggadsGagaGtggggacgaggjcc^aliatt: <WgsggaaGatggg8t8gxgcd.gagtgQgfggtfflGggGggagggaccaagdgaxg?e da

j H)

2016244220 11 Oct 2016

I2G8 V.

cagtetgtgkgacgcagccgeccfcagtgtetgGggGGGBaggaeagB igglGaccatetCG^ ctctggaagcagGtG^acattgggaaiasnatgtatxtggiaccagGagctxaggaacaa GCfXGaaBCiCGkAkpiktecaataakagi^aaxtcagggattGCtgacGgaSctelggGtG | caagidggcaGgfeagccacxtgggGatcaccggadccagaGtggggacgaggxgat^t) tactgcggaasrigggafegGcgcdgagtgctgtggMtcggcggBgggaGGaagdgaGcgt | sets ΐ

--:----:-:---:---——---:-t

GsgtetgtgttgacgeagscgsccIcastg^gGggcecGaggacagaaggtGaGcaiciectg j GtsfggasgGagGtGGBaGa^ggaafeatfe^taixiggtaixagGBgctcxaggBaGag | GccccaaacfccicalitalgacaataataagGgaeccicagggattGcigaccgattGtctggctc ' caagiclggcacgtcBgccaccctgggc^teaccggaciccggactggggacgaggccaatta ctgdgcggaacatgggatatGgg&GtgagtgUtgggtgtfcggGggagggacGaaaetgaccg tecta

Gagtc?gtgclgsctaagcGa(.<'?ckxagGgtctgggaccaccgggcagaggg?caccatdcttgt tciggaagci59itC€aatsieggaat>-iiaGtgigaadggGcca$)cagctcccsggaaeggc

CGcyggadcxTGatetstaGte»ata»stGSgcggecetsaggggigoGtgacGg,3t&tctggGtGC aagtetgt]eacetcagcctGcctggccateagtggactccggidga<)g3igaggciggtitisd gtgGpag-Bgcgggatgagag-xtgaatggtgtggtakcggcggagggaGxagcigBccgicd )1 D'M \A 11H9 V,

Gagfelgtgi'.i.gucfcagccaccckAgGgt-TgggacGGGcgggcagagagksccaicicitgt tdgggagcsgctccsacakggcagiasttatgtataciggtaccagGsgctcciaggagcggc

C{Xcaaada;k;ak,daggaariat<;^gcgga>akAggggta,dga{X.gi:tfcBtgg{:k:c

a.agtdggsa.cdcBgeGtcGctggc<mtcagtgggdccggtcc§aggatgaggctgattattsGt gtgcagcaigggatgacagcctgagigguggyigtLqgi^gagggaccaagctgaGcgtccl

cagtctgtgctgactGagccacxctcagGgtctgggacceagggcagagagteaeeWtctgt tefggaBgcagGtGGa8catGggGagtaattakgtataGtggtaceagcagctc©Gaggagt^gc cGccaaactcctcatGgtaiigagusatasgcggGCGtGaggggtCGdgaGcgatiGictggchx aagtctggGacdcagGdccciggccatcagtgggdGGggtccgaggafgaggGtgaftattBct gk]cagcaigggatgac;igxigagtggttgggtgttGgge§ga§ggacGaagdgaGGgteGt

B m

2016244220 11 Oct 2016

Reference	SEQ ID NO.	Hcdelc Add Sequence
	194	ceg ictgtgciga· :U :agicet;ccicagcgicigggacax· ;gggeagagag icaccad·; ;ttgii dggaagcagdecaacafeggcsgfeattatgfetactggtaccageagciccaeggagcggc eccca33cksiC3tccKaygaslaalea9cgg>x«caggggiccGtga<.cgaUctciggdec aagfciggcaccfeagccfecd.gaccaicagtgggdacggicegaggafgaggdgactaita6 gigcagiialgggaiga^gcidgagtggtigggigUcggcggagggaecaagcigiJfbagtccI &
386¾		iGdQgagcigaciGaggaccGgciglgtelg^gccttgggacagacagteaaga^Gatgec eaggagacagcQcageagttltiatgcaagdggtsccagcagaagccaggacaggccccIgi acikjtctlctaiggiaaaaacaaccggccQcagggatcccagaccgatlclciggciccagcfca ggaaaca{>3gctl.cc0gaccal.cactggggafcaggcgga3gaigaggcigacta6allgfaai tccGgggacsgcagtgfeaccafctggtacfcggcggagggaGcsagcigsccgiccfe .......... ...... : : : ' ' ...........
386 Vu	196	caggtgcagitggtgGsgiclggijgctgagglgaitgaagcckjgggcckagtgaaggiciccig caaggcUciggatoccttcaccggcladalaigcacfgggigcqacaggcccdggacaag ggcUgagtggatgggaiggafcaaccctasGagigglggcacaaactaigcacsgaagtiicag ggcagggicecceigaccagggacacgtccaioagcacagcdacatggagctgagcaggct gagafckiacgaaRggccgkyAUtQgtgcgagagalcaaatgagtakaUatgGttcgggga gitrif.ccccc6actakaeggialggacgfetggggccaagggaecacggtcaccgfetctagt
WE4 VH	197	eaggtgcagctggtgcagictggggcfgaggtgaagaagcdggggcefeagtgaaggicicQ gGaaggcdctggatacaxUcaiKgactacfelatgiactgggtgcgacaggcGXlggscaa gggcttgagtggaigggatggatcagccdaatagtgglggcacaaactatgcccagaagfeca gggcagggtaiccaigaGcagggacacgicfetcAgeacirgccfecatggagcigagfeggcl gagaidgacgacacggcegigfehadgfgigagaggaggaiatagtggctaegcigggetds etca:actacDcgglatggacgtctggggcc8agggaa,acggk;accgtddagi
32H8V;-·	198	.caggtgcagdggigcegtdggggcigagglgaagaagcGiggggcciGagigaaggidca gcaaggctfciggaiacacdicaccgaiiadadacadgggigcgacaggcccdggacaag ggt'dgaglggatgggalggaicaaccxka&agiggSggai&aaadatgcacagaagtOcag ggc^ggtcaccalgaccagggacacgiccatcagcacagcdscaiggagctg^c^gct gagaldgacgaca^gccgigttdactgigcgagaggaaggcagtggdgggcfegactad ggggCGsgggaaccciggicaccgicidagt

I 12

2016244220 11 Oct 2016

Reference	SEQ ID NO.	ftadete Add Sequence
33BSVh	199	gacatccagatgacxagictccalcctcxtglctgGaiciglaggagacagagilaccafiacUg ccgggcaegfcagggahagaaatgaittsggdggtafeagcagaaaccsgggaaagcccc taagGgCGtgatGlalgngGak,eagi.Ugeaaagtggggk;cGak:aagghcagGggGaglgga idgggacagaattcaGtctGacaatcagcagcdgcagxtgaagamtgcaacflatac^fct gcaglafaadacHacxgcfcaciUcggGggagggaccaaggfggagalcaag
11013 W	290	gaggiaGagcfggfggagiQgggggaggcnggtaaagcetggggggfikO^gacycGlg ^gxlc^gaUcsQfteggtaacgcciggaigagdgggtxgxagggteeagggaagg ggdggagfgggSggd^taiiagaagea.aaaetgatggtgggacaacageslacaGfgegcG GgtgaeaggcatgaltGaxatolcaagagalgaMcaaaaaaGacgclgtatofgeaaafgaac agcdgaaaaecgaggacaci)gcogtgiaUi.Gi.gtacOTgatcggaecgggfatagd3ce gctggtctagi.taci8mactg-chf)ggl3fgg3cgicigg<3gGcaag§gaGcacggtea.ecgfef ctagt
9F3	201	gagglgcagQggi.ggagtelggggg8ggdtggtseagcGiggggggfccdfagagfe;Wtgf gcagGciciggafteactUcagtaacgcctggatgagcfgggtccgccaggctceagggaaggg gGtggegtgggttggGGgfalfeaaagcaaaacfgaiggigggacaaxgactaGadgdiccG gigaaaggcagahcaccafctcaagagaigaiieaaaaaacaegdgtetetgcsaatgaaiag cetgaasgecgaggsGacagGcgigtafeetgUwtGagaicggacogggletageatoage tggiciagRaGl3ciaciaciacggl3fggx3Ggfc?ggggcc88gggaccacggtGaccgtcl:cls gt
1 IKS Vi,	202	gaggtacagGrggtgga^ctgggggaggafggiaaagcdggggggtcccifagacfcfcdgi gcagcddggaa^ctti^gtaacgixtgg^^g^W^ggci^^^gsS. gdggagtgggtiggcxianaaaagcaaaactgatggigggacaacagacfaegcigcaccc gfgaaaggxgi)UeaccaictGaa<)agatgafk:aaaaie)cacgc-gtak;igcaaatgaaca gcctgasaaxgsggacBcagxgyatetgtacGaGagatcggaccgggtaiagcsicag etggfctegta-AaGlaetactacggiafggacgiclggggGcaagggac-GacggtGac-Ggfcki agt

13

2016244220 11 Oct 2016

Reference	SEQ 10 NO.	Hncfeie Add Sequence
1H7 Vh	203	gagoMC'^^lggtggagdfgggggaggGffggtegngix.iggggggfccdtegaetetedgi gcagccfcfcgaftcacmcagfaacgxfggaigagcfgggfxgxaggciccagggaaggg gQggagfgggUggccgfadaaaagcacaacigalggtgggacaacagaciacgGlgcaccc gfgaaaggcagancaccatdcaagagatgaftcsaaaaacacgdgtatcfgGaaafgaacs gccigaaaaxgaggaca'GagixgiglatascigiaccacagatitggiiccggatavvgcatGag clggtctagfectaciadaGfaGggfatgga.cgtctggggecaagggaccecggteaGcgietct agt
	204	gagglgcagGlggtggagtelgggggaggcatggtcaagcdggggggiccdgagactctedg IgcagGeidggataGaccbc^ ggcfgg3gtgggi.d.Gaiccaftagiagl8gt3gtagff8cagat3fiacgcngadGag!.gaaggg cGgattcaccatGtGOagagacaacgccaagaadcacigtaldgcaaatgggiagcdgaga gGcgaggacaeggGtgfgfaladgigcgagagaaggggtgtcfggca.gtcgGCgtetagcat cagdggfaegactacditacggtaiggacgtdggggccaagggaccacggtcaccgidcfa Mi,
?E7V;,	205	gaggtgcagctat^gogtGtgggggagggiggiacagxtggggagfccdgagaGtGtectgt g^gcetctgggticaccttegcagdaigccstgagdgggicc-gxgggctccagggaaggg gdggagigggtdcagctettsgiggiaglggtggfcgcacatectecgeagadecgtgaaggg GxggtlxecatcfceagagaGaattGcaa.gaaeaagetgfafeigcaaatgaaiagcctgagag i ccgaggacacggccgtatadadgigcgaaagateaaagggsggtsgggGcgfaiagcagig : gdggdcgadacdefecggiafggacgfciggggccaagggaecacggk<n{xgtddagf: :
3CSVh 12E8 Vh SES Vh	.206	xgglgGagdggiggagtdgggggaggcgiggkxsgcdgggaggxxlgagaddedg tgcagcctctggattcaGdfcagfsgdatggcatg-GadgggixgccaggdGcaggcaaggg gQggi>gfgggiggcagdalttc8digaiggaagic8lc)a8fa1atgGagadixgtgaagggc : cgateccatQxagi^gecatacGaagaa^cgdgtiitctgGaaafgaacagxtgagagG gaggaeacggdgtgdiitcig igcgagagagaggaaaeggg kacgafgteedlatehad adictadaGggiafggscgtdggggccaagggaccaGggoaGcgtettagt

2016244220 11 Oct 2016

Reference	SEQ ID NO.	Nucleic Acid Sequence
4E4V(, 9D4 V - 1611 Vh	207	»ggtgcagcfggtggaatetggggg^g^lggtogccfggg^gicccl.gagacicfccig tgcagcciciggatfcaxtlcagtagctttggcatgcaGigggiGcgGcaggctccaggcaaggg gclggagigggiggcagltalalcadigaiggaagtaUaagtaUclgwigaciccgtgaagggcc gattcaccafGfccagagacaaUcaaagaaGacgcigitl-dgcaaaigaacagcctgcgagcc gaggaca^gctglgtatiactglgcgagagi0cgg(;V;:aattai.4atgaiagiagtggitaiiatea cMcaastactaeggtaiggGcgiaggggc^agggaccaGggm^tctcfagt
1283 Ve	203	caggtgcagctggfggaatctgggggaggcgigglccagcdgggaggtocclgagaeicicctg tgcagcciciggafeaGctiGagiagcftfggGaigc<inggg?ccgccaggcbcagg©aggg gciggagigggiggkagttalaicalfigaiggaagtadaagtactcigtagactccgfgaagggcc gattcaccaiciGcagagacaaircaaacaeGaci^GlgttiGlgcaaatgsacagccigcgagcc gaggaca^gctgigtatiactgigcgagagalcggctcaadaclafgahgtagtggdakaica cteCsaaaiacfacggtciggccgiclggggcGsagggaceacggtcaccgtelcfegt
4H8W	»	gaggigcagcigglggaglclgggggaggcttgglaaagccagggcggtccclgagactcfcc! giacagcUciggadcacctttggtgadatgciatgagciggttccgccaggctccagggaagggg ctcgagkggefaggttfca®3geagcagagcflatggigggac<accagaaf8GgcGg?>gtCigfg saaggcagatteaccatctcaagagafgaifccaaaaccafcgccfaicigcaaaigaacagccl gsaaacGgaggacaeagccgigtefttctgigcfagaggacggggiatfgcegctcgilgggacl 3dggggcGagggai3C£Xfggicaecgictctagl
32H? VH	210	caggfgi^gciggiggagtctgggggaggcgtggiaxga,tgggaggte(;cigagaclck,ctg fg^gegfGfggsffcacGUcagtagcbtggcaigcactgggrccgccaggciGcaggcaagg ggcfggagtgggVggcegliataiggtaigaiggaiigtaibaaaiacOigcagacIccgtgaagg gGcgattceicatciccagagiafeaaiGceagaacecgctgtaXigcaaatgaacagcctgaga gGcgaggacacggctgfgtaitactgtgf^agagcggggggt3tagcagcagctgga,xtacta cfactacggiaiggacgtctggggcxaagggaccacgglGaccgtctcisgt
33E4 VH	211'	caggigcagdec^gGagiggggcgcaggscxitgaagccitcggagacfxtgkxHGagcig cgcigfct<itggtgggtccttcggtggdactactggegGiggatci>gGcagc{XCG3ggga»aggg gctggijgtggattggggaaabaaicatagiggaggcaccaaghcaacccglccctcaagsgl egagtcfrGcaiaicagfagaGacgtccaaggaccagltctixcfgeagdgagctctgtgaecge cgcggaea^gefgtgfattfcigigcgagaggcgafgfagtaggmcmgaciatlggggccagg gaa(xctggfcao2gtefeMgt

2016244220 11 Oct 2016 bitoe o shows the M Q 10 \ds of -, \eiapian wipicic a,'id sequences -.ίρόρρρ; compL’x heavs and light dnnn-g us wail heavy and light chain variable regions, co' exemplary isolated anbgeii~hh:>lh:g proteins, spedto ill\, hLGRP R landing proteins, disclosed hereto,

I abk 9 - Esemplan IK', LC , Yu »nd Vi tetdek Add Sequence Ul Mis

s	a 1 8	a ? 1 1 8	8 a £&	§ a S3 u.
227	175	25$	226	244 '
13H2	175	254	239	267
4K6 i	178	209	230	248
3C8 :	179	286	228	246 i
8F8	ISO	206	237	249
120	151	256	237	268.
1E11	155	257	224	242
40	187	207	229	247
9D4	155	287	232	280
12G8	189	208	238	2S6
WE4	151	157	234	262
11D11	192	200	230	253
11H5	192	282	238	254 :
1H7	193	72»	228	240
9F3	194	251	233	261
385	155	156	227	246
32H7	182	210	240	258

lid

2016244220 11 Oct 2016

s	s 1 ί	a 1 i 1 §	I S lu	o 1ST eg a wt : : >' < IS
32H7CS ;	ids	S3 o:	241	258
32H8	185	108
33BS	177	109
331::4	184	Oil
34E3	ISO	212

\m lew a, ι Is cm etime ,οη,η·: xtitieen bmtimg prox m- nr pontons sbereo'' teg , foH length antibody, heav\ <h tight chant vartabti dmmtm, or ( DR; 11, COEHti, t'DIG la, ( Dlxl 1, CDR I 2, o¹ t'DRl 3) i?ti\ be isolate from li-eel's of o nee tbas have foeu -mmum/ea wtib .5 ( GRP R or unnunOgeiue components theseof, e.g , by unninno-ainj vstiti bsli-length C'GKP R «xomp tsra bo.n I »'i K and P \MR - w ,b me e'tts. bd » derm.n e’⁵ CRE R for psm.ng ev,m-. eltnUi domains of CR! R and RAMRi) wnl- whole eelk ·, xpiewme CGRE R, with membranes prepared foonx cells expressing CGRE E, with fu-aon preRms, eg, Fe fusions, -.ompoxfog CRd R, RAMP I to⁵ rstree-.dl-d a dommrn fo, reefs fused m id, <mti other methods

Id known in the art, for exarnole. as dexu’theb >n the Examples 1-3 hetem. The nnekie aetd may be isolated by eonventional procetiares such AS pelymetwe cham reaction .(..PCR). Phage dt-p av is another example of a known teeltnniuc whereby derivatives of antibodies and other ap'tgen binding proteins may be pteparsd. In one apps'oavb, polypeptides that are components ot m antigen hm-Ctm, ptotem et -moe-ti are express, ti m any ,unable w>omhmam espresoon system, anti she expressed poivpeptides are allowed io assemble to form antigen binding protent moktepifes, she niselete acids provided m tables am exempknv onlv. Due m the degenemev of for genetit ,ode each of she polypeptide sequence's tisted m T.-bk's ,?-^ς or othefw’s-. depict ti nerem are .sti-o encoded by a large number ot omei nueiese atsd s^quesiees oesidt-s tho-e ptoxsded t hie o·'ottius.-ty si,ill m Pie ar wfo χρρη’κ’.ι,’ tbas the m went appl.„<nion fo’-s

2016244220 11 Oct 2016 wto . i \ ; x ό n u J s< i ( r to m x'kf x i iv x> i b fo cj x5i x i <, o tee w p m eneodmt. each antigs'u binding ptotem ^n aso>-ti tnfiher pave ifo’x nucleic feels dint hybndu'e ^fo elder nnet-ie .«'Kts u q .

nut len. aetds comp' w a a . fecm ,k x.qucuc b >R0 et 1 Role ' I ·. tk F I Role ⁰ mid ot SI Q

ID \O‘'2?+ under pameuku by bridi/ohon conditions Method-» for to, bridging mulea.

aci.S are vcb-hnnwis m the >to fo... $.» < uncut Pnitoeuk ns Mohauhn Qio’ogy, John fo th, y fo, Son-, \> {bfo'w (<? oSt V femed ecr-w, »» moxte^f t*el\ stringent hyonei-at-itt condition uses a p-'eviistwig solution -..etinmimg % sodium chief nie odturn -/male (SRC's, thfe SQo, I 0 mM I D; Λ tpH :< Ok hsbt idlest ton butte* of about for’,» totinarnnkn o\ SFV, and a hybfes/afow: temper Uvn, of yx ί to⁵ tobet 'nntlaf' uy b-uh wiwst solutions, su>'b as our ei'tiirttnmg abma 50% lornvnntde wnh a h-hrids/utson tetnperamte ι-f 42'C'i, and washuse conditions effe'C, m 0 5\ SSi ', 0 1%» St)S Λ sfrmgent hybrtdieuman condition hybridizes 1st ps SSC it|S{, fobowcxl by one os niots washes m foi\ SSC, 0 2% S!)S at ffo’'C. f nnhe-mieac, oneo? ->ktti tn the ml can ma nip η lute th< hvbridiearlon and or washing eoudimms to 'n,;e,se ώ\',._ιν t% st irgistes h-bi'du turn cu- h ma; nnehne <η ids lowpt'smp nucleotide sequence¹» mar are .it least p>%, /0%.

idemsc ti to each ofm r sy pwaily r mam hy-feds'/ed to eiwh owes

I he tois»», parameters .pVcetntg he ehotCs fo hMtffuf/atio’t condstiers mid mmkn„e to; -I oe·f'-g MUk'bk' lonxtoi-ws aw -,, i forth by, ref w,<n fee, Sanfeoel , I'ltscli, and \kiedw <2001. Moieeulai Viomrto Λ I abermot\ M»wu,fo ί old rtprutp ibubor Laboratory Press, (.'old

Fprsng H.irbor, fo,Y . vi/eu, and I urrent Protocols tn Molecular Biology, 1995 fousubel cr to., eds, hum Viiley fo Sous, we, -- i-vons 2 10 undo >-ffei, ano _Ιχίη b lefely dfoesinsued fo those h<e, sue oFilmnr» skip m the .to Ivfe on, <,g , Ov length and w b»i-e rerup-'stuen os t|i,nnelmc acid.

Changes can he introduced by mutation into a Kuclek acid, thereby leading to changesIn the ammo acid yequePee of a polypeptide fog., an antibody or antibody derivative) that it encodes, Mutafions can be Introduced using any technique know».· in the art. In one >, mbodimx'rn, owe o⁵' mow particular momo fed residues aw elt.mged nfing. lor example, a stfe-direetcit ntutugene-is protocol bi .mother embodiment, one oi mure rnttdomly selected residues is eltnnged using, for cx-impR. a random mutagenesis protocol, However h is made, a mutant poly peptide can he expressed and screened foi a desued property

Munitions can be ntrrodne»;d isik» a nuekue acid with.mt signibea.utly altering r|i„i'n»l.»yaxU xictwitv ol ,t puiypepudx' ihxti n cncn les lor example, one i an m,dm aucuOi,.k' supstitulious leading to anwo acid sunstputions at non-essenmu ammo aonl rwnducs

II8

2016244220 11 Oct 2016

Aiteroafively, one (fi i«W mutations can be introduced into a niteleie wid. that: Selectively ehuny. s the h-ologfeal aettx ft\ ot a pod peptide that st encodes 1 ot example, ih*. niuudton can qisandfanxc!\ or qualitaitx My ehango the biological activity. examples of quantitative changes include frtercasme, redeem- ->r ehmmahtt^ thr actons I, samples of ,iu:mmtive ensnges include changing: the antigen specificity of an antibody. In one embodiment-, a nucleic acid -,.-t lotbifi? any antigen binding ntotem desesd'-eh Itenein .an be mutated to -diet the aimno aesd sequence Using molecular biology techniques that are wdl-established in die am

Xnodau usipest piiotdes nucleic acid molecules that are suitable lot u-e as runners ot hybttdmaqon probes rbr the detection of rtudete add sequences, Λ imdeic aetd nudeeule can co-uprise only a pomon of a nucleic acid sequence encoding a fall·length polyp-mude, rbr example,: a fragment: that can be used ae a probe or primer or a. fragment encoding an active portion -y e - a CGRP R binding pm don t of a pohpermde

Probes bused on the sequence of a nucleic aetd earn be used to detect the nucleic acid or similar true I etc acids, lor example, transcripts encoding a polypeptide.. The probe cart comprise a label.gtoup, e,.g., a ta-latisofope ,-. fl nor,?-, out < osnpound, an eu/\ me, ot .tn an?·, me ro-fi-c'ou Such probes can be used io idem-fi a cell that expresses the polypeptide xt'omet ispne, pmo, le> >ee om-or pnsun , t 'e .-< d cured ng .-polsm-p-td et .pettiest thereof *oy, a trngment eor-tasmrte on-, ot mote ι'ΠΚχοι one ot mom vat uhl/ reeioti .li’pfjii·; Γ samples of \,t ·>.> o< mde but <-tc no* honk'd \> pxisimds, \u<-i vectors. aon20 epi-oma: rnmmuaban v„',-'ts ,md expie^-aus scetom. fot example, tecombmant espres-Ou vectors 1 he te, omentum! espre.-sioo \ec-ors s' m emnprisv a uuclete <*,d in a form <- uif able fin exptessmn of tne nuei.ue aetd tn a host ecd 1 he omombmant e' pte-sion ret tom include sum or mom regulatory .sequences, selected, on the busts of Ute host -< dis to be used for expres-ion, which is operably linked to the nuclesc- aesd sequence to be expressed Rsgoiauuv svqtisiue-<

tnclnde those dud direct constitutive expression of a nucleotide sequence in many typ.'s of ho-t eePs u v, 3\ fit eatb gen - enbanre-, Rous non- -, ires m-mioier ami e;-tomep-,io\ srnpromoter), those flint dnetd expre-sion of the mieleoftde sequence only m cerium host v, its t, e ,'ixsun^pe.'”e ^?i m-k-.o y seqnen.es ,Ve*\o /, - fifix Λ < n -./ΛΆη ’< ' i ? x~,

Menial--. ,/ o/, rib”. 51 rem , 2 fix 12 A, incorporated Iw -ckreur'c Iseieu'i tn the-; enoreix.”-}, and those that direct indue idle expression of a nucleotide sequence in response to particular ue-.tment ot condition 'o'y, the niexdlodnonu! paui-m.-i m m,unmake, -mils and the tutresponsive and oa smeptoi-n,-, in response e promoter tn both, prokaryotic ami eukaryom, ss d.'tux tsoi, /,/} It wdl he anpieeuted hv fisose -kibed u- Pm ,m mm the do-ivif of tbe s'\p<\'sMon v. c:-u can dep* ltd on such laemts as the enmec of the ho-it cell to be imm-lbtmed.

119

2016244220 11 Oct 2016 foe level of . xpo-ss:on of prob-ro doored, eft The , \po-ss:on vtxrors i an be mtro.bieed soto host cells to thereby pio.btr,- pt'ob-ms or peptides, including fusion, pifodns or peptides, often, tea by to.:· k.>. act J* ;o< describee h.-ivm

Xnother aspect provides host cells into whtdi ,t teeonPmtaul eeptcssiot- \ceto' hu* been p inrodtucd \ he*? -<e:l e,.n oe try proMiy-foe cod Dos e\amp\ ί <.>>/<) _vr euk.ir ode cell <ibt e sample, yeast, insect, or roamm-foan cshs o g, CHO .eb-o) \e-, for O\,\ cat- Κ introduced roto prokaryotic or eukaryotic eeiks »w conventional transformation or transfect Ion tc, tempi's I'm stable transicchoa of osunniJian cells, tt s* known rout, Icpea-hup noon the expression vector and transfection technique used, only u «nndl traction of cells may integrate

H) the foreign DMA info their genome hi ordC’ to identify and select these integrants, a g-cti-c ibat et cooes a -.cketihL t-taforo fi o, to: icsxup.e u- aistibroo,. ο :-, get-etallv nfoodueed {--to tne host cells along with (he gene of roteiesf Pteieoed selectable mtrokera nn hub' Pros- which confer teatsiane>. to dtne*, stud! as <34; fe byi.-moyero and oh thotiexate. Ceils stably transfected veuh foe introduced nuefe^!e mid ear- K tdendfied hv drug < -lection u g., ,χ-lis dial

1.5 have ineorpomted the seiecfohle marker g>.ne wdl survive, while the otliei cells dies, amoinj other methods.

Po-paring Of Antigen Burning Ptoleroa \r'it'hu;n-.m antth<feies that am pros ided can he. tor example, derived from ans anubody -prode. mg ammal, ou.h as roev«e fat, roblm, goaf donfo-y or iron-human pnma;.20 touch ,<s monkey G c , m ο,ηϊίοΜί.χ m tlx.-ns monkey) ot ,-,ρ„ y, .u. ensmpaii/cefe Mott-hnnaan ift’lbo-vhe* can b.- used, fe-r instance, in ->< ego-, cell erthure mad cell culture be*.-J appli-ufoons, oi >-,ns tnher appln-aisoi: w lice an nmnutie ra«pou-O to ihe ai-troo.b, does nol <roi nr ot ts trs’gn'ftc mb can be prev rated is not * cone .-nt, ot i« bro red in e.-tfotr c-thornrooms, the jtn'ibo.hes m q be piodu.ed Ov immur.i, nso anunals u*any meti'ro.is known nt foe at',. -„s dose;food abov t and ot tn bxantples i ) below Ills' esanipm-, efesuibe the generation o; .out; t GRP l< embodies using thtee dilfeiem mtmnnogen preparations - os whole cells expressing fulkk'ngih. v ersions of two mapu >.ompoitettl, of 1XIRP R IGVIPI mid VRLR. t ti i membrane extract·» boro siteh xdl\ and tin) soluble t ’GRP R obuunej by co- -xpressmg and psit ofeitg dse A-letnunai - siiueehulat croman-soO fit R ,-et.i X \\1P^: 1 he .end'-foms m.e, he polyclonal. pvouoelonat ormro, be synthesized m frost cells by „wpr..->.\ing roenmbrouot DMA h nl :y human untihodies may be pn.pare,l as beset foed above by nnmeutenro transeroee animals «.or-tamutg human immautoglobului foes or by sek-vttng a phage d Apfes hbrery that ts sxinessroe a mperiouc of human mfobodies.

120

2016244220 11 Oct 2016

The nsoHiR'Io-irfi utit'boCK's (m \bte -. an be pmducvd b\ a variety x'f txvhuiqves, mnnoeimta embody mePtodcmge , g , m„ st-pyj ed son me „e',i hy bmbzuhen tevinisqnc of Kohler and MsBteifk 1975, Yuno ,?5p'riO5 Altemntw ely, other techniques ibr producing monoclonal antibodies can be employed, .for example, the viral or § oncogerue nee -> Forma non of B-lymphocytes, One stumble aturmri system for preparing ttsb-iriomns i‘~ th,- nnaita· ν,·,ι< m, wlw h is ',ety well es^bl-sbed pioeeti-ae humum 'abuts protocols and techniques for isolation of immunized splenoeytes fur fusion are known to the art and idus'OUoe apptoaehes u>„ ries, Jibed m the 1 >,aswpies helms Bor χηι li niuceriutes, B , elk from immunized mice are p,piealb, fu^d with a suitable nnusmtshucd fusion partner, such as a

H) un:H-:‘ - sm.eioma - ell line, if desired, rats ojufb>..r naomnals besides ears be immunized n^iyad of mice and B cells from such: animals can be fused with the murine myeloma cell line to form hyb'ldmmis Ahetnatsvmy, amyemm i ceil hue dote , sottre, other than mouse may be u-se.l hstsioj. psoeerinses ^!ό making k-oiidomas Jso are w ell known.

he aingk- ehum .embodies than are pros tded may he formed hy linking heavy and right

1.5 chain variable domain ;{Fu .region) fragments nm an amino acid bridge (short peptide linker), ’esiutmg m a smale poispepurie eri „n xim single e'¹ tm 1 \s tseKs' may ee pr.,pa,eri w ItfMug DNA encoding a peptide linker between DMAs encoding hu.· two variable domain pefr peptJes * \\ and Yj. > 1 he wesutimg pels peptides xan fold Pack <m yh/msafres to ''oim ifrnpgen-bmdmg monomers, or they can form mtsbomeix κ g , doners, turners, or temnners).

depending on the length of a ilextbie linker hetw' an tbs' two '.auulue domum- IKortt et m, 1907, Frol £>x, 1U.122, Korn m,fr, 2001, /?bwd Aug, IbAe-lOxt. By combining different \ md Vti -eompusmg peg,peptides, one can fuiin swibimeise set's \ ritat fund to rislfrmut ,p.topes tk.sente am ,< m Did d-wmd 2 >w _X > 1 Rtf 1 vb te„<,' eeselnpee fos the proOij,tfsiriofsiui'b'ibam aimbodtes-neriul'· t: osedis’seifri, d m i. Pat \'o Ί,Ο-Ιο,Ήχ, tout,

antibodies dettv ad from antibodies psostried herein include., but arc not lumtcri ts- sei o comprising the variable domain cembmetsmia nt the heavy ansi bight eualn samsbb' wgtens depicted m '1 able ί,ο* cn’isbitsapons of hght and heasy chant satiable donum- winch include ( Idris deputed to I able- I Wand IB \nribo,kes pt<>\ tried he’xm that ,u- of one mbela-s can be changwl to ammoriics bom a different ,-nbei.os nsnm suhelas» wvitehmi. rnchnds ihtn, igi* t'tubedimmw h, derived {soman lg\l antibody, tbi example, urn'i i?,, ν\.ν>; Xu,h 1/,longue- a-Mw rise psvp nation m new un‘iho,'hes mw poxses- the antigen bmrimu pioprities»»{ a given antibody t the p<aem

2016244220 11 Oct 2016 johbodyi. hw also e\lnWt h-fooufcai properties exso<. iaix-d with .»» awfondy isop.pe or subclass ddkunt to n w-, 11 .he p-a„ antibody toexu tlvt. * i>\ \ ed Kji.srsa- tecn'O^ed i loned Π\Λ erixOibiig partieiriar antibody polypeptides may be -. t«pk>yed «η such pro-, exlures, c PY\ aucodmu me constant domain of an antibody cd the ik-nul isotvpc, < c. <. g, f antm ct ((> c 200.?, .Veto><A 5 A->>', ό\Ά' bM;?03-a to.

Aecoidinalv. tbv antibodies that ate pun hied include ihosc conspiisutg. for example, the variable domain combinations described, m/vn., having a desired Retype Gw example. IgA, IgGb IgCM. igGb lgG4. Igl , ano b’Dt as well as hub os Rah') uapm>, m*· tbewol Morose} d n le* >4 m be-ned. a mm < Iso b„ nexeon to ntredew; a non t mutation :< Ph< 1’ '4 PPt p > oi the bioge ο-ονι» a\ ,tcs_x ? tbcd m Elnom < ?»/, 1' Zfoa > S', gy-a _t o 40~_% sueorposatcd bx rcki.m-„c hereto to aik-viaic a tendency- to term lutrud! eham ehsuifuL bonds that, can lead tx> heterogeneity m the lgG4 antd-odlc^ .Morxovxi, techniques for deny mg antihedixs liaxmu xliffeicni. properties v < , \<nv ng affitrito for thx' antigen io which they bind) ;η\ also known One such tx\nmque, rekrivd m

1.5 us c «am .shutYling, invokes display isig mmiuuoclobishu vuiabn domain gem- tepeinums on the vurlaee oi fiI snvufous toiermphage, often referred to as phage display € bain shuffling has been Used to prepare high d finny mobed'es to foe tinmen ?wbe«yio^vd?oi->o«e, as described by Marks c/ mA 1 dbd, <%A,A< to-ano· Ip '?o

Censer- aux -’ mnditl- noons one, be made to the heavy md light t bam xat Iahle regions described in 1 able e, or the ( PIG described ut tables 4 \ and 4B land corresponding mod ill eat tons to the encoding nuef.de xesdst to pr-Muex' a CGRP P binding protem having certain devtt -.hie functional and, biochetmcid dunaeseiisties Methods for aehmx usg such modifications are described -foo-e

CORP antigen bm.hiug proteins may be further modified ui '«arsons ways. fo> example-,

11 they arc- to be used for therapeutic purposes, they may be eonjugaten wdh polyethylene gly col i pegy 1 atx’d s to ps olong the- sci in « half- It Ie or to -,. tm<m-.. e protx-i n xlelix cry Λ Itx'mat ix et > the \ ixuixm of the subject antibodies m n.gemcm.s thcicof may 1·.- to-d -x ith the I -. ternon of a dd ferent antibody molecule The Fc region used lor this purpose may be modified so font If dor's not bind complement, dins reducing the likelihood of inducing cell tons m the patient ed o u.,'. ri'e ft.-leu pt >w. a-'> Used a·-a t'e ι ape n (<. igent in iddition. the subject nmbod',.-o' inni.fiona! ftagtnents thereof max be - unjumUed wu.lt human semm albumin to enhance the serum halt drib of the antibody m enug.-n binding fragment thereof. Another useful fusion p'zii Win for ihe .intn’tw binding ptotxm·. or fiaernenis thereof is truustbytetin (Ί 1 R i. Γ'1'R has

2016244220 11 Oct 2016 foe capacity to t'otot s tcPum- r, thus an antlbo ,iy - Π P Riston ponem e.m toon >·, w.btsxuk'W 'atttilxtdy.: which, may increase its binding avidity,

Aitcoumv eiy< wtoCinriai modtfiem'ions tn the iuneuonai ,wd orb:o, heoucel characteristics td the antigen binding prcteuts described herein «tsv be achieved by creating .-eubsfituuons in the ammo acid sequence of foe heavy and built chains tout differ significantly a. then etieet as a atm nt-.iso (a) tor spaetute of the mole-, nlat h;-,< Lbone tn da mcaot da substitution for cvimpk. w- a sheet or heiicai confirm nson, to) th., eh. ree or lgdronhobwhy of due tnolecuie al da: target site, o· u. t th>„ bulkmess of ihe side chain \ conservative amnio acid snbstimtion ' may mvoive a subetiturtmt of a nati ve armno acid ryatdnc with g nounstive ” -stone Ι'ηη ha,\ bni,> ,>r no , tte t on toe polatity o^r, barge ot the ammo at, id u¹ due at that position S.v, Ί alto' 4, sn/'-,< I uttnerotore, any native residue in the poly peptide may also be soi'shing'd o «th al.in.ue, <0- has bee·'¹ prev io,isiy dcsenb, d for nl.mme ,se mnoip mat igeneos

Ammo at.id satotrnmons (ok, foci ionisersattvot lon-eo.o.xetv aloes ol the mbieto antibodies can be Implemented bv those «ktlied in toe an bv apply mg routine techniques

Am mo acid substitutions, can. be used to identify important residues of the antibodies pro vided herein, or to increase or tto-;i\as>, die affinity of these urttihodles tor human CORP R or for modifying the binding affinity ot other -mtigen-binding proteins described herein.

' pmssx'i syxfotos and - onsiineP- m the torn oi piaoiiuk, exp csmou \i\tots, trattsei iption or expression cassettes that eotnprts. at least one pnlvnueieeiide as described above are also provided herein, as well host cell· eompristr^siieh expression systems or constructs.

fhe antigen binding proteins provided herein nt.:\ be prepared by any of 5 number of -..onvc'tooiud teehmques t\.i example, CGRP I', anisgeu binding proiem*-- tie* to' prodaa<'.5 is >ecotnbtnant expression vounot, using ,my technique known m the .nt c g,. Motsoeioual Xulfoobtes, I lylxtolcmws \ \ov> Dveeio-ioo w Fholoyu al \n.ily ws Rennet et f b -Is ; Pkuuiu Fh„w, \ew \ot, il'foOi mid vntmod.es \; abo» cot·, Mama, P. Row and I uo„ tnd,> t Cole Spring U.nboi I atov ttopy P«'e>\, Co· I Spring 1 latoot, \ V *

Antkcn binding proteins ean he expicxsed iu hybridoma cell nne- ο .g., m parikniar antibodies may he expressed tn hybridomas) or hi ceil lines other them hybridomas E spressmn eot.xtnu to encoding the ambodv'· e w be used to tmnsfoon a ttiantmah -at, msec? ot mn'rob'Cl inist ceil. transformation mm be performed using any known method for introducing p-eynuehoiides mto a host info nn-inding, on evan-pl · packanun- the j'ttoi.m teotats. m a sons 'or buctcnophuge and tn-msduemg a host cell with. the construct by tranJection procedures

2016244220 11 Oct 2016 known tn tl·? nW a*, eremphtrob hy 1 mn d Sretes Pat re No 4,v»0,3 1 o, No 4,>'>| 2040,

No 4,N0,lh,, No 4 Ihe opt teal tt'tnsQruekon pmo *h?e . mJ w,b ,Lp„:td enoit w hit h ty pe of host ceO re- berog mnistottned Methods fot nmp.inetion of helot morons polynucleotide,·* into nturnmahan ceils arc o cP : ι«.Άη nt the art and include, but are no) limited e to. dm dan mediated fr.m-dection. wdcinro phospk.de pre·. spiinhom polybreue mediated iriitnocGtom prute-pitree tusiotn cleeinnomaijotf, encapsulation ol the poixuneieondets} it; liposomes, mixing wefete add wbh positively-cfearged lipids,. and direct rotcromisedon of the DNA into nueiei.

Reeofnhnnnti expression eonstrtn.t- ts pteul!> somprtse a nuelen. acre! molecule encoding a polypeptide comprising one <r mom of inc tollow trig· rue or more CDRs pros hied herein, a Opp.: cwtm constant re mou, a light chant reroutt'k tegton. a lc aw eh.un eotjstaut tep.ton <c g , C I i ; rod rore _;dt; and os anethm scaftohl portion of n CGRP R antigen Otndtmj pfoietn. These nnelcte ae-d v iptoi» e*< use ure, Bed neo -ui apprrepreafe expression vector using standard kgauon techniques. In,one embodiment, the heavy or light chain constant region is appended to the < -tettntn-as of the anuA GRP re-spedOr ttenxx ot hen? cheat: s triable region and «> hatred into an expression veenu, fhe sector :,·* typically selected to be iau: bond tn die pa^teniar hoct evil etnpiored (,* t , th. >ech>r ts compatible w oh th,· ho*»t eel: rnaeitmctv, permitting empid'reanon and or expression of the gene can occur' In some etnVodnoe us ret to.s me urea fmn employ mOt/iirefiagtncm rotopk'ni.'tOauou assays using ptoteui tepo tex,-*neh asCahvdrt'iolate imluctase in , lot exaroole I x Pat No redAVkA, w hfeh ns hcrCro incorporated bv refeicnc j Suitable ckpres-wren '* cetmx _v,m be purehased tor example, from lu\,uoeeti t ife Ί eciroeiog.es o? BD Btos,rienc>..s iknmuly 'Vinnteeht Dittei ttsokii sectors lor cloning and expressing the annhodiei and fragment*, in Jade there described it: Burnetii and McGrew 200 >, fhmkvh /kto h<u>; h.reereg M.-P’ rea-4, x>* hteh is hetero* rocorporotcd hs rekrerree. Additional snttahh, esptesstott \ reims .ere discussed, for example, tn Vet.ksA Ff,’r«nJ ,\oi IxfiD V Gnedriek-.-b) 1990, New 5 orro -V<nk-tm< Rows

I spieulk. esptes'ion x cetots treed tn am* ol tin. how cell· wilt content reqnencs lot plasmid mnmienanee and tor clotnng .rod expression <u csog>- nous nucleotide sequence*· Sneh sequences. eolk *tixGy* scscocd to a·* flunking seq nene... >*' in cedain embodiments v-h typically include one or mure of dm following nucleotide sequences' a promoter, one or more enhancer scqueixes. uitoiiuiri ot replication, a traureripitoual ietmmaiton sequence, a eompreie iniron sequence eontammg a doner .rod ,receptor *-phce she. t requeue- encoding a reader seuuenee ibi polypeptsds' v * eetnro, .* ribosome hutdmg xU*, a pmy -,denylafion xcqncmx, a

2016244220 11 Oct 2016 poo 1ml ci re gum io· inverting fne -mJ -\ at td encedtnc the poly pepu.le ie be exptevO.I, nn.t a sekv.abk m cxet elemcm beer· oi theso -aqucuees is d'seuss^J below

Optionally, ibe yeetor mas contain a ''ia;?.*eneod;ng sequence..- j an snk;onne!eoiide molecnL located at the ?' 05- 5' end of ihe C’GRR R iundnig pu.«tein votimg sequence, Ibe o! ken ue ieedde sequence encodes poly Hi-> t such ns hexaH is), or another “tag' such us FT AG ', HA (1 temagiutinin tibkieiixa suns}, or ntye, for which eonimcrcntily uxaiiubie ntifthodlex exist 1 his lug is typsc die in-vd to the poiypepode upon expression ef bi,.- polypeptide, and cm sOxe as i me -ais soe aHhniv pui-dfeation ei Octet non id ibe t GRP R binding p'Oien· hem th<, host cell, Affinity purification can be accomplished, for example, by column chromatography using iq ar'ibodn's i>« ,mu the tag a* eu.db'uiy mauiy. Opno-xfiy, Be tag e.,n sitl'sequemA be removed from the purified CORP R binding psotem bv various n.« .ms each as using ecrum pcpiiduxes For -cleavage.·

Flanking sequences niu\ be hoinologous R < , ttom ibe sai':-,. species and m emm a- ibe Ii· «si cellg heterologous < ·„ , Aeso a species ome* than dm- ho«t cd· species or straw, hybrid «?..·., a combination of iiaukmg sequences bom more than one souixe), \vnthetie oi native. As suGix the sonme -.e a 0.0-0 nye -emu-ixe mas be any prokaryotic or eukerveib. ot taoism, any yertbhtare or myertelmtie organism, or any plain, pro', ided that the hanking sequence hr functional m. and can be activated P> th. bo-4 ceil .machinery, flanking seqn·. nces us·, fid ,n the xei tors may be obtuned by ,·.· q. of -wera! methods ο eh know n m the art, I \ pmal i\, thuH.mg sequences useful het cm 0 ill bay c been pres sous?, identified le. mapping and 01 bv restriction endonnUe.ise digestion .md can thus be isolated from the ntepet θ’-su - some c using the app’opriat, scsiomhen endonu, leases In some euses, the b.dl nucleotide sequence of a hanking sequence may be knoyyn, lien,-, the hanking seeeerec ;rc,y t>i s.i hi, mwe tstng t . nGlmns ieseroed nme·-! Rv am. leu . ds.rli.e>

or dotting,

A hohsoi ah -,ti one, .5 portion et'-he hanking xe pienc·,- .\ known, 0 m.e, Ve obtained u-un-. peomecasc- chum reuuton (PGR ? and or by -eixm-umg ·.·, gcnoime hbrmv w-.th a suitable piobe 'fieli as an obgomn k'oitd;· anO os slant,me scq'at nt e fri.>niem *rom fne .same or motm-i sneeit, 'd’lietc the 'among s· tin t >,,- is _{«_{<ΐ so-owr. a bus meut r«f I *\ λ louta asm a haislong eh sequence may be i^.lated from a huger piece of DR \ that may <ont nn, lor example, a ceding scqiiviu e sir ever! mom·. r gene 01 cc-nes Isolation ma·. be accomplished )-', sestnetiou endonuclease digestion to produce the pi'ope? DNA fmumcm followed b> tsvlanon unntg uguiosc cel p'ifdii aiso-i, Qiao.cn' tehn-m chrom a'esy ap>by A h dWoiih. C \h or oibei methods

2016244220 11 Oct 2016 knoon to the shitted astmrot. The selection of suitable en?y mes to accomplish ibis purpose roil!

be readily apparent to one of ordinary skill in the art.

4ϊι origin of replication ro ty pieully part of those prokaryotic expression sectors purchased eornnterctaliv, amt the origin aids in die ampbfieaiion of the vector in a host cell If the vector of choice docs not contain an origin of replication site, one may be chemically sy uthesired bawd on a Lttoro n s \pi,-n, e, and ligated into the sector, rot example, the origan of ’'epbroiiOon fioro tbs' pktsrntd pBl<522 i\e\x I ngUnd Bwlubn, BeseHx, MX) is smtabie for mu-a gtatu-nee Oise bat tcroa, <aut \,u ,mm ·> if J otigms w g „ S\ ep, pnhoma, adc'uex ntm, vesicular teem. tuns \ nns S\ k or pamllomsx traces such as 1 U-M or BP v t oe usehu fo;

Ift > Minng seete>i ·> ro ro eromdsan eeUs 1 hmortdly, Ute ottgm to rep'teatton component ,s not he: ded for maroroulnro expression \ „etors < to; example, tne S\ Ml origin is often used only bee „me d also eo’drorro Me s 'rots ><n m p-ot o\ ;

\ u unset ipoon iron η tun ton ’eqnene',. ts typically located 3' to the end of a poly peptide coditm region and serve·, to terminate tnmxenptivn. ϊmualiy, a tt inscription tevntluatton seemenec tn prokaryotic edis w a <»-(' neb ImgroetU tohoroed by a potyd xetpiutee, Wink' the seqttenee is e-mtly cloned from a library or even purchased eonnncreialiy ;,.·> part of a vector, it e.ei «Be he leadtb, -y ndteu/, d ,οη < ΐ 'ed ods tot roa, 'e'C ,-e d -y 'thesm am h as Moro described herein.

\ select ede ipaiker gene encodes a ptotenn m-t ess my. k„ tbs' sin s mat and groroxth of ,·, liost cell grow u nt a seleerme culture medium I y pteal selection marker genes encode protenw thm y B confer mstsi wee to .intthtotte'- or other tovaro, s. v , arop'edlm, tern. el mo et kanarnyehi tor prokaryodo host ceils; (h) ,eompioment auxotrophic deficiencies of the ceil; or ed supply critical nutrients not available from complex or denned med,a Npcedte v„ leetable markets ere the krovnuystn rcs-stance gene, tin ampnuiro tesmianec gene, and the tetraeycime

2a .esmtanc*. gene MixatUsgeoa-dx, a ,corns cm tesmkaue gene max ,th\o ne troed let s/L\dots in bob, prokaryotic and eukaryote he<u cells i hher selectable genes max be used to amphtx the gene that ro til be expressed. Wnpbfkation m the process xv bet eh, genes hi.,* rox- teromed ho production of a protect wtiicai tbi crom'.rh tu >. el- suiso,d me reOciated tn tandem rothuu the ehtotuosonis's td\ue-.. essme ed geuewpom, of reeort'bro.ipt eebs bx troph- of suit tide scleewbte rn t'-kero for m.> turn slum eelm. include dug, drobdate icdnUase iPtil'R I mid pom,rootles-· tb ,uu,bne kmase genes M'nroroahkro, cell trntisformattfe w· placed under eelesfen pressure whereto only The transforrnanLs are uniquely adapted to sou, roe t'x virtue of the seleet-tble gene present >n the sector, Selection pres,roe ts imposed l>x cutrnruig the transformed ceils undet conditions tn

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2016244220 11 Oct 2016 which the - oiiccnii.im.iii of sclechon -igoin in the medium c< sue- cssreely tnere’ared, there hi leading to die amplification of both the selectable gene and the DV\ that encodes another gene, su-..k ..is mi .tnhgcn binding p-wen· dim emds to Ct m.P is As , resreh mere ire.I qured ere ot red jregt ires .reancedgeG m rn i etc n .reoitk'M.o *ϋ wire amplin>,d l).\ ihresoif'c-hwhiig ‘-'fc i* usually receswuy fot hansutton nub -,non ot n-i\\A and is eii.trivtoozed ⁵w ,, rehtnc Ihdgarno remureree tpnn, snotest ore, ko^ak sequence teuharvotes} he element is tipi.aby located ' totb>, ptowotes end to the coding scqtictfi'e of the poll peptide to he expressed,

1(3 b· some cares such .is wre re gh cosy bn.en ss cesce ί 'η i e-ik.cyoti· he‘t eril expression system, one may manipulate the various pre- o- pit .-sequences to tnipi-we akeosi b ϊ.οπ or y teld t o? -wimple, one may J ter the p -Widuse > ie is.tec site ot a p ehenkr signet peptide, ot ;ukt pros.-queuies, which also ntci affect glvcosy tanon The thud piorem product w tv hr ve. m to, < position u, i mvc ό the firm rmise acid of the nt ton.» proreu'A one

1.5 or .more..additional amino acids trtetdedt to expression., which rnay not. have been totally removed for esempte, the final protein product may have one or two amino acid residues ton:id i-'i the peptidase eh as aye Mie a-Ua, n.-d to the annno-tcrmmu-·. Aifetnain ely, use ot some enzyme ei/avage -'itex may s remit nt a sirehtli truncated wren o-l the dv-ned polvpeptidc. If the crewmc , ms ,ιΐ such un-a wuhui the mature poh’pcpnde

I repression .end riorum, w id typtcaltv- contain a promoter that is ieepeni.red bv the host oreamsrn anti operabtv hr; cd to the molecule encoding u ('GRP R binding protein, Promoters ate taurauseribed scquiinccs located upstieuin (g ;, 4’) ^fo the start codon oka st· sictniat gene ig.-ucmds wnhin uhom 100 to sOdv bp) that maskol non sen poor of die structural eene. Promote!s >·,κ com .-mmn.dly ^youped mto one ofreo ehis-ie-·, inducible promoters nod enitstittitive poimioiere. Inducible promoters minute increased Gi ris of trainer'piton bom

D\'A tind-.r their control in rewpoure to rente thangc in culture conditions sti>. r as the present's ot .erereec o''.-, n.uoem re a sh. ;se,. ct tenmei sti re ( ot euutsve pjornoters or the otn,-. hand, umforeidy trnnsi rtbe a gene to which they arc operably linked, di.n is, w n'h utile or no coiurta user gcuc .„\rscss!oif. Λ hues' number of promoters, recognized by a variety of potential host cells, .are we 13 known,. A so j tah 3 s promoter is operably baked to the DNA encoding hem, y ehaiti ot nwu eh un composing ,-. CGRR R b-ndmu pmucm bv re moi mg the ptemuh - km t the source DNA. by roirictiois enzyme digestion sod inserting the desired promoter sequence into bieveetop

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2016244220 11 Oct 2016

Suitable pmnioters fon UM’ w tin ye -,st bort» ate .-.ho web known m the art Yeast enhane/m are adv uuta'?e<>nsi\ nsfo wsth yeo-t piomolets. Sbfoahk ptoteotets ibt w uh mannt'al· ,n ho-a eelR me w-Ί: known end m, tisde, bm are net hunted ',·«, those cbt need uont the eeutetti t of » ifuses -meh as polyoma virus, fowdpox v u«s ade.no» >ηιχ t -melt a* foemw ttus 2 ·, oo\ me papilloma v urns, ,»o tan s ηνοοία \ uus, cvlotue^alov ires, rmrov irttse» hep units· R V) ts a ni S' e at \ nt.s 4ti t,\\ 44) O',he Mnfobie t \»'tr ah/t ρ»ηρ met - we'de h. ,e o'og»ti's mumroalfon promoters, for example, heetettoek promoters and foe actin promoter,

'.foitiMnal ptoouc.s wtituit tn e, be o« utiesesl tn. hide, btH ate tun fowled tit sY-fo eaifo pu-mutiti «Beno-st aid t 'hambott, I⁰⁵» i Mn'm-e 200.304-310); ('MV promoter BI itorttsert c/fo , i'fo-k B'o\ fob !;<,’<>' t' 3 1 ^x I -'·54~00? p «he promoter contained in the 3^: long (etwinal tepe.0 ot fonts samoma v ens lYanumi-to ¢.' at, Bfob. < ; B 22 ?8?-~4Ή, hetpr* dt» ntlfotie ktnase pumtoi·. r BA apnet < r ufo 1431, rrm . \'nd. Acad. Se( (22 4 ?S. 144424-15). ptmttotet and tegitkituiy ’•eqaeae· •-Own the nti'Ufotihmnme nene Hfonsiet t’fok, jeo ·,») tfo ,d pw's, yene ?n me' * v,eh ,o me oca r ertmis: prorntye*· « Vila k- mamtl w fok, 1978» Fwr. 'for/. .-f.i.'iiB. foe. (25.3. 75:3727-3⁷ U t, or (hofeic promoter.(DeBoer or<fo,, 1933, Woe, iforr. .·!<m2 .See (2524. 30;? I h > Also oi interest are foe follow inc animal mans, .'tpuuntii ennni leg-ms, which e'foot', its».t ’ sp a ilktR md for» e foee ntd'/e-l tn ttansuame nmmaB the rhstase 1 »aene control fewoit that is attise m paeetetite aeuwr cdis iSwift i r <B , 1934. i'_t/( fo fdo-n4»'., Οπηΐ/.’(,»'. Rfofo (fofokwwy /fo.-ow Atm/?, (foerr?' fo'·'··; fo) >99-400, MacDonald, fod,/kp'Bfotg, 2 425-5 fob foe msiuiti u-t>e eon-iel tccn-tt iltat a* :»eii\c nt ρ an.ream beta ceils (Hanahtn. Bfo5, fo?wv AS I fo 1221. the ininainoglohafot i.eue eunttoi tepton foal t,\ aetr» e tn. lymphoid ·. ells < Gross, bed! i i ok. 1034, i 1-.2 fo <''('('?>. .Adames er_;i'/, ptity fo?«y3 2, ?3fo Mexander crfo, G^!>fo kt 2 (<2 fo < ~ 14 >»,-1444), foe r.ottse maner'its *utuot »ii us emilioi ι,·»>;οη tinn'is a. liv· at lesbeniut, breast Bmphotti and mast eclB t kedet«? t> ! ‘fob, i SV 45 fo?-44s L utc athamni gette control region fo<n o active w 11· m iP'nke- >¹ a’, bfor, B,.-^ » »>·</ Z>, «2 i ?os-'7e), the tlpfoi-fotopretetn esiis eo.nttol region that I* set;',., m he et iKruntlaut»/ <,n’,. *035, Vm. Ccd fook 5 BfoBiidS; Hammer w .oh S03ti eew/s 253:53-5^e foe alpha ;-swtfospsm gene i\un';\4 reform that is e.etase in live? (Kelsey cGa/., I⁰*?, o, et >, d ;.(,</ j.26B;~l t. foe bain-foubhi acne i.cttito. s n.ion t. u is ,<.,o<e n r.e, Je d - 21s {Moew.e u fo hhti fomn Ji? 3/4 t {«!, Koliias e( cd, (05(2 ( e(/4b'30-04). the tnyebn baste piotem gens' eompoi leeion that ss uetive in ohuedenfooeyii. edis in (he fomn {Keadheau <7»Β, 1037, Cell Jv 2'h 12), the npoxsin light dwri~2 germeonttol meiort that h ecdve.foskeletal mnsfos (Sant, 1985, ifouwe 31.4::283-28b);

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2016244220 11 Oct 2016 anti the ί;(.ιΐΐ·υloin!p;-. ;eh-asim; hormone gene ,ηηΐίο! region Y ·,ΐ is unto e tn the hy'potiiakm»s (Meson nt <e . 1ΎΡ, St'<<??< ς 234 1372-13⁷M \n enh tne-.-i -- q·:· w e nu\ he m-erted ntio the vector to on rease tenisei mtem of DNA encoding light chum -m hemv chain comp) istug a human ( GRP R t-m-dme ptolcsn Iv t te'. u euhnrwto, Enhancers arc e<->-aeiioe elements ot ONA, u«u.Yv ebon* 3 0-500 bn tn length, that act on the psomoter to -tn.tef.se iumxeriptton buhtneerx ate iJatfv.'k os -eutatioo tmrl poxition independent, h.e, n\e been found ,>t positions noth 5' anti 3' to the irunteriptiog uml Werai enhance· xvipteiRe-t available from mammalian genes an. known ivy,. glohm. ehoauw. albumin, alphaYto-protein anti insulin). I ypteulty, however, an enhancer Rom a \ iris,-- w uxcd.

H) Thf’W 4(t >':iu?i-the - ytemegn'io-nts .’any promoter etih.-n,ex Ye po-yo-na . twain <--wl aticaovhvts enhancers known in the art are exemplary·' enhancing element's &r Ye activation of. enkas voti-e promoters White ,ut etihamer may he positioned m the v-..etor either 5' or *' io a coding sequence, n is o pn ahy located at a vie 5' I tom Y·, ptomoler Λ sequence ene-dutg an apotopri.de name or heieto-o^ous signal sequene/ (l/atier sequence or stemn peptide) can he

IX ituorpomL'd ndo an e\pw *-stou veteer, te promote mhac<. tint a xcrtetion ot the ηηί»'<Μχ, Imchoice of signal peptide or leader depends on the type of host cells in which the antibody·' is to he produced, end a hcterologtitie Ntgrsti sequence cab replace Ye native aigntil sequence, .I.Aampks of .xnmal peptides that ate rtn.a.t.tonal m nvmun^iian host eJls mdnuc tit/ lotiovtne die sigii.il -vguetee tin (rifetk’ttkut- iii -} tie-· rti-ed ni I \ Patent No 4,Ύ5.195; the signal sequence fot interRur m-2 tce«, ptot desetthed m t ovums et id I’Yu, 312 76s. the inte-tieekm 1 receptor signal p<.piide tie--cribed m l· R Patent No 03o ' ?oo, fh/ type I tntei leulnn-1 «eceptet smutti peptide tl>. sei 4><\i m f S Patent No 4,Y>s,Y#~, the rt ρι· 11 imeY/iikm 1 receptor signal peptiti<, tiesteihed in b'P Patent No 4 R>4 s 16 i'lse ispiessmu xecti'is tinti .no pwwtded nno- he .οη-ηο·. ted tsom a siadme xeettc such as u eouviu/re tally avntlabk ,eetot Sneh vectors mav ot may not eontatn all ofthe vle.sired ilatu.sng x--q»‘ in es Whete on- ot mow- of Hu- 11 inkmg sequen·. do-.- -’bed herein are not a heads psexent m te/ vector, thev m.w te ntdiviti-tativ nteawevi anti ligated etio the v .uos Methods u-;>.-ti lot obtaining e «> n of ih.- ti.oiknig seqnene·.-· ate well known to o^e shYeti tn the ait.

Aftev Ihe ' wot h ts bc/ti eonxltt^ted ai>d a nucleic tetti mnSwtic wteodinc huht ehanv, a lt',.avy chain, or a light cham a.nd a heiory chant comprising a CteRP R asnsgcis binding xequene.,- has been inserted into tite proper site ofthe vector, tin.- completed vevtor nmy be st'sesii-.l nun a svniabh· host o.-R tor asuphtie-Unni >md os ρΥνοορί-Ο.- ./sow-ston Ur' tens,io.rmation. of an expression vci/tor for an imtigen-bintirng protem Into .a selected host cell

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2016244220 11 Oct 2016 may be aeeomphshed by well known methods including innisfeetion, inGetioig calcium ehospbux uo-p eumbmo·,. teui-upoxiUO''·, 5 oeon'Ueeuu,. bpoluu.<m, 1 >1, \i -dcoun meduned tramHe. tton. or ether s-mwn leelm-qu-es The method sele·. led w Hi In pun he a function of the type of host cell to he used. These methods and other suitable methods ere well e known to ibe skdkd arttM'U, .mJ ere ->er forth, for ex-tmpk. in \imtbrook oZ, ?R01. wyvv

Λ Host ieii, when enhutod nnUet upp-opriate cot uh {tori'., synthesizes an antigen binding protein that can subsequently be collected item ibe culture medium (if the host cell secretes it turn the medium) ot dsrei.dy from fit-., host. ceil pfodin.ing -t iif n. ts not secreted). The se.teu.ion. of an appropriate host ceil wili depend upon var.om rhetors, such as desired cvptx-stoo levels,

1(1 polypeptide modification* that are de.-as -.Η-ό⁵ o -- cs.-an for aetw-U «such ns glyc<'»\futon or phosphors knots⁵ and -4¾ of Inkling tme a btologiudllv ,₅eto-.e mokvole

Miomnahan cell hues available as hosts for expression are well known,in the art and mebide, nut ,ne t m hunted lo, mtraortah, · d eel' iries available ftom the \m< tuna, 1 q\ Cuhew Coli -enosi i A1C( b including Hu not limiKd M Chine-e hamster mar. ti'HOt eelk,

1.5 1 IvLn veil·;, baby {sums'et kidney till Ik t eelk. monkey kidney eelk ikOSt. human hepahnd lidar card noma eelk u 7 , Hep G.B, ,md a number of othet .,31 hues. In certain enibodnnents, e,’i{ ime\ mm, be ael-s ted through determmun; w huh eeb ime\ hate high express-on levels ano aon-tnuuvdy prodtsee antigen binding proteins wtih CkRR K binding pi-nperfuw hs another embodiment a eel; inn- b--uu the Is ,eh uncage that dom uu- make us own entihods hut has a eapae-k to make and see ck a heteroGg mis a.ittbodv e-an b-, selected Wsi llkSmOT|£AuWGaadMStdiGdd 1 Ik (hpemk .Purposes \nhgen Gndsng ptotetns me usolnl lot dele. UimiR.RP Γ 11 olovieu! samples and identic, at ion of sells or u->mxs tiro product, C'GR.P R lor mstunee, the CGRR R. ami gen tm in e pioVtpv eu be nsec m dtaprosne assavs,. 7 , G ds ,e ..-s 0 s to .Lsc.t <u Io quantum

CGRP R expressed in a. tissue or eeil. Antigen binding proteins that specifically bind m CGRF R can alftO he used in treatment of disease.- related to CORP R m a patient in steed, the?cof in addition,, CGRP R antigen binding proteins cun he used to inhibit CGRF R from forming a complex with its ligand t GRP. thereby modulating the biological aitRily of CORP R in a cell 05 ovate iAempLs of eet-Gim*·' that can be modulated include, but ate tint limited to, inhibiting vasodiabeion and or decrease neurogenic inflammation. Antigen binding proteins that bind to CGRP R tints can modulate and o- block mtetaetion a it b ot he. binding compounds and as such may have therapeutic use in, amulioratiugdiseasea related io CORP R,

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2016244220 11 Oct 2016 indfoationdi-ea--e oi c-mdfoon as'-fomted with human ( oBR R mebtdes uu\ dt-ea-e: or condition who-,-oo-ei in a pan -m i- · aif-.’dbv, at le id η- part, the snt, unuon oft GRP P with it- be.-' d, ('GRP I u- -e-ci t\ of the - i-„a-„ m rend tmr co, -. «> !<«„ e.e't.J o; de-wa-ed ip. the imet.ietton oi ( GRP P wnh ('GBR, b'\amplcs of discuses and conditions that eon be treated wnh the antigen binding pietenr- ik-cribed ketch; include hcad.u.1 <. -. -uch a.- ». lu-tei headaeheig migraine, including migraine beadsohufo chronic pain,, type· 11 diabetes mellite, inil eiimatioa. e g, n.-mogesne 'ufhmurtatioi.,, atefowa-, ol e .h-owle*-, and bettiod- -anm. derangement a—oeuned with endofoxemsa ami <-cpsts.

Kt In part;', tea·' anogen binding p’oteln- doseribed hesein can in- n-etl to ire.u msgriune, eitliei a- an acute treatment eomsncnemg after a nugndne attack has comm-need, and or as a propio. ka in treatment idmniktcred. e g , 'holy w»,d;;y, biweekly, monthly, 1110100101-, biannuatb., foe i to pies cot oe*ednec the t'tequ.Ofo and or -cxertts ol -snipton-.s. e g , pum λ η:>ηι?, as-oei ned w uh rnignnn., tttaeks

I bdiTP-:te. bletlsods s he atrngcp hmdt-tg froi.-ios de-enbed hc<cm can be used for d'uenost'c mirpo >es to det-.-U, eb.ipno-'. w’ moutt-u diseases and o* „ ondfoon-,ι,—ts tat-d with CtiRPP Xl-o pi frtidcd are method- tor the detection ol the p:e--ence of ( GRR R in a -ample using eh.—ucvd uunnsnoie-fologu .0 methods knewn fo tho-e 01 skd> it; the <-r( ic e , Τη-sen, i’t-Ri, /fo;· 0. >

cmK Jbefofo /wwwussutm ¥ol IS (Eds Rdf. Burden and. P.H. van Rmppenberg, fcloc-wfo Asnste'dimi Zola Rfosfoupi fom;/ i hGmm-G foRfomfose--, nr 11’

IStGCRr Pre—. inc 1. h-dlomeu ,z m(. 1335..( (k/Λ Kfo( KB ^20-335: Ul-.wu.m . ,· o(. 1337. ,( Geo kfo( jO3-3(RR'-5t?Gfo The detefoton ol CGRP R can be performed in v/im or in wwp,

Diagnostic applications provided herein Include n-e oi tbe antigen binding, proteins io detect expression of < \jRP B mid biintme of the ligands to ί 'GRR B. L- m.p . - of methodu-. ltd ·η the d deepen of th - pie-em e ot < GRP R m hide -mt'un-oss-.0-, -in b Ge -1 ore i-.nked t-.ninnno-oibent a—,t\ U I IS\) and the ru.honnmtmoa-·-?.', iRl.Vi,

Roi diagnose- mpbt ations, the <-ntsgen bmdmi: protem i-p'e db wtb be Libel d whn 1 defoetabfo fobeut-g gjoup buttabfo iahehng group- eu hide, bfo ,ec not homed to, the following: radioisotopes or radiormcBdcs tfog., Ή. ’''(', ^f'N, Έ, ^M'Y> I'e, ’in, ’Ί. ‘ '^!i}, ficotc-H cm : omp-1, igllK, I'sodemme. lanthanide pho-pi-or-), eu/-u\;p, gi-mn- R g , horseradish peimtd-tse ρ gataetosida-e, hi-Jumise alkaline phospha- t.-eb ehennlummesecm group·-, b.oPssyl g.ioup·-, or psedeformmed pobpepude epitope- recognized Iw a secondary reporter t, g,, leueme ripper pair --opnenee--. binding sir- foi -eeondarv .mtd-odse-, mGal } -v

2016244220 11 Oct 2016 binding domains, epOope tagst hi some embodiments, the labeling group k coupled to the' wigen binding ptounn rfo spacer aims ol wnoo\ length-to teducs' polentnd sferfo hindrance, Matron- molhods for 1-,0-,-1 mg protein- are knowti tn she and may be w-ed

In asanltei aspect an antigen bindsoe pjotent e.m l-c as„d to idetutk a <~„il os eelk mat 5 express CGRP R in a specific cinboduocnt, foe antigen btndma, ponem ts 1 rofoed witb it labeling group amt the l-rodmg of ?l c labeled antigen binding protein ίο ί t IEb‘ R k detected,, tn ,1 further specific embodiment, tlte binding of tlx -mticen binding prokin to CGRR R dete>, ted w co. In ,-. futfoet speed»' embodiment, the t\»RP R mstmen binding; pi-n, m is 00 aKn arc inc.eerree, ussng K'vdn.qnes snoso> in foe <ex \< ,bi evsrope, b’ro/>n romt-on

IAS, '!pr,\-;o<0 ”< I /ο,'ϊο,οΛ-'ί, V,.>«;/<,>( \e« Aofo ί old Sprm$:tfarbo¹led RhM and pet iodic supplements), fofoz· if c G/iga.z, J, fo'fo, <e- »ro/? pr, >λ >< -fo A. Atoifiorofogn How York: John Wiley fo Sous .Another aspect provides for detecting the presence of a lest molecule that competes for binding to ('GRP P with die antigen binding proteins provided. An example of otic such essay would involve detecting the amount of free antigen binding protein in a solution containing an amount of (' GRR R m the preserve m absence ofthe test molecule. An increase In the amount of nee miigeti binding protein 0 < , the unig-..-n binding protein not bound to CGRR R) would indicate that for lest molecule is capable of competing torCGRP R, binding with the antigen bni>.iiug protein in one embodm» tn, the amigen binding prorem is labeled wuh a labeling gtoep Alteowi'v els, the lest rofocenk ts I foe led and tlte amount ι-ί free ie-ο mokane is monitored in the presence and absence of an antigen binding protein, Μ5Μ.|Μ^οίΊ0Υ4ΐ«ηηΡ2Η;Α^1ΜΥ^Ιί£<Ε..Ι;ΑΚη;.ύίΛθ<ηΐΑ^ΚΜΐΜΑ.ίΧ\Α^ηΑη^ιι;ηηρη.

Methods oi using the antigen bmdmg proteins <ne also provided. In some roedtods, tm 'antigen binding protein is provided to a patient Use antigen binding psotem nduhrts binding ofCGRP to human CORP R,

Ph.irmaecn-'A»1 compost nous thro compose a ihorapeun· dk effective iinot-ut ofmroos a phoidio, of the amneen binding proteins hud a phuinmcesnfoatiy acceptable diluent, earriet, solubilize?, enin-aifo r, pro-ervutiv e, and or >Μ|·ο, :ud .ire also proc tded In addition, methods of treatrr- a p went, s' g , lot mnjame, bv .idrotro-foimg such pharos ueuheal -.oroposifroi' ais' tnefodsd. The term “pttdest⁵' includes bttm.tm patients,

Aev'v'ptahie formulation materials ats' uoiitosn- to iceipieuls at the dosages and eora.enfo.mon- employed In specific embodiments, pharmaceutical compositions comprising a themp- teie.dl v elkifovs' amount of human ΐ t IEP K antigen binding proteins are prov ided > -n :·· ix

2016244220 11 Oct 2016 lu eerhim embotintiengs, a,eeptal *c T_uw .sladnn materials pimeruhlx ,ne nuuiueh to rcdpienis at toe dosages and co neerst rations employed, to certain embodiments, the ph<ernb\uoed cmnpossuuo max - ontom tornuuaisou muler'.rs for mocUtying, mnuttosuuig or ptcsetxn'it, Ευ example. the pH. osmolarm,, vfxeossix, dams. color isutonsetA, odor, iterfen, p stopllnx, sate of dissolution tn rel ,-axe, adsorption or ps,netrition of the composition ip such ·, mhtdtme'iis, suitable footinlubon nfateoals uidubs, but use no- boon d to. arunu acids uxu.h ts gixetoe. glutamine, axp.ux.gtoe, arginine or lysines: antismerobi tls: atmnxitomto (,-ueh a-, ass-os to, a. id. \odPiO', subtle os sodium h_?,!rog>, u-sulfituh todieis ton h us horas... bfratbonaie,

I, s ht :. cskates, ortesphates to other organic ac'dto bn 'auu .meid' Hneh ? ? mesutool o, it) gly - me), s bd mng igents ssueh a- etox ieurdsantine tetraaeebe ecto i Γ DTP A)g complexing ay- nt-»tone i ,, s edieuic, pM\' -»t\'p\i'oj ,h<n.,, Oeia-excloeexnn'i o* hxd.O'xpmp·,-beta eyelod.'sn'm), oilers, monosaccharide,!, Oisucehxrides, and otb> r eaH'-ohydtaleo (such as glucose, mannose os dcstotis), pa<Ut'u.s touch as s,-mm dburnsu, gt-kum os immuhitolobithii-), coloring. flavoring and diluting agents, eon· tody uxg a gems, io toophthe pointers isneh a->

petoxmxlpxsiototone). low nioiecsda? weight puupepSsdes. sik-fetmseg counterions (such as sud'tuni, p-eserc tuxes sspelt a.s benodtoesnum Jilonde, beiizem <,dd. sakexhe ueid_: thoncio-asi, plteutobx ί nkohok tnclto. Ip n\fto n, propy Ip tr J\m ehiurh.-xfdfrie -orbie acid or hxdtogen peso\jd.-h sotoents «such as Jxsetm, ρ>ορ->Luu ghee· o< poive.hxL-ie ybce.'}, sn^ai ateohets <,\U- h as in nunfel or sotoslol s, suspending agents, surfat t pas m- weftsng agents touch as pinrouic-. RbG. soitotan e-aer-. potosi-toutcs eneb as polxsosbate 2d potosmhat-, rmon irons.tburntne, ’eetihm, ..noleHeroi, tyloxun tig stetohu enbauting agm*· ouch HiCO'seoi sothdui?, hnm'itx enbau, uig agents (such as ai'sah suet;ί hah.ies, psdemtoy sodnnu ο* p-gassumt ehieruje, m.mmtol sorbitol'!, deuxere xchid.-s diluents, excipients tnd or ph.eniaeeuift ai adpixanis xd . Rf \ll\tl I'OVS Plh'xkM \i '11 IK ,\1 to h|'\< Vto lb '

Edition, ί λ R Gentmo, cell L'tol, Mack Rubbsbing ( ontpanx

In - ettafii embodiments, the uphold pharos ·,, euoeal ·. otnpositgut w di be determined by osu skilled us fee ast depending upon, lot e-s.-eupto. the intended rout», os'udnnmtoraiion, dpi!Ciy ioimto md tit or? d de-age eh. , i<a ,-tofmp\\ RI \H\iJ7O\'S

101 \RM Xtol'l TR ΛΙ SCUM i S, \ ,/w Ineestam embuduticnis, such t omptssUwms ma·.

tnlluenee die phxsival stone, stabilitc rats' of m cor release and e»s of to >v\u clearance of toe ar.tig.. ti binding pioteni·- sMcm-ed In cesium cmbu-.bm.'uts, tbc psuhaix \erode or carries in a pli.u'niaeeube ti com position nta> I'e suher aqueous or non aonvoiis to n nure For example, a

s. da n x - u k os < ο i m e I, wa.~ Set n t,, u t p'xsjohu !, a sa n c -' si et o in ί. I

c. „otesp r „ 'as. po->s dx , spp e tj.uted w d of e; m. e iaK seme on s cor -x'si sons ,o i toix

2016244220 11 Oct 2016 p-r> wemi Ww nAmnnm \etfttal btfl.'.'d sabne or sake.- nnsed wnb seonn dbinntn <r, furthcj exemplary vehicles. in specific embodiment.·', phatmaceuticul eompi isitloits comprise Tris bidfer of abow pH 7.0-8 5, or acetate bitfier of about pi I 4 0-5 ?, and nun. furthi.r Include sorbite! or a.satiable substitute, & certain embodiments, bnmnn CGRP R'antigen binding protein compositions may be prepared for storage by mixing the selected companion having the desired degree of parity vxith optional formulation agents iP.IPvH'xG ION'S I’H \R\tAt. Ft IK Al SOW I R the fern· of,. RoplnR.ed euU or,a. tpueous •oiwdou I'm fet, m cemim cmboilnaents, fee human LGK.P R antigen nmdmg pu Anr. naw In foimalatea as a lyopltihrafe using appropriate excipients such ,v; uicrose

H) Phe ph uv ate„w, <4 t em^fv-Aom , in So sole» 'cd f- u patcifieml dc’ix iy

Mternatoelx. the eemposu onsm.e, be sekxied tbs whahmoo w lor tkiiscA tlnough the dtgestK c tract, such as orally Preparation of such pharmaceutically ae>'> ptaMe compositions is wslhm the skid of the mt ihe tunnulation components are present preferably in. concootratosns th rt mv a; eeptab, m die site id ^oa\n s s A on in >. ita u , rbodiwcnts. biokm me nsec to m at⁴a n tin composition ,n p6ysioleuK.il t'H or at a rimntR km-e* pis, ivpteallv orlnn a pH range of from about 5 to about 8.

W hen paomteml admsm-tsumw ss contemplated. the therapeutic compositions nta\ be provided m the foim Ol a pyloucn-tf, e pdemei JR av.cptalA' aqn< ons solution lowposwc.

the desited human < 'Gl\P R funding ptot.-m nt a pbumaecuiteuh', 'leeteptanl·. veh-e-'e \ puttetu n|y mutable \ duel.- lot n itenkral m-ect.on ό a .-rile dtstih.-d w ,uc· m >\ hteh th.· hiiimw ( t IK P R anm-eu bmdmg protein is lotmuhw J ns a sterile, iviiietfc solution, nioperR preserved In certain embodiments, Ox preparation ecu tmeKc the forotu.buon of the desired mificenie wnh m ,sgent. sn>. Is as wwetalA' rtnesosphew ·-. oto-etodtbic p^rnclex, polx’uette compounds much as poR lactic acid or poRgRe-da, audh bead's oi hposouses, that mas provide controlled or sustained release of the profiKt olu,h - an be del R emd rm depot iitis'ction In cenain embodiments, hyaiumme aesd rutty also be used, has mg the effect of promoting susbmn d dumoon m tee on viai.on In , erlam ,-nmo bwcnis, implwitabie drug delivery desSv.es may be used to tmioducc the tlcsued a-uig^ti binding ptoiem

Certain pharmaceutical emnpositions are formulated for inhalation In -aw embodiments,, human CGRP R. antigen binding proteins are formulated as a dry, inhabibie ponder In specific ..-mbodunems. human 1 ί ΪΚΓ R mt-gen b ndrng protein tnhal m'oo solutions may also be formulated w ith a propellant for aerosol delivery In certain embodiments, solutions mw be nebnlwcol. Rtslmonary udminlslmtiors and lormalutioR

J <1 Λ

2016244220 11 Oct 2016 method* therefore are further described hi hiternaifouin Patent Application No.

1*«' i ϊ SM GO'S a wh'vb ,-1 eo ponded b> i .te.enee am, desct.aes 'ulniei utx d„ i\ ei> o^? ehemicailx modified proteins Rome sot inflations tan iv ndmliiistered oouly. Hitman CORP R. antigen bmdmg proteins that are sadism evicted in tin* fashion can be formulated with or without carrier·, eusfomarity used in the compounding of solid dosage forms such as tablets and sapMUA', hi renum emtio,t-n ruts, a capsule may be designed to release the active poromi ol the formulation at the pomt tu die gnorolnteshnal tract when btoavadabilnv w maximized and pir’*vstcmn dew utation r* intninii/eO Adnm-uiai agents -. an be in, hided to iw dilate absorption of the human ( GRP R antigen bindirm groteni Diluents. l’lu\onng* fow melting ip vepAeble od\, mb'A.n'o sUspr'Al'm’ ig nUA„bk\ di*t' AuiAwe agents and binders max also be employed.

Some plormui.eut.c«i iempo*Oon* .demise an effect”, e qminfoy -, u on. οι i plutainx of hemati CGRP R antigen binding ptotent* m a. unxime o tin non-tox.ie exeipietit.* that are suitable for the manufacture of tabRts Bx dissoix mg ihe tablets hi stenle o oar, or atiothei

1.5 uppoipri Re vehicle solutions nuy be ptepaa ad in miu-dose hum Suitable excipients include. I\n are not limited to. Inert diluents, such a* e.iRium earbomne, sodutm carbonate or bie,xrG'f'.tie. i.ietow, o- - aleww pho*pbat- , -v bmdmg igents such as si uelt, ge-utif' ot u> a. co or tubiteutmg agents -.ucit as magnesium steaiau., -oearie aetd. or tale.

-Vditfomn ph irmuccmicai lompoMUons xvUl in- ev idem :o those skilled m the art.

including foimuh.'.tion-' soxoix ing human CHRP R antigen binding proteins in susUitueb- or eonlroHed-delivesy formulations, Techniques far formulating a variety of oilier sustained- or eo-molf d-dehsen means, such us liposome euuiei*. b'ai-x.'xod't'fo-info.rQp^itfotoor porous I cad* «no depoi insertion*. ar. 11.-,0 known to foose skilled m the ar·, ow, for exnmph hittinations'Patent \ppluat mt No R< 1 I 0000. »νη>. h is 11.,.011105,Urd by wf trine and

2.5 describes eoniroiled, release of porous polymeric aiioropurtielea for delivery of pharmaoeotieal eomposmof's Susi nised- tense po paivimns m.o, wcbi.le s, iruperoieabh' pro, m. i 01 Ui-ees m the form of shaped tie-.es, turns, or mtcrovao-mL-, Sustained relcs-c matrices max us I de w'x am, 'sdt(.»p · s, poR ,<n t. tes ‘ i* ois ο* -lot A ⁿ 0, nt No ί “*K Oj 1 η I bniopeaii Patent Application Pnoh<. anon So, i.R 0554M. cads of 0Inch * meo-porated b) telercneeh -..ooolymers oft glmstmc uc-d and gimma dhxI I elui.tm.ne {Stdm.iu e^! .«/ , R'G3, >m m 2 5u~-xxo), po^!\ |2~hx diosyethvl-n-ffoaci v -ate} ti uniy*i - > it. NS I ) ¢0000 Z

Vm’A'. fo.\, Ip. ip and t anger, Ns?. t Uch. 1? ethylene xmp aech’te «I ai-gsi a >,>/, ί os |, .«ρ,-,ηνί poly~f>{-b)~b.;ji(,\ybutyrtc aeiri Hitiiopcan Patent Application Puhhcatton No, I R IdZNfobs bustatued teleuse comnoMtioo,-·; rnas also include liposomes that

135

2016244220 11 Oct 2016

- κη be prepared by any’ of several methods known in ths.: an 0\v. eg . Γρρ-tem <7 to. P^5. Biot bxs,' 7 > ί Λ I be .was to'A toeopeai Patent Application Peel vm,on \os to'

V?6,('⁷o, ΓΡ ‘Ksytoi. and I E I toto-to. smetporaiea by retmenev

Pharmaceutical, compositions used for in viva administration are typically provided as

Merile preparations Mcniizanost can be accomplished by tlhmfion through ste^ie nitration rtierforanes V, ben foi eomposmon is lyoplnh/evk -fcnh/^ijon tiS'Ugdiix mefood ma\ e-c eon ducted either poor to or following iyophiheatioti and reconstitution. Compositions for paienteial aihtsitnsttatimt can be stored nt lyophilized form os iu a solution. Parcntesai votnpox'tti'nx genemhv are placed mto a container having a -tertle access port lor exame'e. an ft) imravenou¹· oibitioti bagen vial hav mg a stopper pierceable by a hypodetmi- iniee on < edle. lh eerfam enibo.dimsptSj cells.expressing a recombinant antigen binding protein as dm J-weo erne, is _K t apM cce .-rt. e er\ mee. b >esi t tpb h dmol \ ts -G 'v n m 3002 and f’nxc. Nath .head. Sciences i05. tfoto-.θίθ), 200o)

In certain formulations, an antigen binding protein has a concentration of at letst 10 i 7 mg tub 20 me, nd. 50 nig ml, 40 me ml, mg mh P0 mg nd. 70 mg rah Ml me nil, 00 mg ml,

100 tngZ mJ or 150 ntg/ml. Gome formulations contain a buffer, siiemse and polysorbate, Ac .example of a fersru.httion is one contanung 50- i 00 mg mi of antigen binding poyieiti, 5-20 mM -atomm acci-ite, itito-w v sumo-e, anti 0 002 Opals ww $ pr-Rsotbats t'ertant, tin mnhitiww, tof uwtatifc, comam to-5 mg mi of et antigen bmfong piete-u m 0-i 1 mM sodnnn acetate Outlet totO'tow'v -merrwc and 0 ops,0,00ms. w v polv,sorbate fhepllef certain such ηητηυΙηΟοηχ ts in the range of 4.5-6. Other terrmtiatiens have a pH of $.0-5.5 I.' g , pH of 5.0, $.2 ot 5 45

Once the pbarmaeeaticai composition has been fortmtkned, it may he stored In sterile tods as a solution, suspem-on, get. e?rnd-mu. solid, crest,ti. ot a- a deity Orated ot lyophtiwed pew ties ouch formulations mat be stored Cither tn a rewR-io-nsr toon rs m a form (me , lyophihxedl that t.-> imeoustimted prior to adinmistixithm. KO- for prodm.ine a -mgie-dooe administration unit are also provided, (ertairs kits contain a first container having a dried ptitmin mid a second eoMamet it:-,vine an aipjcotis Otimyiaiieo bi rertnin embodiment-, bus containing single and mnhi-ehartibcrcii pre-tilled syringes R.g., begad syringes and lyosgi nxce-o are provided Ik therapeutical!} eftceto,.- .mx-oent of a bmtxan ( GRP k antigen binding proteiti-coutammg pharmaceutical composition to be employed will depend, for example, upon the tlieran-entie context and objectives. One skit led in the mi ά ill appreciate that the mp root safe dowga !, v,<ls w tit stnu t-t wd⁵ vaty depending. m pmt, upon the momento delivered, the indication for which the human CGRP R antigen binding protein »s heme e»- d,

136

2016244220 11 Oct 2016 *11 f> x ,C o* a if U ,’dth \ w dm 1' «t?i< U »Jt cn’OHVJ.nM { do» condition (the age and genetai health t of the patient. 1st certain embodiments, the e it scow 3!,r ο?-, r the do-ape ,wd nm-hb In,' wete of αίτηοο-ηνοοπ *o obt dn the xipnotnl thewpetdic \ typical do-see m.o range tro-nt about i ug kg to up to tbotn ??> mg ho or more, depending on the faetots οκηΡοη/Ο uunx' In -peGfic embodiments, the dosage may range from It? ng'kg up to about % mg kg, option die from f> > mg kg up to about ed mg kg xibctmu-oeiv now 0 > mg kg up to -,bout 20 ng kg sn smt-.e epplu awn-stoke dosage is Row 0,5 use kg tn 20 mg kg In some insiattecs, xtn antigen binding prutcni closed at 0 > mg kg.

0 5tng kg. I mg kg. ? mg kg, ?0 mg kg, or Ό sup hg. I be dosage schedule in some treatment regimes is at a dose of 03 nta, kg qfo. 03mg kg qW, I mp Lg qW, 4 nig ku qfo.. It; mg kg q'O, or 20 rug Lg x{ W

Dosing fiequettev st HI depend upon the phiawacekmctsc parameters ol the particsdat humen V (IRR R untsgett binding protein in the formulation used. Typically, a clinician

1.5 aditsanstef s the composition until a do-;me ts cached shut achieves the desired effect. The composition may· therefore be administered as a Rngic dow. or as two or mom do-w- (whseit may or may. not e»mt;un the -anse amount of th>, desued woE'cnn t o<et Ome, o? \s a continuous infusion <3 art tmpiantaiton dev see or catheter. Appsopnate dowac- may l»< as-eerffotixid through to-e of appropriate do'te-respon'te data In certain embodiment-, the antigen binding snubur- e»nt be admuii'iteted to patients itnofeumt an e\ten<ied time pe;io<t ( hrome edm;mstrau<ni of an mt.gen binding pro^fem tmmmoe- we ad'-er-.- nnwuue ot ei'.eggtc tespouse eoiumousy associated with stsuigen bmdmg protein- that, at-' not Only human, for example an antibodx raised against a human antigen »u a non-human animal, ?'m example, u non-fully human antibody of iimi-hum m annbofo piodu-.ed as a isoo-lmmnn -pceies fhe mute of adoum-nation ol the pnatmucenurat eompo-nton ss $n ^torn w uh know st methods, _t g , osuily, ihmngh wiauioft by intravenous, intrnpernyneak mu ace rubral isw'r.i·p eneh wdkhd ee-. ro-uutn alas nt i nw-dm ut a oet t ts co! mt tons o; imraiesiitnnl metes-, ny sststamrd release system'- or by implantation device- In tV’tsun -> mbottnncms, fhe 'aenposWoi-s us«y bx' .shmai s',co d bv bolus m.'ut.un o> .ontumoiisly by infts.wtR. or by inipluntaliou devise,

Ihx' composition afe may b<.. administered locally ska impkmtntion of a nninluaiu.', sponge ot another .ippfopn w„- msstertal onio which the dte.-in.-d molecule has been absorbed or ertCxip-nluted, In eerisln embodiments, w here an implantation device ts wed, the device may

2016244220 11 Oct 2016 t'c implanted >r-m ,uiy suitabO ossue ot m pan, and densely of die desired nydceme mas be >¹.

dClusion, itmerCtelsaxs bolus, or continuous adminitOrarion,

It also may be Oitsiru-de lo is--.? human CORP P, antigen binding protesu pharmaceutical eompmutmnx m v;vo in such instances- cells, tissues or organs that base been s'emoxed from the patient are exposed to human CORP R antigen binding protein pbarrnaeeetieel

--ompusi turns abes ss htelt the -.-ells, i-vou *- and οι ο,ρ,ϊ w are -sib-,; qie/tu Is implant-, d twek ode the patient.

in pnrieiua 1mm m * 'GRP R mdgen binding, inotxin- , asi b·, riehs cied in i.mptammu ϊ-erum eMls Put base been petKiieaib engmeered, using' metltods such -as those dcserRcd

u.m-m io express and >ce,-*,' Re pob pepode in .'eitam embodiments, so- b eelN nun 9., animal oi 'finnan evils, and mas be autologous. h-tesologoux, >u xumgi. ueue in eedam embodiments the eel’s m.n I» mersoruh ed in -uhw' embodiment-, m oixh r to d, t ie ise the chance of an immunological iespouse, the ceils may be cncapodated to axoid intonation ot surrounding tissues, in further embodtnivuts, rli.,- encapsulation mntertab are typically i 5 bioeoirspatib⁵'*. semi -pen neaiue polymeric enclosures or membranes tiled allow the iciease of the protein pivdueris) but presen* the destruction of the -ells bs the ρ,ηΐχητ'- immune -sstesn ot b> -nti,* detsm ema' factors oom the suitonud.na tis-atw

I be following example-, meittdmg the experiment- conducted and the merit- aebtesed, are provided Im rihisir.tfixe psnpo,;,.:- only and are not to be cssn-inie-l as homing the scope of the appended claims.

A. MoReufer cioning of liuman CRIB and MAMFl

Human t' i\l il, l>\ \ 111*. i d he ik Accession No. 1' I 4 ” n Si G I ft Nt. t 11 and R A Ml'* I

2> el>NA RsenHatd AveesSson No AJOOiOU. M-G ID NO,^sl s' esc cloned mn< the mammalian eel' ’\pr,W'iuu ky’o'o :u l)N A t ¹ -/ v ,im1 pel)\ \ 1 I -1C ρ t no. ·ηο> :, V iris'- tri. { \\ msp>. noe’s, bn uac-leGion- of III K 2'Gl.bNA eeOs tire, otoecr-t as dose* shed below t be hVRI R - DN A and hP AMP! - i'JN A svere also cionM into the pIC-riGR i xeGo*' (Run. ΙΠ , t al, i Ins, Detru Symp, Psoe. COOTS 1.2 riX-ri't- lot nansieelioti- of AM-I Cl IO cells jC, S.

Patent Number o,21OriM11

B, StahR-TransfeeRii < 'eh 1 rite ilii.K 2^fOCBN,A celts (avuilabR from A'i'C'G or bis urogen) ',vesc eded at a density of i.dxib' ceils per SOOmm dish. After 2-4 Imam, the cells wete uO-hansiccted with bigg

I3S

2016244220 11 Oct 2016

2Θ hneari.osi D\A- ol buR AMR! pcO'SAa I -He.g and huCIst R pt f)\ A- !-7eo with ΓυΗοηι,Τ * bn iiiogcn. ( arlsbad, CA) Follow mg m-unieiion- oippbed by bn mogen After tv o dav-e die cells w re tnpsmi/od. .nwl suK ultme.l mto growth medium eooiasnmg lOCyg mi hygromv m ' d5?fiig mt cement .Mier two weeks, the te-niftne drug resistant colonies vese Ren-nu?ed and combined into pools. The poets wvre subjected to four rounds of FACS sorting an Aleva 0--17labeled I'GRIG - peptide analog obe-ei dud below 1 Tbs' highest ΐ% otAxpiessmu ceils wete codec ted at each round,

VfidkAsXue^

AI 1 ί HO s„ Rut seaiiii *K„ ,/ομπ s ted>.- adep.ee \ - t,mt touts rei HO OHI H ,Mu tent cell hue dzscfiU d m t H.uib «ndi basm, -^f7w, On/ !,.. / om 7, d?lo J9s0i, we-'e seeded at .1,5x10'' cells per 100mm dish. After 24 hours, the cells were eo-umtsteeted with linearized 4 pg DMAs each of pDSRt<24.-huR AMP I and pDSRn?-l Ind’Ri R with F'uGeneO (invitrogen, Carlsbad, CA) follow lug instructions supplied by invUrogen The transfected eel Iwere ovpsnuced 2 dam- after trutskemm atut seeded into OHO PHl R seR-uo c growth medium containing lOT, dialyzed FBS and without hypo sunt tunc ihymidiiu. supplement. Mmr ? weeks the rv-jhing nansfeeted eoknnc- were trop-miaed and pooled she pooG were sublet led to F \C\ sorting ;·ηαι\-ίχ ‘ Suihk eyptes-to-iofburjian adienomedtiljin jA\H i tp Hl R.....Τ,ΟΙΊΑΛ,celh ?fOb'H\ A celG we·'.- seeded sn 100mm d\she\ Ό 1 5\iV ceds dish m DMI M ibtgu glucose) M-iBS H¹., Ml M non essential antsno aet<ts l¹ < sodium pv nr.ne fhe loliow mg d p, the cells worn co ir.m,sf„-eted Using Ht st\F o imnsfection reagent (Roche! w uh p. DR ΐ renem huCRt R piu-, pefA V 1 dsvpnmisciu hub, \MP2 Both i)\ \ eu'tstiaets wete linearized w fib IGpt After G hums die cells were subcultures! into lOOmnt divite-ai e . . . . .. . . κ . . ,ς . . . .> .... . . . .

-...di Jen-ntes <SHu , ^; 2x10 , R\iO i elG ih.xb) m growth medium i.onusuimg dOOun ml zeocm I hs medium να- rbanged twice weekly Atid one w ..ek the plates were led wfih medunn emm-aumg Mating ml h\g:om\> m - 200pg ml z -υ· :n Mvt two w eeks, <3- ,ol,mt.> were isolated with cloning rmgs Ihe t emantnu. colonies wete eolicetcd into a smgie poo!

> pi turn Flu· clone-- anil pools w>. re essayed mr tin. n respot -e to smuidaum by reeepim agoUis', or lor-kohn Sevens! <. tones showed - good tespouse, and one was seh, eied ha u-e m sub.-eqitem evpenntenis

Sfibh· sG.ffs\s-son of esno C URP R. m Hi.K \ eeik

2^fi,’H:H\ eelR- were seeded in lOOmm dashes at I ,χχ 10' veils cash m HMI.M thigh J.u>se; ^K , s BS ¹ Ml M on-ess t Pal mnoacn.s ' \odt. npvHvat the h'dow mg da\ the <,e!G were eo-uanstieh J usutg I uGl \Γ o w tth

139

2016244220 11 Oct 2016 pci')N V ί ?eo-·η - y mCRI R ρ! is ροΠΝ A i hy.-omy, .n - pnR V-dPI ffofo Ο'ΠΜηιιis were linearized w uh INpl, \lk-r 4K hours the cell·- wem 'stibetihured ntto growth medium eoni'iimm; ?O0pg ml zee·. ·η - lOOug ml by gton-y m e nkmow fo 1 '0 ί *·0. I 100, ;m,l I 200 The medium was elenimd tv- ice weeUv. Vtcr two weeks, to transG-et-.d eoiomes ? were isolated u*.mg cloning rugs 1 he - hones were as-,used for iheu response to sitmuhiiton by ('GRP hger-d. Several Gones shewed -fotnl n In-,Is kvcls ofsesr-n-.se .md one was sek-led fm use nt subsequent experiments·, <2, hnhsthm of high ww pressing f.'GRR receptor cells

Λ CGRH.e- eeptsde asiak.-g was synthesized Ovbbv-est Bio- leers hie, I Ahets. LM woh foe \equeme below

Ac-WViURl Aid 1 toSGuYk RONI VR fO\ GPi \i --, .- tS! 0) ID Vfe f he pern-lo v.jfebe⁵- d wnh \lcs,t (' fell¹- follow mg die maim Lu f me? N if'-stmci-osis (Mok-cuku foobes, bs>. Cm λ 2Pt)P) Ihe Mesa M~-L'.heie-1 CGRP --showed »peetik stoning of CGRP receptor traasfec-od cells and not the non-rmnsfoeted parental cells ;u:ti -as used os th- l'\( x fcagent, hr hui 'GRR receptor tranmeeted 2'GEBN A .md AM I ( GO evil pofe -generated aabove) were sorted repeatedly up to four fees pools using with Alesa 647~lsbefod OGEife peptide Ils_ch expressing culls were collected at each sorb expanded and after the feu srrtntg bo/. - ο-.- \iak Mk- AM-: OR) l-f('( jRP P .elk wew- used lot mwu-m/num as d-w, toe I resow asm th. 29R-RN \ huGGRR R eeiR - ,ae usee for titering tnouw sera aftet immunization and m Itodinc screens of the hybridorna supernaimtK

IX Generation nf soluble GGRR receptor

Soluble CGRP receptor polypeptides containing the N terminal extracellular domains y-( Ito of unman ( RI R tel U 1F> NO ot .md htmum R \MRI -St Q IP NO M wow jecemt-d by tran-sentIs co-trensfocustg 2°5 6b cells t Duroeher, rz M , .Mn'/em ,foto AL -. 30R0 ι2002t) with vectors roniainiug tbe corresponding eDNA*; t'SEQ ID NX):? or SP.Q If) ROM? as 0^--.110-,0 ^Ke (<'t is'tonN used tag-1 ml z|lis,; H \ - -J _tv J <i we-c eumk-yed to t » ilhaw- so,-ebon ,md -m sub*eqnent pmtfie.niem \ .-«foible «..eoidsmziie f YsRR R hi D los ,.1 to I e was pier e< d by ^CR , S-umig n¹ ?0 the appropriate primers mm me transient m.prm-stort' eetot pi 1 e dforoeher - * d , wwto The CKl. R N-terminal bCD~be consisted of the N-lettomd cxfracclhfot? domain off'RI R. tSEO 10 N0:6) Rt.sed to human IgG I Fc- I he RAMP! ECO-be contains the extracellular donums ot'R WIFI iSVQ 10 NO Xt fo-ed to hum m RO I be in Imfo e -.ses, th.-te -as , Imkei vf-tsist.ng >,l Pv v. si-'tsceat v. Gw betv- „en ίη„ 1.( 0 dm urns and I c

140

2016244220 11 Oct 2016

The soluble heterodimeric CGRP receptor was exptessed by eo-fi-jtixfecting the two emtstruetsa* fellows >G-<ri ceils at I \Id’ cells m» nt shake flasks were ouitsfeck-d with P 5mg I G\ \ foCRi Is \-fer f'C D-ί e nf Γ5 and fotR W1R1 Μ D-Γ, pfF.x; wfo- Cm Obi mg DBA tit 1 rccStvIe 2fo’ media t Iroitfogenh 1 eb* weie grown m suspension tn I teeStyh. 2^-» expression nt,:diuro supplemented with 0 PG Pluroroe Vbk and 50 ug ml Ceneiicm tor days and harvested for pnrifeafton.

Pnririeahons from conditioned media (GM”) were performed by buffering foe CM w Uh the addition of.eOmM I its, -»00ο-,Μ sodmm mlmde, «nd uriptslnig Ihe pH to s * 30-,. buffered CM was then passed over a Protein A affinity column equilibrated in 50rnM Tris.

gQfi'uM sodivin ehra'.e and pH .-.dj-isied to pH k 5 The Proiem A toforon was washed with Pho .raj me let., on piote-n Jmca wph 0 \ HG \e Hs: e'uted nea. eonumuv oom t RI R and fCAMPI components when tmted by western blot uong rodwideal uiti'u<idt--s spei die to either CRi R oi RAMP I, I'uifhe; I C-MS and \-terminal se.tuene-ng eomnroed foe preootieeof boih <'Pi R R.'xMPI hefet'odime* irodf PIJCCPLP homodime’ in approximately

I X «? 3» raho This 'sohfefo ( GRP m.cptor'' w <s shown to compete m M?x.m4~ kfoeled < GRIP j- binding u- f 'CRR receptor expressing meombm iro cells m the I'M \ 1' analyst,*, ilrbough it faded to brod ( GRP bound as defetmmed n.-ang Bra.ose »esfrog The mat, oai v, -.., used <n an immunogen as fosettled tn ^sample, despite, intet aba, ns hcterogcncits and lack of CGRP ligand, bfodfog,.

2b E. Generatiou of membrane wracK from ree-ombhrom CGRP raeepmr expressing Cells

Membrane extracts were psepated front CgRR seeeptm exps easing cells using a method described py Bos,->e, k. w ,u foGrowri m/fororow ,C.n 'x>7<-..wec, 3> H ?\x 2’C.pi-m» Briefly··, approximately grams ot eel! paste were pelleted nt 50 mi of PBS at 5,000 rpm lor 10 nun at T< and ic-stixpettdeil m 50 ml of cold b sis builet (25 ro.M Ht RlAk pi I 4,5 ro.M

MsCI phfs on, Ro,he protease ndubnoi eookf.nl tabb t 50nil ) Th - lysate wa* boroo,.x nr/e,I wdh Gia* Col t teflon glass homocem/sn with Mo strok-.*,;; >,00?) rpm and man m a 1 MI rotov <u. 20,000 rpm few 15 rnro A d'i This proems w mpe tied p*xv more and the rintd pellet, was re-snsp,eutie.l m - M no im-.l pebeC Onrie· i25 mM HERTS, pH a, t mM Mgt ⁵ , i0 A. gw x) ,sue^fo*,- phis one Poehe protease inhibim ·„οΗ:ι nl table» ?Otnl) i he membrane extra-, ts w-,.te situated bv passing, through It* G ami 25 tl needle* 2-ⁱ t-nte* Total membrane proamn concentration we,* determined v itb a Mwropkne BG \ Proiem Aswx iPwrec’

2016244220 11 Oct 2016

FXVMgLtj

S8Stt*:aa£.g£ AsaaaMBa TO.caw.»BcnanR

ImmnnieKmns wux. eondueu/xi esme the follow nw forms of ί 'GRP sceq-ΐοι antigens, .prepart d ts desen twd in Example R

o) YU-I ClP) iransl-ectmts expiessmg tub lengtis human t Rt.R and RAMP; at the cell surface, obtained by i,o-trau-,focttng CHO cells w hit human foil length GRLR cDNA ($S5Q ID NO I) encodes,.¹, a pohpeptide h omm the sequence SEQ ID \i* 2, «ltd RAY1R1 d Rx A <SEQ ti.) to ei encoding a polx pepttde hax mg the sgqucju'C SI Q 10 \O,4 ini memhiane to tract fivtn foe ecus Oesi ιιΐχχί «η g, 5 «bexc, and t nil soluble CGRP tee/ptos obtained bx eo-expscssiug· ano peril· mg foe A-tetnintni

I ί Π of ί Rl R (SI Q if) RO 6? and the extra, dltslar domain (FC Ot of R WIFI tSPQ 0)

ΝΟΆ) as described tn ibatnpk? 1.

XFNOMOOSP tntntals were immunized with purified soluble CORP receptor protein to and pniAivd < GRP R meMhmncx pfeoate.l ftom WC1 < IP) .e'ds -,ΐαΐηχ cxpicssuw CC’RF R in the same manner using doses ot' 10 gg.'mouse end 150 pg mouse respectively CGR.R meruhrartea were prepared iwirtg toedtoda described above,.

Subsequent boosts were admits tsieted .0 desex of ten pg mouse of soluble ( GRP R os to η,;-'’ 0 if bed t GRP R m,'tomato's MAifoO't SF amm A w dxoimm ni-^d wsfo £() CGRP rccepior-expiessjug reds nsmg doses of 3,4 x to' (to IRP R tranvb ctcd edA mouse and subsequent boosts were of I x to' CGRP R tr.msseeAto e/its Plots/ inweuon toes as/fo wu'e combinahotfs oi subcutaneous I^-:-01-tail ;md itma-Atmme.d hsunum/amms w-,.rc petm-uned in accordance xxith methods disclosed m t'.S, Patent 'xumbe; totolw 1 b filed february to, 2002, the dtockiMire ei white is hewfoy meo-'roraletl Ip rcfeienee Adjuvants I'm?: Max (mid totgnia eu - I2otog \lumti M tot gent Pulp .md t. het mei v 0 Wutor. \.L c u ' to; 2 250s were p’epared according to mnnmh- mrcr-f mstruclions and mixed in a IΊ t ttlo os' adits •cant emulsion io antigen solution,

Sc> , ~ol\\ ted 4-d w,c\s r, ' .to? 'upnoo'» <md spo, to ole s wotc

-I.'V?mined 1·χ I xG- xtsa^sr ,o^! i-.otrbtrant GGRP teecpha- sp^wsung 20 »1 PWA cGls

Msec w /re imtunnsccel xxuh cube; cells meothanes expressing sub length i'GRR R ceils os suiiti'ie< GRP R extra-, cfoslai doiwun, wsth a t -.nge ot 11 to untunim-aU-mso\.u -, period of approxtmately one to three and onefoalf worsfow Mice with the highesr sew titer wete .d.m'obcd ,-.nd snopared tot htendoma s;euer,stion The lOinmm mtoms xsetc pc.'foimed u2016244220 11 Oct 2016 groups ofmnhiple mice, t>ph ally ten Popliteal and iugnui-xl lymph node- and spleen tissues roere fxpictdtx pooled from each group for'generating felons,

B, Prepnnofon of Monoclonal Antibodies

Auiifrfe exhibiting suitable titers xxere identified, and Emphoeytes xvere obtained from.

draining lymph, nodes and, if necessary, pooled tor each cohort. Lymphocytes mere >l)\\o< infod t',<m' ixrop,' on,, s-m. a , s,nt ml, o < proto t'e. .sample 1>,!1« ,eo\ Mo Hied tropic Med'um; HMI M, obi,on hie from luxKronen, kb:Μ\,J, f \} to role tsc the eebs from ihe Us'-uex, ano siropeo led n· DMFM B veils xxete -eteeted an.'· ot espandvd usno a sn-uEx' method and htscd x\r,h sxuiuHe fusem p-Oinct, for example, irons .-csetoix' mveloma l(t ps’Xi,? \A o53 ,e’h iAni/ruan Typ, I uhmei ofreetton ( PI ESp kenrino et al 7 feroroE. 123, 1979, l54frMS30).

y mpiiocy n s mere nused oh trodon paimer t ell·-, <n a mOe of t 4 The · eh mixture wa- geuth pelleted by, cent ti frugal ton at 400 s, g tor 4 minutes, the Mtpejnatato decanted, and the cod tnixtroe gently mixed by using a I ml pipette, fusion was induced with PEG DMSO

E tpoBcfrt) lette glx < ot dim· lux' sulloxnle, obtained front Sigma-Mdo, h. Si IrouExlG ί ro! per million of lymphocytes) PFGOMSO was slowly added xx ith gentle agitation oves one mintite followed, by one minute ol'mixmg ID MEM (DMEM withoutgfrttanroie, 2 ml per million ol'B „eiiE ·> a- then added ox cr 2 minutes xx nh romPc agitation, ftΉοο<.d bx additional IDViF.Y! fo ml per tell I ion B-eeiEi vxiih'b was added oxer 3 m roiti--, fixe friscd exits xxetc gently pelleted tMlt) \ g t< minutes» and resuspended nt 20 ml x',e>.tion m.-dia Go- .sample, DMPM eon\un,ng V 'serine and, Hxpoxnrfren,-1 HA j ,ud o'her roppleroemal nt Ueiialxa*. nceessaix t per million B-eelo ( ehs w„o utC'd'atcd t-'t 20~fri minutes at 3'7 -md -hen re.-uspert ded tn 200 ml frebrodn’t media and cultured ter three te four -hys su f'l ?*> rfeks puot to Έ-xveb pEiing (Vhs xx esc msp ibuted n'4t< M - x- el ί phucs usuro standard frcnnuiues ro mroxroit.ro eronuhty, of the teaming eolonfe, Mier sex^ral days oi culture, dn- bybndotna ouperoatnnP» xxere eolteeud ano subjected to sxroermu assax - as denoted ro the esixmp'c-. u„low, rodeoing - ηηίΙηί’ίΐΡππ ot binding to human ( GRP re·, eptor. idenufri,uhm of bloekmg antibodies by a hg,wd binding xoropentiois assay and evaluation of eios·—re-a Pxro, with ntiio teecpro-is related to < 'GPP receptor ifor example, human A-drenomedudin receptor) Ρο,-dtix e relfr xx ere further selected ,,nd -ObjeUe.l te standard clenrou and subt lomng techniques I 'tonal hues xxere expanded in vitro, and the secreted human, antibodies obtained for analysis, t-M

2016244220 11 Oct 2016

Sequence Vutiysis of Selected Oonnelonut Antibodies

Selected snbcloned ιηουοΗοηο! antibodies wete «sequenced using standard R'l -RCR methods ΐ tide ?. \ shows the umino a< id xeqf5enee«· pt the tighi t hams of ·,?\',-ηιρ; try antibodies ib-<n«sod Login 1 able 2B -ag'-s s the annuo aetd sequences ot th„ neaw Uiano ot ? sS'cntpbny anhbodtes ifeetiiscq here tn

Amino fed xeqsumecs eonespondutg io ('DR teutons of sequenced antihotkes were aligned and the .ihgrtroents were t^ed io group the clones by stmiianfy.

Seqnetu.e ahgnme-rm ot light ehaut Cs >R\ from clones Lome kappa tight chains, and eenatu co.fosnombiig eenssttsus sequ-nues,«m shown m t tc- a.\ amt Of, it) Sequence dtgsneems of hnht - ham CHRs hoot, fees km mg titmb.tn tight th.uns, and certain corresponding consensus Sequences,, arc shown in Fig, 4,

Sequence alignments of hem. y chain CDRx of exemplary a-mfedfe disckssed herein, and emtina .ottesponutng -..ousensus seqnene’s, ate shown nt !\gs 5 51k 5C, ?D ano H f'enam cormmsus scotroces of gv crop fey heovv chant t 'DRs dts-fesed hemm are 15 shown in big 5b'

A, Selection of CGHP receptor specific binding antibodies by FMAT

Auer i -t Pays of culture, hytiriditma supernatants we?e screened tin C'ttiRP R-spcedh 20 moheelu',,! e,neetA< ,w 1 kotmtuu c M . o', t< one fm eehnolom, tt Μ V ; t 'cml eh

Bios', stems, Fo.xtcr t 'ny, (At, The supernatant·, were screened ma md either the AM I ( HO htj(\,«RR R, eetis ot wx otubmant 1 II K 2Ή cods One wete uant-'m ted mob hnitnot ( tiRR R and counter·screened oguttw pnemai HI K?9? >„elU tprepared as described t.n fcxample i),

Bnefiy, the cells in freestyle media Hnvitrogen, Canfeui, ( A) were seeded nmo A4~ 25 web I-Μ \ 1 pk?os nn a «.olurne of ^A0 ui wHl at,»density ot appioxunat/l. --150(1 cells wHl fet die stable uawf,h tang-, anti e a density o: appwmm'ateb, 16,000 e Ox w ti lor the oa'ental veil·; e.nd cells wew' incubated oxcrueeht at d'M J'bstt, 10 nt web ofsupefimt^it wu·, added and ptin>. « we’ ’ incubated On ,ιίγωυηυ’Λ tri ’bout ti c«'{ , <e tei winch 10 tft weRo* ,-^6hunt -,n Ig(s-( \ 5 seconder·, antibody t Lv..!„>on immnno'escaich, VMm ί lime, R \) was added at a concent!atieu of ? b ng ml (IdOne ml final <eneemr,mfe t fl.ucc, w ere then incubated for om.· hour nt 47 . and ilneteseencv wa- read using an ΓΜ \f m-a.rot.tmk'Cal seaune· lApplwd Biosy si ems, Foster City, CA),

Rb

2016244220 11 Oct 2016 ro, -mantes xueenx the p :r> nBl AM-! GBOe.’Oxot Bi X ? B ceils w reseeded \!ra as λ -nJ stmet',atat',s v reeue 11 \ ! \l\i res these -el * ι„ ^Λ-ea lei t' ri ri.re re he and elhnutat-,. hybndotnas binding to eebal.tr proteins, hut not to the CGRP receptor IX IdeatlHcaGon of blocking antibodies by ilgaml bimimg competition assay Ihenugh EM VT

A itgand hrodmg ,oropetu ton method was ti** etopee -o :ricnsh\ antibodies reu tin hybiidetoa ,-uperniiiarttxd that bind ( GRP receptor and Meeh CGRP ligand btnd-.ttg eh-bwslls plate·' t Got nntg Cosine. Cat. -ΌΊ 2} were prepared vuh 5,00() Wire InsCGRR R Poo; 2 eelk and 2(1,900 unit aits feetcd t BO-S celts to each welt, 2(htl of tron-CGRP P, hybridoma oupernat.mt wore iddred ts? eajo well. and the plains were roenb u>ed for ihr it tooto tcmpemhite ΙΟμΙ ot 2.hug its! Adexa04''-('< iRP- *- peptsib. w-re then oddest to each writ and the plates were utenb tree for a fnrt'ber 3 nonrs at ?ootn temperature The amontO of Alex m4~~ *N 1RO, - boreal ίο B=>. ee<!\ wa- a^stoed on a ! Μ \ f 6200 Hu! -: D,.teet.ton System t Vnphed Blo-osteiitsi Output dre:· wu'e broh a numre seal hi t sales' ot signal intensity ’higher bi 1 vdttes indicate Moore signal intensity) and also .tn image of the * ells

The experiments included negtstive control hybridotna supernatant,- The average Ftl value observed tn tn-e-e negative centre! expeojneuts wxxadophxl rerebe maximum poxoHe signal Dr ?he assto, L spertmetnat supernatants woe et-mparad to the* nrexsroitro signal and a per. ent uilniierot w.ts ealetthsiest fro each wed V’-, inhib-hon (J gf I ⁵ c¹'the em-.-< GOP P ttyhridoma supernataut Maximum ELI signal ti.

An overview eg the data re *hov\n m trig o In this experiment, TOO? anteCGRl' R *opem Pants w.-re tested uxim> Ore roeephn he eid assay H.e lata w ere tank otdetesi using the average prevent inhibition, Ninety supernatants had ''25% average inhibition, 3! of these were >50% and 7 ere ' 70’’« average inhibition

An ahhrex tated data -et ts show si m Table !0. hemw Sample 03 Nos i -5 illustrate examples oGants-CGRP 0 hybrtdorea supernatant,- which inhibited thebmpinv AiesaO-'-”f'GRP,..- peptide to f'GRP receptor and Sample ID Txos ’< re 540 iIhtstsat.. examples of anttGtiRP P hybodome xupereaktntx winch Pot nsU tnhtbh Ore h ndme >a the Alexap4A tn-i\ peptide to tire ('< iRP reecpioi.

145

2016244220 11 Oct 2016

Bared on die binding crenpriititm as*;e. s, approximately 50 supernatants were selected for further char&cieftreMion.

ACmiTV OF CGftP RFAFFTOR SPFORC BLOCKING MONOCi.ONAt

A.yniM)PfES.i\.A eAMB rvvfnoAAi.,ASSAY A, (GRt* receptor atostonjb aeOvhy.

Selected C’ORP receptor antibodies were screened in an in vitro COR? receptor ntedreted , AMP ,re t> ie determine intrinsic potency 1 Ire re e??.i eAMH re-say empire eel a

140

2016244220 11 Oct 2016 hurt \ ne, ’ob'.'sfoma-eef ve-Ked u ? tXKAAK ' >1ο et a :l^,r'd d'di obtained from ATCC (ATCC Number 11 1BMP. J11 B-liKells' ι ΠI BdO eelis espresI Rt R and SAWlPRvvmchfomJ GRP?ec-p\trO A! MJ mine et J, I'’ Μι A’GEBYA v.J I n„ \n vvt!i ,ev<m on » * ovi m aus ( ids! K was i\v tUd ts ee-v' Kd n ' * np s e 1, .md a rj I '’ eel! hra expressing mi i GRP receptor w >-obtained from the AI Ci iC kt 145K).

¹ h.J Wfb e AMP <>s>> ty kit B\wutblmer Boston MA'> wa- m-ad m Pro sc’cenmg, fhe assays weie pet Ibtmed tn w hue ob-w eh plates -,n a trual volume ot bO nt . Bt scih, oil the day of the assav, tK Iro/eit ΚΙ BBO v „ ils wete thawed at ,W V, sells wete washed once with <»s.s> hnd'et ar-o :? »1 of cell ‘uspen-fon torflamnig Η)ΟΟΠ »'JBmixed wuh kkse-dabjed auR-eAMP antsGids was added into °6 half-area white plates ARu addmg Kid (’ IBP iee-cff-or anubvJy, the mixune was incubated tor 5R tmti at room temperature Then 1 ?nl ! GRP see- nfor igomst hum-m O GRP <J nM fund tonvemrataoni w.ro added and ttrntb-. r incubated lor 15 min at. room temperature. After human oi'GPP stimulation, 51 ul„ ot s dete- iron mo was added and roenhat-.d for o(t t'lUVites at remit t-.mpetatnro' and me Jat-w we--. ied η» t. n\ isio.i mstrument t Perkin! dnroro Boston, \|.\t at I rnooeo.M 15.da wete processed and analyzed iw Pn?m iGtspltPad XoRw ov In, tor Veto m, B,we JDB> t.

Fig, 7A shows exemplary data obtained as described above using the It! !'.1P,P reeeptorex pressing ceil iiucMTB-IO for three antibodies -- .TfR, foHeand iF.I 1 Too data are plotted as pete-,.ntaee ove- . out-.ol f Pi K'”⁴ ns a luuction ofantmody « R b, I el 12 m | |'|{ j i owvenmttion, and are fiRed w oh stand rd nonhnaar regression curves to yield the B 5R \ Joes dhovoft. at the: bottom of the figure,

II Lack of antibody activity Is related receptors, t e'l-. spie-saig < ateu. leeey'o's BP till R ?fwv ,s cvptexson fo'Ri E '-R WB'2

D R Poyner, et al, Pharrntteo logs eat rev row, MJ55-5Ί0, ZOBJ, WI5ti I IO cells expressing hCkf R uRAktP?, f) Is Ffoyoer, ,1 u, Rhsrmji<5oi>ie,il tev>. w, - : ? Wm , ?R(P' s or human arov ir \M\tee,pk»t pvH I -^; ecds p< IP,-hRxMPI AAei h r Iron, e'al, AR-eenlat phdtmneuios’y, 5? I B-dJ 175, ί Po~ I weie used to determine 'foe xeux tony of the tested anubod».- Phe Λ XI i-erpi'cs-mg I lb'lx 5^Q1 eeli lute w-,s romera'icd as vlest rtbed in broample L alrow e 1 fro AAI? ,Λpre-sine ! GO eJl Rue w j- pureh.>-c»d from rureSereen <,oow

Pv'ilvinl hue?, ha and tiro human amyltn ΛΜΧ ⁵ ieseplvu-esprossu--, X1C! -7 <. eP luro (Zumnerroann et al. Journal of Endocrinology, 125-151, I RR'J, was obtained from the ATCG

ΒΓΓΒ-'Ή P\ mp-a y ;e,- Its pfott s', ts des, itbed .foov ,»e shown nt fwy· ~B ;b Wli-Bfk velht. ' *;h \M5-GB(»ecilsi and D (hAMY-MCI cells). Note that none of the tested

147

2016244220 11 Oct 2016 antibodies had significant inhibitory activity against b AM I, hAM2 or h AM V I receptors over the range tested.

Vw'k; ,'\p,”'pne its were υ -rn.?rm..A.t tt-ftn- re,on'b-n -an ΗΓΚ t elk expwxsimt eynomoietr- CGRP receptors and rat 1 6 cells expressing rat CGRP receptor »A 1( t3, Date.

> from these -indies, is wed as additional K e-0 j,ua -'bt,fined desentxd ip pen A of this

Esjtnple. ate shown in die ' cAMP” columns m Table I ⁵, below Note that the K'50 '·. aloes tgam-t the human md ..vue CGRP recephns .a; nt the wmonxslur mnge, wnvrets-utusfies agamst rid (.'GRP txn.eptm. and human AMI, ΛΜ2 and WIYI teeeptois. as well as MCE? cells expressing calcitonin tdate not shown s are all create? than I rmcrmnnkir, The difference in IC50 between human (. ifiRP receptor and human -ΆΙΙ, AM? wny ho ind i.ih itonin recento;s illnsbteas the Infos s„leet?wh of tne these antibodies {05 the (’. IRE r<c„ntor <».es relnted receptors formed, in part of fob anme receptor components, JCSO bhtahmd, «sing: bdmau and eyttomolg.ns ( GRE receptor.'·; wme similar, whesea- the tested imsibotbe.x did not appetu to cross· react with mt CORE receptor.

1.5 Table M

Clone	c.A.toP way	J -'i U'S.IV
hCGRF R If 50 fo.M)	Cyno CGRP R 1(75-9 fn\l}	Ifoi CGRP R K'5P uAD	hAmyhn I IC50 (nM i	St AMI K 50 inM't	KAM2 1C50 tnM)	ifinnan CGRP K.t iaM;
01 π i 1.2	1,77	2.79	/>1000	>1000	>1000	>1000	0.030
one 2	3.27	4.74	1000	>1000	>1000	>1000	0.079
02A10,I	I 1.81	17.6	1000	>1000	>1000	>1000	0.291
02 b 7 2	6.30	5.51	>1000	>1000	> 1000	>1600	0,117
03A5.1	9.89	28,9	>1000	>1000	>1000	>1000	0,093
03B61	2.74		>1000	>1000	>1000	>1000	0,033
08C8.2	0.66	5.32	>1000	>1000	>1000	>1000	0,044
OEtlh.2	10,84	10,0	>1000	>1000	M000	>1000	0,.11.1
04 R4 2	2.38	8:,52	>1000	>1.000	>1000	>1000	0,015
04116.1	3,78	' sO	>1000	>1000	>1000	>1000	0,052
O5F5.1	4.79	4 X	>1000	' Ovo	>1000	>1000	0.147
07/12.1	8,96		>1000	' ooo	M00O	>1000	0,1 lo
0033 I	10,2	I 1 '	>1000	- non	>1000	> 1000	0 127
ICE I 1	8381	10.5	>1000	'' 000	>1000	>1000	0,140
OSBI1.2	10,7	17.()	>1000	-1 OOo	>1000	>1000	0,118

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09042	i.4b	2.46	>1000	>1000	>1000	>1000	0.023
09I7.2	3.06	4,44	>1000	>1000	>1000	>1000	0.043
I0E4.2	3,00	3.23	>1000	>1000	>1000	>1000	0.100
11Λ0.1	10. Γ	477	>1000	>1000	>1000	>1.000	03.57
11 DILI	4,93	375	>1000	>1000	- 0500	>1000	0.044
11B9J	4.56	3,0?	>1000	>1000	>1000	>1.000	0,0.57
1217 2	2 93	4,13	'000	>1,000	--1000	>1000	0.097
i 2Gs 2	2 14	2.74	i >1000	>1000	>1000	>1000	0.01?
1300,2	03	117	>1000	>1000	1000	>1000	0,055
1362,2	IO	-19,2	>1000	>1000	>1000	>1000	0.12S
1302,2	I 95	Ol	>1000	>1000	>4000	>1000	0.033
3207 1G		1.93		>1000	>1000	>1000

EXAMPLE 5

ΒΆαιαπ<^^

BECEriORBLOCKiMLANTIBOjHES .5 ^! Ί-labeied CGP.P tAntersifam Biosefetj. es, Piscataway, MJ) and ecll membranes bom ffTB»l 0 cells (PerkhvElnter Inc,, Walfh;am, Massaehnsetts) were used fe radioligand binding e\nefi«m m w the pi·, seixe of ν a sous , om entmtioos o' the ΐ.-χ- mmhtnb.'x to A, iej ,?nm the corresponding Ki values, The CORP tending assay was set up at room tenrperatnre.in 96-well plates etmtaeune, 1 05 p! htndtng Iwffe; < '9 m fi I'tx-i Η I, pIG 5, $ F m\) \b'M)4, tt * B\ \ iMgmat. I tablet oft omelet; fVI'50 ml butter ta protease inhuman!: 20 Hi test compound ί 10X0 20 td 'T-haCGRP ( Amersham Rkweiem'es', iPM t; and 50 td human m.-m'ohl<o-amt<i cd BUB 10) nxmbtms. \,>>ρ<ιΜ>η «;0'tc 'Xt we I Pctkwi ti ten I tx t'Satcx w„,e ex fi ,xed a; room temperature tor T hours with shaking at 60 rpru, and then the contents of each well were loieteti o\ ,a ON*, nob, · tm, \ neritwe tFldbtse end (to- ' hate -we hunt) Cd G ⁿo-w elf iPtef > t'latex 1 he CF ί' fiber pbtes were v t,\bed six times unit tee eted ?0 m.M 1 ns pH ' ? ,md dtx'ti m ,tn ο',ό at 55 V fot 1 h-m- { he bottoms ,o *h * td < pfatk^{* 1}- weie then seated 4ί5 ,f Voetowntn*'' 20 wax added a- each wCi, tlx' topx ofthe f ih' ί plates were wadco h tth fopSeal ^xi-.\ pi pnss~on adhesive seating film}, ami itiv Cd' C plates woe eomued vvith I opt outti A \ I t Pmt.exB I he data wese mtalv/ed nxttm Pttem tGfapbPa.l SY'tw'ue hx 1

2,0 Eseu'pi.s-'y data nth Kt vfingx <Y _Λ txd using nntUaxlnx 3Ch, G'lV a?xl :PG are x'mmtt ι η ϊ o’ S

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The nghkmo-rt , churn in T dde i I above, lists the RI value-- of the indicated ntAbs tn the radiolabeled ' 'l-{ GRpeompURiottbinding ass.iv to 11IB-i0 cell rnembtr.ns's Ihedata de novt< te f tt the < 'GRP teeepio' antd'om s were It' >h'y . 00-0 ttttve 2 2' sab-waro’roG:

range) agam-t CGRP bind mg

EXAMPLE b £MSJHM>nsiASSWJt<M^

BiajCHSG ANTIBOMBS

I he allIt⁵: ties of nnt-i \iRP R nt Xb-s fie f '< IR P teccptor- r \ ge -, *-sed on 1 ells w e;e determined using a I ,VS method. BrtetB. A.,Xb1 v IR) htR'GPR R-espmsstng eeik, prepatud j- dt-v,, idbed -.t'ove, were plated ui 96-wed plates 0 densities v¹' fc.000 of BOj'nlO _u-;i- pet we^;l nt GXILXi medium (.otitatnmg RX'-bBS. Si PS, L Glut, SGA'r .end 0 05% sodntm azide 1 GRP feoepuir ;otiibodses w’v-re titrated tn die suite ine-duno from ^ς0 tt\l to 1 pXI and tnenhated with -..elk Xfter <m ov e.mtght uxubulion at 4 Y nt y tt rial volume ot 120 pi, on a plate -h.-k/·, fix ejls were w tslxd ?\ wuh ^:>BS BS, eenfidfrarg tad chacerdtnu supernatant each time, 100 μI weli ofu unR~t Inlet 'y 5 < 5ng mi , Jackson JwftttvinoRcscareh I nbomtones 'me , XX e-f t it.ne, P-X, I S X1 com mme 'Λ XI) t >pl wen tw ts inm tdded and tnenhated ,tt T X fin R) m n i'be v'e:k wetc w tsh,-d 2S with PBS' ?%FBS, e,-mt iftsgntg and dtseardtng the supernatant each time. IRQ nl PBS 2'*-a-BS i'u tier was tlxu added and nuuk/ed by P \{’Rto defertrnnen die hm.img geomean, 'Fhr Re wa<-lahvGtv’d g-mi,- ΥΥΧ-Χ software: by taking the negative geomeaa at each antibody eoneoovhan as the amount of five Ab present RMhwaswamt ei aL Biochemical end A/eyZnwk'ciZ AeawreA OvtmftefimRePs 334 <20d5) 1004 BP ) Π-e data obtained at the fveo ddfeiu-t Cv R roue. mmRors were analy. < ,1 by n-.urve -maly-ds to determine the Rd and fix 95% runhdetXi, interval a< described m Ruhiaua.swami,; %?/., Bn.· hcmicct and Bioph^wi: R/'ceex h Ci momma acorn 334 {2005}

1004-1013.

Feempiai v ,t>na w nh t ottespoodiog ·, nn e ft's ov show n m log t0 for annl'oRy 12tY 2 ¹ h. vi oa o' /lek wlnYrng anttPe»if.- e.nemted m stmpett of dx pjesvot ib-e'gsuje are shown hi 131%, - 1 3 Ore of the antibodies t XBro was am-iy/ed or two dtllerenf days 1 he f mo 0' Γ’ o obt-aned tot trv. espetutsent w tttt 11>R <, elk mdseat-, ·- turn the anttpen tom emsamn is predicted an 0.0.X the Kd and hence the curve obtained by dt% eqxrimem ts a Kd <oruroiled curve It c..·,η be -eppteeiatvd that the Kd values obtain-,4 tn de-, in mner wem nt die low stngledmit uetxmtoiat mngefof dl k-a/d totdvdx?

2016244220 11 Oct 2016 η

	N curve analysis
	W)	Kd tnw | Kd High (uM) [ (.n.M)	% error	Ratio I OK
1H7	1.9	1.5 3	:3,5	0-001
l· <2EA '	1.5	0,7' j 3.4	6 3	0,19
1 3B6 La)	4.2	U 1 '-2,7	5,3	0,060
; 38ft (bi	2,0	1.6 | 2.6	3,2	0,21
| 4E4	1.3	0,.9 2.05	3.9	0,1 ft
4H6	2.4	1.73 -1 5ft	3,3	0,970
| 9D4	2.5	1.6 I 4.39	4,3	0,060
I 12E6	2.3	R53 1 3,30	3,7	0.55
| 12G8 ;	1.4	n m 1 z> *?] *.λ:?.μ.· s 4a..d,.i ::	3.6	0,94

uKP RECEP 1OR BEOCKESG

ΒΪΜ71Μ3 ΕΟΜΒΕΪΤΠΟΑ

8«.,eo:e . nlss<m, R e' al, ίίί.>/>«λΛ ί C ·>/ι/\η >\> V<. ?/?,',A <«'

6' Ή- BO t H04) e,,,?<* ₍atned «.«η· as follows In-mobth/ tbosi of nnb-CGRP teeeples antibod-cs to the < 'M5 senses chip -on face a a-- p.-tferned aeroi'tong te masnstocinsef h'sirnedons us>n$:a tonsso.iou<> Ocxx of i-tonM HE'PFS, si 1 ?\l \a( 1, 4 4ηΛ! EDVA, d to»?^ι\.

Odd, nl 1 ? 4 (HBS-EP bullet t (.'at boss 1 vi'iMps on *he s;-n-,ni _vhip surfaces w ere activated t\v istieetu-tg ^Λίι pi of a rns\ts,tA' eoreeniuy,¹ o ? \1 \ entx-J \' ien'KtfxlaminorrooxiK«rbo<iier'de (1 IX ) and U O'~< \f Vhx «busy so-. eunnu ,ie g\t ISt Spot die mu e^e-· xxeseobtained by inteefinn MO μ! to anti-OGRE receptor tnobo-ly diluted in to mM acetate, nG 1 0 at s - o' s, uitatiu', to' kt t s u'f I s< ,ss 'M, t)\s p ears >,\ fe sedaes \ wets' xkae⁺'x^wt: I \ ntieeinit bd μΙ of I M ethanobamitu-, Fsu.d nniutodued lex els lords; suur dual ustobcdies w\re as ft «flews.

Antibody Rexoonncs I 'lists f RI^; t

1119 to -5,900

Lift -7,200

4H6 --GO0O

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PGb GfOO

9E5 6/.00

34B3 -3,700

A blank, mock-coupled reference surface w us also prepared on the sensor chip. Soluble 5 huCGR P receptor nt a -oncemmtion ol 1 OOnM was captured on sensor chips having one o! Ore sis'tmnobbi/ed at ubodtes fere'· med .GweGlD-i, BStgdpp, PGRofsot Gi 1,5 ( .<J ol the 20 test imtt-CGRF R antibodies was then injected over the captured huCG'RP receptor. If the injected antibody recogn.tzed a distiuei epitope relative to that recognized. by the immobtltzed. wonbody, a second binding: event would be observed. If the antibodi es tecogntee tire same or very zonular epitopes, only tbs' binding of the huCGRP r,reepto^r would be observed.

Fsrenpnny data obtained nreng .1 -eusor ehm co tt- d w sth nntnobdized antibody arc damn ut Pre ^iJ 3 Tbs' bun daces an data, obi oued using until<odie- 11,1 I, dbd, 21 and 12Gb in the injected solunon IB cuts during ihe experiment are represented by letters, with ' V , re respondent V uu.i taut id link GPP R-I'e. 'B' , onespondutg to end id lbs ret. GkP Kbc osjecnou, C. corresoonumg to tntvemm of second mAb. and ’Ό' corresponding to end sreond m*b uipzt lion and s-are ol tbs' buffer wash Note dun there is no mdbatiosi of any binding stgttel frf'tri am of the uneeted antibody utt the immobilized antibody surface, redst anew that tbs' fore uue- red anuhodres ,·,ρρ.η zitoy se- οι nure tire same sir veiy suwskn epdopci re as the immobilized antibody. 1 srentieliv the same results were observed with ail tested blocking antibodies washed over esch the five tmmohtlued neutralizing antibody sUft.tees indicating that ad tested amv-luR GRP «cscptur btoeknigt antibodies recognize the otUUc or very reimiai and strongly overlappingepitotretsk hi corniest, as shown n- pare m Figs tog or and to), the low tested turn-blocking, ( GRP tctepiorspecto; auttoodtes 12HR GBe, 551-d and MIG faded to compete with I IP! I relap·, not shown), 3fh> ι fig GB), I 3Gk {fig toft and GFy (dat.·, not shown) although 5-11 ?< was able to coitspste with -IHo u ig toto and weakly with GIG (data not show id, 521 lb laded to souipote woh 3p,o,dB:P, Pus, to 5 ,κ the non duo. k mg anybody s.'d's g,_lt ν<β> 5ϋ'4 uinhl compete w uh die non-blocking antibody Mb. 1 1 he data tor ail blocking and non30 blocking anuhodres arc sntmn ndztd hi fable 13, below \B'^! indicates no modmg' indicates significant binding, and ' Weak null, ate- weak binding

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Table 13

	hunanbilOed Antibodies
\b In SobOfon	non	306	4H6	no	9E5	34E3
ΙΕΠ	MB	MB	MB	MB	MB
m?	MB	MB	MB	MB	MB	A.......
2E7	MB	MB	MB	MB	MB	-M -
3R6	MB	MB	MB	MB	MB	Η· ;
3C3	MB	MB	MB	MB	MB	··:·
4E4	MB	MB	MB	MB	MB	< ·?
4H6	MB	MB	MB:	MB	MB	MB
SFS	MB	MB	MB	MB	MB	A
904	MB	MB	MB	MB	MB	A
W5	MB	MB	MB	MB	MB	A
W E4	MB	MB	MB	MB	MB	A
11011	MB	: MB	MB	MB	MB
1109	MB	MB	MB	MB	MB	A :
i®	MB	MB	MB	MB	NB	A
ncs	MB	MB	MB	MB	MB	A:
1302	MB	MB	MB	MB	NB	;:.y: : Λ Λ
32.07	MB	MB	MB	mb	NB	Weak
5208	w’f	: *r :<	Ύ	'V	1'	e
33BS	A .....		a-	(Η'	4'	NB
35E4	M-y	..,., y	-j- ...... i	B-: :	e	MB

As can ne apoteentted from the data, ,«h thg ?>>wd hloefonu or ncnttithrtng autibodis's bind to the same region as the fixe imtnobtifA'd blos'king antsbodn.s. ι e , nil ni the tested iteuitah/itte antibodies fond du same reeion of ihe t GRP K moieenL Gn theolbet hand me non-blocking antibodies dnl not generdly compete w nh ihe immobilized bkn f mg embodies, indicating that die non-blocking antibodies pttmariM fond a different region of ( GKP K,

EMAMOTES

RECEPTOR IN WES I ERA BLOT thiee ivpivM-utidoel GRPieeepti»? blocking antibodies were tested using Western foot* bn fondim; io a soluble CGRP iceci'tin-Ord'e lusto'· piotem

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RfOn u p ifoi’Ui'TR-f t!i\ ip vj.e, jtu mu k> ι-d,- tl,d w ο .K ( GRd* R-hnK e-e<„p* the m-*u-c le wa- us-.d and the linker between RAMRI or ('Rl R K’D are r td e w.o hrf'; tt to AAAA Α)\ IXAA AA»\ (SI Q ID \<> * 151) w.-- dibit d tr PR's with PAi IP -ample buffot wnh (red-te-di or wtthom snonweduced) Fcia-mereuploettumo!

r|AII t nt 15,5% vOiweniTiision, The -uranic connraitng pMF was then Aided fo? 4 tnin Re hte\i are mr~>.ou,e 1 wavde- w ra'o.i, doislo-. lawth 4~?ο’, h--~gRe te e,— (feviirogen) with alteraattng bites of CGRP R-Fe protein and wolecelhr weight raorirars i luxitrogeu; GM- wete eieehobloked onm O.Mou nmoeeikdo-e whet- (kwiitogen) Ί heblots wer».u-h-d w tlis 1 rfs-hutfored -aura. < Ph- I ween 2R r i RS 1t and then Flocked with CBS I <

t(? 5A> pow emd dry milk for ?0irmi The Idol- were >.td rate strip*- along hu- mofoetnaf xeendn market fonc-, Otic Http each wnh seduced atid n<>n-reduced ( GRR R-mul'e wete incubated ν,ιιηριηιϋ dhuC'GRR R .tntfkt. he- B : Oj v _v5 iffora -pp M-mon n s'BSi - '% red-t, goat jiUt-huRAYlRi X-20 ί1:.500: Santa Crtrz Bmtcenuoioex, ute). rabbit anif-nitmse kAs-T-..f IRR 11 :0.000 s tRietee ( or gout eras human IgC 1 :- e 1 t R R 11' 1R 000) Rieiw ι Blots w ere itunkaled xsd.-i the ankbodie- for one note followed lw G Imran w >,-he- wdb Ί BM 1 * milk. The blots treated w tilt the kuf GR P R anttbod'-es w ere then incubated w kh goat anti mouse IgG-Fc-HRP {1 -10.000 in TEST - 1Ά milk) trad die blots treated w 1th anii-titsRAMP 1 <\-2u anti-RAMRl ,„<.iat poRebmat MttiFodx. Aetna Cwt/ Biotech, ( \t wer: nuulsded with rabbit md-goat kA'fofo-i iRp $ | 10,000! for dOsntn Bit ft- were washed e\ i cmin with IRST

2(i I lie hfo'GRR R Mid anlt-ht-R AMRt uuitbodx blots were treated with Ihetec Xupc rsigmd (Vest Iheo Defouion r/aeent a-td th; -etri mouse and anti human IgG 1 e BRR Mots were treated wski ihete-. -tamtam Draw imp Reuueul t ί tutu s Blot- w cm uic, ,-xpe-ed wnh Rod ,.- fFomaMw S r,e, film .All of the tluec (GRR reecplot tuinkodtc-. 4R4, 01 and IBP were aide to detect the soluble CGRR IGrauFe {corsiamtug RAMRI-I CD ano 1 Rl R l-('D) undet non-redueed condition Fid not trader reduced condition indit .niim that die k-irsdim; epdope ofthe-w: CGRP R antjhodte- wt-„- etralorms.tional and -cu-itwe to the di-tdfide linkage- t * pan'- m RAMRI -1-( D and * pub's in ( Rl R A-;?- F'CD? In cooti'a-t, foe conanew rd ,rao-R AMR! nmbodx \-?0 tMma i'rue Ben-1 hi hout.u R AMR1 uneet Fob seduced and no seduc-d eo-'-draon- mem .utne that the binding site for N-20 antibody wa,- primarily linear and not sensitive to dfotdiide Imkaggs,

2016244220 11 Oct 2016

EXAMPLE 9

........ iiss»

CGRF receptors fonrto of either «.tin e RAMFI with chimeric CRLR, or native CR'LR p w ith x him, rie R-\ ΜΗ I, w e«e used to ukntslN ('GRP r.veptor sequences m\ oh cd in antibody binding S nee ail of the human i'( iRP r-eecntos blocking antibodies tested faded to show funettondl activity to ihe rat (' < «RF receptor, the chimeric components contained regions of rat won-, nt e in a hnnam sequen.e ba. k.uooad Hu- mihux me ,?hnneias sxeie yen-, rated h« biudiw .«naosis ^!w f ACv

RAMP? dmacmM tQ2f m AM); SEQ.ID NOG ?7 \;nmo aem i .-odne- Q2h to AeI m tee naroan Is k x’Fi weie senkved w ito the corresponding sequence* * from ia« RAMP! ibis siren h included ihe amino at id residue,* that are different between human and rat RAMP!

RA>nQjdfGeiaKjQj32ql?MMIdli[LNQ?B

Amino acid residues ()4.4 to 1:)5.4 in the.human R \MP' wow replaesd with..the co-· espeudve seqcerbv* (asm mt RAMPI 1 nts stwkb included m\ ammo ’ctd wsidves tn it are ddieiem Veto - en huoi.-n and iat R AMP i

Antuiii ae«d revalues Rn’’ to Ev m the human R V4Pi were w-pbeed xsuh the cc-· responding sequences from mt RAOsIPI this stretch nteluded seven ammo acid residues that are ddferetn between human and rat RA.MFE £ΈΙ:Ε.Χ!ΐη)ηΜ?.1..ίΙ24. to.Qgei.SEQjQ.Ntt.r,)

Ammo acid residue* ϊ 2 ; to Qee so die human (.RtR we«e replaced with «faun Ospon.lnuj sequences saim mt ( Ri R i'bis stmo b mein,led e-yin .onnto ae-d re«siGe·' th.u are differed between humas and: mt CRL-R,

Fig 11 show* an uhgnmef ot P.AMPi ammo .a-nj sequene-,κ horn ,ynowvlgu* monks iS|,Q iQ NO 21?--). human iSLQ iD NO It, »at tbi-Q ID NO 2 ί It and, ihems monkes <M Q ID NO ?'bt, ^foo>'the witn * i.q ” -, e* o-'R WIP¹ Dime , * {M Q ID NO 21 'a *2 tM'O ID NOGIN) mid rirmc λ {SEQ IO NO 2bb $ -g* 12 \ and 121$ -h-wx an alignment of CP.LP. amino aekl -,..-qwm<e* from human (SEQ ID NOG), eynornolgus monkey iSl Q ID NO 22 ί), fm-ws monkes ₍SI Q ID NO 223), i«i uM O ID NO 220) οι I, as well as th-, amino m.d ,*equenec of € RI R dinners - I tSEQ ID \OG23)

2° Dei red* \*c-e imjistendy m-jisfected, wdb CORP Ruhimera DN \ constructs 0 Ri R wi · RAMP) Q2S-A5-I f RI R sxt RAMP) Q-Q-105. ( RI R xst < RAMPl Ro%

155

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Γ'ΧΡΡΙ R I 24 Q.fo E AMP wt, GE! E - RAMRi -.ο^Π,Μιχίο· ,οΜπ,Ι) 1 elkwere harvested after ⁷2hr, washed with BBS · 0.5% BSA. and emimed Each iramdected ceil line wa- resuspended m a -jilttdon of % Id' _xelk pet t)0u.l ΡβΑ'!Ρχ A ί 0(tu 1 of evil snspetw.on was ahquot pet w dt m a ‘ M- welt e'end bottom plate d e.Icoui fhe eetk were pelleted at r< t ?oprpm fo? > nun fhe set’s.πι,η,ον s a-> r -moved and reelaeed w oh tOPgl conbindnu 0 Mie pm died hut '< ,RP R mini'odies IIP, J,. Bto. df5, 41fo, 12(-8, EX ItiU, 111)1!, GDS, m 3385, Control wells were treated with sutbDMR htflgG* (O.SttgX Alexa64?-€GRP peptide < O.dug). or PBS BSA alone, ( ells wetu mt ubatc-1 on see lot 1 ht and then '-wished tw ,et. svnh PBS BS w iheeeik wen. iesu-pended -n lOOul well PBS BSA eoinanijiq. antt-hng-Hd IK {Oxtgt te\e·..pt tor \Ιο\>Μ-ΓΒ GRP ir, afed , elk) t ell·; were hieth.noed on ice in the dark for thr and ih-.ts wu-hed twue with PB\ BS \ ( ell- wetc resuspended in 200ul PBS BSA and ui.tlyeed nsmg n !- AC'S Caitbur lee tepies.mtatke koekfug am-t'-ebes t 'Be, 'P A 4Ih>, :2G\ E s, 10P4, 12! 17. 4R4.

11D11 and 1H ' ι and two non block mp antibody < 3 2! lb and 3385? w er,- toatod. Representative to d ,'a A*R5 antibody'> a.ta shown m Py- 1 t\ PB e d 1 E Gg P \-hew s tinstinn io foe w ltd-type ('GRP receptor big !5B show binding te- ('GR!¹ receptors cm training the ( EL R 1 2 t-oB - toiler -, -et 1 ('- let show ‘m df\ to ( ¢. 4'P '-a e?s>'x commi'me die P AtoPi Q2X A3 5 chnnern. I iu P \Cs anal'- sis showed, that ail 12 antibodies bate w it-d ivpr human CGE.P i’-eeeptin - owti'td .--s espe, led Alt ;2 antibodies showed sigmftejntiy reditee-d binding its an> oi the tntee R \MP t chimera R AM Pt iQ2S AMb-tQ-Dd tot and (Rn“ tG'Si fins eould ι.χ',ιΐί from ί 11 the expression lev el of the ehnnera meeptor was much tow ·;?1 the RA MPI chimera impair <d ttts' folding with human CR! R mid idi-md the . onformuPon of die receptor eomptes, and or (.MOkwc three sek\fed regions on R \MPt arc dhwfo- invoked In the binding of these antibodies to CGRP ieecrna·.

(Vlut) me 1A< 'S iiacftsg wso. can. 31-' include t-nlv the '- er- -ιη-ιΐΐ 'espres-nig ' cct I populations, the nonfotockhtg antibodies 55B7 and 321 ?b nppe.neti to -otwuweidty bind less well dower Geo ''-leans'* η- the RAMP1 <Me 1 53 elnm-.r ι e-s u-mpmed to the Plot,I? toy antibodies, suggesting h-ud-ng to Me RAMP: ().ρ,.Γ'Μ teg mt may be more nnpoii-mt fin- the non-etoeking antibodies t tn ihe et het h.-.nd, ¹ »B5 and 12! IS eonoBfeutly hound hotter to the ed R (Mpf Rn' PM dtimem th tn tp bfoei-omanttlv-dic% stingcstuto the P.AMPI Rp *' I 'd xeipwia e nay- be mote fittpo: tout hu th-c bio-, l-oun antitto-.h-. *AH Cl iRP re·,eptor antibodies tested bound reasonably wdi to the G'RIE ohntoertt tL24-Q.Gi. suggesting this site is not essential tb’ binding of blocking .ifitibodR--.

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In \-uumsry, the data Mow ihai three dRemdinoous regions nn RAMPi — (QGR-AT!). (G-G P53) and iBM-l-'·;) -- could he invoked m ('GRP reeaptot antibody bmehov, with (Po -f Mi mete unpo¹ tent G''he bio, Amp uot'bo.oes The N-ν 'm'n.d - <;U-u ,w il ? MUG of CPU P, did not appeat to hecrutetriR invoked in binding fot the CGRP teeeptm antibodies as analyzed by this method This approach dees net rule out additional binding site- that share uliuitteji ei sm-das sequences hetxv et- hnmei .e-d hit CGRP leeepiotx winch w en not tasgeud hi the analysts,

.....

Kt NEUTRALIZING ANTIBODIES BA’ PROTEASE. PROTECTION ASSAY

The CRLR portion in the mature fern of the CRER-Fe fusion molecule (with signal peptide removed; disclosed he-mni as SPQ if) NG; iOi contains 1 Κ» amino acids iprecednig the gRemc hnhc*) and has th-ce hire- loop sUuet-ues t icarttl bv unmanon of uuee disulfide bonds 1 ne three dtrtriodc bonds in CRLR ere <. yU at -equzncv poshing > tali ('PI P

1A sequence ρο’-Ριοη- iisied n- ba- pumvtaph 'ee vit ! icspeet m ttie ntutuie sequence piesetned us SEQ ||) NO: 10} linked to Cys3 at sequence position 52 {referred to as f Ri. R ( I -Of Cys2 -u see's'tsi, e p-'siuon-P Hiked m r yM at x. qu m-e ροοοοπ M iiet'e-vd to.isCRl kf?-( Ά Cys-1 td sequence position oo linked to Cysb at sequence position i(G treieoed to us CR1.R C-f ('pt RAMP I pom,so us m,diuv foo.i ,n RAMP’4 e 'h-uut melceuh' eoutumx B muno acid- tSl-0 ll> NO' 111 preceding the glycine linker, winch also forms three iniosmrdeenlur disulfide bends 1 Its' three dfrrriode oond- in R M1P; am Cm I -d sequence position t ml; RAMP! sequence portions listed m tins pamgtaph a-e w-th lespeef to the mature sequemx nrmented ts SbO ID NG t ihus/d to Cys? tt s.,git nee pqsmm< ?o p'efet'ted to o R MV·*!

C MU, < vs2 ,U sequence position 14 linked to < >\4 at sequence nosUion 4ο uefened to ,is

RAMPI < MA Ό (Me ,n scquens'e postlton e t hnke<l to<Mo ut sequence po-dtou Ά (reietn ri to a- P, AMP! Ce-T M

Reetonsof the human ( gRP receptor pmtvtn b<'und by utttt-f'GRR oenuahrmg mminclonu' embodies were GeruttL-d by hupmeunnuh ( gRP R ;mo p.-phdes wuh speed'sc piotea-es, and ric-'crmmhig the sequence of tbv lesuh-ng 9 CGRP R peptides ft c , both dtsui'dde and not· ih-erind?-_tom«ining pepbds' fragments for CR1 R .ad R AMP? pomens! A ptotease ήτοι-, emm a-say was tiwn performed to dete-mme the pioieobrtie dige-hon of h( GRP

R to the presence of binding monoclonal antibodies. The, general prtuetplc of rids assay is that

Of* dnig of a tu.\b t'o t. < IRP R i ao lesuh m 'piotci don ot , ettum sp.-erin proiea-e eieu', ay. site2016244220 11 Oct 2016 <tnd dos mtofmrorors can be used h, deuronroc the i croon or porta m oi CORP R when- the nt \h binds to,

R.tefh, I pepude ebgesis wcie v bjeroeo fo HP! C n...rfo<le mappmg, t , π,ΡχΜη d peaks w, etc collected, and the peptides nknhrtcd and mapped by on-ltnc ekctro<iprav ionicittion I( -Mb PSI ί f MSt muly-,es and or by N -torminai sequencing ΛII HP!. C anal-s', *- fo; these studies wetc pm-boned nsme ,·. natron Irosc tcsCfs'e-pbeec t 'IS eoiuntn td 1 ntm rod, ’< 15 cot length; Xortros 1Q0SB. ? urn, Agtk-nt leehnoiogiest for iiff line analysis and irorog a -..apdlen iexesse phase Cl* column (Iffrom t.d. s 25 esu Yydav CIS MS, 5 aim The Sepasairost Group* feu 1 i -MS HPLG peptide map-pure ’va< performed xx ith a Itoem· gradient

Ip Horn 0 05'*, u.Hoorn -,>, ei,e amp <pssron>, phase X'· to 'M^! < <-.eero’uitti>,' ut ts 0^ςΉ if rbioroaeeiic aetd t oluntns xxer„ developed oxer °0 minutes ai ,-, flow sate of 0 25 nil mm for nanoxx bore HP11 lerxdf-upeoi osoifu 1 y-MS aralysvs and 0 OlP ml mm bm t aptllatx HPH for online 1 t -MS .niafxses

Mature iorm human f HRP R w<gs digested xx ;tb Mp\ (which elea-es tiler tsgarttc

1.5 acid and some glutamic add residues at die amino end) by incubating about .100 g.g of GGR.P b' a ΐ I 0 nm nb in 0 1M sodium phosphate tpH 6 e > for ,b· hrs at 3 Z 3' with ? qg <7 AspX

HPI ί ehi-'-ntatogrecl'o.' of Pro \spS digests generated a peptide prolde »>-> -,hex' n in I tg M ;cich sample >C^!ug injecteds. eluent utoemro labeled Ά fo; HGRP R alnm {concentration i mg'ntl 5, wt-foe a ooufrol digestrot xx tilt.-- surular amount of < Xakb R i’0 neuifnb/ing arohbodx, clone 1 ?t sf, ,-drox' s that the antibody, ro ese-nn illy testsurot to Ύ·ρ\ cneoptokmusv. tdeoniutoin nn fobcicd H; PajRF Ifoautibodx race, 100 2. I Oil ?,

100:20,xx'elght bx weight, respectively? Sequent e analyses χχ·,ην eonduek-χΐ by on-nne I t Mb MS and Px I dinar: sequencing on the peptide peaks teeoseted from HP! t Ou-hne PS!

I C MS eegRys^s of the p„pm!c faces! were p^rfotm-O to dete-mme the precise mas,- wd segU'.nt a ot the pvphdes th U w etc sep;,· eed by 111Ί C 1'he identities of seset d pepnd-, pro,cm tn the peptide pmfe from the \sp\ dive «lion were thus determined Hndix.tud us rounbew d peaks ,n fog I -H 1 able 14, below , shows -he foeaiions of the-ro peptidx’s-, quf· ru es nt the eerie spending component o: 'Rl R or k \ Mb 11 of me .hC.X.,R.P R, A capital lette: ( lb'lox'.ed bx c numoe: or \ '/p;, s >m- a peptide fj, rhib d as a CP 1 P perm-le, >i ,apo< 1 texfet R ex) follow („d be a unrobe? or X a RA.Mbi peptide and H e' represents the lat ue, undigested 1 e fragment released from the CRLR-Fc and RAMP 1 -be feion meleeulo;

158

Table H

2016244220 11 Oct 2016

CR LR and RAMFt oepiidef identified .fey peptide 'mapping of CGRP K AspH digefokm
Peptide	Seq nonce DButlide (#> location	Intact mas-	Origin
(.4	h! 11A 122	0	1(359	CRLR
a	D5.GA58	0	670	CRLR
C5	□55-505	O	880	CRLR
C4	DOXQ71	Q	571	CR I. R
C5	D55-P6?.· 080043:10		n d.	CRLR
C6	D8~Y74	0	19A	CRLR
C7	E25-O32/D48A54	1	3955	CRLR
CA		3	tut.	CRLR
Rl	052- \44	0	3622	R AllO
R2	L 12~A ?.P D4S-,X51	3	1939	RAMPS
P-X	G3-RB6	1	113049	RAMSO
S:c			2(i$t)0	RAMRCCRLR

rig, 15 shews u comparison oi an A-pX digestion experiment teach sample SOgg noeeh,-J) with < GEL* R «lone oJ:nmiaiogruw labeled A) w?ih one pe:lbim-.-d in du. ptesc^ee of neuh'aSt/uw anttfoxl- 12( If iehtowaingiam Libeled B) I Ik v> eight raito id'OGRP R antibuds wa- 1 ! $>, \eiid peek- ;C\ ( t\ ntd CM -ho'- a de- teased -n peak lienda o thtrnna ogiaru B reBti-c to eitrematogiam \, white too edict p>„,ik»(i\\ eno P. ?<*> shew co sncieas. at peak height ai ehretnatnginni B wlanse to -'hainiaiesmam A A similar peptide snap piste,-η: -να- also obs.av ed d a different lieidruL.-iitg antj-C GRP E antibody 11 Ot 4, /Be, .<< h m 4s 4} ,-j a ed similar qa met- tea- pre-ent ut the dfge-hen sample as seen m the chroma ingmot labeled C Both t b ..aid C⁷ ate tb-nlisde Snd-ed neplfd- - whis'h . ev et a m yo: petiton ot the ( Ri R •ntaSeeu!'· whiteC5 ts a 1 'PIP non ds-ullide -omamune peptide residing .it fhe X terminal end oi the oioOeuk and e petnu lunate io the disulfide pi glide, P. ak < A contain- thi.-e CRl R disulfide bonds w uh multiple sCdtienees, indicating at least two io three peptides are hrtl-ed

I59

2016244220 11 Oct 2016 rogribet by dretutfdo bonds. i'be hut fh<« peak CA ba*; increased peak height nt a CreRP P digest re tire- presence of ('GRF neurreih/tog anttbedy nviudtes that the mtbbods has protected ί GRP k'tout \sp\ In *»Ροη at *< \etri Gee,a< e s<, w η .me-GsCmt I \*ps I antibody dees net appear to hate a xtgntttmnit piokstixe cffec* on A-tpe * and Asp?2 as peak intensity for peptides € 3 and f '4 did nm de*reuse at all fbereiore the antibody appears to bind io a region of ( R( R w Inch includes tire CRLR Cl ~C5 and ( Rl R ί 4-C'Oibstdlide region together with fire loop region between Gy see and <.\s66, the Asp.\ mapping of h( reRP P also -deuttfied « R WIRI dretdf-de peptide (R2) and a RAMPi non-disit’fide pep-trie tRG (see tank id and I n. id) in the presence of any of the above-mentioned tree Ma I:,η n<; antibodies 112GN Idl'd, 4b'4_s 5Rp os 5( S n peptide R A rests t ex erected at a -sgmfu-antb, htgbet pcA retenstiy than rebat reas obtained horn the ibee-roon with no antibody in the sample. Mass and seqnefine analysesshowed that R.-x contains a stogie poly peptide ebam eot responding to tire RAMPI seemenee between Cyst and Argbo. These xApcrimengs indie ito dre! CGRP R n/ntralreing antibody can pm-met a significant region of

1.5 RAMP I from A*-pN prcteolytu digestion ϊ o assess w hetoer fire protective effeet of ί l iRP R Vp\ mvieoly sis ,-reetoe io

CORF Rote «Rabat ng (blocking) soRhodteMkR coin pared redid and-CGRiP R nouAiGtoreTiGng arttood e-k an \xp\ dre'et-ore- o* t GRP R was pereowned re tou re'ere-me et an untelated - otitrrti ntnnoeknnd antibody winch does not nentutiox-1 'GRP R at to hre The resulre ,ne

2(1 shown in fig. 15 in chromatogram D. fhe non-neuiodizing antibody (does not show any srenme.mt blocking effere sin (ASPR R As»A preteoAsts, indeed the peptide reap preftR f, hrematogrenn ft s re neatly rodretineroxhal-ro m the teles ant aspects m the ptoble det r, ,-4 Here digs store off GRP R «'.one Anrom,noeram A'

The proteolyses protection effect reus dependent on the eonecntration added to fhe digestion sample, As seen nt f to. 16, a fixed CGRP R quantify in the sample :1OOng) with rent -,He nnonnis ot ann-CGRP R neutralizing antibody »l'-i R GPP R'untibody ratio tn rnterogrttnts, 100.2; lObre; 100:20,weight by weight, respectively '> was performed tor Aspen pml.-oRs-s Tn<- preUeenou ptofde can be Greened and toe prole- tto'·» re _tuit:ho4y co i: ee n fra t i o- t-depei i de- ti.

Taken together, these dare demoftstrate that blocking or nereruHGng anti-C GRP R antreodu th'-. breed hetero ran Go-G*. f'GRP R son both CRT R and R WIFI corepoueres} Ootn AspN proteolysis, suggesting that the hkukinv anti bodies bind to both CRLR and RAMFI whew M- 'CartfooL ·, koto, m to. ( GRP ret epto-- froth, tribe inor,, t-roi. to.-et ts.mitoous160

2016244220 11 Oct 2016 ϊ on- etomtiuh dependeiU These resuhs dsoindK.it mh-a'CGRP R neetmlDmg .mhboibes bind h« common reweiis on hn-tna's C'GIsR R which me Uix the As? \ clem-age -he....... SOlJb ίΜΜίικ

Ci me i set u , R-a-a Lbie antibodies directed aeamst one oi theothet sotnponein<R AMPI or i 'R i R ί ei the htanmt CGRP rxeptnr wem serwned m the ('GRP receptor mediated -, AMP a-say using I fTB-li) eeiC as described w Fsantpie 4, atowc. te determine wbethet tits' amd-ndie- had btotog-eA ton tty, ; he dm.-, ate pse-ented et i able J 5, toJow ϊ he aphbodies Had either no Octet tahC f'ND'd, very we A t AAV't or w eah ι'ΑΑ’Ί i'ltdegn at aide be e\ era concentration I'anee where the exentphuv antd-t’dfes dts<Jo-a cl herent had stiom,· bi ologt eat -activity.

Tti hie 15 ( -mmiv tv iaby -a\ adaPto atoihede net- - itv

Name	Source	ot epitope	Vendor	HI BAR aettollv
CRLR anhhedy I 'th 18164 5	Rahhh. polyclonal Ab	\~teia- -η,,! I t, f) nt h( Is! Is	Abewn toe , Cambridge. MA	ND
CAlCRi antibody	Rabbit pobelonni \b	N-tcrminnl PCD ofhCRi.R	(ienY> ay Biotech, toe,, San Diego, ( A	NS.)
CRT R i M- i $}	Goat·'polyclonal Ab	epoch-,, mapping near terminus ofhCRLR	Santo Cruz Biotech	yw
CRLR (H-42)	Rabbb polyclonal Ab	a«2.G64 of ItCRLR	Santo Com Biotech	ND
CAI..CR1. .Antibody (A01)	Mouse poly etonal Ah	mC5-!33 of hCRIJ?	A o\ us Biologicals, toe.	vw
RAM PI (N'6 20}	Goat polyclonal Ab	epochs mapping at AWcmbnns of hCRl. R	Santa t ni? Biotech	NO
RAMP1 Antibody	Mouse polyclonal Ab	mA 7-118 of hRAMP)	town- Binh<gjeals,	i : w.

16!

2016244220 11 Oct 2016

(MO!)			Inc., Littleton, CO
RAMP) An- foody {I h 11	Mouse monoclonal Ab	aa.fel If hRAMP)	of	Nov ax RioiogteaN, hie	NO
RAMP1 antibody (abb? 15.1)	Mouse poh,.Iona! \h	foil length hRAMPi	of	Abeam, )no.	W
LAMP! (Π,~ 148),	Rabbit polyclonal Ab·	ft·)! hRAMPi	length	Santa Cruz Lsetech, Santa Cm/.. CA	NO

2-4\iff cells wete tnfseted pet eella plug Uatcgra I ftiebeieoves Co , RUinsboro. \b

Coha plugs wc?e embedded m 0( Ϊ medium {Sekuta PineiM kb.'., Torrinti e. C Iro/eu at Ji'C and ui! into 20 μηι sections esnw a ervostat Sections were lived wuh 4C pnralbit'ttaidehydc for I hoar at room temperature HCI) and subsequently washed m phosphatcOuleieti salute «_vPI>S* Fadvg mons p-iw.d.ixe wa<- bloeke I wtib 7', Ο O Piis lot ί' nan and vcuehs were incubated nt blocking «nbittou (PHO with fe norrn.h gnat scrum foeeu.r Labs, Surhngarne, CA) and 0,3¾ triton XMOQ) for ) boar, Subsequently, sections were na abated nt human auit-t. ORR ie>. uptot p*tntar, am.isxc fo2)i”,iO}’ - 0.....1 i.ig tin} at. 4' ( nv,r night, washed hi RBS anti incubated m seenndaty antibody ibiottio kned go.it snh-hurnan tgC hv tmgmvjtr, t Sf-fo Jackson hnmui'ior.weeri.h, -eoifowe, P-M ft< fe notmO eo.e semm PBS fo for i bon: at R) hnmnaoreaeti.ity was amplified using die Vector Fhte Re aeeoobng n? the inanufaetnrer's instruct ions i Vector Labs, Burlingame, (At and stamina was de’, efopen using hVM^'-nnebe''¹ ^dme-mi. kei <e ebounogen (Sigmafeidn· b fo. Louts, MO) Semiona wmv Ceased with feem. and ee.et slipped with Ret mount (l-'tslter Chesrufes i so lawn, Nj'., linmunoreaettvity was analyzed using a Nikon P-AQQ microscope util issou.it>. d software feikon. Melville, A λ ,

Beta front cells ,,-spressmt. dtherent iCveptor ><otn?onmix Os identified befool usme at obe.h, Oil a.s devo led above esc,led presm me co statute fet I Ifo ia.,L ..xptess ay recombinant human CGRP rerepter (CKLRs-B AMP I; CHCCGRP R cells} ,«nd weakes Ousnusg ol SR~N~\1C cells that endogenouh, express t'GRp iceeptots {,|ne to much lowet

LA

2016244220 11 Oct 2016 ’t.no ie'-sUv ΐ \o sta m _S ύό·Κ m\) life's, t'JIO t Γ'u e srraxs'ro;

an unrelated recombinant piotero ίΊΕΡΜΜ (iRH'GKP R eeife attet prea bviuptiot, wuii foe era responding 3?dl antigen, GIO cell·: expressing seenntbrnani human ulreitonieduiiin mec'fo-' 2 C R^! R ΕΜΙΡΗ. WI ’ wis eud<acno„d' espros.ma a n> an racemes. HI k cells exprcscing iceofobincnt human adrenomedulbu. receptor 1 (CMJMRAMPd), or the p e> m HI k .eh* fhe d tra from these expeomems ,-, e sonets,,? rove, m I Cide Its helms Table Ib Imrouuohtstochcmic»! sfetnlug intensity of indicated cells

Cell line	Staining intensity (vUoal scare)
lGRPCHO	•Ή
kfek-MC	C
CHG	0
TRPMfeCHO	e
CGRP 'CHO pmndsorbed	0
am:oho	6
MCI·'-?	0
Mil Hhk	0
BEK

Mi patents and other publications identified are exprosslv met epos ated hetent bx

I 0 mdet'enee for the purpose o{ dascnbtng end draeiosmg, tor example, the methodologies deset’K-tl tn such pnbikxufons that nnijbi be iraed in cm meet ton with the safeero matter disclosed herein 1 hcsc pubbrauems .tra- prox ided c-olefe for then' d'-selosura’ prior to the fdmg dine of foe pteseut eppb.aften kotitme in do* ι.-gatd should be construed as an adinm-On that the no eiders ate no? entdied to antedate sneli dtselosnic by onia. of prim' iro foiion o; fo? am f ' fora i season Al⁵ s'' 'Cements <n io ?H Can, o< ; p> ’xentano-i a* io fo e-um-ut* of these document* ts based .'tt the foira'idatson available to the applicants ami doe* .not constitute any a, n *sot >ts g> i e toio. messo fo. d a*o ,omef m Irast o<,i in it*

I be

2016244220 16 Dec 2016

Claims (17)

1. A recombinant antibody that specifically binds to human calcitonin gene-related peptide (CGRP) receptor comprising a heavy chain and a light chain, wherein the antibody is isolated from a host cell that expresses a heavy chain nucleic acid comprising a sequence selected from SEQ. ID NOs: 242-258 and a light chain nucleic acid comprising a sequence selected from SEQ ID NOs: 224-241.

2. The recombinant antibody of claim 1, wherein the host cell secretes the antibody and the antibody is isolated from the culture medium of the host cell.

3. The recombinant antibody of claim 1 or claim 2, wherein:

(a) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 244 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 226;

(b) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 257 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 239;

(c) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 248 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 230;

(d) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 246 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 228;

(e) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 249 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 231;

(f) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 255 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 237;

(g) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 242 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 224;

(h) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 247 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 229;

(i) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 250 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 232;

(j) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 256 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 238;

(k) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 252 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 234;

(l) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 253 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 235;

164

2016244220 23 Apr 2018 (m) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 254 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 236;

(n) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 243 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 225;

5 (o) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 251 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 233;

(p) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 245 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 227;

(q) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 258 and the 0 light chain nucleic acid comprises the sequence of SEQ ID NO: 240; or (r) the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 258 and the light chain nucleic acid comprises the sequence of SEQ ID NO: 241.

4. The recombinant antibody of claim 3, wherein the heavy chain nucleic acid comprises .5 the sequence of SEQ ID NO: 247 and the light chain nucleic acid comprises the sequence of

SEQ ID NO: 229.

5. The recombinant antibody of claim 3, wherein the heavy chain nucleic acid comprises the sequence of SEQ ID NO: 251 and the light chain nucleic acid comprises the sequence of

0 SEQ ID NO: 233.

6. A pharmaceutical composition comprising the antibody of any one of claims 1 to 5 and a pharmaceutically acceptable excipient.

25 7. A pharmaceutical composition comprising the antibody of claim 4 and a pharmaceutically acceptable excipient.

8. Use of the antibody of any one of claims 1 to 5 in the manufacture of a medicament for treating a condition associated with CGRP receptor-mediated vasodilation or neurogenic

30 inflammation in a patient in need thereof.

9. The use of claim 8, wherein the condition is headache.

165

2016244220 23 Apr 2018

10. The use of claim 8, wherein the condition is migraine.

11. The use of any one of claims 8 to 10, wherein the treating comprises prophylactic 5 treatment.

12. A method for treating or preventing headache in a patient in need thereof comprising administering to the patient an effective amount of the antibody of any one of claims 1 to 5 or the pharmaceutical composition of claim 6 or claim 7.

13. A method for treating or preventing migraine in a patient in need thereof comprising administering to the patient an effective amount of the antibody of any one of claims 1 to 5 or the pharmaceutical composition of claim 6 or claim 7.

.5 14. A method of making an antibody that specifically binds to human CGRP receptor comprising:

culturing a host cell comprising a first nucleic acid encoding an antibody heavy chain and a second nucleic acid encoding an antibody light chain under conditions that allow expression of the antibody heavy chain and antibody light chain, wherein the first nucleic acid

0 comprises a nucleotide sequence selected from SEQ ID NOs: 242-258, and the second nucleic acid comprises a nucleotide sequence selected from SEQ ID NOs: 224-241; and isolating the antibody formed by the heavy and light chains from the host cell, wherein the antibody specifically binds to the human CGRP receptor.

25 15. The method of claim 14, wherein:

(a) the first nucleic acid comprises a sequence of SEQ ID NO: 244 and the second nucleic acid comprises a sequence of SEQ ID NO: 226;

(b) the first nucleic acid comprises a sequence of SEQ ID NO: 257 and the second nucleic acid comprises a sequence of SEQ ID NO: 239;

30 (c) the first nucleic acid comprises a sequence of SEQ ID NO: 248 and the second nucleic acid comprises a sequence of SEQ ID NO: 230;

166

2016244220 23 Apr 2018 (d) the first nucleic acid comprises a sequence of SEQ ID NO: 246 and the second nucleic acid comprises a sequence of SEQ ID NO: 228;

(e) the first nucleic acid comprises a sequence of SEQ ID NO: 249 and the second nucleic acid comprises a sequence of SEQ ID NO: 231;

5 (f) the first nucleic acid comprises a sequence of SEQ ID NO: 255 and the second nucleic acid comprises a sequence of SEQ ID NO: 237;

(g) the first nucleic acid comprises a sequence of SEQ ID NO: 242 and the second nucleic acid comprises a sequence of SEQ ID NO: 224;

(h) the first nucleic acid comprises a sequence of SEQ ID NO: 247 and the second 0 nucleic acid comprises a sequence of SEQ ID NO: 229;

(i) the first nucleic acid comprises a sequence of SEQ ID NO: 250 and the second nucleic acid comprises a sequence of SEQ ID NO: 232;

(j) the first nucleic acid comprises a sequence of SEQ ID NO: 256 and the second nucleic acid comprises a sequence of SEQ ID NO: 238;

.5 (k) the first nucleic acid comprises a sequence of SEQ ID NO: 252 and the second nucleic acid comprises a sequence of SEQ ID NO: 234;

(l) the first nucleic acid comprises a sequence of SEQ ID NO: 253 and the second nucleic acid comprises a sequence of SEQ ID NO: 235;

(m) the first nucleic acid comprises a sequence of SEQ ID NO: 254 and the second 0 nucleic acid comprises a sequence of SEQ ID NO: 236;

(n) the first nucleic acid comprises a sequence of SEQ ID NO: 243 and the second nucleic acid comprises a sequence of SEQ ID NO: 225;

(o) the first nucleic acid comprises a sequence of SEQ ID NO: 251 and the second nucleic acid comprises a sequence of SEQ ID NO: 233;

25 (p) the first nucleic acid comprises a sequence of SEQ ID NO: 245 and the second nucleic acid comprises a sequence of SEQ ID NO: 227;

(q) the first nucleic acid comprises a sequence of SEQ ID NO: 258 and the second nucleic acid comprises a sequence of SEQ ID NO: 240; or (r) the first nucleic acid comprises a sequence of SEQ ID NO: 258 and the second 30 nucleic acid comprises a sequence of SEQ ID NO: 241.

167

2016244220 23 Apr 2018

16. The method of claim 15, wherein the first nucleic acid comprises a sequence of SEQ ID NO: 247 and the second nucleic acid comprises a sequence of SEQ ID NO: 229.

17. The method of claim 15, wherein the first nucleic acid comprises a sequence of SEQ ID 5 NO: 251 and the second nucleic acid comprises a sequence of SEQ ID NO: 233.

18. The method of any one of claims 14 to 17, wherein the host cell secretes the antibody and the antibody is isolated from the culture medium of the host cell.

0 19. An antibody when prepared according to the method of any one of claims 14 to 18.

20. An antibody when prepared according to the method of claim 16.

21. A pharmaceutical composition comprising an antibody of claim 20 and a .5 pharmaceutically acceptable excipient.

168

1/17

2016244220 11 Oct 2016

CYNO_RAMP1 Π) HGMAN_RAMP1 (1) RAT_RAMP1 (1) C¥NG__RAMP1 155) HUMAR_RAMP1 (55) RATJ1AMP1 (55) CYMQJRAMP1 (109 5 RUMAN_RAMP1 (109 ί RATJRAMPl (109}

1 10

20 30 40

MARAIjCRLPQRGLWLLLAHHLFMATACQEAKYGALLQEIiCI.TQFQVDMEAVGET t4ARALCRLPRRGLKL.LL?iHHLRHTTACQEASYG?i_iLRBlCLTQFQVDMSAVGET

MAPGLRGLPRRGLWLLI.AHHLFMVTACRDPDYGTLIQELCLSRFKEDMETXGKT

SO 70 80 90 100

LWCDWGRTIGS'XREIADCTWKMAEKLGCFWPKABVDRFFLAVHGHYFHACPISG

LWCDWGRTXRSYREIADCTWKMAEKLGCFWPNAEVDRFFLAVHGRYFRSCPISG

LWCDWGKTIGSyGSLTHCTKLVANKrGCWPNPSVDXPPIAVHHRYFSKCPVSG

110 120 130 140

RAVRDP PGSVLYP FIWPITVTLLVTAL WWQS KRTEGIV RAVRDPPGSILYPFIVVPITVTLLVTALVVWQSKRTEGIV RALS.DP PNS1LCP FI VLPITVTLLMTALWWRS KRTEGIV

2/17

2016244220 11 Oct 2016

CYNOCRLR (1) HUCRLR Cl) RATCRLR (1) CYNOCRLR (57) HUCRLR (57) RATCRLR ¢57) CYNOCRLR(1145 HUCRLR (114) RATCRLR {114} CYNOCRLR{171} HUCRLR {171} RATCRLR {171} CYNOCRLR(228) HUCRLR {228} RATCRLR {228} CYNOCRLR(285) HUCRLR ¢285) RATCRLR (285) CYNOCRLR(342) HUCRLR (342) RATCRLR {342}

1 IQ 20 30 40 50

-MBKKCTLYFLVLLPPFMIFVTAELEESPSDS1QLGVTRNKIMTAQYECYQKIMQDP -MEKKCTLYFLVLLPFFMILVTAELEESPSDSIQLGVTRNKXMTAQYECYQKIMQDP MMDKKCTLCFLFLLLLNMALIAAESEEGANQT-DLGVTRNKIMTAQYECYQKIMQDP

SO 70 80 90 100 110

IQQASGVYCNRTMDGULCWNNVAAGTESMQLC PDYFQD FDPSEKVTKICDQDGNWFR TQQAEGVYCNRTWDGNLCWNDVAAGTESMOLCPDYFQDFDPSEKVTKICDQDGNWFR XQQGEGLYCafRTWDGWLCWNDVAAGTESMQYCPDYFQDFDPSEKVTKICDQDGNWFR

120 130 140 150 ISO 170

HPASNRTWTNYTQCNVNTHE KVKTALNLFYLTI1GHGLSIAS LLISLGIFFYFKSLS HPASNRTWTNYTQCNVNTHE KVKTALNLFYLTII GHGLS IASLLISLGIFFYFKSLS HPDSNRTNTNYTLCNNSTHE KVKTALNLF YLT1I GHGLS XASL1I SL 1X FFYFKSLS

180 190 .200 210 22 0

CQRITLHBNLFFSFVCNSWTIXHLTAVANNQALVATNPVSCKVSQPXHLYLMGCNY

CQRXTLHKNXiFFSFVCNSWTIIHLTAVANNQALVATNPVSCKVSQFXHLYLMGCNY

CQRXTLHKNLFFSFVCNSXVTIIHLTAVANNQALVATNPVSCKVSQFIHLYLMGCNY

230 240 250 260 270 250

FWMLCEGIYLHTLXWAVFAEIQHLMNYYFLGWGFPLIPACIHAIARSLYYNDNCWI

FWLCEGIYLHTLXWAVFAEKQHLMWYYFLGWGFPLXPACIHAIARSLYYNDNCWI

FWMLCEGXYLHTLIWAVFAEKQHLMWYYFLGWGFPLLPACXKAXARSLYYNDNCWI

290 300 310 320 330 340

SSDTHLLYIIHGPICAALLWLFFLLNIVRVLITKLKVTHQASSNLYMKAVRATLXL SSDTHLLYIXHGPXCAALLVNLFFLLNXVRVLXTKLKVTHQASSNLYMKAVRATLIL SSDTHLLYIXHGPICAALLVNLPFLLNIVRVLXTKLKVTHQABSNLYMKAVRATLXL

350 3SG 370 380 390

VPLLGXEFVLIPWRPEGKIAEEVYDYXMHXUiHFQGLLVSTXFCFFNGEVQAXLRRN VPLLGISFVLXPWRPEGKXAEEVYDYXMiiXLMKFQGLLVSTXFCFFNGEVQAXLRRN VPLLGISFVLFPWRPEGKVAEEVYDYVMHILMHYQGLLVSTIFCFFNGEVQAILRRN

400 410 420 430 440 450

CYNOCRLR ί 3 99 j WNQYKIQFGNSFSNSEALRSASYTVSTISDGPGYSHDCPSEIiLNGKSIHDXEN'WLK HUCRLR ί 3 9 9) WNQYKIQFGNSFSNSEALRSASYTVSTXSDGFGYSHDCPSEHLNGKS XHDXENVLLK RATCRLR (399) WNQYKXQFGNGFSKSDALRSASYTVSTISDVQGYSHDCPTEHX^GKSIQDISNVALK

CYNOCRLR(456)

HUCRLR (456) RATCRLR (4 56)

460

PENLYN--PENLYN--PEKMYDLVM

3/17

2016244220 11 Oct 2016

Kappa X1 SEQ SEQ SEQ CDR1 5D MO: CDR2 30 MO: CDR3 3D MO; 2E7 RASQG i R M D L G 48 AASSLQS 49 IQYNIYPWT 50 13H2 RASQGi R K D I G 88 G A S S L Q S 67 LQYMSFPWT 58 K1 Consensus RASQG i R S D L G 103 AASSLQS 104 LQYM 3 YPWT 105 K G SF Kappa K4 SEQ SEQ SEQ CDR1 SO MO: CQR2 SO NO: CDR3 SD MO: 32H7 R A S Q S V S S G Y L T 89 GASSRAT 70 QQYGNSLCR 71 32H7a RASQSVSSGYLT 89 6 A S S R A T 70 QQY6NSLSR 72 K4 Consensus RASQSVSSGYLT 63 GASSRAT 70 QQYGNSLSR C 106 SEQ SEQ SEQ CDR1 3D MQ: CDR2 ID MD: COR3 SD MO: Kappa K1,4 Cons RASQSVSSGYLT 107 GASSRAT 108 QQYGMS LCR 109 G 5 Rti D G A LQS L MTYPWT

K F S

Kappa K2 SEQ 3D MO: 57 CDR2 L G SNRA S SEQ !DMO: 58 CDR3 MQALQTF FT SEQ 3D MO: 53 4H6 CORI RSSQSLLHSFGYMYLD Kappa K3 SEQ SEQ SEQ CDR1 30 MO; CDR2 3D MG: CDR3 3D MO: 3C8 KSSQSLLHSAGKTYLY 54 E V S N R F S 55 MQSFPLPLT 56 5F5 KSSQSLLHSDGKTYLY SO E V S M R F S 55 MQSFPLP LT 55 12ES KSSQSLLHSDGRNYLY 65 E V S N R F S 55 MQSFPLPLT 56 K3 Consensus KSSQSLLHSDGRNYLY 110 E V S N R F S 55 MQSFPLPLT 56 A KT SEQ SEQ SEQ CORI 3D MO: COR2 !D MO: CDR3 3D MO; Kappa K2,3 Cons RSSQSLLHSFGYMYLD 111 L G S M R A S 112 MQALQTFFT 113 K D R T Y £ V F SFPL L

A K

4/17

2016244220 11 Oct 2016

Lambda Li 1E11 CDR1 SGSSSNiGNNYVS SEQ ID NO: 42 CQR2 D N N K R P S SEQ IQ NO: 43 CQR3 GTWDSRL SAW SEQ ID NQ: 44 4E4 S G S S S N i G N N Y V S 42 0 N N K R P S 43 G TWD SR LS A V V 44 904 S G S S S N i G N N Y V S 42 D N N K R P S 43 GTWDSRL SAW 44 12G8 S G S S S N i G N N Y V S 42 QNNKRPS 43 GTWDSRL SAW 44 L1 Consensus SGSSSN ί G N N Y V S 42 0 N N K R P S 43 GTWDSRLSAW 44 Lambda L2 SEQ SEQ SEQ CORI ID NQ: CDRZ !O NO: CDR3 SD NO: 1SE4 S G S S S N ! G S N T V N 52 T NNQRPS 63 AARDES LNGVV 64 Lambda L3 SEQ SEQ SEQ COR1 ID NO: CDRZ IQ NQ: CQR3 SD NO: 11011 S G S S S N 1 G S N Y V Y 45 R N N Q R P 5 61 AAWODSLSGWV 47 11HS S G S S S N ί G S N Y V Y 45 R N N Q R P S 61 AAWOD S LSGWV 47 1H7 S G S S S N ! G S N Y V Y 45 R S N Q R P S 46 AAWODS LSGWV 47 9F5 S G S S S N I GSNYVY 45 R N N Q R P S 61 AAWODSLSGWV 47 L3 Consensus S G S S S N 1 GSKYVY 45 RNRQRRS S 114 AAWODS L SGWV 47 Lambda L4 SEQ SEQ SEQ CORI ID NG: COR2 IQ NO: CQR3 SD NO: 386 QG DS L R S F Y A S 54 G K N N R P 5 52 NSRDSSVYHLV 53 SEQ SEQ SEQ CORI SO NQ: CDRZ IQ NO: CQR3 ID NO: Lam LI,2,3 Cons SGSSSH ί G N N Y V S 115 ONNKRPS 116 GTWOSRLSAVV 117 5 T N T S Q AAR DS NG Y R SEQ SEQ SEQ CORI ID NO: CDRZ IQ NO: CQR3 IQ NO: Lambda Al! Cons S G S S S N 1 G N N Y V S 11S ONNKRPS 119 STWDSRLSAVV 120 Q - Q - LRS FTAN OK N N S R QSVYRL Y TS Q A A NG

R

5/17

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8/17

2016244220 11 Oct 2016 cAMP content m cels expressing hCGRP R stimulated with 1nM hCGRP ¹²⁵I»CGRP binding to human CGRP receptor

Fig 8

9/17

2016244220 11 Oct 2016

120' cAhIR content in foAMl-HEK ceils

100n y

P 801 θ SO· c

40·

20· ! ί '--“4—.....

3 -12 -11 -10 -9

T“

T” concentration, log M

3C8

13H2

1E11

Fig 7B cAMP content In hAI$2-CHQ cells

3C8

13H2

1E11

Fig 7C

CAMP content in MCF-7 ceils (expressing homan amylin receptors)

120 η $ °-13 -12.....-11.....-10.....-9 ?8.......-7.......-0.....-5 concentration, log M

Fia 7D

10/17

2016244220 11 Oct 2016

Time (sec) £

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11/17

2016244220 11 Oct 2016 'aiup* fc δ

a, sfl «3

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S'

200 400 600 800 1000 1200 1400

Time (sec)

Time (sec)

12/17

2016244220 11 Oct 201

FACS Kd determination mAh 12GS

Log concentration of mAh (M)

Fig 10

CRLR: RA^P1 Wild Type FtQ 1 3 A

CRLR L24-G33: RAMPt

CRLR: RAMPt Q28-A34

Fig 13C

13/17

2016244220 11 Oct 2016 cyno._RAliFl hurnaiwRAYsP 1 huRAMPl(Q23-A34)) huRAMPl{Q4 3-E5 3} huRAMPliS6?~E73} rat_RAMPl rh <3 s u s._RAM P1 cyno_RAHPl huraan_RAMPl huRAMPlί Q23-A34)} huRAMPl(Q43-S53) huRAMPl(SS7-S78) rat_RAMPl rhesus RA5»JP1 cyno_RAM?i human__RAMPl huRAMPl(Q28-A34)} huRAMPl{Q43-E53) huRAMPliR67-E78) rat_RAMPl rhesus_RAMPl

1 SO

MARALCRLPQ RGLWLLLAHH LFMATACQSA KYGALLQ3LC LTQFQVDMEA MARALCRLPR RGLWLLLAHH LFMTTACQBA NYGALLRSLC LTQFQVDMSA MARALCRLPR RGLWLLLAHH LFMTTACRDP DYGTLLR2LC LTQFQVDMEA MARALCRLPR RGLWLLLAHH LFMTTACQBA NYGALLRSLC LTRFKSDMET MARALCRLPR RGLWLLLAHH LFMT7ACQEA NYGALLRELC LTQFQVDMSA MAPGLRGLPR RGLWLLLAHH LFMVTACRDP DYGTLIQSLC LSRFKEDMET MARALCRLPQ RGLWLLLAHH LFMATACQEA NYGALLQELC LTQFQVDMEA

Si 100

VGETLWCDWG RTIGSYRBLA DCTWHMAEKL GCFWPNASVD RFFLAVHGHY VGETLWCDWG RTIRSYRBLA DCTWHMAEKL GCFWPNAEVD RFFLAVHGRY VGETLWCDWG RTIRSYRELA DCTWHMAEKL GCFWPMAEVD RFFLAVHGRY IGKTLWCDWG RTIRSYRELA DCTWHMAEKL GCFWPMAEVD RFFLAVHGRY VGETLWCDWG RTIRSYGELT HCTKLVANKL GCFWPMAEVD RFFLAVHGRY IGKTLWCDWG KTIOSYGELT HCTKLVANKI GCFWPNPEVD KFFIAVHHRY VGETLWCDWG RTIGSYRSLA DCTWHMAEKL GCFWPMAEVD RFFLAVHGHY

101 148

FRACPISGRA VRDPPGSVLY PFIWPITVT LLVTALWWQ SKKTEGIV FRSCPISGRA VRDPPGSILY PFIWPITVT LLVTALWWQ SKRTEGIV FRSCPISGRA VRDPPGSILY PFIWPITVT LLVTALWWQ SKRTEGIV FRSCPISGRA VRBPPGSILY PFIWPITVT LLVTALWWQ SKRTEGIV FRSCPISGRA VRDPPGSILY PFIWPITVT LLVTALWWQ SKRTEGIV FSKCPVSGRA LRDPPNSILC PFIVLPITVT LLMTALWWR SKRTEGIV FRACPISGRA VRDPPGSVLY PFIWPITVT LLVTALWWQ SKHTESIV

14/17

2016244220 11 Oct 2016 huCRLR cynoCRLR rhesusCRLR rafcCRLR huCRLR(L24-Q33)

Consensus huCRLR CynoCRLR rhesusCRLR ratCRLR huCRLR (1.24-033)

Consensus huCRLR cynoCRLR rhesusCRLR rafcCRLR huCRLR(L24-Q335

Consensus huCRLR cynoCRLR rhesusCRLR rafcCRLR huCRLR(L24-Q33)

Consensus huCRLR cynoCRLR rhesusCRLR rafcCRLR huCSLR{L24-Q33)

Consensus

1 50

MEKKCTLYF LVLLPFFMXL VTAELEBSPB DSXQLGVTRB KIMTAQYECY MEKKCTLYF LVLLPFFMIF VTAELEBSPB DSXQLGVTRK KIMTAQYECY MEKKCTLYF LVLLPFFMIF VTAELBBSPE DSXQLGVTRB KXMTAQYECY

MMDKKCTLCF LFLLLLSMAL IA&ESEEGAN QT-DLGVTR.K KXMTAQYECY MEKKCTLYF LVLLPFFMXL VTAESBBGAN QT-DLGVTSN KIMTAQYECY MeKKCTLyF LvLLpffMil -tAE-BE--- ----LGVTRN KXMTAQYECY

51 100

QKIMQDPIQQ ABGVYCMRTW DGKLCKNDVA AGTESMQLC? DYFQDFDPSE QKIMQDPIQQ AEGVYCMRTK DGWLCWNVA AGTESMQLCP DYFQDFDPSE QKIMQDPIQQ ABGVYCNSTK DGWLCKNNVA AGTESMQLCP DYFQDFDPSE QKIMQDPIQQ GSGLYCHRTW DGMLCWNDVA AOTSSKQYCP DYFQDFDPSE QKIMQDPIQQ AEGVYCNRTW DGMLCWDVA AGTESMQLCP DYFQDFDPSE QKIMQDPIQQ aBG-YCNRTM DGWLCMM-VA AGTESMQ1CP DYFQDFDPSE

101 150

KVTKICDQDG WFRHPASKR TWTMYTQCKV MTHEKVKTAL NLFYLTIIGH KVTKICDQDG WFRKPASKR TMTMYTQCKV NTHBKVXTAL NLFYLTIIGH KVTKICDQDG WFRHPASNR TWTMYTQCNV NTHBKVKTAL NLFYLTIIGH KVTKICDQDG WFRKPDSKR TKTNYTLCKN STHEKVXTAL NLFYLTIIGH KVTKICDQDG NWFRHPASNR TWTNYTQCKV NTHBKVKTAL NLFYLTIIGH KVTKICDQDG WFRKPaSNR TWTNYTqCNv nTHBKVKTAL NLFYLTIIGH

151 200

GLSIASLLIS LGIFFYFKSL SCQRITLHKN LFFSFVCNSV VTIIHLTAVA GLSIASLLIS LGIFFYFKSL SCQRITLHKN LFFSFVCNSV VTIXHLTAVA GLSIASLLIS LGIFFYFKSL SCQRITLHKN LFFSFVCNSV VTIXHLTAVA GLSXASLIIS LIIFFYFKSL SCQRITLHKN LFFSFVCKSI VTIXHLTAVA GLSIASLLIS LGIFFYFKSL SCQRTTLKKN LFFSFVCNSV VTIXHLTAVA GLSIASL-IS LgIFFYFKSL SCQRITLKXN LFFSFVCKS- VTIIKLTAVA

201 250

NNQALVATNP VSCKVSQFIH l.YLMGCNYFW MLCEGIYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCEGIYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCEGIYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCBGXYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCBGXYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCBGXYLHT LXWAVFAEK huCRLR cynoCRLR rhesusCRLR rafcCRLR huCRLR(L24-Q335

Consensus

251

QHLMWYYFLG

QHLMWYYFliG

QHLMWYYFLG

QKLMWYYFLG

QHLMWYYFLG

QHLMWYYFLG

WGFPLIPACI WGFPLXPACX WGFPLLPACI WGFPLLPACI WGFPLIPACX WGFPL-PACI

HAIARSLYYN

HAIARSLYYN

HAIARSLYYN

HAIARSLYYN

HAIARSLYYN

HAIARSLYYN

DNCWISSDTH

DHCWISSDTH

DNCWISSDTH

DNCWISSDTH

DNCWISSDTH

DNCWISSDTH

300

L-LYIIHGPIC

LLYIIHGPIC

LLYIIHGPIC

LLYIIHGPIC

LLYIIHGPIC

LLYIIHGPIC

15/17

2016244220 11 Oct 2016

301 350 fcuCRLR AALLWLFFb WXVRVLXTK LKVTHQASSN LYMKAVRATL ILVPLLGISF

cynoCRLR rbesusCRDR ratCRLR huCRLR'L24-Q33} Consensus AALLVNLFFL L3SXVRVLXTK LXVTRQA3SK AALLWLFFL LNXVRVLXTK IjKVTKQABSN AALLWLFFL LSIVRVLITR LKVTHQASS1J AALLVNLFFI: LNIVRVLITK LKVTHQAKSN LYMKAVRATL LYMKAVRATL LYMKAVRATL LYMKAVRATL LYMKAVRATL XLVPLLGXEF ILVPLLGISF XLVPLLGXEF ILVPLLGIEF XLVPLLGXEF AALLVNLFFL LNIVKVLITK LKVTHQASSN 351 4 00 huCRLR VLXPWRPEGK IAEEVYDYIM HILMHFQGLL VSTIFCFFNG EVQAXLRRNS4 cynoCRLR VLI5WRPEGK XASEVYDYIM HILMHPQGLL VSTIFCFFNG EVQATLRRNW rhesusCSLR VLIPWRPEGK XAEEVYDYIM HILMHFQGLL VSTIFCFFNG EVQATLRRNW ratCRLR VLFPWRPEGK VASEVYDYVM HXLMHYQSLL VSTIFCFFNG EVQAILRSNW huCRLR(L24-Q335 VLIPWRPEGK IA3BVY0YIM HILMHFQGLL VSTIFCFFNG EVQAILRRNW Consensus VLiPWRPEGK -AEEVYDY-M HILKH-QGLL VSTIFCFFNG EVQAILRRNW 4 01 450 buCRI.R MQYKXQFGKS FSNSSALRSA SYTVSTXSDG PGYSHDCPSE HLNGKSIHDI cynoCKLR NQYKIQFGNS FSNSSALRSA SYTVSTXSDG PGYSHDCPSE HLNGKSIHDI rhesusCRLR KQYKIQFGNS FSNSSALRSA SYTVSTXSDG PGYSHDCPSE HLNGKSIHDI ratCRLR NQYKIQFGNG FSHSDALRSA SYTVSTISDV QGYSBDCPTR BLKGKSXQDI huCRLR(L24-Q33} NQYKXQFGSJS FSNSSALRSA SYTVSTXSDG PGYSHDCPSE HLNGKSIHDI Consensus NQYKIQFGKS FSnSeALRSA SYTVSTXSDg pGYSHDCP-E HLKGKSXhDX 451 45 5 huCRLR ENVLLKPENL YN-..... cynoCRLR SNVVLKPEKL YN--- rnesusCRLR EJSfWLKPENL YN- - - ratCRLR ENVALKPEKM YDLVM huCRLRU24-Q33; ENVLLKPSNL YN--- Consensus ENV-LKPEn- Y----

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A1472PCT. t xt SEQUENCE LI STI NG <11 0> AM3EN I NC.

<120> HUIVAN CGRP RECEPTOR BI NDI NG PRQTEI NS <130> A- 1472- W> PCT <140>

<141 >

<1 50> 61/264, 622 <151> 2009-11-25 <1 50> 61/203, 569 <151 > 2008- 12-23 <1 60> 261 <170> Pat ent I n version 3.5 <210> 1 <211> 1419 <212> DNA <213> Homo sapi ens <400> 1

at gt t at aca gcat at 11 ca 1111 gget t a at gat ggaga aaaagt gt ac cct gt at 111 60 ct ggt t ct ct t gcct 11111 t at gat t ct t gt t acagcag aat t agaaga gagt cct gag 120 gact caat t c agt t gggagt t act agaaat aaaat cat ga cagct caat a t gaat gt t ac 180 caaaagat t a t gcaagaccc cat t caacaa gcagaaggcg 111 act gcaa cagaacct gg 240 gat ggat ggc t ct get ggaa egat gt t gca gcaggaact g aat caat gca get ct gccct 300 gat t act 11 c aggact 11 ga t ccat cagaa aaagt t acaa agat ct gt ga ccaagat gga 360 aact ggt 11 a gacat ccagc aagcaacaga acat ggacaa at t at accca gt gt aat gt t 420 aacacccacg agaaagt gaa gact gcact a aat 11 gt 111 acct gaccat aat t ggacac 480 ggat t gt ct a 11 gcat cact get t at ct eg ct t ggcat at t ct 111 at 11 caagagcct a 540 agt t gccaaa ggat t acct t acacaaaaat ct gt t ct t ct cat 11 gt 11 g t aact ct gt t 600 gt aacaat ca 11 cacct cac t gcagt ggee aacaaccagg cct t agt age cacaaat cct 660 gt t agt t gca aagt gt ccca gt t cat t cat ct 11 acct ga t ggget gt aa 11 act 111 gg 720 at get ct gt g aaggcat 11 a cct acacaca ct cat t gt gg t ggccgt gt t t gcagagaag 780 caacat 11 aa t gt ggt at t a 1111 ct t ggc t ggggat 11 c cact gat t ee t get t gt at a 840 cat gccat t g ct agaaget t at at t acaat gacaat t get ggat cagt t c t gat acccat 900 ct cct ct aca 11 at ccat gg cccaat 11 gt get get 11 ac t ggt gaat ct 111111 ct t g 960 11 aaat at t g t aegegt t ct cat caccaag 11 aaaagt t a cacaccaagc ggaat ccaat 1020 ct gt acat ga aaget gt gag aget act ct t at ct t ggt gc cat t get t gg cat t gaat 11 1080 gt get gat t c cat ggcgacc t gaaggaaag at t gcagagg aggt at at ga ct acat cat g 1140 cacat cct t a t gcact t cca gggt ct 111 g gt ct ct acca 1111 ct get t ct 11 aat gga 1200 gaggt t caag caat t ct gag aagaaact gg aat caat aca Page 1 aaat ccaat t t ggaaacagc 1260

A1472PCT. t xt

2016244220 11 Oct 2016

1111 ccaact cagaagct ct t cgt agt gcg t ct t acacag t gt caacaat cagt gat ggt ccaggt t at a gt cat gact g t cct agt gaa cact t aaat g gaaaaagcat ccat gat at t gaaaat gt t c t ct t aaaacc agaaaat 11 a t at aat t ga

1320

1380

1419 <210> 2 <211> 472 <212> PRT <213> Homo sapi ens <400> 2

IVfet 1 Leu Tyr Ser I I e Phe Hi s 5 Phe Gy Leu IVbt 10 IVbt Q u Lys Lys Cys 15 Thr Leu Tyr Phe Leu Val Leu Leu Pr o Phe Phe IVbt I I e Leu Val Thr 20 25 30 Al a G u Leu G u G u Ser Pr o G u Asp Ser I I e G n Leu Gy Val Thr 35 40 45 Arg Asn Lys I I e IVbt Thr Al a G n Tyr G u Cys Tyr G n Lys I I e IVbt 50 55 60 G n Asp Pr o I I e G n G n Al a G u Gy Val Tyr Cys Asn Arg Thr Tr p 65 70 75 80 Asp Gy Tr p Leu Cys Tr p Asn Asp Val Al a Al a Gy Thr G u Ser IVbt 85 90 95 G n Leu Cys Pr o Asp Tyr Phe G n Asp Phe Asp Pr o Ser G u Lys Val 100 105 110 Thr Lys I I e Cys Asp G n Asp Gy Asn Tr p Phe Arg Hi s Pr o Al a Ser 115 120 125 Asn Arg Thr Tr p Thr Asn Tyr Thr G n Cys Asn Val Asn Thr Hi s G u 130 135 140 Lys Val Lys Thr Al a Leu Asn Leu Phe Tyr Leu Thr I I e I I e Gy Hi s 145 150 155 160 Gy Leu Ser I I e Al a Ser Leu Leu I I e Ser Leu Gy I I e Phe Phe Tyr 165 170 175 Phe Lys Ser Leu Ser Cys G n Arg I I e Thr Leu Hi s Lys Asn Leu Phe 180 185 190 Phe Ser Phe Val Cys Asn Ser Val Val Thr I I e I I e Hi s Leu Thr Al a 195 200 205 Val Al a Asn Asn G n Al a Leu Val Al a Thr Asn Pr o Val Ser Cys Lys

210 215 220

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Val 225 Ser G n Phe I I e Hi s 230 Leu Tyr Leu IVbt Q y Cys 235 Asn Tyr Phe Tr p 240 IVbt Leu Cys G u G y I I e Tyr Leu Hi s Thr Leu I I e Val Val Al a Val 245 250 255 Phe Al a G u Lys G n Hi s Leu IVbt Tr p Tyr Tyr Phe Leu Gy Tr p Gy 260 265 270 Phe Pr o Leu I I e Pr o Al a Cys I I e Hi s Al a I I e Al a Arg Ser Leu Tyr 275 280 285 Tyr Asn Asp Asn Cys Tr p I I e Ser Ser Asp Thr Hi s Leu Leu Tyr I I e 290 295 300 I I e Hi s Gy Pr o I I e Cys Al a Al a Leu Leu Val Asn Leu Phe Phe Leu 305 310 315 320 Leu Asn I I e Val Arg Val Leu I I e Thr Lys Leu Lys Val Thr Hi s G n 325 330 335 Al a G u Ser Asn Leu Tyr IVbt Lys Al a Val Arg Al a Thr Leu I I e Leu 340 345 350 Val Pr o Leu Leu Gy I I e G u Phe Val Leu I I e Pr o Tr p Arg Pr o G u 355 360 365 Gy Lys I I e Al a G u G u Val Tyr Asp Tyr I I e IVbt Hi s I I e Leu IVfet 370 375 380 Hi s Phe G n Gy Leu Leu Val Ser Thr I I e Phe Cys Phe Phe Asn G y 385 390 395 400 G u Val G n Al a I I e Leu Arg Arg Asn Tr p Asn G n Tyr Lys I I e G n 405 410 415 Phe Gy Asn Ser Phe Ser Asn Ser G u Al a Leu Arg Ser Al a Ser Tyr 420 425 430 Thr Val Ser Thr I I e Ser Asp Gy Pr o Gy Tyr Ser Hi s Asp Cys Pr o 435 440 445 Ser G u Hi s Leu Asn Gy Lys Ser I I e Hi s Asp I I e G u Asn Val Leu 450 455 460 Leu Lys Pr o G u Asn Leu Tyr Asn

465 470 <210> 3 <211> 447

Page 3

A1472PCT. t xt

2016244220 11 Oct 2016 <212> DNA <213> Homo sapi ens <400> 3 at ggcccggg ccct gt gccg cct cccgcgg cgcggcct ct ggct get cct ggcccat cac 60 et ct t cat ga ccact gcct g ccaggaggct aact aeggt g ccct cct ccg ggaget ct gc 120 ctcacccagt tccaggtaga catggaggee gtcggggaga egetgtggtg tgactggggc 180 aggaccatca ggagetacag ggagetggee gactgcacct ggcacatggc ggagaagetg 240 ggct get t ct ggcccaat gc agaggt ggac aggt t ct t cc t ggcagt gca t ggeeget ac 300

11 caggagct gccccat ct c aggcagggcc gt gcgggacc cgcccggcag cat cct ct ac 360 ccct t cat eg t ggt ccccat cacggt gacc ct get ggt ga cggcact ggt ggt ct ggcag 420 ageaagegea ct gagggcat t gt gt ag 447 <210> 4 <211> 148 <212> PRT <213> Homo sapi ens

<400> 4 IVbt 1 Al a Ar g Al a Leu Cys Arg Leu 5 Pr o Arg 10 Arg Gy Leu Tr p Leu 15 Leu Leu Al a Hi s Hi s Leu Phe N/fet Thr Thr Al a Cys G n G u Al a Asn Tyr 20 25 30 Q y Al a Leu Leu Arg G u Leu Cys Leu Thr G n Phe G n Val Asp IVfet 35 40 45 G u Al a Val G y G u Thr Leu Tr p Cys Asp Tr p G y Arg Thr I I e Arg 50 55 60 Ser Tyr Arg G u Leu Al a Asp Cys Thr Tr p Hi s IVfet Al a G u Lys Leu 65 70 75 80 G y Cys Phe Tr p Pr o Asn Al a G u Val Asp Arg Phe Phe Leu Al a Val 85 90 95 Hi s G y Arg Tyr Phe Arg Ser Cys Pr o I I e Ser G y Arg Al a Val Arg 100 105 110 Asp Pr o Pr o G y Ser I I e Leu Tyr Pr o Phe I I e Val Val Pr o I I e Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p G n Ser Lys Arg Thr 130 135 140 G u G y I I e Val 145

<210> 5

Page 4

A1472PCT. t xt

2016244220 11 Oct 2016 <211> 414 <212> DNA <213> Homo sapi ens <400> 5 at ggagaaaa agt gt accct gt at 111 ct g gt t ct ct t gc ct 111111 at gat t ct t gt t 60 acagcagaat t agaagagag t cct gaggac t caat t cagt t gggagt t ac t agaaat aaa 120 at cat gacag ct caat at ga at gt t accaa aagat t at gc aagaccccat tcaacaagca 180 gaaggcgttt actgcaacag aacctgggat ggatggctct getggaacga tgttgcagca 240 ggaact gaat caat gcagct ct gccct gat t act 11 cagg act 11 gat cc at cagaaaaa 300 gttacaaaga tctgtgacca agatggaaac tggtttagac atccagcaag caacagaaca 360 tggacaaatt atacccagtg taatgttaac acccacgaga aagtgaagac tgca 414 <210> 6 <211> 138 <212> PRT <213> Homo sapi ens <400> 6

IVfet G u Lys Lys Cys Thr Leu Tyr Phe Leu Val Leu Leu Pr o Phe Phe 1 5 10 15 IVfet I I e Leu Val Thr Al a G u Leu G u G u Ser Pr o G u Asp Ser I I e 20 25 30 G n Leu G y Val Thr Arg Asn Lys I I e IVbt Thr Al a G n Tyr G u Cys 35 40 45 Tyr G n Lys I I e IVbt G n Asp Pr o I I e G n G n Al a G u Gy Val Tyr 50 55 60 Cys Asn Arg Thr Tr p Asp Gy Tr p Leu Cys Tr p Asn Asp Val Al a Al a 65 70 75 80 Gy Thr G u Ser IVbt G n Leu Cys Pr o Asp Tyr Phe G n Asp Phe Asp 85 90 95 Pr o Ser G u Lys Val Thr Lys I I e Cys Asp G n Asp Gy Asn Tr p Phe 100 105 110 Arg Hi s Pr o Al a Ser Asn Arg Thr Tr p Thr Asn Tyr Thr G n Cys Asn 115 120 125 Val Asn Thr Hi s G u Lys Val Lys Thr Al a

130 135

<21 0> 7 <211> 351 <212> DNA <213> Homo sapi ens <400> 7

Page 5

2016244220 11 Oct 2016

A1472PCT. t xt at ggcccggg ccct gt gccg cct cccgcgg cgcggcct ct ggct get cct ggcccat cac 60 et ct t cat ga ccact gcct g ccaggaggct aact aeggt g ccct cct ccg ggaget ct gc 120 ctcacccagt tccaggtaga catggaggee gtcggggaga egetgtggtg tgactggggc 180 aggaccatca ggagetacag ggagetggee gactgcacct ggcacatggc ggagaagetg 240 ggct get t ct ggcccaat gc agaggt ggac aggt t ct t cc t ggcagt gca t ggeeget ac 300 ttcaggagct gccccatctc aggcagggcc gtgcgggacc cgcccggcag c 351 <210> 8 <211> 117 <212> PRT <213> Homo sapi ens <400> 8

l\/bt 1 Al a Ar g Al a Leu 5 Cys Arg Leu Pr o Ar g Ar g 10 Q y Leu Tr p Leu 15 Leu Leu Al a Hi s Hi s Leu Phe IVbt Thr Thr Al a Cys G n G u Al a Asn Tyr 20 25 30 G y Al a Leu Leu Arg G u Leu Cys Leu Thr G n Phe G n Val Asp IVfet 35 40 45 G u Al a Val G y G u Thr Leu Tr p Cys Asp Tr p G y Arg Thr I I e Arg 50 55 60 Ser Tyr Arg G u Leu Al a Asp Cys Thr Tr p Hi s IVfet Al a G u Lys Leu 65 70 75 80 G y Cys Phe Tr p Pr o Asn Al a G u Val Asp Arg Phe Phe Leu Al a Val 85 90 95 Hi s G y Arg Tyr Phe Arg Ser Cys Pr o I I e Ser G y Arg Al a Val Arg 100 105 110

Asp Pr o Pr o Gl y Ser 115

<210> 9 <211> 31 <212> PRT <213> Homo sapi ens <400> 9 Trp Val Thr Hi s Arg Leu Al a G y Leu Leu Ser Arg Ser G y G y 1 5 10 15 Val Ar g Cys Asn Phe Val Pr o Thr Asp Val G y Pr o Phe Al a Phe 20 25 30

<210> 10 <211> 116 <212> PRT

Page 6

A1472PCT. t xt

2016244220 11 Oct 2016 <213> Homo sapi ens <400> 10

Q u Leu Gl u Gl u Ser Pr o Q u Asp Ser I I e 10 Q n Leu Gy Val Thr 15 Arg 1 5 Asn Lys I I e K/bt Thr Al a G n Tyr G u Cys Tyr G n Lys I I e K/fet G n 20 25 30 Asp Pr o I I e G n G n Al a G u Gy Val Tyr Cys Asn Arg Thr Tr p Asp 35 40 45 Gy Tr p Leu Cys Tr p Asn Asp Val Al a Al a Gy Thr G u Ser K/fet G n 50 55 60 Leu Cys Pr o Asp Tyr Phe G n Asp Phe Asp Pr o Ser G u Lys Val Thr 65 70 75 80 Lys I I e Cys Asp G n Asp Gy Asn Tr p Phe Arg Hi s Pr o Al a Ser Asn 85 90 95 Arg Thr Tr p Thr Asn Tyr Thr G n Cys Asn Val Asn Thr Hi s G u Lys 100 105 110 Val Lys Thr Al a

115 <210> 11 <211> 91 <212> PRT <213> Homo sapi ens <400> 11

Cys G n G u Al a Asn Tyr Gy Al a Leu Leu Arg G u Leu Cys Leu Thr 1 5 10 15 G n Phe G n Val Asp IVfet G u Al a Val Gy G u Thr Leu Tr p Cys Asp 20 25 30 Tr p Gy Arg Thr I I e Arg Ser Tyr Arg G u Leu Al a Asp Cys Thr Tr p 35 40 45 Hi s K/fet Al a G u Lys Leu G y Cys Phe Tr p Pr o Asn Al a G u Val Asp 50 55 60 Arg Phe Phe Leu Al a Val Hi s Gy Arg Tyr Phe Arg Ser Cys Pr o I I e 65 70 75 80 Ser Gy Arg Al a Val Arg Asp Pr o Pr o Gy Ser 85 90

<210> 12 <211> 238 <212> PRT

Page 7

A1472PCT. t xt

2016244220 11 Oct 2016 <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 12

l\/bt 1 Asp K/bt Arg Val 5 Pr o Al a Q n Leu Leu Q y 10 Leu Leu Leu Leu 15 Tr p Leu Arg Qy Al a Arg Cys Q n Ser Val Leu Thr Q n Pr o Pr o Ser Val 20 25 30 Ser Q u Al a Pr o Qy Q n Lys Val Thr I I c Ser Cys Ser Qy Ser Ser 35 40 45 Ser Asn I I c Qy Asn Asn Tyr Val Ser Tr p Tyr Q n Q n Leu Pr o Qy 50 55 60 Thr Al a Pr o Lys Leu Leu I I c Tyr Asp Asn Asn Lys Arg Pr o Ser Qy 65 70 75 80 I I c Pr o Asp Arg Phe Ser Qy Ser Lys Ser Qy Thr Ser Al a Thr Leu 85 90 95 Qy I I c Thr Qy Leu Q n Thr Qy Asp Q u Al a Asp Tyr Tyr Cys Qy 100 105 110 Thr Tr p Asp Ser Arg Leu Ser Al a Val Val Phe Qy Qy Qy Thr Lys 115 120 125 Leu Thr Val Leu Qy Q n Pr o Lys Al a Asn Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser Q u Q u Leu Q n Al a Asn Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I I c Ser Asp Phe Tyr Pr o Qy Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 Asp Qy Ser Pr o Val Lys Al a Qy Val Q u Thr Thr Lys Pr o Ser Lys 180 185 190 Q n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 Q u Q n Tr p Lys Ser Hi s Arg Ser Tyr Ser Cys Q n Val Thr Hi s Q u 210 215 220 Qy Ser Thr Val Q u Lys Thr Val Al a Pr o Thr Q u Cys Ser

225 230 235

Page 8

A1472PCT. t xt

2016244220 11 Oct 2016 <210> 13 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 13

l\/bt 1 Asp IVfet Arg Val 5 Pr o Al a Q n Leu Leu Q y 10 Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a Arg Cys G n Ser Val Leu Thr G n Pr o Pr o Ser Al a 20 25 30 Ser Gy Thr Pr o Gy G n Arg Val Thr I I e Ser Cys Ser Gy Ser Ser 35 40 45 Ser Asn I I e Gy Ser Asn Tyr Val Tyr Tr p Tyr G n G n Leu Pr o Gy 50 55 60 Al a Al a Pr o Lys Leu Leu I I e Phe Arg Ser Asn G n Arg Pr o Ser G y 65 70 75 80 Val Pr o Asp Arg Phe Ser Gy Ser Lys Ser Gy Thr Ser Al a Ser Leu 85 90 95 Al a I I e Ser Gy Leu Arg Ser G u Asp G u Al a Asp Tyr Tyr Cys Al a 100 105 110 Al a Tr p Asp Asp Ser Leu Ser Gy Tr p Val Phe Gy Gy Gy Thr Lys 115 120 125 Leu Thr Val Leu Gy G n Pr o Lys Al a Asn Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser G u G u Leu G n Al a Asn Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I I e Ser Asp Phe Tyr Pr o Gy Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 Asp Gy Ser Pr o Val Lys Al a Gy Val G u Thr Thr Lys Pr o Ser Lys 180 185 190 G n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 G u G n Tr p Lys Ser Hi s Arg Ser Tyr Ser Cys G n Val Thr Hi s G u 210 215 220 Gy Ser Thr Val G u Lys Thr Val Al a Pr o Thr G u Cys Ser Page 9

2016244220 11 Oct 2016

A1472PCT. t xt

225 230 235 <210> 14 <211> 236 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 14

l\/bt 1 Asp IVfet Arg Val 5 Pr o Al a Q n Leu Leu Q y 10 Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a Arg Cys Asp I I e G n IVbt Thr G n Ser Pr o Ser Ser 20 25 30 Leu Ser Al a Ser Val Gy Asp Arg Val Thr I I e Thr Cys Arg Al a Ser 35 40 45 G n Gy I I e Arg Asn Asp Leu Gy Tr p Phe G n G n Lys Pr o Gy Lys 50 55 60 Al a Pr o Lys Arg Leu I I e Tyr Al a Al a Ser Ser Leu G n Ser Gy Val 65 70 75 80 Pr o Ser Arg Phe Ser Gy Ser Gy Ser G y Thr G u Phe Thr Leu Thr 85 90 95 I I e Ser Ser Leu G n Pr o G u Asp Leu Al a Thr Tyr Tyr Cys Leu G n 100 105 110 Tyr Asn I I e Tyr Pr o Tr p Thr Phe Gy G n Gy Thr Lys Val G u I I e 115 120 125 Lys Arg Thr Val Al a Al a Pr o Ser Val Phe I I e Phe Pr o Pr o Ser Asp 130 135 140 G u G n Leu Lys Ser G y Thr Al a Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pr o Arg G u Al a Lys Val G n Tr p Lys Val Asp Asn Al a Leu 165 170 175 G n Ser Gy Asn Ser G n G u Ser Val Thr G u G n Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr 195 200 205 G u Lys Hi s Lys Val Tyr Al a Cys G u Val Thr Hi s G n Gy Leu Ser 210 215 220

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Ser Pro Val Thr Lys Ser Phe Asn Arg Qy Qu Cys 225 230 235 <210> 15 <211> 236 <212> PRT <213> Art i f i ci al Sequence

<220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 15

IVbt 1 Asp IVfet Arg Val 5 Pr o Al a G n Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a 20 Arg Cys Ser Ser G u 25 Leu Thr G n Asp Pr o 30 Thr Val Ser Val Al a 35 Leu Gy G n Thr Val 40 Lys I I e Thr Cys G n 45 Gy Asp Ser Leu Arg 50 Ser Phe Tyr Al a Ser 55 Tr p Tyr G n G n Lys 60 Pr o Gy G n Al a Pr o 65 Val Leu Val Phe Tyr 70 Gy Lys Asn Asn Arg 75 Pr o Ser Gy I I e Pr o 80 Asp Arg Phe Ser Gy 85 Ser Ser Ser Gy Asn 90 Thr Al a Ser Leu Thr 95 I I e Thr Gy Al a G n 100 Al a G u Asp G u Al a 105 Asp Tyr Tyr Cys Asn 110 Ser Arg Asp Ser Ser 115 Val Tyr Hi s Leu Val 120 Leu Gy Gy Gy Thr 125 Lys Leu Thr Val Leu 130 Gy G n Pr o Lys Al a 135 Asn Pr o Thr Val Thr 140 Leu Phe Pr o Pr o Ser 145 Ser G u G u Leu G n 150 Al a Asn Lys Al a Thr 155 Leu Val Cys Leu I I e 160 Ser Asp Phe Tyr Pr o 165 Gy Al a Val Thr Val 170 Al a Tr p Lys Al a Asp 175 Gy Ser Pr o Val Lys 180 Al a Gy Val G u Thr 185 Thr Lys Pr o Ser Lys 190 G n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o G u G n

195 200 205

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Tr p Lys Ser Hi s Arg Ser Tyr Ser Cys G n Val Thr Hi s G u G y Ser 210 215 220 Thr Val G u Lys Thr Val Al a Pr o Thr G u Cys Ser

225 230 235 <210> 16 <211> 241 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 16

IVbt 1 Asp IVbt Arg Val 5 Pr o Al a Q n Leu Leu Q y 10 Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a Arg Cys Asp I I e I I e Leu Al a G n Thr Pr o Leu Ser 20 25 30 Leu Ser Val Thr Pr o Gy G n Pr o Al a Ser I I e Ser Cys Lys Ser Ser 35 40 45 G n Ser Leu Leu Hi s Ser Al a Gy Lys Thr Tyr Leu Tyr Tr p Tyr Leu 50 55 60 G n Lys Pr o Gy G n Pr o Pr o G n Leu Leu I I e Tyr G u Val Ser Asn 65 70 75 80 Arg Phe Ser Gy Val Pr o Asp Arg Phe Ser Gy Ser Gy Ser Gy Thr 85 90 95 Asp Phe Thr Leu Lys I I e Ser Arg Val G u Al a G u Asp Val Gy I I e 100 105 110 Tyr Tyr Cys K/bt G n Ser Phe Pr o Leu Pr o Leu Thr Phe Gy Gy Gy 115 120 125 Thr Lys Val G u I I e Lys Arg Thr Val Al a Al a Pr o Ser Val Phe I I e 130 135 140 Phe Pr o Pr o Ser Asp G u G n Leu Lys Ser G y Thr Al a Ser Val Val 145 150 155 160 Cys Leu Leu Asn Asn Phe Tyr Pr o Arg G u Al a Lys Val G n Tr p Lys 165 170 175 Val Asp Asn Al a Leu G n Ser Gy Asn Ser G n G u Ser Val Thr G u 180 185 190

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G n Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 195 200 205 Ser Lys Al a Asp Tyr G u Lys Hi s Lys Val Tyr Al a Cys G u Val Thr 210 215 220 Hi s G n Gy Leu Ser Ser Pr o Val Thr Lys Ser Phe Asn Arg Gy G u 225 230 235 240 Cys

<210> 17 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

<400> 17 Q n Leu Leu 10 Q y Leu Leu Leu Leu 15 Tr p K/fet 1 Asp IVfet Arg Val 5 Pr o Al a Leu Arg Gy Al a Arg Cys G n Ser Val Leu Thr G n Pr o Pr o Ser Val 20 25 30 Ser Al a Al a Pr o Gy G n Lys Val Thr I I e Ser Cys Ser Gy Ser Ser 35 40 45 Ser Asn I I e Gy Asn Asn Tyr Val Ser Tr p Tyr G n G n Leu Pr o Gy 50 55 60 Thr Al a Pr o Lys Leu Leu I I e Tyr Asp Asn Asn Lys Arg Pr o Ser Gy 65 70 75 80 I I e Pr o Asp Arg Phe Ser Gy Ser Lys Ser Gy Thr Ser Thr Thr Leu 85 90 95 Gy I I e Thr Gy Leu G n Thr Gy Asp G u Al a Asp Tyr Tyr Cys Gy 100 105 110 Thr Tr p Asp Ser Arg Leu Ser Al a Val Val Phe Gy Gy Gy Thr Lys 115 120 125 Leu Thr Val Leu Gy G n Pr o Lys Al a Asn Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser G u G u Leu G n Al a Asn Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I I e Ser Asp Phe Tyr Pr o Gy Al a Val Thr Val Al a Tr p Lys Al a

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165 170 175 Asp Qy Ser Pr o Val Lys Al a Qy Val Q u Thr Thr Lys Pr o Ser Lys 180 185 190 Q n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 Q u Q n Tr p Lys Ser Hi s Arg Ser Tyr Ser Cys Q n Val Thr Hi s Q u 210 215 220 Qy Ser Thr Val Q u Lys Thr Val Al a Pr o Thr Q u Cys Ser

225 230 235 <210> 18 <211> 241 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

<400> 18 Vfet 1 Asp Vfet Arg Val 5 Pr o Al a Q n Leu Leu 10 Q y Leu Leu Leu Leu 15 Tr p Leu Arg Qy Al a Arg Cys Asp I I e Val Vfet Thr Q n Ser Pr o Leu Ser 20 25 30 Leu Pr o Val Thr Pr o Qy Q u Pr o Al a Ser I I e Ser Cys Arg Ser Ser 35 40 45 Q n Ser Leu Leu Hi s Ser Phe Qy Tyr Asn Tyr Leu Asp Tr p Tyr Leu 50 55 60 Q n Lys Pr o Qy Q n Ser Pr o Q n Leu Leu I I e Tyr Leu Qy Ser Asn 65 70 75 80 Arg Al a Ser Qy Val Pr o Asp Arg Phe Ser Qy Ser Qy Ser Qy Thr 85 90 95 Asp Phe Thr Leu Lys I I e Ser Arg Val Q u Al a Q u Asp Val Qy Val 100 105 110 Tyr Tyr Cys Vfet Q n Al a Leu Q n Thr Pr o Phe Thr Phe Qy Pr o Qy 115 120 125 Thr Lys Val Asp I I e Lys Arg Thr Val Al a Al a Pr o Ser Val Phe I I e 130 135 140 Phe Pr o Pr o Ser Asp Q u Q n Leu Lys Ser Q y Thr Al a Ser Val Val 145 150 155 160

Page 14

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Cys Leu Leu Asn Asn 165 Phe Tyr Pr o Val Asp Asn Al a 180 Leu G n Ser Gy G n Asp Ser 195 Lys Asp Ser Thr Tyr 200 Ser Lys 210 Al a Asp Tyr G u Lys 215 Hi s Hi s 225 G n Gy Leu Ser Ser 230 Pr o Val Cys <210> 19 <211> 241 <212> PRT <213> Art i f i ci al Sequence

Arg G u 170 Al a Lys Val G n Tr p 175 Lys Asn 185 Ser G n G u Ser Val 190 Thr G u Ser Leu Ser Ser Thr 205 Leu Thr Leu Lys Val Tyr Al a 220 Cys G u Val Thr Thr Lys Ser Phe Asn Arg Gy G u

235 240 <220>

<221> source <223> I not e= Descr i pt i on of Arti

1 ί zdz-l

pol ypept i de Al a G n <400> 19 Pr o IVbt 1 Asp IVbt Arg Val 5 Leu Arg Gy Al a 20 Arg Cys Asp I I e Leu Ser Val 35 Thr Pr o Gy G n Pr o 40 G n Ser 50 Leu Leu Hi s Ser Asp 55 Gy G n 65 Lys Pr o Gy G n Pr o 70 Pr o G n Arg Phe Ser Gy G u 85 Pr o Asp Arg Asp Phe Thr Leu 100 Lys I I e Ser Arg Tyr Tyr Cys 115 K/bt G n Ser Phe Pr o 120

f i ci al Sequence: Synt het i c

Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p I I e 25 Leu Thr G n Thr Pr o 30 Leu Ser Al a Ser I I e Ser Cys 45 Lys Ser Ser Lys Thr Tyr Leu 60 Tyr Tr p Tyr Leu Leu Leu I I e 75 Tyr G u Val Ser Asn 80 Phe Ser 90 Gy Ser Gy Ser Gy 95 Thr Val 105 G u Al a G u Asp Val 110 Gy Thr Leu Pr o Leu Thr Phe 125 Gy Gy Gy

Page 15

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Thr Lys 130 Val G u I I e Lys Arg 135 Thr Phe 145 Pr o Pr o Ser Asp G u 150 G n Leu Cys Leu Leu Asn Asn 165 Phe Tyr Pr o Val Asp Asn Al a 180 Leu G n Ser Gy G n Asp Ser 195 Lys Asp Ser Thr Tyr 200 Ser Lys 210 Al a Asp Tyr G u Lys 215 Hi s Hi s 225 G n Gy Leu Ser Ser 230 Pr o Val Cys <210> 20 <211> 238 <212> PRT <213> Art i f i ci al Sequence

Val Al a Al a Pr o 140 Ser Val Phe I I e Lys Ser Gy 155 Thr Al a Ser Val Val 160 Arg G u 170 Al a Lys Val G n Tr p 175 Lys Asn 185 Ser G n G u Ser Val 190 Thr G u Ser Leu Ser Ser Thr 205 Leu Thr Leu Lys Val Tyr Al a 220 Cys G u Val Thr Thr Lys Ser 235 Phe Asn Arg Gy G u 240

<220>

<221> source <223> I not e= Descr i pt i on of Arti pol ypept i de <400> 20 f i ci al Sequence: Synt het i c

IVbt 1 Asp IVfet Arg Val 5 Pr o Al a G n Leu Arg Gy Al a 20 Arg Cys G n Ser Ser Al a Al a 35 Pr o Gy G n Lys Val 40 Ser Asn 50 I I e Gy Asn Asn Tyr 55 Val Thr 65 Al a Pr o Lys Leu Leu 70 I I e Tyr I I e Pr o Asp Arg Phe Ser Gy Ser

Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p Val 25 Leu Thr G n Pr o Pr o 30 Ser Val Thr I I e Ser Cys Ser 45 Gy Ser Ser Ser Tr p Tyr G n 60 G n Phe Pr o Gy Asp Asn Asn 75 Lys Arg Pr o Ser Gy 80 Lys Ser 90 Gy Thr Ser Al a Thr 95 Leu

Page 16

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Gy lie Thr G y Leu G n Thr 100 Q y Asp 105 Q u Al a Asp Tyr Tyr 110 Cys Q y Thr Tr p Asp 115 Ser Arg Leu Ser Al a Val 120 Val Phe G y G y 125 Gy Thr Lys Leu Thr Val 130 Leu Gy Q n Pro 135 Lys Al a Asn Pro Thr Val 140 Thr Leu Phe Pr o 145 Pro Ser Ser Q u Q u Leu 150 G n Al a Asn Lys Al a Thr 155 Leu Val Cys 160 Leu I I e Ser Asp Phe Tyr Pro 165 G y Al a Val Thr Val Al a 170 Tr p Lys Al a 175 Asp G y Ser Pr o Val Lys Al a 180 G y Val 185 Q u Thr Thr Lys Pr o 190 Ser Lys G n Ser Asn 195 Asn Lys Tyr Al a Al a Ser 200 Ser Tyr Leu Ser 205 Leu Thr Pro G u G n Trp Lys Ser Hi s Arg 210 215 G y Ser Thr Val G u Lys Thr 225 230 <210> 21 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> source Ser Tyr Val Al a Ser Cys Q n Val 220 Pro Thr Q u Cys 235 Thr Ser Hi s Q u <223> 1 not e= Descr i pt i on of pol ypept i de <400> 21 Ar t i f i ci al Sequence: Synt het i c IVbt 1 Asp IVbt Ar g Val Pr o Al a 5 Q n Leu Leu Q y Leu Leu 10 Leu Leu Trp 15 Leu Arg G y Al a Ar g Cys Q n 20 Ser Val 25 Leu Thr Q n Ser Pr o 30 Ser Al a Ser G y Thr 35 Pro Gy Q n Arg Val Thr 40 I I e Ser Cys Ser 45 Gy Ser Ser Ser Asn I I e 50 Q y Ser Asn Tyr 55 Val Tyr Tr p Tyr Q n Q n 60 Leu Pr o G y Al a 65 Al a Pr o Lys Leu Leu I I e 70 Leu Arg Asn Asn Qn Arg 75 Pr o Ser G y 80 Val Pr o Asp Ar g Phe Ser G y Ser Lys Ser G y Thr Ser Page 17 Al a Ser Leu

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85 90 95 Thr I I e Ser Q y Leu Arg Ser Q u Asp G u Al a Asp Tyr Tyr Cys Al a 100 105 110 Al a Tr p Asp Asp Ser Leu Ser Gy Trp Val Phe G y G y G y Thr Lys 115 120 125 Leu Thr Val Leu Gy Q n Pro Lys Al a Asn Pro Thr Val Thr Leu Phe 130 135 140 Pro Pro Ser Ser Q u Q u Leu Q n Al a Asn Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I I e Ser Asp Phe Tyr Pro Gy Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 Asp Q y Ser Pr o Val Lys Al a Q y Val G u Thr Thr Lys Pro Ser Lys 180 185 190 Q n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pro 195 200 205 G u G n Tr p Lys Ser His Arg Ser Tyr Ser Cys G n Val Thr Hi s G u 210 215 220 Q y Ser Thr Val G u Lys Thr Val Al a Pro Thr Q u Cys Ser 225 230 235 <210> 22 <211> 238 <212> PRT <213> Art i f i ci al Sequence <220> <221> source <223> / not e= = Descr i pt i on of Ar t i f i ci al Sequence: Synt het i c pol ypept i de <400> 22 IVbt Asp IVbt Arg Val Pro Al a Q n Leu Leu Q y Leu Leu Leu Leu Trp 1 5 10 15 Leu Ar g Q y Al a Arg Cys Q n Ser Val Leu Thr Q n Pr o Pr o Ser Al a 20 25 30 Ser Q y Thr Pro Gy Q n Arg Val Thr I I e Ser Cys Ser Q y Ser Ser 35 40 45 Ser Asn lie Q y Ser Asn Thr Val Asn Trp Tyr Q n Q n Leu Pr o Q y 50 55 60 Thr Al a Pro Lys Leu Leu I I e Tyr Thr Asn Asn Q n Ar g Pr o Ser Q y 65 70 75 80 Page 18

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Val Pr o Asp Ar g Phe 85 Ser Gy Ser Lys Ser 90 Gy Thr Ser Al a Ser 95 Leu Al a I I e Ser G y Leu G n Ser G u Asp G u Al a Asp Phe Tyr Cys Al a 100 105 110 Al a Arg Asp Q u Ser Leu Asn Gy Val Val Phe Gy Gy Gy Thr Lys 115 120 125 Leu Thr Val Leu G y G n Pr o Lys Al a Asn Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser G u G u Leu G n Al a Asn Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I I e Ser Asp Phe Tyr Pr o Gy Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 Asp Gy Ser Pro Val Lys Al a Gy Val G u Thr Thr Lys Pr o Ser Lys 180 185 190 G n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 G u G n Trp Lys Ser Hi s Arg Ser Tyr Ser Cys G n Val Thr Hi s G u 210 215 220 G y Ser Thr Val G u Lys Thr Val Al a Pr o Thr G u Cys Ser 225 230 235 <210> 23 <211 > 238 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > source <223> / not e= Descr i pt i on of Ar t i f i ci al ! Sequence: Synt het i c pol ypept i de <400> 23 IVbt Asp IVbt Ar g Val Pr o Al a G n Leu Leu G y Leu Leu Leu Leu Tr p 1 5 10 15 Leu Arg G y Al a Arg Cys G n Ser Val Leu Thr G n Pr o Pr o Ser Al a 20 25 30 Ser G y Thr Pro G y G n Arg Val Thr I I e Ser Cys Ser G y Ser Ser 35 40 45 Ser Asn I I e G y Ser Asn Tyr Val Tyr Tr p Tyr G n G n Leu Pr o Gy 50 55 60

Page 19

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Al a Al a Pr o Lys 65 Leu Leu 70 lie Phe Arg Asn Asn Qn Arg 75 Pr o Ser Gy 80 Val Pr o Asp Arg Phe Ser Gy Ser Lys Ser Gy Thr Ser Al a Ser Leu 85 90 95 Al a I I e Ser Gy Leu Arg Ser G u Asp G u Al a Asp Tyr Tyr Cys Al a 100 105 110 Al a Tr p Asp Asp Ser Leu Ser Gy Tr p Val Phe Gy Gy Gy Thr Lys 115 120 125 Leu Thr Val Leu Gy G n Pr o Lys Al a Asn Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser G u G u Leu G n Al a Asn Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I I e Ser Asp Phe Tyr Pr o Gy Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 Asp Gy Ser Pr o Val Lys Al a Gy Val G u Thr Thr Lys Pr o Ser Lys 180 185 190 G n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 G u G n Tr p Lys Ser Hi s Arg Ser Tyr Ser Cys G n Val Thr Hi s G u 210 215 220 Gy Ser Thr Val G u Lys Thr Val Al a Pr o Thr G u Cys Ser

225 230 235 <210> 24 <211> 241 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 24

IVbt 1 Asp IVbt Arg Val 5 Pr o Al a G n Leu Leu Q y 10 Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a Arg Cys Asp I I e Thr Leu Thr G n Thr Pr o Leu Ser 20 25 30 Leu Ser Val Ser Pr o Gy G n Pr o Al a Ser I I e Ser Cys Lys Ser Ser 35 40 45

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Q n Ser Leu Leu Hi s A1472PCT. t xt Leu Ser Asp 55 Gy Arg Asn Tyr Leu Tyr 60 Tr p Tyr 50 G n 65 Lys Pro Gy Q n Pr o 70 Pr o G n Leu Leu I I e 75 Tyr G u Val Ser Asn 80 Arg Phe Ser Q y Leu 85 Pr o Asp Arg Phe Ser G y 90 Ser G y Ser Gy 95 Thr Asp Phe Thr Leu Lys 100 I I e Ser Arg Val 105 G u Al a Q u Asp Val 110 Gy I I e Tyr Tyr Cys D/bt Q n 115 Ser Phe Pr o 120 Leu Pro Leu Thr Phe 125 Gy Gy Gy Thr Lys 130 Val Guile Lys Arg 135 Thr Val Al a Al a Pro Ser 140 Val Phe I I e Phe 145 Pr o Pro Ser Asp G u 150 G n Leu Lys Ser G y 155 Thr Al a Ser Val Val 160 Cys Leu Leu Asn Asn 165 Phe Tyr Pr o Arg G u Al a 170 Lys Val G n Tr p 175 Lys Val Asp Asn Al a Leu 180 G n Ser Gy Asn 185 Ser Q n Q u Ser Val 190 Thr G u G n Asp Ser Lys Asp 195 Ser Thr Tyr 200 Ser Leu Ser Ser Thr 205 Leu Thr Leu Ser Lys 210 Al a Asp Tyr G u Lys 215 Hi s Lys Val Tyr Al a Cys 220 G u Val Thr Hi s Q n Gy Leu Ser Ser Pro 225 230 Cys <210> 25 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> source Val Thr Lys Ser 235 Phe Asn Arg Gy G u 240 <223> 1 not e= Descr i pt i on of pol ypept i de <400> 25 Ar t i f i ci al Sequence: Synt het i c IVbt 1 Asp IVbt Ar g Val 5 Pr o Al a G n Leu Leu Q y 10 Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a Arg Cys G n Ser Val Leu Thr Page 21 Q n Pro Pr o Ser Val

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20 25 30 Ser Al a Al a Pr o Gy G n Lys Val Thr I I e Ser Cys Ser Gy Ser Ser 35 40 45 Ser Asn I I e Gy Asn Asn Tyr Val Ser Tr p Tyr G n G n Leu Pr o Gy 50 55 60 Thr Al a Pr o Lys Leu Leu I I e Tyr Asp Asn Asn Lys Arg Pr o Ser Gy 65 70 75 80 I I e Pr o Asp Arg Phe Ser Gy Ser Lys Ser Gy Thr Ser Al a Thr Leu 85 90 95 Gy I I e Thr Gy Leu G n Thr Gy Asp G u Al a Asp Tyr Tyr Cys Gy 100 105 110 Thr Tr p Asp Ser Arg Leu Ser Al a Val Val Phe Gy Gy Gy Thr Lys 115 120 125 Leu Thr Val Leu Gy G n Pr o Lys Al a Asn Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser G u G u Leu G n Al a Asn Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I I e Ser Asp Phe Tyr Pr o Gy Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 Asp Gy Ser Pr o Val Lys Al a Gy Val G u Thr Thr Lys Pr o Ser Lys 180 185 190 G n Ser Asn Asn Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 G u G n Tr p Lys Ser Hi s Arg Ser Tyr Ser Cys G n Val Thr Hi s G u 210 215 220 Gy Ser Thr Val G u Lys Thr Val Al a Pr o Thr G u Cys Ser

225 230 235 <210> 26 <211> 236 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 26

IVht Asp IVht Arg Val Pro Al a On Leu Leu Q y Leu Leu Leu Leu Trp 15 10 15

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Leu Arg G y Al a 20 Arg Cys Asp I I e Q n IVfet 25 Thr Q n Ser Pr o 30 Ser Ser Leu Ser Al a Ser Val Gy Asp Arg Val Thr I I e Thr Cys Arg Al a Ser 35 40 45 G n Gy I I e Arg Lys Asp Leu Gy Tr p Tyr G n G n Lys Pr o Gy Lys 50 55 60 Al a Pr o Lys Arg Leu I I e Tyr Gy Al a Ser Ser Leu G n Ser Gy Val 65 70 75 80 Pr o Ser Arg Phe Ser Gy Ser Gy Ser G y Thr G u Phe Thr Leu Thr 85 90 95 I I e Ser Ser Leu G n Pr o G u Asp Phe Al a Thr Tyr Tyr Cys Leu G n 100 105 110 Tyr Asn Ser Phe Pr o Tr p Thr Phe Gy G n Gy Thr Lys Val G u I I e 115 120 125 Lys Arg Thr Val Al a Al a Pr o Ser Val Phe I I e Phe Pr o Pr o Ser Asp 130 135 140 G u G n Leu Lys Ser G y Thr Al a Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pr o Arg G u Al a Lys Val G n Tr p Lys Val Asp Asn Al a Leu 165 170 175 G n Ser Gy Asn Ser G n G u Ser Val Thr G u G n Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr 195 200 205 G u Lys Hi s Lys Val Tyr Al a Cys G u Val Thr Hi s G n Gy Leu Ser 210 215 220 Ser Pr o Val Thr Lys Ser Phe Asn Arg Gy G u Cys

225 230 235 <210> 27 <211> 235 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

Page 23

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<400> 27 Phe Leu Leu Leu Leu Trp Leu Pr o l\/bt 1 G u Thr Pr o Al a 5 G n Leu Leu 10 15 Asp Thr Thr G y G u I I e Val Leu Thr G n Ser Pr o Gy Thr Leu Ser 20 25 30 Leu Ser Pr o Gy G u Arg Al a Thr Leu Ser Cys Arg Al a Ser G n Ser 35 40 45 Val Ser Ser Gy Tyr Leu Thr Tr p Tyr G n G n Lys Pr o Gy G n Al a 50 55 60 Pr o Arg Leu Leu I I e Tyr Gy Al a Ser Ser Arg Al a Thr Gy I I e Pr o 65 70 75 80 Asp Arg Phe Ser Gy Ser Gy Ser Gy Thr Asp Phe Thr Leu Thr I I e 85 90 95 Ser Arg Leu G u Pr o G u Asp Phe Al a Val Tyr Tyr Cys G n G n Tyr 100 105 110 Gy Asn Ser Leu Cys Arg Phe Gy G n Gy Thr Lys Leu G u I I e Lys 115 120 125 Arg Thr Val Al a Al a Pr o Ser Val Phe I I e Phe Pr o Pr o Ser Asp G u 130 135 140 G n Leu Lys Ser Gy Thr Al a Ser Val Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pr o Arg G u Al a Lys Val G n Tr p Lys Val Asp Asn Al a Leu G n 165 170 175 Ser Gy Asn Ser G n G u Ser Val Thr G u G n Asp Ser Lys Asp Ser 180 185 190 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr G u 195 200 205 Lys Hi s Lys Val Tyr Al a Cys G u Val Thr Hi s G n Gy Leu Ser Ser 210 215 220 Pr o Val Thr Lys Ser Phe Asn Arg Gy G u Cys 225 230 235

<210> 28 <211> 235 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source

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A1472PCT. t xt <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 28

l\/bt 1 Q u Thr Pr o Al a 5 Q n Leu Leu Phe Leu Leu Leu Leu Trp Leu Pr o 10 15 Asp Thr Thr Q y Q u I I e Val Leu Thr Q n Ser Pr o Qy Thr Leu Ser 20 25 30 Leu Ser Pr o Qy Q u Arg Al a Thr Leu Ser Cys Arg Al a Ser Q n Ser 35 40 45 Val Ser Ser Qy Tyr Leu Thr Tr p Tyr Q n Q n Lys Pr o Qy Q n Al a 50 55 60 Pr o Arg Leu Leu I I e Tyr Qy Al a Ser Ser Arg Al a Thr Qy I I e Pr o 65 70 75 80 Asp Arg Phe Ser Qy Ser Qy Ser Qy Thr Asp Phe Thr Leu Thr I I e 85 90 95 Ser Arg Leu Q u Pr o Q u Asp Phe Al a Val Tyr Tyr Cys Q n Q n Tyr 100 105 110 Qy Asn Ser Leu Ser Arg Phe Qy Q n Qy Thr Lys Leu Q u I I e Lys 115 120 125 Arg Thr Val Al a Al a Pr o Ser Val Phe I I e Phe Pr o Pr o Ser Asp Q u 130 135 140 Q n Leu Lys Ser Qy Thr Al a Ser Val Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pr o Arg Q u Al a Lys Val Q n Tr p Lys Val Asp Asn Al a Leu Q n 165 170 175 Ser Qy Asn Ser Q n Q u Ser Val Thr Q u Q n Asp Ser Lys Asp Ser 180 185 190 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Q u 195 200 205 Lys Hi s Lys Val Tyr Al a Cys Q u Val Thr Hi s Q n Qy Leu Ser Ser 210 215 220 Pr o Val Thr Lys Ser Phe Asn Arg Qy Q u Cys 225 230 235 <210> 29 <211 > 478 <212> PRT <213> Art i f i ci al Sequence

Page 25

A1472PCT. t xt

2016244220 11 Oct 2016 <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 29

K/bt 1 Asp IVfet Arg Val 5 Pr o Al a G n Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a 20 Arg Cys G n Val G n 25 Leu Val G u Ser Gy 30 Gy Gy Val Val G n 35 Pr o Gy Arg Ser Leu 40 Arg Leu Ser Cys Al a 45 Al a Ser Gy Phe Thr 50 Phe Ser Ser Phe Gy 55 IVfet Hi s Tr p Val Arg 60 G n Al a Pr o Gy Lys 65 Gy Leu G u Tr p Val 70 Al a Val I I e Ser Phe 75 Asp Gy Ser I I e Lys 80 Tyr Ser Val Asp Ser 85 Val Lys Gy Arg Phe 90 Thr I I e Ser Arg Asp 95 Asn Ser Lys Asn Thr 100 Leu Phe Leu G n IVbt 105 Asn Ser Leu Arg Al a 110 G u Asp Thr Al a Val 115 Tyr Tyr Cys Al a Arg 120 Asp Arg Leu Asn Tyr 125 Tyr Asp Ser Ser Gy 130 Tyr Tyr Hi s Tyr Lys 135 Tyr Tyr Gy IVbt Al a 140 Val Tr p Gy G n Gy 145 Thr Thr Val Thr Val 150 Ser Ser Al a Ser Thr 155 Lys Gy Pr o Ser Val 160 Phe Pr o Leu Al a Pr o 165 Cys Ser Arg Ser Thr 170 Ser G u Ser Thr Al a 175 Al a Leu Gy Cys Leu 180 Val Lys Asp Tyr Phe 185 Pr o G u Pr o Val Thr 190 Val Ser Tr p Asn Ser 195 Gy Al a Leu Thr Ser 200 Gy Val Hi s Thr Phe 205 Pr o Al a Val Leu G n 210 Ser Ser Gy Leu Tyr 215 Ser Leu Ser Ser Val 220 Val Thr Val Pr o Ser 225 Ser Asn Phe Gy Thr 230 G n Thr Tyr Thr Cys 235 Asn Val Asp Hi s Lys 240 Pr o Ser Asn Thr Lys Val Asp Lys Thr Val G u Arg Lys Cys Cys Val

Page 26

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245 250 255 G u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a G y Pr o Ser Val Phe 260 265 270 Leu Phe Pr o Pr o Lys Pr o Lys Asp Thr Leu IVbt I I e Ser Arg Thr Pr o 275 280 285 G u Val Thr Cys Val Val Val Asp Val Ser Hi s G u Asp Pr o G u Val 290 295 300 G n Phe Asn Tr p Tyr Val Asp Q y Val G u Val Hi s Asn Al a Lys Thr 305 310 315 320 Lys Pr o Arg G u G u G n Phe Asn Ser Thr Phe Arg Val Val Ser Val 325 330 335 Leu Thr Val Val Hi s G n Asp Tr p Leu Asn Gy Lys G u Tyr Lys Cys 340 345 350 Lys Val Ser Asn Lys Q y Leu Pr o Al a Pr o I I e G u Lys Thr I I e Ser 355 360 365 Lys Thr Lys Q y G n Pr o Arg G u Pr o G n Val Tyr Thr Leu Pr o Pr o 370 375 380 Ser Arg G u G u IVbt Thr Lys Asn G n Val Ser Leu Thr Cys Leu Val 385 390 395 400 Lys Q y Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn G y 405 410 415 G n Pr o G u Asn Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser Asp 420 425 430 Q y Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Tr p 435 440 445 G n G n Q y Asn Val Phe Ser Cys Ser Val IVbt Hi s G u Al a Leu Hi s 450 455 460 Asn Hi s Tyr Thr G n Lys Ser Leu Ser Leu Ser Pr o G y Lys 465 470 475

<210> 30 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

Page 27

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<400> 30 IVbt 1 Asp IVbt Arg Val 5 Pr o Al a Leu Arg G y Al a Ar g 20 Cys G u Leu Val Lys 35 Pr o G y Gy Ser Phe Thr Phe 50 Ser Asn Al a Tr p 55 Lys 65 Q y Leu G u Tr p Val 70 Gy Thr Thr Asp Tyr Al a 85 Al a Pr o Asp Asp Ser Lys Asn 100 Thr Leu G u Asp Thr 115 Al a Val Tyr Tyr I I e Ser Trp 130 Ser Ser Tyr Tyr 135 G n 145 G y Thr Thr Val Thr 150 Val Val Phe Pro Leu Al a 165 Pr o Cys Al a Leu Q y Cys Leu 180 Val Lys Ser Tr p Asn 195 Ser G y Al a Leu Val Leu Q n 210 Ser Ser Gy Leu 215 Pr o 225 Ser Ser Asn Phe Gy 230 Thr Lys Pro Ser Asn Thr 245 Lys Val Val Q u Cys Pro Pro Cys Pr o

Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p G n 25 Leu Val G u Ser Gy 30 Gy Gy Arg Leu Ser Cys Al a 45 Al a Ser Gy Ser Tr p Val Arg 60 G n Al a Pr o Gy I I e Lys Ser 75 Thr Thr Asp Gy Gy 80 Lys Gy 90 Arg Phe Thr I I e Ser 95 Arg Leu 105 G n IVfet Asn Ser Leu 110 Lys Thr Thr Thr Asp Arg Thr 125 Gy Tyr Ser Tyr Tyr Gy IVbt 140 Asp Val Tr p Gy Ser Al a Ser 155 Thr Lys Gy Pr o Ser 160 Arg Ser 170 Thr Ser G u Ser Thr 175 Al a Tyr 185 Phe Pr o G u Pr o Val 190 Thr Val Ser Gy Val Hi s Thr 205 Phe Pr o Al a Ser Leu Ser Ser 220 Val Val Thr Val Thr Tyr Thr 235 Cys Asn Val Asp Hi s 240 Lys Thr 250 Val G u Arg Lys Cys 255 Cys Pr o Pr o Val Al a Gy Pr o Ser Val

265 270

260

Page 28

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Phe Leu Phe 275 Pr o Pr o Lys Pr o Lys 280 Asp Thr Leu K/fet I I e 285 Ser Arg Thr Pr o G u Val Thr Cys Val Val Val Asp Val Ser Hi s G u Asp Pr o G u 290 295 300 Val G n Phe Asn Tr p Tyr Val Asp G y Val G u Val Hi s Asn Al a Lys 305 310 315 320 Thr Lys Pr o Arg G u G u G n Phe Asn Ser Thr Phe Arg Val Val Ser 325 330 335 Val Leu Thr Val Val Hi s G n Asp Tr p Leu Asn Gy Lys G u Tyr Lys 340 345 350 Cys Lys Val Ser Asn Lys Gy Leu Pr o Al a Pr o I I e G u Lys Thr I I e 355 360 365 Ser Lys Thr Lys G y G n Pr o Arg G u Pr o G n Val Tyr Thr Leu Pr o 370 375 380 Pr o Ser Arg G u G u l\/bt Thr Lys Asn G n Val Ser Leu Thr Cys Leu 385 390 395 400 Val Lys G y Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn 405 410 415 G y G n Pr o G u Asn Asn Tyr Lys Thr Thr Pr o Pr o K/fet Leu Asp Ser 420 425 430 Asp Gy Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 435 440 445 Tr p G n G n G y Asn Val Phe Ser Cys Ser Val K/fet Hi s G u Al a Leu 450 455 460 Hi s Asn Hi s Tyr Thr G n Lys Ser Leu Ser Leu Ser Pr o Gy Lys

465 470 475 <210> 31 <211> 478 <212> PRT

<213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Descr i pt i on of pol ypept i de Ar t i f i ci al Sequence: Synt het i c <400> 31 K/fet Asp K/fet Arg Val Pro Al a Q n Leu Leu Gy Leu Leu Leu Leu Trp 1 5 10 15

Page 29

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Leu Arg Gy Al a 20 Arg Cys G u Val G n 25 Leu Leu G u Ser Gy 30 Gy Gy Leu Val G n 35 Pr o Gy G u Ser Leu 40 Arg Leu Ser Cys Al a 45 Al a Ser Gy Phe Thr 50 Phe Ser Ser Tyr Al a 55 IVbt Ser Tr p Val Arg 60 G n Al a Pr o Gy Lys 65 Gy Leu G u Tr p Val 70 Ser Al a I I e Ser Gy 75 Ser Gy Gy Arg Thr 80 Tyr Tyr Al a Asp Ser 85 Val Lys Gy Arg Phe 90 Thr I I e Ser Arg Asp 95 Asn Ser Lys Asn Thr 100 Leu Tyr Leu G n IVbt 105 Asn Ser Leu Arg Al a 110 G u Asp Thr Al a Val 115 Tyr Tyr Cys Al a Lys 120 Asp G n Arg G u Val 125 Gy Pr o Tyr Ser Ser 130 Gy Tr p Tyr Asp Tyr 135 Tyr Tyr Gy IVbt Asp 140 Val Tr p Gy G n Gy 145 Thr Thr Val Thr Val 150 Ser Ser Al a Ser Thr 155 Lys Gy Pr o Ser Val 160 Phe Pr o Leu Al a Pr o 165 Cys Ser Arg Ser Thr 170 Ser G u Ser Thr Al a 175 Al a Leu Gy Cys Leu 180 Val Lys Asp Tyr Phe 185 Pr o G u Pr o Val Thr 190 Val Ser Tr p Asn Ser 195 Gy Al a Leu Thr Ser 200 Gy Val Hi s Thr Phe 205 Pr o Al a Val Leu G n 210 Ser Ser Gy Leu Tyr 215 Ser Leu Ser Ser Val 220 Val Thr Val Pr o Ser 225 Ser Asn Phe Gy Thr 230 G n Thr Tyr Thr Cys 235 Asn Val Asp Hi s Lys 240 Pr o Ser Asn Thr Lys 245 Val Asp Lys Thr Val 250 G u Arg Lys Cys Cys 255 Val G u Cys Pr o Pr o 260 Cys Pr o Al a Pr o Pr o 265 Val Al a Gy Pr o Ser 270 Val Phe Leu Phe Pr o 275 Pr o Lys Pr o Lys Asp 280 Thr Leu IVbt I I e Ser 285 Arg Thr Pr o

Page 30

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G u Val 290 Thr Cys Val Val Val 295 Asp Val Ser Hi s Q u Asp 300 Pr o G u Val Q n Phe Asn Tr p Tyr Val Asp G y Val G u Val Hi s Asn Al a Lys Thr 305 310 315 320 Lys Pr o Arg G u G u G n Phe Asn Ser Thr Phe Arg Val Val Ser Val 325 330 335 Leu Thr Val Val Hi s G n Asp Tr p Leu Asn Gy Lys Q u Tyr Lys Cys 340 345 350 Lys Val Ser Asn Lys G y Leu Pr o Al a Pr o I I e Q u Lys Thr I I e Ser 355 360 365 Lys Thr Lys G y G n Pr o Arg G u Pr o G n Val Tyr Thr Leu Pr o Pr o 370 375 380 Ser Arg G u G u IVbt Thr Lys Asn G n Val Ser Leu Thr Cys Leu Val 385 390 395 400 Lys Q y Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn G y 405 410 415 Q n Pro G u Asn Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser Asp 420 425 430 G y Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Tr p 435 440 445 G n G n G y Asn Val Phe Ser Cys Ser Val IVbt Hi s Q u Al a Leu Hi s 450 455 460 Asn Hi s Tyr Thr G n Lys Ser Leu Ser Leu Ser Pr o G y Lys 465 470 475 <210> 32 <211> 478 <212> PRT <213> Art i f i ci al Sequence <220> <221> source <223> / not e= = Descr i pt i on of Ar t i f i ci al ! Sequence: Synt het i c pol ypept i de <400> 32 IVbt Asp IVfet Arg Val Pr o Al a G n Leu Leu G y Leu Leu Leu Leu Tr p 1 5 10 15 Leu Arg Gy Al a Arg Cys G n Val G n Leu Val Q n Ser Gy Al a G u

20 25 30

Page 31

2016244220 11 Oct 2016

Val Lys

Tyr Thr 50

G n G y 65

Asn Tyr

Ser I I e

Thr Al a

Arg G y 130

G y Thr 145

Phe Pro

Leu Q y

Tr p Asn

Leu Q n 210

Ser Ser 225

Pro Ser

Q u Cys

Leu Phe

G u Val 290

Lys Pr o 35

Phe Thr

Leu Q u

Al a G n

Ser Thr 100

Val Tyr 115

Val Phe

Thr Val

Leu Al a

Cys Leu 180

Ser G y 195

Ser Ser

Asn Phe

Asn Thr

Pro Pro 260

Pro Pro 275

Thr Cys

G y Al a

G y Tyr

Trp IVfet 70

Lys Phe 85

Al a Tyr

Phe Cys

Pro Pro

Thr Val 150

Pr o Cys 165

Val Lys

Al a Leu

Q y Leu

G y Thr 230

Lys Val 245

Cys Pr o

Lys Pr o

Val Val

Ser Val 40

Tyr IVfet 55

G y Tr p

G n G y

IVbt Q u

Al a Ar g 120

Tyr Tyr 135

Ser Ser

Ser Arg

Asp Tyr

Thr Ser 200

Tyr Ser 215

G n Thr

Asp Lys

Al a Pr o

Lys Asp 280

Val Asp 295

A1472PCT. t xt Lys Val Ser Cys

Hi s Tr p

I I e Asn

Arg Val 90

Leu Ser 105

Asp Q n

Tyr G y

Al a Ser

Ser Thr 170

Phe Pro 185

G y Val

Leu Ser

Tyr Thr

Thr Val 250

Pr o Val 265

Thr Leu

Val Ser

Val Arg 60

Pro Asn 75

Thr IVbt

Arg Leu

IVbt Ser

IVbt Asp 140

Thr Lys 155

Ser Q u

G u Pro

Hi s Thr

Ser Val 220

Cys Asn 235

G u Arg

Al a G y

IVbt lie

Hi s Q u 300

Lys Al a 45

G n Al a

Ser G y

Thr Ar g

Arg Ser 110 lie lie 125

Val Trp

G y Pr o

Ser Thr

Val Thr 190

Phe Pro 205

Val Thr

Val Asp

Lys Cys

Pro Ser 270

Ser Arg 285

Asp Pr o

Ser G y

Pr o G y

G y Thr 80

Asp Thr 95

Asp Asp

IVbt Leu

G y G n

Ser Val 160

Al a Al a 175

Val Ser

Al a Val

Val Pr o

Hi s Lys 240

Cys Val 255

Val Phe

Thr Pro

G u Val

Page 32

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G n 305 Phe Asn Tr p Tyr Val 310 Asp Q y Val G u Val 315 Hi s Asn Al a Lys Thr 320 Lys Pr o Arg G u G u G n Phe Asn Ser Thr Phe Arg Val Val Ser Val 325 330 335 Leu Thr Val Val Hi s G n Asp Tr p Leu Asn Gy Lys G u Tyr Lys Cys 340 345 350 Lys Val Ser Asn Lys G y Leu Pr o Al a Pr o I I e G u Lys Thr I I e Ser 355 360 365 Lys Thr Lys G y G n Pr o Arg G u Pr o G n Val Tyr Thr Leu Pr o Pr o 370 375 380 Ser Arg G u G u IVbt Thr Lys Asn G n Val Ser Leu Thr Cys Leu Val 385 390 395 400 Lys G y Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn G y 405 410 415 G n Pr o G u Asn Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser Asp 420 425 430 Gy Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Tr p 435 440 445 G n G n G y Asn Val Phe Ser Cys Ser Val IVbt Hi s G u Al a Leu Hi s 450 455 460 Asn Hi s Tyr Thr G n Lys Ser Leu Ser Leu Ser Pr o G y Lys 465 470 475 <210> 33 <211 > 477 <212> PRT <213> Art i f i ci al Sequence <220> <221 > source <223> / not e= = Descr i pt i on of Ar t i f i ci al Sequence: Synt het i c pol ypept i de <400> 33 l\/bt Asp IVfet Arg Val Pr o Al a G n Leu Leu G y Leu Leu Leu Leu Tr p 1 5 10 15 Leu Arg G y Al a Arg Cys G n Val G n Leu Val G u Ser G y G y G y 20 25 30 Val Val G n Pr o G y Arg Ser Leu Arg Leu Ser Cys Al a Al a Ser G y 35 40 45 Phe Thr Phe Ser Ser Tyr Gy IVbt Hi s Tr p Val Arg G n Al a Pr o Gy Page 33

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A1472PCT. t xt

50 55 60

Lys 65 Gy Leu G u Tr p Val 70 Al a Val I I e Ser Tyr 75 Asp Gy Ser Hi s G u 80 Ser Tyr Al a Asp Ser 85 Val Lys Gy Arg Phe 90 Thr I I e Ser Arg Asp 95 I I e Ser Lys Asn Thr 100 Leu Tyr Leu G n IVbt 105 Asn Ser Leu Arg Al a 110 G u Asp Thr Al a Val 115 Tyr Phe Cys Al a Arg 120 G u Arg Lys Arg Val 125 Thr IVbt Ser Thr Leu 130 Tyr Tyr Tyr Phe Tyr 135 Tyr Gy IVbt Asp Val 140 Tr p Gy G n Gy Thr 145 Thr Val Thr Val Ser 150 Ser Al a Ser Thr Lys 155 Gy Pr o Ser Val Phe 160 Pr o Leu Al a Pr o Cys 165 Ser Arg Ser Thr Ser 170 G u Ser Thr Al a Al a 175 Leu Qy Cys Leu Val 180 Lys Asp Tyr Phe Pr o 185 G u Pr o Val Thr Val 190 Ser Tr p Asn Ser Gy 195 Al a Leu Thr Ser Gy 200 Val Hi s Thr Phe Pr o 205 Al a Val Leu G n Ser 210 Ser Gy Leu Tyr Ser 215 Leu Ser Ser Val Val 220 Thr Val Pr o Ser Ser 225 Asn Phe Gy Thr G n 230 Thr Tyr Thr Cys Asn 235 Val Asp Hi s Lys Pr o 240 Ser Asn Thr Lys Val 245 Asp Lys Thr Val G u 250 Arg Lys Cys Cys Val 255 G u Cys Pr o Pr o Cys 260 Pr o Al a Pr o Pr o Val 265 Al a Gy Pr o Ser Val 270 Phe Leu Phe Pr o Pr o 275 Lys Pr o Lys Asp Thr 280 Leu IVbt I I e Ser Arg 285 Thr Pr o G u Val Thr 290 Cys Val Val Val Asp 295 Val Ser Hi s G u Asp 300 Pr o G u Val G n Phe 305 Asn Tr p Tyr Val Asp 310 Gy Val G u Val Hi s 315 Asn Al a Lys Thr Lys 320 Pr o Arg G u G u G n Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu

Page 34

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325 330 335 Thr Val Val Hi s Q n Asp Tr p Leu Asn Q y Lys Q u Tyr Lys Cys Lys 340 345 350 Val Ser Asn Lys Q y Leu Pr o Al a Pr o lie Q u Lys Thr I I e Ser Lys 355 360 365 Thr Lys Q y Q n Pro Arg Q u Pro G n Val Tyr Thr Leu Pro Pro Ser 370 375 380 Ar g G u G u I\/bt Thr Lys Asn Q n Val Ser Leu Thr Cys Leu Val Lys 385 390 395 400 Q y Phe Tyr Pr o Ser Asp lie Al a Val G u Tr p G u Ser Asn Q y Q n 405 410 415 Pro Q u Asn Asn Tyr Lys Thr Thr Pro Pro IVfet Leu Asp Ser Asp Q y 420 425 430 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Q n 435 440 445 Q n Q y Asn Val Phe Ser Cys Ser Val IVfet Hi s G u Al a Leu Hi s Asn 450 455 460 Hi s Tyr Thr Q n Lys Ser Leu Ser Leu Ser Pro Gy Lys 465 470 475 <210> 34 <211> 469 <212> PRT <213> Art i f i ci al Sequence <220> <221> source <223> / not e= ^'Description of Artificial Sequence: Synthetic pol ypept i de <400> 34 IVbt Asp IVbt Ar g Val Pr o Al a Q n Leu Leu Q y Leu Leu Leu Leu Trp 1 5 10 15 Leu Ar g Q y Al a Ar g Cys Q u Val Q n Leu Val Q u Ser Gy Gy Gy 20 25 30 Leu Val Lys Pro Gy Arg Ser Leu Arg Leu Ser Cys Thr Al a Ser Q y 35 40 45 Phe Thr Phe Q y Asp Tyr Al a K/bt Ser Tr p Phe Ar g Q n Al a Pro Gy 50 55 60 Lys Q y Leu Q u Tr p lie Gy Phe lie Ar g Ser Ar g Al a Tyr G y G y 65 70 75 80 Page 35

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2016244220 11 Oct 2016

Thr Pr o Q u Tyr Al a 85 Al a Ser Val Lys Qy 90 Arg Phe Thr I I e Ser 95 Arg Asp Asp Ser Lys 100 Thr I I e Al a Tyr Leu 105 Q n Vfet Asn Ser Leu 110 Lys Thr Q u Asp Thr 115 Al a Val Tyr Phe Cys 120 Al a Arg Qy Arg Qy 125 I I e Al a Al a Arg Tr p 130 Asp Tyr Tr p Qy Q n 135 Qy Thr Leu Val Thr 140 Val Ser Ser Al a Ser 145 Thr Lys Qy Pr o Ser 150 Val Phe Pr o Leu Al a 155 Pr o Cys Ser Arg Ser 160 Thr Ser Q u Ser Thr 165 Al a Al a Leu Qy Cys 170 Leu Val Lys Asp Tyr 175 Phe Pr o Q u Pr o Val 180 Thr Val Ser Tr p Asn 185 Ser Qy Al a Leu Thr 190 Ser Qy Val Hi s Thr 195 Phe Pr o Al a Val Leu 200 Q n Ser Ser Qy Leu 205 Tyr Ser Leu Ser Ser 210 Val Val Thr Val Pr o 215 Ser Ser Asn Phe Qy 220 Thr Q n Thr Tyr Thr 225 Cys Asn Val Asp Hi s 230 Lys Pr o Ser Asn Thr 235 Lys Val Asp Lys Thr 240 Val Q u Arg Lys Cys 245 Cys Val Q u Cys Pr o 250 Pr o Cys Pr o Al a Pr o 255 Pr o Val Al a Qy Pr o 260 Ser Val Phe Leu Phe 265 Pr o Pr o Lys Pr o Lys 270 Asp Thr Leu Vfet I I e 275 Ser Arg Thr Pr o Q u 280 Val Thr Cys Val Val 285 Val Asp Val Ser Hi s 290 Q u Asp Pr o Q u Val 295 Q n Phe Asn Tr p Tyr 300 Val Asp Qy Val Q u 305 Val Hi s Asn Al a Lys 310 Thr Lys Pr o Arg Q u 315 Q u Q n Phe Asn Ser 320 Thr Phe Arg Val Val 325 Ser Val Leu Thr Val 330 Val Hi s Q n Asp Tr p 335 Leu Asn Qy Lys Q u Tyr Lys Cys Lys Val Ser Asn Lys Qy Leu Pr o Al a

340 345 350

Page 36

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Pr o I I e G u 355 Lys Thr I I e Ser Lys 360 Thr Lys Gy G n Pr o Ar g 365 G u Pr o G n Val Tyr Thr Leu Pr o Pr o Ser Arg G u G u IVbt Thr Lys Asn G n 370 375 380 Val Ser Leu Thr Cys Leu Val Lys G y Phe Tyr Pr o Ser Asp I I e Al a 385 390 395 400 Val G u Tr p G u Ser Asn G y G n Pr o G u Asn Asn Tyr Lys Thr Thr 405 410 415 Pr o Pr o IVbt Leu Asp Ser Asp G y Ser Phe Phe Leu Tyr Ser Lys Leu 420 425 430 Thr Val Asp Lys Ser Arg Tr p G n G n G y Asn Val Phe Ser Cys Ser 435 440 445 Val IVbt Hi s G u Al a Leu Hi s Asn Hi s Tyr Thr G n Lys Ser Leu Ser 450 455 460 Leu Ser Pr o Gy Lys

465 <210> 35 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

<400> 35 IVbt 1 Asp IVbt Arg Val 5 Pr o Al a Q n Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p Leu Arg G y Al a Arg Cys G u Val G n Leu Val G u Ser G y G y G y 20 25 30 Leu Val Lys Pr o G y G y Ser Leu Arg Leu Ser Cys Al a Al a Ser G y 35 40 45 Phe Thr Phe Ser Asn Al a Tr p IVfet Ser Tr p Val Arg G n Al a Pr o G y 50 55 60 Lys Gy Leu G u Tr p Val Gy Arg I I e Lys Ser Lys Thr Asp Gy Gy 65 70 75 80 Thr Thr Asp Tyr Thr Al a Pr o Val Lys G y Arg Phe Thr I I e Ser Arg 85 90 95

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Asp Asp Ser Lys 100 Asn Thr Leu Tyr Leu 105 G n IVfet Asn Ser Leu 110 Lys Al a G u Asp Thr 115 Al a Val Tyr Tyr Cys 120 Thr Thr Asp Arg Thr 125 Gy Tyr Ser I I e Ser 130 Tr p Ser Ser Tyr Tyr 135 Tyr Tyr Tyr Gy IVbt 140 Asp Val Tr p Gy G n 145 Gy Thr Thr Val Thr 150 Val Ser Ser Al a Ser 155 Thr Lys Gy Pr o Ser 160 Val Phe Pr o Leu Al a 165 Pr o Cys Ser Arg Ser 170 Thr Ser G u Ser Thr 175 Al a Al a Leu Gy Cys 180 Leu Val Lys Asp Tyr 185 Phe Pr o G u Pr o Val 190 Thr Val Ser Tr p Asn 195 Ser Gy Al a Leu Thr 200 Ser Gy Val Hi s Thr 205 Phe Pr o Al a Val Leu 210 G n Ser Ser Gy Leu 215 Tyr Ser Leu Ser Ser 220 Val Val Thr Val Pr o 225 Ser Ser Asn Phe Gy 230 Thr G n Thr Tyr Thr 235 Cys Asn Val Asp Hi s 240 Lys Pr o Ser Asn Thr 245 Lys Val Asp Lys Thr 250 Val G u Arg Lys Cys 255 Cys Val G u Cys Pr o 260 Pr o Cys Pr o Al a Pr o 265 Pr o Val Al a Gy Pr o 270 Ser Val Phe Leu Phe 275 Pr o Pr o Lys Pr o Lys 280 Asp Thr Leu IVbt I I e 285 Ser Arg Thr Pr o G u 290 Val Thr Cys Val Val 295 Val Asp Val Ser Hi s 300 G u Asp Pr o G u Val 305 G n Phe Asn Tr p Tyr 310 Val Asp Gy Val G u 315 Val Hi s Asn Al a Lys 320 Thr Lys Pr o Arg G u 325 G u G n Phe Asn Ser 330 Thr Phe Arg Val Val 335 Ser Val Leu Thr Val 340 Val Hi s G n Asp Tr p 345 Leu Asn Gy Lys G u 350 Tyr Lys Cys Lys Val Ser Asn Lys Gy Leu Pr o Al a Pr o I I e G u Lys Thr I I e

355 360 365

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Ser Lys Thr 370 Lys Gy G n Pr o 375 Arg G u Pr o G n Val 380 Tyr Thr Leu Pr o Pr o Ser Arg G u G u K/fet Thr Lys Asn G n Val Ser Leu Thr Cys Leu 385 390 395 400 Val Lys G y Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn 405 410 415 Q y G n Pr o G u Asn Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser 420 425 430 Asp G y Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 435 440 445 Tr p G n G n G y Asn Val Phe Ser Cys Ser Val IVbt Hi s G u Al a Leu 450 455 460 Hi s Asn Hi s Tyr Thr G n Lys Ser Leu Ser Leu Ser Pr o Gy Lys

465 470 475 <210> 36 <211> 475 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 36

IVbt Asp IVfet Arg Val Pr o Al a G n Leu Leu G y Leu Leu Leu Leu Tr p 1 5 10 15 Leu Arg G y Al a Arg Cys G n Val G n Leu Val G n Ser G y Al a G u 20 25 30 Val Lys Lys Pr o Gy Al a Ser Val Lys Val Ser Cys Lys Al a Ser Gy 35 40 45 Tyr Thr Phe Thr Asp Tyr Tyr IVbt Tyr Tr p Val Arg G n Al a Pr o Gy 50 55 60 G n G y Leu G u Tr p IVbt G y Tr p I I e Ser Pr o Asn Ser G y G y Thr 65 70 75 80 Asn Tyr Al a G n Lys Phe G n G y Arg Val Thr IVbt Thr Arg Asp Thr 85 90 95 Ser I I e Ser Thr Al a Tyr IVbt G u Leu Ser Arg Leu Arg Ser Asp Asp

100 105 110

Page 39

2016244220 11 Oct 2016

Thr Al a

Leu Tyr 130

Val Thr 145

Al a Pr o

Leu Val

G y Al a

Ser G y 210

Phe G y 225

Thr Lys

Pr o Cys

Pr o Lys

Cys Val 290

Trp Tyr 305

G u G u

Val Hi s

Asn Lys

G y G n 370

Val Tyr 115

Ser Hi s

Val Ser

Cys Ser

Lys Asp 180

Leu Thr 195

Leu Tyr

Thr G n

Val Asp

Pr o Al a 260

Pr o Lys 275

Val Val

Val Asp

Q n Phe

Q n Asp 340

Q y Leu 355

Pr o Ar g

Tyr Cys

Tyr Tyr

Ser Al a 150

Arg Ser 165

Tyr Phe

Ser G y

Ser Leu

Thr Tyr 230

Lys Thr 245

Pro Pro

Asp Thr

Asp Val

G y Val 310

Asn Ser 325

Trp Leu

Pr o Al a

G u Pro

Val Arg 120

Q y K/fet 135

Ser Thr

Thr Ser

Pro G u

Val Hi s 200

Ser Ser 215

Thr Cys

Val G u

Val Al a

Leu K/fet 280

Ser Hi s 295

G u Val

Thr Phe

Asn Q y

Pr o lie 360

G n Val 375

A1472PCT. t xt Gy Gy Tyr Ser

Asp Val

Lys Q y

Q u Ser 170

Pr o Val 185

Thr Phe

Val Val

Asn Val

Ar g Lys 250

G y Pr o 265

I I e Ser

Q u Asp

Hi s Asn

Arg Val 330

Lys Q u 345

Q u Lys

Tyr Thr

Tr p G y 140

Pro Ser 155

Thr Al a

Thr Val

Pr o Al a

Thr Val 220

Asp Hi s 235

Cys Cys

Ser Val

Ar g Thr

Pro G u 300

Al a Lys 315

Val Ser

Tyr Lys

Thr lie

Leu Pro 380

G y Tyr 125

G n G y

Val Phe

Al a Leu

Ser Trp 190

Val Leu 205

Pro Ser

Lys Pr o

Val G u

Phe Leu 270

Pro G u 285

Val G n

Thr Lys

Val Leu

Cys Lys 350

Ser Lys 365

Pro Ser

Al a G y

Thr Thr

Pro Leu 160

Q y Cys 175

Asn Ser

Q n Ser

Ser Asn

Ser Asn 240

Cys Pr o 255

Phe Pro

Val Thr

Phe Asn

Pr o Ar g 320

Thr Val 335

Val Ser

Thr Lys

Arg G u

Page 40

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G u K/bt Thr Lys Asn G n Val Ser Leu Thr Cys Leu Val Lys Gy Phe 385 390 395 400 Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn Gy G n Pr o G u 405 410 415 Asn Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser Asp G y Ser Phe 420 425 430 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Tr p G n G n Gy 435 440 445 Asn Val Phe Ser Cys Ser Val IVbt Hi s G u Al a Leu Hi s Asn Hi s Tyr 450 455 460 Thr G n Lys Ser Leu Ser Leu Ser Pr o Gy Lys

465 470 475 <210> 37 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 37

IVbt 1 Asp IVbt Arg Val 5 Pr o Al a G n Leu Leu Q y 10 Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a Arg Cys G u Val G n Leu Val G u Ser Gy Gy Gy 20 25 30 Leu Val Lys Pr o Gy Gy Ser Leu Arg Leu Ser Cys Al a Al a Ser Gy 35 40 45 Phe Thr Phe Gy Asn Al a Tr p IVfet Ser Tr p Val Arg G n Al a Pr o Gy 50 55 60 Lys Gy Leu G u Tr p Val Gy Arg I I e Lys Ser Lys Thr Asp Gy Gy 65 70 75 80 Thr Thr Asp Tyr Al a Al a Pr o Val Lys Gy Arg Phe Thr I I e Ser Arg 85 90 95 Asp Asp Ser Lys Asn Thr Leu Tyr Leu G n IVfet Asn Ser Leu Lys Thr 100 105 110 G u Asp Thr Al a Val Tyr Phe Cys Thr Thr Asp Arg Thr Gy Tyr Ser 115 120 125 I I e Ser Tr p Ser Ser Tyr Tyr Tyr Tyr Tyr Gy IVbt Asp Val Tr p Gy Page 41

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A1472PCT. t xt

130 135 140

G n 145 Gy Thr Thr Val Thr 150 Val Ser Ser Al a Ser 155 Thr Lys Gy Pr o Ser 160 Val Phe Pr o Leu Al a 165 Pr o Cys Ser Arg Ser 170 Thr Ser G u Ser Thr 175 Al a Al a Leu Gy Cys 180 Leu Val Lys Asp Tyr 185 Phe Pr o G u Pr o Val 190 Thr Val Ser Tr p Asn 195 Ser Gy Al a Leu Thr 200 Ser Gy Val Hi s Thr 205 Phe Pr o Al a Val Leu 210 G n Ser Ser Gy Leu 215 Tyr Ser Leu Ser Ser 220 Val Val Thr Val Pr o 225 Ser Ser Asn Phe Gy 230 Thr G n Thr Tyr Thr 235 Cys Asn Val Asp Hi s 240 Lys Pr o Ser Asn Thr 245 Lys Val Asp Lys Thr 250 Val G u Arg Lys Cys 255 Cys Val G u Cys Pr o 260 Pr o Cys Pr o Al a Pr o 265 Pr o Val Al a Gy Pr o 270 Ser Val Phe Leu Phe 275 Pr o Pr o Lys Pr o Lys 280 Asp Thr Leu IVbt I I e 285 Ser Arg Thr Pr o G u 290 Val Thr Cys Val Val 295 Val Asp Val Ser Hi s 300 G u Asp Pr o G u Val 305 G n Phe Asn Tr p Tyr 310 Val Asp Gy Val G u 315 Val Hi s Asn Al a Lys 320 Thr Lys Pr o Arg G u 325 G u G n Phe Asn Ser 330 Thr Phe Arg Val Val 335 Ser Val Leu Thr Val 340 Val Hi s G n Asp Tr p 345 Leu Asn Gy Lys G u 350 Tyr Lys Cys Lys Val 355 Ser Asn Lys Gy Leu 360 Pr o Al a Pr o I I e G u 365 Lys Thr I I e Ser Lys 370 Thr Lys Gy G n Pr o 375 Arg G u Pr o G n Val 380 Tyr Thr Leu Pr o Pr o 385 Ser Arg G u G u IVbt 390 Thr Lys Asn G n Val 395 Ser Leu Thr Cys Leu 400 Val Lys Gy Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn

Page 42

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405 Gy G n Pr o G u 420 Asn Asn Tyr Lys Asp Gy Ser 435 Phe Phe Leu Tyr Ser 440 Tr p G n 450 G n Gy Asn Val Phe 455 Ser Hi s Asn Hi s Tyr Thr G n Lys Ser

465 470

A1472PCT. t xt 410 415 Thr 425 Thr Pr o Pr o IVfet Leu 430 Asp Ser Lys Leu Thr Val Asp 445 Lys Ser Arg Cys Ser Val IVfet 460 Hi s G u Al a Leu Leu Ser Leu 475 Ser Pr o Gy Lys

<210> 38 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Arti

1 ί zdz-l

pol ypept i de Al a G n <400> 38 Pr o IVfet 1 Asp IVfet Arg Val 5 Leu Arg Gy Al a 20 Arg Cys G u Val Leu Val Lys 35 Pr o Gy Gy Ser Leu 40 Phe Thr 50 Phe Gy Asn Al a Tr p 55 IVfet Lys 65 Gy Leu G u Tr p Val 70 Gy Arg Thr Thr Asp Tyr Al a 85 Al a Pr o Val Asp Asp Ser Lys 100 Asn Thr Leu Tyr G u Asp Thr 115 Al a Val Tyr Tyr Cys 120 I I e Ser 130 Tr p Ser Ser Tyr Tyr 135 Tyr G n 145 Gy Thr Thr Val Thr 150 Val Ser

f i ci al I Sequence: Synt het i c Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p G n 25 Leu Val G u Ser Gy 30 Gy Gy Arg Leu Ser Cys Al a 45 Al a Ser Gy Ser Tr p Val Arg 60 G n Al a Pr o Gy I I e Lys Ser 75 Lys Thr Asp Gy Gy 80 Lys Gy 90 Arg Phe Thr I I e Ser 95 Arg Leu 105 G n IVfet Asn Ser Leu 110 Lys Thr Thr Thr Asp Arg Thr 125 Gy Tyr Ser Tyr Tyr Gy IVfet 140 Asp Val Tr p Gy Ser Al a Ser 155 Page 43 Thr Lys Gy Pr o Ser 160

A1472PCT. t xt

2016244220 11 Oct 2016

Val Phe Pr o Leu Al a 165 Pr o Cys Ser Arg Ser 170 Thr Ser G u Ser Thr 175 Al a Al a Leu G y Cys Leu Val Lys Asp Tyr Phe Pr o G u Pr o Val Thr Val 180 185 190 Ser Tr p Asn Ser G y Al a Leu Thr Ser G y Val Hi s Thr Phe Pr o Al a 195 200 205 Val Leu G n Ser Ser G y Leu Tyr Ser Leu Ser Ser Val Val Thr Val 210 215 220 Pr o Ser Ser Asn Phe G y Thr G n Thr Tyr Thr Cys Asn Val Asp Hi s 225 230 235 240 Lys Pr o Ser Asn Thr Lys Val Asp Lys Thr Val G u Arg Lys Cys Cys 245 250 255 Val G u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a G y Pr o Ser Val 260 265 270 Phe Leu Phe Pr o Pr o Lys Pr o Lys Asp Thr Leu IVbt I I e Ser Arg Thr 275 280 285 Pr o G u Val Thr Cys Val Val Val Asp Val Ser Hi s G u Asp Pr o G u 290 295 300 Val G n Phe Asn Tr p Tyr Val Asp G y Val G u Val Hi s Asn Al a Lys 305 310 315 320 Thr Lys Pr o Arg G u G u G n Phe Asn Ser Thr Phe Arg Val Val Ser 325 330 335 Val Leu Thr Val Val Hi s G n Asp Tr p Leu Asn Gy Lys G u Tyr Lys 340 345 350 Cys Lys Val Ser Asn Lys Gy Leu Pr o Al a Pr o I I e G u Lys Thr I I e 355 360 365 Ser Lys Thr Lys G y G n Pr o Arg G u Pr o G n Val Tyr Thr Leu Pr o 370 375 380 Pr o Ser Arg G u G u IVbt Thr Lys Asn G n Val Ser Leu Thr Cys Leu 385 390 395 400 Val Lys G y Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn 405 410 415 Gy G n Pr o G u Asn Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser

420 425 430

Page 44

A1472PCT. t xt

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Asp Qy Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 435 440 445 Tr p Q n Q n Qy Asn Val Phe Ser Cys Ser Val IVbt Hi s Q u Al a Leu 450 455 460 Hi s Asn Hi s Tyr Thr Q n Lys Ser Leu Ser Leu Ser Pr o Qy Lys

465 470 475 <210> 39 <211> 478 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 39

IVbt 1 Asp IVfet Arg Val 5 Pr o Al a Q n Leu Leu 10 Qy Leu Leu Leu Leu 15 Tr p Leu Arg Qy Al a 20 Arg Cys Q n Val Q n 25 Leu Val Q u Ser Qy 30 Qy Qy Val Val Q n 35 Pr o Qy Arg Ser Leu 40 Arg Leu Ser Cys Al a 45 Al a Ser Qy Phe Thr 50 Phe Ser Ser Phe Qy 55 IVfet Hi s Tr p Val Arg 60 Q n Al a Pr o Qy Lys 65 Qy Leu G u Tr p Val 70 Al a Val I I e Ser Phe 75 Asp Qy Ser I I e Lys 80 Tyr Ser Val Asp Ser 85 Val Lys Qy Arg Phe 90 Thr I I e Ser Arg Asp 95 Asn Ser Lys Asn Thr 100 Leu Phe Leu Q n IVbt 105 Asn Ser Leu Arg Al a 110 Q u Asp Thr Al a Val 115 Tyr Tyr Cys Al a Arg 120 Asp Arg Leu Asn Tyr 125 Tyr Asp Ser Ser Qy 130 Tyr Tyr Hi s Tyr Lys 135 Tyr Tyr Qy Leu Al a 140 Val Tr p Qy Q n Qy 145 Thr Thr Val Thr Val 150 Ser Ser Al a Ser Thr 155 Lys Qy Pr o Ser Val 160 Phe Pr o Leu Al a Pr o 165 Cys Ser Arg Ser Thr 170 Ser Q u Ser Thr Al a 175 Al a

Page 45

A1472PCT. t xt

2016244220 11 Oct 2016

Leu Q y Cys Leu 180 Val Lys Asp Tyr Phe 185 Pr o Q u Pr o Val Thr 190 Val Ser Tr p Asn Ser Q y Al a Leu Thr Ser Q y Val Hi s Thr Phe Pr o Al a Val 195 200 205 Leu Q n Ser Ser Q y Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pr o 210 215 220 Ser Ser Asn Phe Q y Thr Q n Thr Tyr Thr Cys Asn Val Asp Hi s Lys 225 230 235 240 Pr o Ser Asn Thr Lys Val Asp Lys Thr Val Q u Arg Lys Cys Cys Val 245 250 255 Q u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a Q y Pr o Ser Val Phe 260 265 270 Leu Phe Pr o Pr o Lys Pr o Lys Asp Thr Leu Vfet I I e Ser Arg Thr Pr o 275 280 285 Q u Val Thr Cys Val Val Val Asp Val Ser Hi s Q u Asp Pr o Q u Val 290 295 300 Q n Phe Asn Tr p Tyr Val Asp Q y Val Q u Val Hi s Asn Al a Lys Thr 305 310 315 320 Lys Pr o Arg Q u Q u Q n Phe Asn Ser Thr Phe Arg Val Val Ser Val 325 330 335 Leu Thr Val Val Hi s Q n Asp Tr p Leu Asn Qy Lys Q u Tyr Lys Cys 340 345 350 Lys Val Ser Asn Lys Q y Leu Pr o Al a Pr o I I e Q u Lys Thr I I e Ser 355 360 365 Lys Thr Lys Q y Q n Pr o Arg Q u Pr o Q n Val Tyr Thr Leu Pr o Pr o 370 375 380 Ser Arg Q u Q u Vfet Thr Lys Asn Q n Val Ser Leu Thr Cys Leu Val 385 390 395 400 Lys Q y Phe Tyr Pr o Ser Asp I I e Al a Val Q u Tr p Q u Ser Asn Q y 405 410 415 Q n Pr o Q u Asn Asn Tyr Lys Thr Thr Pr o Pr o Vfet Leu Asp Ser Asp 420 425 430 Qy Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Tr p

435 440 445

Page 46

A1472PCT. t xt

2016244220 11 Oct 2016

G n G n Gy Asn Val Phe Ser Cys Ser Val K/fet Hi s G u Al a Leu Hi s 450 455 460 Asn Hi s Tyr Thr G n Lys Ser Leu Ser Leu Ser Pr o Gy Lys 465 470 475

<210> 40 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 40

l\/bt 1 Asp IVfet Arg Val 5 Pr o Al a G n Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a 20 Arg Cys G u Val G n 25 Leu Val G u Ser Gy 30 Gy Gy Leu Val Lys 35 Pr o Gy Gy Ser Leu 40 Arg Leu Ser Cys Al a 45 Al a Ser Gy Tyr Thr 50 Phe Ser Thr Tyr Ser 55 IVfet Asn Tr p Val Arg 60 G n Al a Pr o Gy Lys 65 Gy Leu G u Tr p Val 70 Ser Ser I I e Ser Ser 75 Ser Ser Ser Tyr Arg 80 Tyr Tyr Al a Asp Ser 85 Val Lys Gy Arg Phe 90 Thr I I e Ser Arg Asp 95 Asn Al a Lys Asn Ser 100 Leu Tyr Leu G n K/fet 105 Ser Ser Leu Arg Al a 110 G u Asp Thr Al a Val 115 Tyr Tyr Cys Al a Arg 120 G u Gy Val Ser Gy 125 Ser Ser Pr o Tyr Ser 130 I I e Ser Tr p Tyr Asp 135 Tyr Tyr Tyr Gy K/fet 140 Asp Val Tr p Gy G n 145 Gy Thr Thr Val Thr 150 Val Ser Ser Al a Ser 155 Thr Lys Gy Pr o Ser 160 Val Phe Pr o Leu Al a 165 Pr o Cys Ser Arg Ser 170 Thr Ser G u Ser Thr 175 Al a Al a Leu Gy Cys 180 Leu Val Lys Asp Tyr 185 Phe Pr o G u Pr o Val 190 Thr Val

Page 47

2016244220 11 Oct 2016

Ser Tr p Asn 195 A1472PCT. t xt Ser G y Al a Leu Thr 200 Ser Gy Val Hi s Thr 205 Phe Pr o Al a Val Leu G n Ser Ser G y Leu Tyr Ser Leu Ser Ser Val Val Thr Val 210 215 220 Pr o Ser Ser Asn Phe G y Thr G n Thr Tyr Thr Cys Asn Val Asp Hi s 225 230 235 240 Lys Pr o Ser Asn Thr Lys Val Asp Lys Thr Val G u Arg Lys Cys Cys 245 250 255 Val G u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a G y Pr o Ser Val 260 265 270 Phe Leu Phe Pr o Pr o Lys Pr o Lys Asp Thr Leu IVbt I I e Ser Arg Thr 275 280 285 Pr o G u Val Thr Cys Val Val Val Asp Val Ser Hi s G u Asp Pr o G u 290 295 300 Val G n Phe Asn Tr p Tyr Val Asp G y Val G u Val Hi s Asn Al a Lys 305 310 315 320 Thr Lys Pr o Arg G u G u G n Phe Asn Ser Thr Phe Arg Val Val Ser 325 330 335 Val Leu Thr Val Val Hi s G n Asp Tr p Leu Asn Gy Lys G u Tyr Lys 340 345 350 Cys Lys Val Ser Asn Lys Gy Leu Pr o Al a Pr o I I e G u Lys Thr I I e 355 360 365 Ser Lys Thr Lys G y G n Pr o Arg G u Pr o G n Val Tyr Thr Leu Pr o 370 375 380 Pr o Ser Arg G u G u IVbt Thr Lys Asn G n Val Ser Leu Thr Cys Leu 385 390 395 400 Val Lys G y Phe Tyr Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn 405 410 415 G y G n Pr o G u Asn Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser 420 425 430 Asp Gy Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 435 440 445 Tr p G n G n G y Asn Val Phe Ser Cys Ser Val IVbt Hi s G u Al a Leu 450 455 460

Page 48

2016244220 11 Oct 2016

Hi s Asn Hi s Tyr Thr 465

Q n Lys Ser 470

A1472PCT. t xt Leu Ser Leu Ser

475

Pro Q y Lys <210> 41 <211> 474 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 41

l\/bt 1 Asp IVfet Arg Val 5 Pr o Al a G n Leu Leu 10 Gy Leu Leu Leu Leu 15 Tr p Leu Arg Gy Al a 20 Arg Cys G n Val G n 25 Leu Val G u Ser Gy 30 Gy Gy Val Val G n 35 Pr o Gy Arg Ser Leu 40 Arg Leu Ser Cys Al a 45 Al a Ser Gy Phe Thr 50 Phe Ser Ser Tyr Gy 55 IVfet Hi s Tr p Val Arg 60 G n Al a Pr o Gy Lys 65 Gy Leu G u Tr p Val 70 Al a Val I I e Tr p Tyr 75 Asp Gy Ser Asn Lys 80 Tyr Tyr Al a Asp Ser 85 Val Lys Gy Arg Phe 90 I I e I I e Ser Arg Asp 95 Lys Ser Lys Asn Thr 100 Leu Tyr Leu G n IVbt 105 Asn Ser Leu Arg Al a 110 G u Asp Thr Al a Val 115 Tyr Tyr Cys Al a Arg 120 Al a Gy Gy I I e Al a 125 Al a Al a Gy Leu Tyr 130 Tyr Tyr Tyr Gy IVbt 135 Asp Val Tr p Gy G n 140 Gy Thr Thr Val Thr 145 Val Ser Ser Al a Ser 150 Thr Lys Gy Pr o Ser 155 Val Phe Pr o Leu Al a 160 Pr o Cys Ser Arg Ser 165 Thr Ser G u Ser Thr 170 Al a Al a Leu Gy Cys 175 Leu Val Lys Asp Tyr 180 Phe Pr o G u Pr o Val 185 Thr Val Ser Tr p Asn 190 Ser Gy Al a Leu Thr 195 Ser Gy Val Hi s Thr 200 Phe Pr o Al a Val Leu 205 G n Ser Ser Gy Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pr o Ser Ser Asn Phe

Page 49

2016244220 11 Oct 2016

210 A1472PCT. t xt 215 220 G y Thr G n Thr Tyr Thr Cys Asn Val Asp Hi s Lys Pr o Ser Asn Thr 225 230 235 240 Lys Val Asp Lys Thr Val G u Arg Lys Cys Cys Val G u Cys Pr o Pr o 245 250 255 Cys Pr o Al a Pr o Pr o Val Al a G y Pr o Ser Val Phe Leu Phe Pr o Pr o 260 265 270 Lys Pr o Lys Asp Thr Leu IVbt I I e Ser Arg Thr Pr o G u Val Thr Cys 275 280 285 Val Val Val Asp Val Ser Hi s G u Asp Pr o G u Val G n Phe Asn Tr p 290 295 300 Tyr Val Asp G y Val G u Val Hi s Asn Al a Lys Thr Lys Pr o Arg G u 305 310 315 320 G u G n Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val 325 330 335 Hi s G n Asp Tr p Leu Asn Gy Lys G u Tyr Lys Cys Lys Val Ser Asn 340 345 350 Lys Gy Leu Pr o Al a Pr o I I e G u Lys Thr I I e Ser Lys Thr Lys Gy 355 360 365 G n Pr o Arg G u Pr o G n Val Tyr Thr Leu Pr o Pr o Ser Arg G u G u 370 375 380 IVbt Thr Lys Asn G n Val Ser Leu Thr Cys Leu Val Lys G y Phe Tyr 385 390 395 400 Pr o Ser Asp I I e Al a Val G u Tr p G u Ser Asn G y G n Pr o G u Asn 405 410 415 Asn Tyr Lys Thr Thr Pr o Pr o IVbt Leu Asp Ser Asp G y Ser Phe Phe 420 425 430 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Tr p G n G n G y Asn 435 440 445 Val Phe Ser Cys Ser Val IVbt Hi s G u Al a Leu Hi s Asn Hi s Tyr Thr 450 455 460 G n Lys Ser Leu Ser Leu Ser Pr o G y Lys 465 470

<210> 42

Page 50

A1472PCT. t xt

2016244220 11 Oct 2016 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 42

Ser Q y Ser Ser Ser Asn lie 1 5

Artificial Sequence: Synthetic

Q y Asn Asn Tyr Val Ser 10 <210> 43 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 43

Asp Asn Asn Lys Arg Pro Ser 1 5

Artificial Sequence: Synthetic <210> 44 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 44

Gy Thr Trp Asp Ser Arg Leu 1 5 <210> 45 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 45

Ser Q y Ser Ser Ser Asn lie 1 5

Artificial Sequence: Synthetic

Ser Al a Val Val 10

Artificial Sequence: Synthetic

Q y Ser Asn Tyr Val Tyr 10 <210> 46 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de

Artificial Sequence: Synthetic

Page 51

A1472PCT. t xt

2016244220 11 Oct 2016 <400> 46

Arg Ser Asn Gl n Arg Pro Ser 1 5

<21 0> 47 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Des icr i pt i on of pept i de <400> 47 Al a Al a Trp Asp Asp Ser Leu 1 5 <21 0> 48 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> I not e= Des icr i pt i on of pept i de <400> 48 Arg Al a Ser Q n Gy lie Arg 1 5 <21 0> 49 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Des icr i pt i on of pept i de <400> 49 Al a Al a Ser Ser Leu Q n Ser 1 5 <21 0> 50 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> I not e= Des icr i pt i on of pept i de <400> 50 Leu Q n Tyr Asn I I e Tyr Pr o 1 5 <21 0> 51 <211> 11

Artificial Sequence: Synthetic

Ser G y Tr p Val 10

Artificial Sequence: Synthetic

Asn Asp Leu Q y 10

Artificial Sequence: Synthetic

Artificial Sequence: Synthetic

Trp Thr

Page 52

A1472PCT. t xt

2016244220 11 Oct 2016 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 51

Qn Qy Asp Ser Leu Arg Ser 1 5

Artificial Sequence: Synthetic

Phe Tyr Al a Ser 10 <210> 52 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 52

Qy Lys Asn Asn Arg Pro Ser 1 5

Artificial Sequence: Synthetic <210> 53 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 53

Asn Ser Arg Asp Ser Ser Val 1 5 <210> 54 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 54

Lys Ser Ser Q n Ser Leu Leu 1 5

Artificial Sequence: Synthetic

Tyr Hi s Leu Val 10

Artificial Sequence: Synthetic

Hi s Ser Al a Q y Lys Thr Tyr Leu Tyr 10 15 <210> 55 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de

Artificial Sequence: Synthetic

Page 53

A1472PCT. t xt

2016244220 11 Oct 2016 <400> 55

Q u Val Ser Asn Arg Phe Ser 1 5 <210> 56 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 56

IVbt Q n Ser Phe Pro Leu Pro Leu Thr

1 5 <210> 57 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 57

Arg Ser Ser GI n Ser Leu Leu Hi s Ser Phe Q y Tyr Asn Tyr Leu Asp 15 10 15 <210> 58 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 58

Leu Q y Ser Asn Arg Al a Ser

1 5 <210> 59 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 59

IVbt Q n Al a Leu Q n Thr Pro Phe Thr 1 5 <210> 60 <211> 16 <212> PRT

Page 54

A1472PCT. t xt

2016244220 11 Oct 2016 <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 60

Lys Ser Ser Gl n Ser Leu Leu 1 5

Artificial Sequence: Synthetic

Hi s Ser Asp Q y Lys Thr Tyr Leu Tyr 10 15 <210> 61 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 61

Arg Asn Asn Q n Arg Pro Ser 1 5

Artificial Sequence: Synthetic <210> 62 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 62

Ser Q y Ser Ser Ser Asn lie 1 5

Artificial Sequence: Synthetic

Q y Ser Asn Thr Val Asn 10 <210> 63 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 63

Thr Asn Asn Q n Arg Pro Ser 1 5

Artificial Sequence: Synthetic <400> 64 <210> 64 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de

Artificial Sequence: Synthetic

Page 55

A1472PCT. t xt

2016244220 11 Oct 2016

Al a Al 1 a Arg Asp Q u Ser Leu 5 Asn Q y Val 10 Val <21 0> 65 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence pept i de <400> 65 Lys Ser Ser Gl n Ser Leu Leu Hi s Ser Asp i Gy Arg 1 5 10 <21 0> 66 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence pept i de <400> 66 Arg Al a Ser Q n Gy lie Arg Lys Asp Leu G y 1 5 10 <21 0> 67 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence pept i de <400> 67 G y Al a Ser Ser Leu Q n Ser 1 5 <21 0> 68 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence pept i de <400> 68 Leu Q n Tyr Asn Ser Phe Pro Trp Thr 1 5 <21 0> 69 <211> 12 <212> PRT <213> Ar t i f i ci al Sequence

Synt het i c

Asn Tyr Leu Tyr 15

Synt het i c

Synt het i c

Synt het i c

Page 56

A1472PCT. t xt

2016244220 11 Oct 2016 <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: pept i de <400> 69

Arg Al a Ser Gl n Ser Val Ser Ser Q y Tyr Leu Thr 1 5 10

Synt het i c <210> 70 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: pept i de <400> 70

Q y Al a Ser Ser Arg Al a Thr

1 5

Synt het i c <210> 71 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: pept i de <400> 71

Q n Q n Tyr Q y Asn Ser Leu Cys Arg

1 5 <210> 72 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: pept i de <400> 72

G n G n Tyr Gy Asn Ser Leu Ser Arg

1 5

Synt het i c

Synt het i c <210> 73 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: pept i de <400> 73

Ser Phe Q y IVfet Hi s

Synt het i c

Page 57

A1472PCT. t xt

2016244220 11 Oct 2016 <210> 74 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 74

Val lie Ser Phe Asp Q y Ser I I e Lys Tyr Ser Val Asp Ser Val Lys 15 10 15

Gy <210> 75 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 75

Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gy Tyr Tyr His Tyr Lys Tyr 15 10 15

Tyr Q y IVbt Al a Val 20 <210> 76 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 76

Asn Al a Tr p IVbt Ser

1 5 <210> 77 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 77

Arg lie Lys Ser Thr Thr Asp Gy Gy Thr Thr Asp Tyr Al a Al a Pro Page 58

2016244220 11 Oct 2016

Val Lys Q y <210> 78 <211> 20 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 78

Asp Arg Thr Gl y Tyr Ser lie 1 5

Q y IVbt Asp Val 20 <210> 79 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 79

Ser Tyr Al a K/bt Ser 1 5

<21 0> 80 <211> 17 <212> PRT <213> Ar t i f i ci al Seque ;nce <220> <221 > sour ce <223> I not e= Des ;cri pt i on of pept i de <400> 80 Al a I I e Ser Q y Ser G y Gy 1 5 Gy

<21 0> 81 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce

<223> / not e= Descr i pt i on of

A1472PCT. t xt

10 15

Artificial Sequence: Synthetic

Ser Trp Ser Ser Tyr Tyr Tyr Tyr Tyr 10 15

Artificial Sequence: Synthetic

Artificial Sequence: Synthetic

Arg Thr Tyr Tyr Ala Asp Ser Val Lys 10 15

Artificial Sequence: Synthetic Page 59

A1472PCT. t xt

2016244220 11 Oct 2016 pept i de <400> 81

Asp On Arg Glu Val Q y Pro Tyr Ser Ser Q y Trp Tyr Asp Tyr Tyr 15 10 15

Tyr Q y IVfet Asp Val 20 <210> 82 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 82

Q y Tyr Tyr K/bt Hi s

1 5 <210> 83 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 83

Trp lie Asn Pro Asn Ser Q y Q y Thr Asn Tyr Al a Q n Lys Phe Q n 15 10 15

Gy <210> 84 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 84

Asp Q n IVfet Ser lie lie IVbt Leu Arg Q y Val Phe Pro Pro Tyr Tyr 15 10 15

Tyr Q y IVfet Asp Val 20 <210> 85 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence

Page 60

A1472PCT. t xt <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 85

Ser Tyr Q y Vht Hi s

1 5

2016244220 11 Oct 2016 <210> 86 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 86

Val lie Ser Tyr Asp Q y Ser Hi s Q u Ser Tyr Al a Asp Ser Val Lys 15 10 15

Qy <210> 87 <211> 20 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 87

Q u Arg Lys Arg Val Thr IVfet Ser Thr Leu Tyr Tyr Tyr Phe Tyr Tyr 15 10 15

Q y IVbt Asp Val 20 <210> 88 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 88

Asp Tyr Al a Vht Ser

1 5 <210> 89 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence

Page 61

A1472PCT. t xt <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 89

Phe I I e Arg Ser Arg Al a Tyr G y G y Thr Pro G u Tyr Al a Al a Ser 15 10 15

2016244220 11 Oct 2016

Val Lys Q y <210> 90 <211> 10 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 90

G y Arg G y I I e Al a Al a Ar g Tr p Asp Tyr

1 5 10 <210> 91 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 91

Arg lie Lys Ser Lys Thr Asp Gy Gy Thr Thr Asp Tyr Thr Ala Pro 15 10 15

Val Lys Q y <210> 92 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 92

Asp Tyr Tyr IVfet Tyr

1 5 <210> 93 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence

Page 62

A1472PCT. t xt <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 93

Trp lie Ser Pro Asn Ser Q y 1 5

2016244220 11 Oct 2016

Gy <210> 94 <211> 18 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 94

G y G y Tyr Ser Gy Tyr Al a 1 5

Asp Val <210> 95 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 95

Arg lie Lys Ser Lys Thr Asp 1 5

Val Lys Q y <210> 96 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de <400> 96

Asp Arg Leu Asn Tyr Tyr Asp 1 5

Artificial Sequence: Synthetic

Q y Thr Asn Tyr Al a Q n Lys Phe Q n 10 15

Artificial Sequence: Synthetic

Q y Leu Tyr Ser Hi s Tyr Tyr Q y IVht 10 15

Artificial Sequence: Synthetic

Gy Gy Thr Thr Asp Tyr Al a Al a Pro 10 15

Artificial Sequence: Synthetic

Ser Ser Q y Tyr Tyr Hi s Tyr Lys Tyr 10 15

Page 63

A1472PCT. t xt

2016244220 11 Oct 2016

Tyr Q y Leu Al a Val 20 <210> 97 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 97

Thr Tyr Ser IVbt Asn

1 5 <210> 98 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 98

Ser I I e Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Al a Asp Ser Val Lys 15 10 15

Gy <210> 99 <211> 22 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 99

G u G y Val Ser Gy Ser Ser Pro Tyr Ser lie Ser Trp Tyr Asp Tyr 15 10 15

Tyr Tyr Q y IVfet Asp Val 20 <210> 100 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 100

Page 64

A1472PCT. t xt

2016244220 11 Oct 2016

Ser Tyr Q y IVht Hi s 1 5 <210> 101 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 101

Val I I e Trp Tyr Asp Q y Ser Asn Lys Tyr Tyr Al a Asp Ser Val Lys 15 10 15

Gy <210> 102 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 102

Ala Qy Gy I I e Al a Al a Al a Q y Leu Tyr Tyr Tyr Tyr Q y Lfet Asp 15 10 15

Val <210> 103 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (8) . . (8) <223> / r epi ace=Lys <220>

<221 > rri sc_f eat ur e <222> (8) . . (8) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 103

Arg Al a Ser Q n Q y lie Arg Asn Asp Leu Q y

1 5 10

Page 65

A1472PCT. t xt

2016244220 11 Oct 2016 <210> 104 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / repl ace=G y <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 104

Al a Al a Ser Ser Leu Q n Ser

1 5 <210> 105 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (5) . . (5) <223> / repl ace=Ser <220>

<221 > VARI ANT <222> (6) . . (6) <223> / repl ace= Phe <220>

<221 > rri sc_f eat ur e <222> (5) . . (6) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 105

Leu Q n Tyr Asn I I e Tyr Pro Trp Thr

1 5 <210> 106 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic

Page 66

A1472PCT. t xt

2016244220 11 Oct 2016 pept i de <220>

<221 > VARIANT <222> (8) . . (8) <223> / repl ace=Cys <220>

<221 > rri sc_f eat ur e <222> (8) . . (8) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 106

G n G n Tyr Gy Asn Ser Leu Ser Arg

1 5 <210> 107 <211> 12 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (5) . . (5) <223> / repl ace=Q y <220>

<221 > VARI ANT <222> (6) . . (6) <223> / repl ace= I I e <220>

<221 > VARI ANT <222> (7). . (7) <223> / repl ace=Arg <220>

<221 > VARI ANT <222> (8) . . (8) <223> / r epi ace= Asn or Lys <220>

<221 > rri sc_f eat ur e <222> (5) . . (8) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> ( 10) . . ( 10) <223> I r epi ace= Asp <220>

<221 > rri sc_f eat ur e <222> ( 10) . . ( 10) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

Page 67

A1472PCT. t xt

2016244220 11 Oct 2016 <221 > VARIANT <222> ( 12) . . ( 12) <223> / repi ace=G y <220>

<221 > rri sc_f eat ur e <222> ( 12) . . ( 12) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 107

Arg Al a Ser Gl n Ser Val Ser Ser Q y Tyr Leu Thr

1 5 10 <210> 108 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / repi ace=AI a <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> (5) . . (5) <223> / repi ace=Leu <220>

<221 > VARI ANT <222> (6) . . (6) <223> / repi ace=G _n <220>

<221 > VARI ANT <222> (7). . (7) <223> / repi ace=Ser <220>

<221 > rri sc_f eat ur e <222> (5). . (7) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 108

Q y Al a Ser Ser Arg Al a Thr

1 5 <210> 109 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence

Page 68

A1472PCT. t xt

2016244220 11 Oct 2016 <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / r epi ace=Leu <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI AhTT <222> (4) . . (4) <223> I r epi ace= Asn <220>

<221 > VARI AlsTT <222> (5) . . (5) <223> / repl ace=Thr <220>

<221 > VARI AlsTT <222> (6) . . (6) <223> / repl ace= Tyr or Phe <220>

<221 > VARI AlsTT <222> (7). . (7) <223> / repl ace= Pro <220>

<221 > VARI AlsTT <222> (8) . . (8) <223> / repl ace=Trp or Ser <220>

<221 > VARI AlsTT <222> (9) . . (9) <223> / repl ace=Thr <220>

<221 > rri sc_f eat ur e <222> (4) . . (9) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 109

Q n Q n Tyr Gl y Asn Ser Leu Cys Arg

1 5 <210> 110 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de

Page 69

A1472PCT. t xt

2016244220 11 Oct 2016 <220>

<221 > VARI ANT <222> ( 10) . . ( 10) <223> / repl ace=AI a <220>

<221 > rri sc_f eat ur e <222> ( 10) . . ( 10) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> ( 12) . . ( 12) <223> / repl ace=Lys <220>

<221 > VARI ANT <222> ( 13) . . ( 13) <223> / repl ace=Thr <220>

<221 > rri sc_f eat ur e <222> ( 12) . . ( 13) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 110

Lys Ser Ser Gl n Ser Leu Leu Hi s Ser Asp Q y Arg Asn Tyr Leu Tyr 15 10 15 <210> 111 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / repl ace=Lys <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> ( 10) . . ( 10) <223> / repl ace= Asp or Ala <220>

<221 > rri sc_f eat ur e <222> ( 10) . . ( 10) <223> I not e= Resi due given i n t he sequence has no preference with respect to those i n t he annotations for said position <220>

<221 > VARI ANT

Page 70

A1472PCT. t xt

2016244220 11 Oct 2016 <222> ( 12) . . ( 12) <223> / repl ace= Arg or Lys <220>

<221 > VARIANT <222> ( 13) . . ( 13) <223> / repl ace=Thr <220>

<221 > rri sc_f eat ur e <222> ( 12) . . ( 13) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> ( 16) . . ( 16) <223> / repl ace=Tyr <220>

<221 > rri sc_f eat ur e <222> ( 16) . . ( 16) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 111

Arg Ser Ser Gl n Ser Leu Leu Hi s Ser Phe Q y Tyr Asn Tyr Leu Asp 15 10 15 <210> 112 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / repl ace=Q u <220>

<221 > VARI ANT <222> (2) . . (2) <223> / repl ace= Val <220>

<221 > rri sc_f eat ur e <222> (1)..(2) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (6) . . (6) <223> / repl ace= Phe <220>

<221 > rri sc_f eat ur e <222> (6) . . (6) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position

Page 71

A1472PCT. t xt

2016244220 11 Oct 2016 <400> 112

Leu Q y Ser Asn Arg Al a Ser 1 5 <210> 113 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (3) . . (3) <223> / repl ace=Ser <220>

<221 > VARI ANT <222> (4) . . (4) <223> / repl ace= Phe <220>

<221 > VARI ANT <222> (5) . . (5) <223> / repl ace= Pro <220>

<221 > VARI ANT <222> (6) . . (6) <223> / repl ace=Leu <220>

<221 > rri sc_f eat ur e <222> (3) . . (6) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (8) . . (8) <223> / repl ace=Leu <220>

<221 > rri sc_f eat ur e <222> (8) . . (8) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 113

K/bt Q n Al a Leu Q n Thr Pro Phe Thr

1 5 <210> 114 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de

Page 72

A1472PCT. t xt

2016244220 11 Oct 2016 <220>

<221 > VARIANT <222> (2) . . (2) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (2) . . (2) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 114

Arg Asn Asn Gl n Arg Pro Ser

1 5 <210> 115 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (9) . . (9) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (9) . . (9) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> (11)..(11) <223> / repl ace=Thr <220>

<221 > rri sc_f eat ur e <222> (11)..(11) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> ( 13) . . ( 13) <223> / r epi ace= Asn or Tyr <220>

<221 > rri sc_f eat ur e <222> ( 13) . . ( 13) <223> / not e= Resi due given i n t he sequence has no preference with respect to those i n t he annotation for said position <400> 115

Ser Q y Ser Ser Ser Asn I I e Q y Asn Asn Tyr Val Ser

1 5 10 <210> 116 <211> 7

Page 73

A1472PCT. t xt

2016244220 11 Oct 2016 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / repl ace= Thr or Arg <220>

<221 > VARI ANT <222> (2) . . (2) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (1)..(2) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (4) . . (4) <223> / repl ace=G _n <220>

<221 > rri sc_f eat ur e <222> (4) . . (4) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 116

Asp Asn Asn Lys Arg Pro Ser

1 5 <210> 117 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(2) <223> / repl ace=AI a <220>

<221 > VARI ANT <222> (3) . . (3) <223> / repl ace=Arg <220>

<221 > rri sc_f eat ur e <222> (1)..(3) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions

Page 74

A1472PCT. t xt

2016244220 11 Oct 2016 <220>

<221 > VARIANT <222> (5) . . (5) <223> I r epi ace= Asp <220>

<221 > VARI ANT <222> (6) . . (6) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (5) . . (6) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (8) . . (8) <223> I r epi ace= Asn <220>

<221 > VARI ANT <222> (9) . . (9) <223> / repl ace=G y <220>

<221 > rri sc_f eat ur e <222> (8) . . (9) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 117

Q y Thr Trp Asp Ser Arg Leu Ser Al a Val Val

1 5 10 <210> 118 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / repl ace=Q n <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> (3) . . (3) <223> / repl ace= <220>

<221 > VARI ANT <222> (4) . . (4) <223> / r epi ace= Asp

Page 75

A1472PCT. t xt

2016244220 11 Oct 2016

<220> <221 > <222> <223> rri sc f eat ur e (3). . (4) / not e= Resi dues given in r espect t o t hose i n t he the sequence have no preference wi t h annot at i ons f or sai d posi t i ons <220> <221 > VARI ANT <222> (6). (6) <223> /replace^ <220> <221 > VARI ANT <222> (7). (7) <223> / r epi ace= Leu <220> <221 > VARI ANT <222> (8). (8) <223> / r epi ace= Ar g <220> <221 > VARI ANT <222> (9)--(9) <223> / r epi ace= Ser <220> <221 > VARI ANT <222> (10).. (10) <223> / repl ace= Phe <220> <221 > VARI ANT <222> (11)--(11) <223> /repl ace=Thr <220> <221 > VARI ANT <222> (12). (12) <223> /repl ace=AI a <220> <221 > VARI ANT <222> (13). (13) <223> / r epi ace= Asn or Tyr <220> <221 > rri sc f eat ur e <222> (6). . (13) <223> / not e= Resi dues given in t he sequence have no pr ef er ence wi t h r espect t o t hose i n t he annot at i ons f or sai d posi t i ons <400> 118 Ser G y Ser Ser Ser Asn lie Q y Asn Asn Tyr Val Ser 1 5 10 <21 0> 119 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de

Page 76

A1472PCT. t xt

2016244220 11 Oct 2016 <220>

<221 > VARIANT <222> (1)..(1) <223> / r epi ace= Q y or Thr or Arg <220>

<221 > VARI ANT <222> (2) . . (2) <223> / r epi ace= Lys or Ser <220>

<221 > rri sc_f eat ur e <222> (1)..(2) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (4) . . (4) <223> / repl ace= Asn or Gn <220>

<221 > rri sc_f eat ur e <222> (4) . . (4) <223> / not e= Resi due given i n t he sequence has no preference with respect to those i n t he annotations for said position <400> 119

Asp Asn Asn Lys Arg Pro Ser

1 5 <210> 120 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / repl ace= Asn or Ala <220>

<221 > VARI ANT <222> (2) . . (2) <223> / repl ace= Ser or Ala <220>

<221 > VARI ANT <222> (3) . . (3) <223> / repl ace=Arg <220>

<221 > rri sc_f eat ur e <222> (1)..(3) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (5) . . (5)

Page 77

A1472PCT. t xt

2016244220 11 Oct 2016 <223> I r epi ace= Asp <220>

<221 > VARIANT <222> (6) . . (6) <223> / repl ace=Ser <220>

<221 > VARI ANT <222> (7). . (7) <223> / repl ace= Val <220>

<221 > VARI ANT <222> (8) . . (8) <223> / repl ace= Tyr or Asn <220>

<221 > VARI ANT <222> (9) . . (9) <223> / r epi ace= Hi s or Qy <220>

<221 > VARI ANT <222> ( 10) . . ( 10) <223> / repl ace=Leu <220>

<221 > rri sc_f eat ur e <222> (5) . . ( 10) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 120

Q y Thr Trp Asp Ser Arg Leu Ser Al a Val Val

1 5 10 <210> 121 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / r epi ace= Asp <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> (5) . . (5) <223> / repl ace=Tyr <220>

<221 > rri sc_f eat ur e <222> (5) . . (5)

Page 78

2016244220 11 Oct 2016

A1472PCT. t xt <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 121

Q y Tyr Tyr IVfet Hi s

1 5 <210> 122 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (3) . . (3) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (3) . . (3) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 122

Trp lie Asn Pro Asn Ser Qy Qy Thr Asn Tyr Ala Qn Lys Phe Q n 15 10 15

Gy <210> 123 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(2) <223> / repl ace=Q y <220>

<221 > VARI ANT <222> (3) . . (3) <223> / repl ace=Tyr <220>

<221 > rri sc_f eat ur e <222> (1)..(3) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT

Page 79

A1472PCT. t xt

2016244220 11 Oct 2016 <222> (5) . . (5) <223> / repl ace=Q y <220>

<221 > VARIANT <222> (6) . . (6) <223> / repl ace=Tyr <220>

<221 > VARI ANT <222> (7). . (7) <223> / repl ace=AI a <220>

<221 > VARI ANT <222> (8) . . (9) <223> / repl ace= <220>

<221 > rri sc_f eat ur e <222> (5) . . (9) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (11)..(11) <223> / repl ace=Leu <220>

<221 > VARI ANT <222> ( 12) . . ( 12) <223> / repl ace=Tyr <220>

<221 > VARI ANT <222> ( 13) . . ( 13) <223> / repl ace=Ser <220>

<221 > VARI ANT <222> ( 14) . . ( 14) <223> / repl ace=Hi s <220>

<221 > rri sc_f eat ur e <222> (11)..(14) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> ( 17) . . ( 17) <223> / repl ace= <220>

<221 > rri sc_f eat ur e <222> ( 17) . . ( 17) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 123

Asp G n l\/bt Ser lie lie IVfet Leu Ar g Q y Val Phe Pro Pro Tyr Tyr 1 5 10 15 Tyr Gy l\/bt Asp Val

Page 80

A1472PCT. t xt

2016244220 11 Oct 2016 <210> 124 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (5) . . (5) <223> / repl ace=Thr <220>

<221 > rri sc_f eat ur e <222> (5) . . (5) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARIANT <222> ( 14) . . ( 14) <223> / repl ace=AI a <220>

<221 > rri sc_f eat ur e <222> ( 14) . . ( 14) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 124

Arg lie Lys Ser Lys Thr Asp Gy Gy Thr Thr Asp Tyr Thr Ala Pro 15 10 15

Val Lys Q y <210> 125 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARIANT

Page 81

A1472PCT. t xt

2016244220 11 Oct 2016 <222> (3) . . (3) <223> / repl ace=AI a <220>

<221 > rri sc_f eat ur e <222> (3) . . (3) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARIANT <222> (5) . . (5) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (5) . . (5) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 125

Thr Tyr Ser IVht Asn

1 5 <210> 126 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / repl ace=AI a <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> (4) . . (4) <223> / repl ace=G y <220>

<221 > rri sc_f eat ur e <222> (4) . . (4) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARI ANT <222> (6) . . (7) <223> / repl ace=G y <220>

<221 > VARI ANT <222> (8) . . (8) <223> / repl ace=Arg

Page 82

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2016244220 11 Oct 2016 <220>

<221 > VARIANT <222> (9) . . (9) <223> / repl ace=Thr <220>

<221 > rri sc_f eat ur e <222> (6) . . (9) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 126

Ser I I e Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Al a Asp Ser Val Lys 15 10 15

Gy <210> 127 <211> 22 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / r epi ace= Asp <220>

<221 > VARIANT <222> (2) . . (2) <223> / repl ace=G _n <220>

<221 > VARIANT <222> (3) . . (3) <223> / repl ace=Arg <220>

<221 > VARIANT <222> (4) . . (4) <223> / repl ace=G _U <220>

<221 > VARIANT <222> (5) . . (5) <223> / repl ace= Val <220>

<221 > VARIANT <222> (6) . . (6) <223> / repl ace=G y <220>

<221 > VARIANT <222> (7). . (7) <223> / repl ace= <220>

<221 > rri sc_f eat ur e

Page 83

A1472PCT. t xt

2016244220 11 Oct 2016 <222> (1)..(7) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARIANT <222> (11)..(11) <223> / repl ace=Ser <220>

<221 > VARIANT <222> ( 12) . . ( 12) <223> / repl ace=Q y <220>

<221 > rri sc_f eat ur e <222> (11)..(12) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 127

G u G y Val Ser Gy Ser Ser Pro Tyr Ser lie Ser Trp Tyr Asp Tyr 15 10 15

Tyr Tyr Q y IVbt Asp Val 20 <210> 128 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (2) . . (2) <223> / repl ace=Tyr <220>

<221 > rri sc_f eat ur e <222> (2) . . (2) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <400> 128

Ser Phe Q y K/bt Hi s

1 5 <210> 129 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

Page 84

A1472PCT. t xt

2016244220 11 Oct 2016 <221 > VARIANT <222> (4) . . (4) <223> / repi ace=Tyr <220>

<221 > rri sc_f eat ur e <222> (4) . . (4) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARIANT <222> (8) . . (8) <223> / repi ace=Hi s <220>

<221 > rri sc_f eat ur e <222> (8) . . (8) <223> / not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position <220>

<221 > VARIANT <222> (11)..(11) <223> / repi ace=Tyr <220>

<221 > VARIANT <222> ( 12) . . ( 12) <223> / repi ace=AI a <220>

<221 > rri sc_f eat ur e <222> (11)..(12) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 129

Val lie Ser Phe Asp Q y Ser I I e Lys Tyr Ser Val Asp Ser Val Lys 15 10 15

Gy <210> 130 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / repi ace=G _U <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position

Page 85

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2016244220 11 Oct 2016 <220>

<221 > VARIANT <222> (3) . . (3) <223> / repl ace=Lys <220>

<221 > VARIANT <222> (4) . . (4) <223> / repl ace=Arg <220>

<221 > VARIANT <222> (5) . . (5) <223> / repl ace= Val <220>

<221 > VARIANT <222> (6) . . (6) <223> / repl ace=Thr <220>

<221 > VARIANT <222> (7). . (7) <223> / repl ace=M3t <220>

<221 > rri sc_f eat ur e <222> (3) . . (7) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARIANT <222> (9) . . (9) <223> / repl ace=Thr <220>

<221 > VARIANT <222> ( 10) . . ( 10) <223> / repl ace=Leu <220>

<221 > rri sc_f eat ur e <222> (9) . . ( 10) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARIANT <222> ( 13) . . ( 13) <223> / repl ace=Tyr <220>

<221 > VARIANT <222> ( 14) . . ( 14) <223> / repl ace= <220>

<221 > VARIANT <222> ( 15) . . ( 15) <223> / repl ace= Phe <220>

<221 > rri sc_f eat ur e <222> ( 13) . . ( 15) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions

Page 86

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2016244220 11 Oct 2016 <220>

<221 > VARI ANT <222> ( 19) . . ( 19) <223> / repl ace=Leu <220>

<221 > VARI ANT <222> (20) . . (20) <223> I r epi ace= Asp <220>

<221 > rri sc_f eat ur e <222> ( 19) . . (20) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 130

Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Qy Tyr Tyr His Tyr Lys Tyr 15 10 15

Tyr Q y IVfet Al a Val 20 <210> 131 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARI ANT <222> (1)..(1) <223> / repl ace=Ser <220>

<221 > VARI ANT <222> (2) . . (2) <223> / repl ace= Tyr or Phe <220>

<221 > VARI ANT <222> (3) . . (3) <223> / r epi ace= Al a or Qy <220>

<221 > rri sc_f eat ur e <222> (1)..(3) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARI ANT <222> (5) . . (5) <223> / repl ace=Hi s <220>

<221 > rri sc_f eat ur e <222> (5) . . (5) <223> I not e= Resi due given i n t he sequence has no preference with respect to that i n t he annotation for said position

Page 87

A1472PCT. t xt

2016244220 11 Oct 2016 <400> 131

Asn Al a Tr p IVbt Ser 1 5 <210> 132 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / r epi ace= Al a or Val <220>

<221 > rri sc_f eat ur e <222> (1)..(1) <223> I not e= Resi due given i n t he sequence has no preference with respect to those i n t he annotations for said position <220>

<221 > VARI ANT <222> (3) . . (3) <223> / repl ace= Ser or Trp <220>

<221 > VARIANT <222> (4) . . (4) <223> / repl ace=G y or Phe or Tyr <220>

<221 > VARIANT <222> (5) . . (5) <223> / repl ace=Thr or <220>

<221 > VARIANT <222> (6) . . (6) <223> / repl ace= <220>

<221 > VARIANT <222> (7). . (7) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (3) . . (7) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARIANT <222> (9) . . (9) <223> / repl ace=Ser <220>

<221 > VARIANT <222> ( 10) . . ( 10) <223> / repl ace=Arg or lie or Asn or His

Page 88

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2016244220 11 Oct 2016 <220>

<221 > VARIANT <222> (11)..(11) <223> / repl ace=Lys <220>

<221 > VARIANT <222> ( 12) . . ( 12) <223> / repl ace=Tyr <220>

<221 > VARIANT <222> ( 13) . . ( 13) <223> / repl ace=Ser <220>

<221 > VARIANT <222> ( 14) . . ( 14) <223> / r epi ace= Al a or Val <220>

<221 > VARIANT <222> ( 15) . . ( 15) <223> I r epi ace= Asp <220>

<221 > VARIANT <222> ( 16) . . ( 16) <223> / repl ace=Ser <220>

<221 > rri sc_f eat ur e <222> (9) . . ( 16) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 132

Arg lie Lys Ser Lys Thr Asp Gy Gy Thr Thr Asp Tyr Thr Ala Pro 15 10 15

Val Lys Q y <210> 133 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / r epi ace= Al a or Gu <220>

<221 > VARIANT <222> (2) . . (2) <223> / repl ace=Q n or Gy <220>

<221 > VARIANT

Page 89

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2016244220 11 Oct 2016

<222> <223> (3). (3) / r epi ace= Ar g or Leu <220> <221 > VARI ANT <222> (4). (4) <223> / r epi ace= G u or Asn <220> <221 > VARI ANT <222> (5). (5) <223> / r epi ace= Val or Al a <220> <221 > VARI ANT <222> (6). (6) <223> / r epi ace= G y or Tyr <220> <221 > VARI ANT <222> (7). (7) <223> / r epi ace= Pro or Asp <220> <221 > VARI ANT <222> (8). (8) <223> / r epi ace= Tyr or II II <220> <221 > VARI ANT <222> (9)--(9) <223> / r epi ace= Ser or Thr <220> <221 > VARI ANT <222> (10).. (10) <223> / r epi ace= G y or Leu <220> <221 > VARI ANT <222> (11)--(11) <223> I r epi ace= G y or Leu <220> <221 > VARI ANT <222> (12). (12) <223> / r epi ace= Tyr or II II <220> <221 > VARI ANT <222> (13). (13) <223> / r epi ace= Hi s <220> <221 > VARI ANT <222> (14). (14) <223> / r epi ace= Asp or II II <220> <221 > VARI ANT <222> (15). (15) <223> / r epi ace= Lys or Phe <220> <221 > VARI ANT <222> (16). (17) <223> / r epi ace= II

G y or

I I e or

Al a or

Al a or

Tyr

Lys

Arg

Thr

Page 90

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2016244220 11 Oct 2016 <220>

<221 > rri sc_f eat ur e <222> (1)..(17) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARIANT <222> ( 19) . . ( 19) <223> / repl ace=|_eu <220>

<221 > VARIANT <222> (20) . . (20) <223> / repl ace=AI a <220>

<221 > rri sc_f eat ur e <222> ( 19) . . (20) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions

<400> 133 Asp Ar g Thr Gy Tyr Ser I I e Ser 1 5 Tyr G y IVbt Asp Val 20

Trp Ser Ser Trp Tyr Tyr Tyr Tyr 10 15 <210> 134 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1) <223> / r epi ace= Q y or Asp or Ser or Ala <220>

<221 > VARIANT <222> (2) . . (2) <223> / repl ace= Phe or Tyr <220>

<221 > VARIANT <222> (3) . . (3) <223> / r epi ace= Tyr or Ala or Gy <220>

<221 > VARIANT <222> (4) . . (4) <223> / repl ace=|_eu <220>

<220>

<221 > VARIANT <222> (5) . . (5) <223> / repl ace=Hi s

Page 91

A1472PCT. t xt

2016244220 11 Oct 2016 <221 > rri sc_f eat ur e <222> (1)..(5) <223> I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 134

Asn Al a Tr p IVfet Ser 1 5 <210> 135 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of pept i de t i f i ci al Sequence: Synt het i c or Val or Ser or Phe <220>

<221 > VARIANT <222> (1)..(1) <223> / repl ace=Trp or Ala <220>

<221 > <222> <223> rri sc f eat ur e (1)--(1) / not e= Resi due r espect to t ho: gi ven i n t h an ;e i n t he <220> <221 > VARI ANT <222> (3). (3) <223> I r epi ace= Asn or Ser or <220> <221 > VARI ANT <222> (4). (4) <223> / repl ace= Pro or G y or <220> <221 > VARI ANT <222> (5). (5) <223> /repl ace=Thr or Arg or <220> <221 > VARI ANT <222> (6). (6) <223> /repl ace=AI a or II II <220> <221 > VARI ANT <222> (7). (7) <223> I r epi ace= Asn or Hi s or <220> <221 > VARI ANT <222> (8). (9) <223> / r epi ace= Ser <220> <221 > VARI ANT <222> (10).. (10) <223> /repl ace=G _y or Arg or

Trp or Arg

Phe or Tyr

II II

Ser or Tyr <220>

e sequence has no preference with notations for said position lie or Asn or His or Tyr

Page 92

A1472PCT. t xt

2016244220 11 Oct 2016 <221 > <222> <223>

<220> <221 > <222> <223>

<220> <221 > <222> <223>

VARI ANT (11)--(11) / r epi ace= Lys or Arg or Pro

VARI ANT (12). (12) / repl ace=Asn or Tyr or Gu

VARI ANT (13). (13) / r epi ace= Ser <220> <221 > <222> <223>

VARI ANT (14). (14) / repl ace=AI a or Val <220> <221 > <222> <223>

<220> <221 > <222> <223>

<220> <221 > <222> <223>

VARI ANT (15). (15) / repl ace=G n or Asp

VARI ANT (16). (16) /repl ace= Lys or Ser

VARI ANT (17). (17) /repl ace= Phe <220> <221 > <222> <223>

VARI ANT (18). (18) /repl ace=Q n <220> <221 > <222> <223>

<400> Arg I I 1 rri sc_f eat ur e (3). . (18)

I not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions

135 e Lys Ser Lys Thr Asp Q y Q y Thr Thr Asp Tyr Thr Al a Pro 5 10 15

Val Lys Q y <210> 136 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

<221 > VARIANT <222> (1)..(1)

Page 93

2016244220 11 Oct 2016

<223> /repl ace=Q y or Al a or A1472PCT. t xt G u <220> <221 > VARI ANT <222> (2). (2) <223> /repl ace=Q y or G n <220> <221 > VARI ANT <222> (3). (3) <223> /repl ace= IVfet or Tyr or Arg or Leu or Gy <220> <221 > VARI ANT <222> (4). (4) <223> / r epi ace= Ser or G u or Asn or lie or Arg <220> <221 > VARI ANT <222> (5). (5) <223> /repl ace= I I e or G y or Val or Ala <220> <221 > VARI ANT <222> (6). (6) <223> /repl ace= I I e or Tyr or Gy or Ala or Thr <220> <221 > VARI ANT <222> (7). (7) <223> /repl ace= IVfet or Al a or Pro or Asp <220> <221 > VARI ANT <222> (8). (8) <223> / r epi ace= Leu or Tyr or II II <220> <221 > VARI ANT <222> (9)--(9) <223> / r epi ace= Ar g or Ser or Thr or <220> <221 > VARI ANT <222> (10).. (10) <223> /repl ace=Q y or Leu <220> <221 > VARI ANT <222> (11)--(11) <223> /repl ace= Val or Leu or Gy or Tyr <220> <221 > VARI ANT <222> (12). - (12) <223> / r epi ace= Tyr or Tr p or II II <220> <221 > VARI ANT <222> (13). - (13) <223> / repl ace= Pro or Ser or Hi s

Lys <220>

<221 > VARIANT <222> ( 14) . . ( 14) <223> / repl ace= Pro or Asp or His or <220>

Page 94

A1472PCT. t xt

2016244220 11 Oct 2016 <221 > VARIANT <222> ( 15) . . ( 15) <223> /repl ace= Lys or Phe <220>

<221 > VARIANT <222> ( 16) . . ( 17) <223> / repl ace= <220>

<221 > rri sc_f eat ur e <222> (1)..(17) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <220>

<221 > VARIANT <222> ( 19) . . ( 19) <223> / repl ace=Leu <220>

<221 > VARIANT <222> (20) . . (20) <223> / repl ace=AI a <220>

<221 > rri sc_f eat ur e <222> ( 19) . . (20) <223> / not e= Resi dues given i n t he sequence have no preference with respect to those i n t he annotations for said positions <400> 136

Asp Arg Thr Gly Tyr Ser 1 5 e Ser Trp Ser Ser Phe Tyr Tyr Tyr 10 15

Tyr

Tyr Q y K/bt Asp Val 20 <210> 137 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 137

G n Ser Val Leu Thr G n Pr o Pr o Ser Val Ser G u 1 5 10 Lys Val Thr I I e Ser Cys Ser G y Ser Ser Ser Asn 20 25 Tyr Val Ser Tr p Tyr G n G n Leu Pr o G y Thr Al a 35 40 I I e Tyr Asp Asn Asn Lys Arg Pr o Ser Gy I I e Pr o 50 55 60 Gy Ser Lys Ser Gy Thr Ser Al a Thr Leu Gy I I e

G n

Asn

Leu

Ser

Thr G y Leu G n

Page 95

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2016244220 11 Oct 2016

65 70 75 80 Thr G y Asp Q u Al a Asp Tyr Tyr Cys Q y Thr Tr p Asp Ser Arg Leu 85 90 95 Ser Al a Val Val Phe G y G y G y Thr Lys Leu Thr Val Leu

100 105 110 <210> 138 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 138

G n Ser Val Leu Thr G n Pr o Pr o Ser Al a Ser Gy Thr Pr o G y G n 1 5 10 15 Arg Val Thr I I e Ser Cys Ser Gy Ser Ser Ser Asn I I e G y Ser Asn 20 25 30 Tyr Val Tyr Tr p Tyr G n G n Leu Pr o Gy Al a Al a Pr o Lys Leu Leu 35 40 45 I I e Phe Arg Ser Asn G n Arg Pr o Ser Gy Val Pr o Asp Arg Phe Ser 50 55 60 Gy Ser Lys Ser Gy Thr Ser Al a Ser Leu Al a I I e Ser Gy Leu Arg 65 70 75 80 Ser G u Asp G u Al a Asp Tyr Tyr Cys Al a Al a Tr p Asp Asp Ser Leu 85 90 95 Ser Gy Tr p Val Phe Gy Gy Gy Thr Lys Leu Thr Val Leu

100 105 110 <210> 139 <211> 107 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 139

Asp I I e G n IVbt Thr G n Ser Pr o Ser Ser Leu Ser Al a Ser Val Gy 1 5 10 15 Asp Ar g Val Thr I I e Thr Cys Arg Al a Ser G n Gy I I e Arg Asn Asp

20 25 30

Page 96

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2016244220 11 Oct 2016

Leu Gy Tr p Phe G n G n Lys Pr o Gy Lys Al a Pr o Lys Arg Leu I I e 35 40 45 Tyr Al a Al a Ser Ser Leu G n Ser Gy Val Pr o Ser Arg Phe Ser Gy 50 55 60 Ser Gy Ser Gy Thr G u Phe Thr Leu Thr I I e Ser Ser Leu G n Pr o 65 70 75 80 G u Asp Leu Al a Thr Tyr Tyr Cys Leu G n Tyr Asn I I e Tyr Pr o Tr p 85 90 95 Thr Phe Gy G n Gy Thr Lys Val G u I I e Lys

100 105 <210> 140 <211> 108 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 140

Ser 1 Ser G u Leu Thr 5 G n Asp Pr o Thr Val 10 Ser Val Al a Leu Q y Q n 15 Thr Val Lys I I e Thr Cys G n Gy Asp Ser Leu Arg Ser Phe Tyr Al a 20 25 30 Ser Tr p Tyr G n G n Lys Pr o Gy G n Al a Pr o Val Leu Val Phe Tyr 35 40 45 Gy Lys Asn Asn Arg Pr o Ser Gy I I e Pr o Asp Arg Phe Ser Gy Ser 50 55 60 Ser Ser Gy Asn Thr Al a Ser Leu Thr I I e Thr Gy Al a G n Al a G u 65 70 75 80 Asp G u Al a Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Val Tyr Hi s 85 90 95 Leu Val Leu Gy Gy Gy Thr Lys Leu Thr Val Leu 100 105

<210> 141 <211> 112 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic

Page 97

A1472PCT. t xt

2016244220 11 Oct 2016 pol ypept i de <400> 141

Asp 1 I I e I I e Leu Al a 5 G n Thr Pr o Leu Ser 10 Leu Ser Val Thr Pr o 15 Gy G n Pr o Al a Ser I I e Ser Cys Lys Ser Ser G n Ser Leu Leu Hi s Ser 20 25 30 Al a Gy Lys Thr Tyr Leu Tyr Tr p Tyr Leu G n Lys Pr o Gy G n Pr o 35 40 45 Pr o G n Leu Leu I I e Tyr G u Val Ser Asn Arg Phe Ser Gy Val Pr o 50 55 60 Asp Arg Phe Ser Gy Ser Gy Ser Gy Thr Asp Phe Thr Leu Lys I I e 65 70 75 80 Ser Arg Val G u Al a G u Asp Val Gy I I e Tyr Tyr Cys IVbt G n Ser 85 90 95 Phe Pr o Leu Pr o Leu Thr Phe Gy Gy Gy Thr Lys Val G u I I e Lys

100 105 110 <210> 142 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 142

Q n Ser Val Leu Thr On Pro Pro Ser Val Ser Al a Al a Pro Qy Qn 15 10 15

Lys Val Thr I I e Ser Cys Ser Q y Ser Ser Ser Asn I I e Q y Asn Asn 20 25 30

Tyr Val Ser Trp Tyr Q n Q n Leu Pro Qy Thr Al a Pro Lys Leu Leu 35 40 45

I I e Tyr Asp Asn Asn Lys Arg Pro Ser Qy lie Pro Asp Arg Phe Ser 50 55 60

Q y Ser Lys Ser Q y Thr Ser Thr Thr Leu Q y I I e Thr Q y Leu Q n 65 70 75 80

Thr G y Asp G u Al a Asp Tyr Tyr Cys G y Thr Trp Asp Ser Arg Leu 85 90 95

Ser Al a Val Val Phe Q y Q y Q y Thr Lys Leu Thr Val Leu 100 105 110

Page 98

A1472PCT. t xt

2016244220 11 Oct 2016 <210> 143 <211> 112 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 143

Asp 1 I I e Val D/bt Thr 5 Q n Ser Pr o Leu Ser 10 Leu Pr o Val Thr Pr o 15 Gy G u Pr o Al a Ser I I e Ser Cys Arg Ser Ser G n Ser Leu Leu Hi s Ser 20 25 30 Phe Gy Tyr Asn Tyr Leu Asp Tr p Tyr Leu G n Lys Pr o Gy G n Ser 35 40 45 Pr o G n Leu Leu I I e Tyr Leu Gy Ser Asn Arg Al a Ser Gy Val Pr o 50 55 60 Asp Arg Phe Ser Gy Ser Gy Ser Gy Thr Asp Phe Thr Leu Lys I I e 65 70 75 80 Ser Arg Val G u Al a G u Asp Val Gy Val Tyr Tyr Cys IVbt G n Al a 85 90 95 Leu G n Thr Pr o Phe Thr Phe Gy Pr o Gy Thr Lys Val Asp I I e Lys 100 105 110

<210> 144 <211> 112 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 144

Asp 1 lie lie Leu Thr 5 G n Thr Pro Leu Ser 10 Leu Ser Val Thr Pr o 15 Gy G n Pr o Al a Ser I I e Ser Cys Lys Ser Ser G n Ser Leu Leu Hi s Ser 20 25 30 Asp Gy Lys Thr Tyr Leu Tyr Tr p Tyr Leu G n Lys Pr o Gy G n Pr o 35 40 45 Pr o G n Leu Leu I I e Tyr G u Val Ser Asn Arg Phe Ser Gy G u Pr o

50 55 60

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Asp 65 Arg Phe Ser Qy Ser 70 Qy Ser Qy Thr Asp Phe 75 Thr Leu Lys I I e 80 Ser Arg Val Q u Al a Q u Asp Val Qy Thr Tyr Tyr Cys IVbt Q n Ser 85 90 95 Phe Pr o Leu Pr o Leu Thr Phe Qy Qy Qy Thr Lys Val Q u I I e Lys

100 105 110 <210> 145 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 145

Q n Ser Val Leu Thr Q n Pr o Pr o Ser Val Ser Al a Al a Pr o Q y Q n 1 5 10 15 Lys Val Thr I I e Ser Cys Ser Qy Ser Ser Ser Asn I I e Q y Asn Asn 20 25 30 Tyr Val Ser Tr p Tyr Q n Q n Phe Pr o Qy Thr Al a Pr o Lys Leu Leu 35 40 45 I I e Tyr Asp Asn Asn Lys Arg Pr o Ser Qy I I e Pr o Asp Arg Phe Ser 50 55 60 Q y Ser Lys Ser Qy Thr Ser Al a Thr Leu Q y I I e Thr Qy Leu Q n 65 70 75 80 Thr Qy Asp Q u Al a Asp Tyr Tyr Cys Qy Thr Tr p Asp Ser Arg Leu 85 90 95 Ser Al a Val Val Phe Qy Qy Qy Thr Lys Leu Thr Val Leu

100 105 110 <210> 146 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 146

Q n Ser Val Leu Thr Q n Ser Pr o Ser Al a Ser Qy Thr Pr o Q y Q n 1 5 10 15 Arg Val Thr I I e Ser Cys Ser Qy Ser Ser Ser Asn I I e Qy Ser Asn

20 25 30

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Tyr Val Tyr Tr p Tyr G n G n Leu Pr o Gy Al a Al a Pr o Lys Leu Leu 35 40 45 I I e Leu Arg Asn Asn G n Arg Pr o Ser Gy Val Pr o Asp Arg Phe Ser 50 55 60 Gy Ser Lys Ser Gy Thr Ser Al a Ser Leu Thr I I e Ser Gy Leu Arg 65 70 75 80 Ser G u Asp G u Al a Asp Tyr Tyr Cys Al a Al a Tr p Asp Asp Ser Leu 85 90 95 Ser Gy Tr p Val Phe Gy Gy Gy Thr Lys Leu Thr Val Leu

100 105 110 <210> 147 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

<400> 147 G n Ser Val Leu Thr G n Pr o Pr o Ser Al a Ser Gy Thr Pr o G y G n 1 5 10 15 Arg Val Thr I I e Ser Cys Ser Gy Ser Ser Ser Asn I I e G y Ser Asn 20 25 30 Thr Val Asn Tr p Tyr G n G n Leu Pr o Gy Thr Al a Pr o Lys Leu Leu 35 40 45 I I e Tyr Thr Asn Asn G n Arg Pr o Ser Gy Val Pr o Asp Arg Phe Ser 50 55 60 G y Ser Lys Ser Gy Thr Ser Al a Ser Leu Al a I I e Ser Gy Leu G n 65 70 75 80 Ser G u Asp G u Al a Asp Phe Tyr Cys Al a Al a Arg Asp G u Ser Leu 85 90 95 Asn Gy Val Val Phe Gy Gy Gy Thr Lys Leu Thr Val Leu 100 105 110

<210> 148 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source

Page 101

2016244220 11 Oct 2016

A1472PCT. t xt <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 148

G n Ser Val Leu Thr G n Pr o Pr o Ser Al a Ser Gy Thr Pr o G y G n 1 5 10 15 Arg Val Thr I I e Ser Cys Ser Gy Ser Ser Ser Asn I I e G y Ser Asn 20 25 30 Tyr Val Tyr Tr p Tyr G n G n Leu Pr o Gy Al a Al a Pr o Lys Leu Leu 35 40 45 I I e Phe Arg Asn Asn G n Arg Pr o Ser Gy Val Pr o Asp Arg Phe Ser 50 55 60 Gy Ser Lys Ser Gy Thr Ser Al a Ser Leu Al a I I e Ser Gy Leu Arg 65 70 75 80 Ser G u Asp G u Al a Asp Tyr Tyr Cys Al a Al a Tr p Asp Asp Ser Leu 85 90 95 Ser Gy Tr p Val Phe Gy Gy Gy Thr Lys Leu Thr Val Leu

100 105 110 <210> 149 <211> 112 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 149

Asp I I e 1 Thr Leu Thr 5 G n Thr Pro Leu Ser 10 Leu Ser Val Ser Pr o 15 Gy G n Pr o Al a Ser I I e Ser Cys Lys Ser Ser G n Ser Leu Leu Hi s Ser 20 25 30 Asp Gy Arg Asn Tyr Leu Tyr Tr p Tyr Leu G n Lys Pr o Gy G n Pr o 35 40 45 Pr o G n Leu Leu I I e Tyr G u Val Ser Asn Arg Phe Ser Gy Leu Pr o 50 55 60 Asp Arg Phe Ser Gy Ser Gy Ser Gy Thr Asp Phe Thr Leu Lys I I e 65 70 75 80 Ser Arg Val G u Al a G u Asp Val Gy I I e Tyr Tyr Cys IVbt G n Ser 85 90 95 Phe Pr o Leu Pr o Leu Thr Phe Gy Gy Gy Thr Lys Val G u I I e Lys Page 102

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A1472PCT. t xt

100 105 110 <210> 150 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 150

G n Ser Val Leu Thr G n Pr o Pr o Ser Val Ser Al a Al a Pr o G y G n 1 5 10 15 Lys Val Thr I I e Ser Cys Ser Gy Ser Ser Ser Asn I I e G y Asn Asn 20 25 30 Tyr Val Ser Tr p Tyr G n G n Leu Pr o Gy Thr Al a Pr o Lys Leu Leu 35 40 45 I I e Tyr Asp Asn Asn Lys Arg Pr o Ser Gy I I e Pr o Asp Arg Phe Ser 50 55 60 Gy Ser Lys Ser Gy Thr Ser Al a Thr Leu Gy I I e Thr Gy Leu G n 65 70 75 80 Thr Gy Asp G u Al a Asp Tyr Tyr Cys Gy Thr Tr p Asp Ser Arg Leu 85 90 95 Ser Al a Val Val Phe Gy Gy Gy Thr Lys Leu Thr Val Leu

100 105 110 <210> 151 <211> 107 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 151

Asp I I e G n IVbt Thr G n Ser Pr o Ser Ser Leu Ser Al a Ser Val Gy 1 5 10 15 Asp Arg Val Thr I I e Thr Cys Arg Al a Ser G n Gy I I e Arg Lys Asp 20 25 30 Leu Gy Tr p Tyr G n G n Lys Pr o Gy Lys Al a Pr o Lys Arg Leu I I e 35 40 45 Tyr Gy Al a Ser Ser Leu G n Ser Gy Val Pr o Ser Arg Phe Ser Gy

50 55 60

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Ser Qy Ser Qy Thr Q u Phe Thr Leu Thr I I e Ser Ser Leu Q n Pr o 65 70 75 80 Q u Asp Phe Al a Thr Tyr Tyr Cys Leu Q n Tyr Asn Ser Phe Pr o Tr p 85 90 95 Thr Phe Qy Q n Qy Thr Lys Val Q u I I e Lys

100 105 <210> 152 <211> 108 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 152

Q u 1 lie Val Leu Thr 5 Q n Ser Pr o Q y Thr 10 Leu Ser Leu Ser Pr o 15 Qy Q u Arg Al a Thr Leu Ser Cys Arg Al a Ser Q n Ser Val Ser Ser Qy 20 25 30 Tyr Leu Thr Tr p Tyr Q n Q n Lys Pr o Qy Q n Al a Pr o Arg Leu Leu 35 40 45 I I e Tyr Qy Al a Ser Ser Arg Al a Thr Qy I I e Pr o Asp Arg Phe Ser 50 55 60 Qy Ser Qy Ser Qy Thr Asp Phe Thr Leu Thr I I e Ser Arg Leu Q u 65 70 75 80 Pr o Q u Asp Phe Al a Val Tyr Tyr Cys Q n Q n Tyr Qy Asn Ser Leu 85 90 95 Cys Arg Phe Qy Q n Qy Thr Lys Leu Q u I I e Lys

100 105 <210> 153 <211> 108 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 153

Qu lie Val Leu Thr Q n Ser Pro Qy Thr Leu Ser Leu Ser Pro Qy

15 10 15

Qu Arg Al a Thr Leu Ser Cys Arg Al a Ser Q n Ser Val Ser Ser Q y Page 104

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20 25 30 Tyr Leu Thr Tr p Tyr Q n Q n Lys Pr o Qy Q n Al a Pr o Arg Leu Leu 35 40 45 I I e Tyr Qy Al a Ser Ser Arg Al a Thr Qy I I e Pr o Asp Arg Phe Ser 50 55 60 Q y Ser Qy Ser Qy Thr Asp Phe Thr Leu Thr I I e Ser Arg Leu Q u 65 70 75 80 Pr o Q u Asp Phe Al a Val Tyr Tyr Cys Q n Q n Tyr Qy Asn Ser Leu 85 90 95 Ser Arg Phe Qy Q n Qy Thr Lys Leu Q u I I e Lys

100 105 <210> 154 <211> 113 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

<400> 154 Thr 5 Q n Ser Pro Asp Ser 10 Leu Al a Val Ser Leu 15 Qy Asp 1 lie Val Vfet Q u Arg Al a Thr I I e Asn Cys Lys Ser Ser Q n Ser I I e Leu Asp Ser 20 25 30 Ser Asn Asn Asp Asn Tyr Leu Al a Tr p Tyr Q n Q n Lys Pr o Qy Q n 35 40 45 Pr o Pr o Lys Leu Leu I I e Tyr Tr p Al a Ser Thr Arg Q u Ser Qy Val 50 55 60 Pr o Asp Arg Phe Ser Qy Ser Qy Ser Qy Thr Asp Phe Thr Leu Thr 65 70 75 80 I I e Ser Ser Leu Q n Al a Q u Asp Val Al a Val Tyr Tyr Cys Q n Q n 85 90 95 Tyr Tyr Asn Thr Pr o Phe Thr Phe Qy Pr o Qy Thr Lys Val Asp I I e 100 105 110

Lys <210> 155 <211> 107

Page 105

A1472PCT. t xt

2016244220 11 Oct 2016 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 155

Asp 1 I I e Q n l\/bt Thr 5 G n Ser Pro Ser Ser 10 Leu Ser Al a Ser Val 15 Gy Asp Arg Val Thr I I e Thr Cys Arg Al a Ser G n Gy I I e Arg Asn Asp 20 25 30 Leu Gy Tr p Tyr G n G n Lys Pr o Gy Lys Al a Pr o Lys Arg Leu I I e 35 40 45 Tyr Val Al a Ser Ser Leu G n Ser Gy Val Pr o Ser Arg Phe Ser Gy 50 55 60 Ser Gy Ser Gy Thr G u Phe Thr Leu Thr I I e Ser Ser Leu G n Pr o 65 70 75 80 G u Asp Phe Al a Thr Tyr Tyr Cys Leu G n Tyr Asn Thr Tyr Pr o Leu 85 90 95 Thr Phe Gy Gy Gy Thr Lys Val G u I I e Lys 100 105

<210> 156 <211> 108 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 156

G u I I e Val l\/bt Thr G n Ser Pr o Al a Thr Leu Ser Val Ser Pr o Gy 1 5 10 15 G u Arg Al a Thr Leu Ser Cys Arg Al a Ser G n Ser Val Arg Ser Asn 20 25 30 Leu Al a Tr p Tyr G n G n Lys Pr o Gy G n Al a Pr o Arg Leu Leu I I e 35 40 45 Hi s Asp Al a Ser Pr o Arg Thr Al a Gy I I e Pr o Al a Arg Phe Ser Gy 50 55 60 Ser Gy Ser Gy Thr G u Phe Thr Leu Thr I I e Asn Ser Leu G n Ser 65 70 75 80

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Q u Asp Phe Al a Val Tyr Tyr Cys Q n Q n Tyr Asn Tyr Trp Thr Pro 85 90 95

I I e Thr Phe Gl y Q n Gy Thr Arg Leu Guile Lys 100 105 <210> 157 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 157

G n Ser Val Leu Thr G n Pr o Pr o Ser IVbt Ser Al a Al a Pr o G y G n 1 5 10 15 Lys Val Thr I I e Ser Cys Ser Gy Ser Ser Ser Asn I I e G y Asn Asn 20 25 30 Tyr Val Ser Tr p Tyr G n G n Leu Pr o Gy Thr Al a Pr o Lys Leu Leu 35 40 45 I I e Tyr Asp Asn Asn Lys Arg Pr o Ser Gy I I e Pr o Asp Arg Phe Ser 50 55 60 G y Ser Lys Ser Gy Thr Ser Al a Thr Leu G y I I e Thr Gy Leu G n 65 70 75 80 Thr Gy Asp G u Al a Asn Tyr Cys Cys Gy Thr Tr p Asp I I e Gy Leu 85 90 95 Ser Val Tr p Val Phe Gy Gy Gy Thr Lys Leu Thr Val Leu

100 105 110 <210> 158 <211> 130 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 158

G n Val 1 Q n Leu Val 5 G u Ser G y G y Gy 10 Val Val G n Pr o Gy 15 Arg Ser Leu Arg Leu Ser Cys Al a Al a Ser Gy Phe Thr Phe Ser Ser Phe 20 25 30 Gy IVbt Hi s Tr p Val Arg G n Al a Pr o Gy Lys Gy Leu G u Tr p Val

35 40 45

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Al a Val 50 I I e Ser Phe Asp Gy 55 Ser Lys 65 Gy Arg Phe Thr I I e 70 Ser Arg Leu G n IVbt Asn Ser 85 Leu Arg Al a Al a Arg Asp Arg 100 Leu Asn Tyr Tyr Lys Tyr Tyr Gy IVbt Al a Val Tr p

115 120

I I e Lys Tyr Ser 60 Val Asp Ser Val Asp Asn Ser 75 Lys Asn Thr Leu Phe 80 G u Asp 90 Thr Al a Val Tyr Tyr 95 Cys Asp 105 Ser Ser Gy Tyr Tyr 110 Hi s Tyr Gy G n Gy Thr Thr Val Thr Val

125

Ser Ser 130 <210> 159 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 159 G u 1 Val Q n Leu Val Q u Ser Gy Gy Gy Leu Val Lys Pro Gy Gy 5 10 15 Ser Leu Arg Leu Ser Cys Al a Al a Ser Q y Phe Thr Phe Ser Asn Al a 20 25 30 Tr p IVbt Ser Trp Val Arg Q n Al a Pro Q y Lys Q y Leu Q u Trp Val 35 40 45 Gy Arg lie Lys Ser Thr Thr Asp Gy Gy Thr Thr Asp Tyr Al a Al a 50 55 60 Pr o 65 Val Lys Q y Arg Phe Thr I I e Ser Arg Asp Asp Ser Lys Asn Thr 70 75 80 Leu Tyr Leu Q n IVfet Asn Ser Leu Lys Thr Q u Asp Thr Al a Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gy Tyr Ser lie Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Q y IVfet Asp Val Trp Gy Qn Gy Thr Thr Val Thr 115 120 125

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Val Ser Ser 130 <210> 160 <211> 130 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 160

G u 1 Val G n Leu Leu 5 G u Ser Gy Gy Q y Leu Val 10 Q n Pro G y G u 15 Ser Leu Arg Leu Ser Cys Al a Al a Ser Gy Phe Thr Phe Ser Ser Tyr 20 25 30 Al a IVbt Ser Tr p Val Arg G n Al a Pr o Gy Lys Gy Leu G u Tr p Val 35 40 45 Ser Al a I I e Ser Gy Ser Gy Gy Arg Thr Tyr Tyr Al a Asp Ser Val 50 55 60 Lys Gy Arg Phe Thr I I e Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu G n IVbt Asn Ser Leu Arg Al a G u Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Lys Asp G n Arg G u Val Gy Pr o Tyr Ser Ser Gy Tr p Tyr Asp 100 105 110 Tyr Tyr Tyr Gy IVbt Asp Val Tr p Gy G n Gy Thr Thr Val Thr Val

115 120 125

Ser Ser 130 <210> 161 <211> 130 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 161

Q n Val Qn Leu Val Q n Ser Qy Ala Qu Val Lys Lys Pro Qy Al a

15 10 15

Ser Val Lys Val Ser Cys Lys Al a Ser Q y Tyr Thr Phe Thr Q y Tyr Page 109

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20 25 30 Tyr K/bt Hi s Tr p Val Arg G n Al a Pr o Gy G n Gy Leu G u Tr p IVbt 35 40 45 Gy Tr p I I e Asn Pr o Asn Ser Gy Gy Thr Asn Tyr Al a G n Lys Phe 50 55 60 G n Gy Arg Val Thr IVbt Thr Arg Asp Thr Ser I I e Ser Thr Al a Tyr 65 70 75 80 l\/bt G u Leu Ser Arg Leu Arg Ser Asp Asp Thr Al a Val Tyr Phe Cys 85 90 95 Al a Arg Asp G n IVbt Ser I I e I I e IVfet Leu Arg Gy Val Phe Pr o Pr o 100 105 110 Tyr Tyr Tyr Gy IVbt Asp Val Tr p Gy G n Gy Thr Thr Val Thr Val

115 120 125

Ser Ser 130 <210> 162 <211> 129 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

<400> 162 Leu Val 5 G u Ser Gy G y G y Val 10 Val G n Pro Gy Arg 15 G n 1 Val G n Ser Leu Arg Leu Ser Cys Al a Al a Ser Gy Phe Thr Phe Ser Ser Tyr 20 25 30 Gy IVbt Hi s Tr p Val Arg G n Al a Pr o Gy Lys Gy Leu G u Tr p Val 35 40 45 Al a Val I I e Ser Tyr Asp Gy Ser Hi s G u Ser Tyr Al a Asp Ser Val 50 55 60 Lys Gy Arg Phe Thr I I e Ser Arg Asp I I e Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu G n IVbt Asn Ser Leu Arg Al a G u Asp Thr Al a Val Tyr Phe Cys 85 90 95 Al a Arg G u Arg Lys Arg Val Thr IVbt Ser Thr Leu Tyr Tyr Tyr Phe 100 105 110

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Tyr Tyr Q y IVbt Asp Val Trp Gly Qn Qy Thr Thr 115 120

Val Thr Val Ser 125

Ser <210> 163 <211> 121 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 163

G u Val 1 G n Leu Val 5 G u Ser Q y Q y Q y Leu Val 10 Lys Pr o Gy 15 Arg Ser Leu Arg Leu Ser Cys Thr Al a Ser Gy Phe Thr Phe G y Asp Tyr 20 25 30 Al a IVbt Ser Tr p Phe Arg G n Al a Pr o Gy Lys Gy Leu G u Tr p I I e 35 40 45 Gy Phe I I e Arg Ser Arg Al a Tyr Gy Gy Thr Pr o G u Tyr Al a Al a 50 55 60 Ser Val Lys Gy Arg Phe Thr I I e Ser Arg Asp Asp Ser Lys Thr I I e 65 70 75 80 Al a Tyr Leu G n IVfet Asn Ser Leu Lys Thr G u Asp Thr Al a Val Tyr 85 90 95 Phe Cys Al a Arg Gy Arg Gy I I e Al a Al a Arg Tr p Asp Tyr Tr p Gy 100 105 110 G n Gy Thr Leu Val Thr Val Ser Ser 115 120

<210> 164 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 164

Q u Val Qn Leu Val Q u Ser Qy Qy Qy Leu Val Lys Pro Qy Qy

15 10 15

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Ser Leu Arg Leu Ser Cys Al a Al a Ser G y Phe Thr Phe Ser Asn Al a 20 25 30 Tr p IVfet Ser Tr p Val Arg G n Al a Pr o Gy Lys Gy Leu G u Tr p Val 35 40 45 Gy Arg I I e Lys Ser Lys Thr Asp Gy Gy Thr Thr Asp Tyr Thr Al a 50 55 60 Pr o Val Lys Gy Arg Phe Thr I I e Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu G n IVbt Asn Ser Leu Lys Al a G u Asp Thr Al a Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gy Tyr Ser I I e Ser Tr p Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gy IVbt Asp Val Tr p Gy G n Gy Thr Thr Val Thr

115

120

125

Val Ser Ser 130 <210> 165 <211> 127 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 165

G n Val G n Leu Val G n Ser G y Al a G u Val Lys Lys Pr o G y Al a 1 5 10 15 Ser Val Lys Val Ser Cys Lys Al a Ser Gy Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr IVbt Tyr Tr p Val Arg G n Al a Pr o Gy G n Gy Leu G u Tr p IVbt 35 40 45 Gy Tr p I I e Ser Pr o Asn Ser Gy Gy Thr Asn Tyr Al a G n Lys Phe 50 55 60 G n G y Arg Val Thr IVbt Thr Arg Asp Thr Ser I I e Ser Thr Al a Tyr 65 70 75 80 IVbt G u Leu Ser Arg Leu Arg Ser Asp Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Val Arg Gy Gy Tyr Ser Gy Tyr Al a Gy Leu Tyr Ser Hi s Tyr Tyr

Page 112

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A1472PCT. t xt

100 105 110

Q y Lfet Asp Val Trp Gy Qn Gy Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 166 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 166

Q u Val 1 Q n Leu Val 5 Q u Ser Q y Q y Q y Leu Val 10 Lys Pr o Qy 15 Qy Ser Leu Arg Leu Ser Cys Al a Al a Ser Qy Phe Thr Phe Q y Asn Al a 20 25 30 Tr p IVfet Ser Tr p Val Arg Q n Al a Pr o Qy Lys Qy Leu Q u Tr p Val 35 40 45 Gy Arg I I e Lys Ser Lys Thr Asp Qy Qy Thr Thr Asp Tyr Al a Al a 50 55 60 Pr o Val Lys Gy Arg Phe Thr I I e Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu G n IVbt Asn Ser Leu Lys Thr Q u Asp Thr Al a Val Tyr 85 90 95 Phe Cys Thr Thr Asp Arg Thr Qy Tyr Ser I I e Ser Tr p Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Qy IVbt Asp Val Tr p Qy Q n Qy Thr Thr Val Thr 115 120 125

Val Ser Ser 130 <210> 167 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 167

G u Val Gn Leu Val Q u Ser Gy Gy Gy Leu Val Lys Pro Gy Gy

15 10 15

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Ser Leu Arg Leu Ser 20 Cys Al a Al a Ser 25 G y Phe Thr Phe Gy 30 Asn Al a Tr p IVfet Ser Tr p Val Arg G n Al a Pr o Gy Lys Gy Leu G u Tr p Val 35 40 45 Gy Arg I I e Lys Ser Lys Thr Asp Gy Gy Thr Thr Asp Tyr Al a Al a 50 55 60 Pr o Val Lys Gy Arg Phe Thr I I e Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu G n IVbt Asn Ser Leu Lys Thr G u Asp Thr Al a Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gy Tyr Ser I I e Ser Tr p Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gy IVbt Asp Val Tr p Gy G n Gy Thr Thr Val Thr 115 120 125 Val Ser Ser

130 <210> 168 <211> 130 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 168

Q n Val Gl n Leu Val Q u Ser Qy Qy Gly Val Val Qn Pro Qy Arg 15 10 15

Ser Leu Arg Leu Ser Cys Al a Al a Ser Q y Phe Thr Phe Ser Ser Phe 20 25 30

Q y IVfet Hi s Trp Val Arg Q n Al a Pro Q y Lys Q y Leu Qu Trp Val 35 40 45

Al a Val lie Ser Phe Asp Q y Ser I I e Lys Tyr Ser Val Asp Ser Val 50 55 60

Lys Qy Arg Phe Thr I I e Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Q n IVbt Asn Ser Leu Arg Al a Qu Asp Thr Al a Val Tyr Tyr Cys 85 90 95

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Al a Arg Asp Arg 100 Leu Asn Tyr Tyr Asp 105 Ser Ser Qy Tyr Tyr 110 Hi s Tyr Lys Tyr Tyr Qy Leu Al a Val Tr p Qy Q n Qy Thr Thr Val Thr Val

115 120 125

Ser Ser 130 <210> 169 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 169

Q u Val 1 Q n Leu Val 5 Q u Ser Q y Q y Q y 10 Leu Val Lys Pr o Q y Q y 15 Ser Leu Arg Leu Ser Cys Al a Al a Ser Qy Tyr Thr Phe Ser Thr Tyr 20 25 30 Ser IVbt Asn Tr p Val Arg Q n Al a Pr o Qy Lys Qy Leu Q u Tr p Val 35 40 45 Ser Ser I I e Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Al a Asp Ser Val 50 55 60 Lys Qy Arg Phe Thr I I e Ser Arg Asp Asn Al a Lys Asn Ser Leu Tyr 65 70 75 80 Leu Q n IVbt Ser Ser Leu Arg Al a Q u Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Arg Q u Qy Val Ser Qy Ser Ser Pr o Tyr Ser I I e Ser Tr p Tyr 100 105 110 Asp Tyr Tyr Tyr Qy IVbt Asp Val Tr p Qy Q n Qy Thr Thr Val Thr 115 120 125 Val Ser Ser

130 <210> 170 <211> 126 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

Page 115

A1472PCT. t xt

2016244220 11 Oct 2016 <400> 170

G n 1 Val G n Leu Val 5 G u Ser Gy G y G y Val 10 Val G n Pr o Gy 15 Arg Ser Leu Arg Leu Ser Cys Al a Al a Ser Gy Phe Thr Phe Ser Ser Tyr 20 25 30 Gy IVfet Hi s Tr p Val Arg G n Al a Pr o Gy Lys Gy Leu G u Tr p Val 35 40 45 Al a Val I I e Tr p Tyr Asp Gy Ser Asn Lys Tyr Tyr Al a Asp Ser Val 50 55 60 Lys Gy Arg Phe I I e I I e Ser Arg Asp Lys Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu G n IVfet Asn Ser Leu Arg Al a G u Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Arg Al a Gy Gy I I e Al a Al a Al a Gy Leu Tyr Tyr Tyr Tyr Gy 100 105 110 IVfet Asp Val Tr p Gy G n Gy Thr Thr Val Thr Val Ser Ser

115 120 125 <21 0> 171 <211> 118 <212> PRT <213> Ar t i f i ci al Sequence <220> <221 > sour ce <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence: Synt het i c

pol ypept i de <400> 171

G n Val 1 Q n Leu Val 5 Q n Ser G y Al a G u 10 Val Lys Lys Pro Gy Al a 15 Ser Val Lys Val Ser Cys Lys Al a Ser Gy Tyr Thr Phe Thr Al a Tyr 20 25 30 Tyr Leu Hi s Tr p Val Arg G n Al a Pr o Gy G n Gy Leu G u Tr p IVfet 35 40 45 Gy Tr p I I e Asn Pr o Hi s Ser Gy Gy Thr Asn Tyr Al a G n Lys Phe 50 55 60 G n Gy Arg Val Thr IVfet Thr Arg Asp Thr Ser I I e Ser Thr Al a Tyr 65 70 75 80 IVfet G u Leu Ser Arg Leu Arg Ser Asp Asp Thr Al a Val Phe Tyr Cys 85 90 95

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Al a Arg Qy Arg Qn Trp Leu Q y Phe Asp Tyr Trp Gy Gn Gy Thr 100 105 110

Leu Val Thr Val Ser Ser 115 <210> 172 <211> 117 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 172

G n Val G n Leu G n G n Tr p Gy Al a G y Leu Leu Lys Pr o Ser G u 1 5 10 15 Thr Leu Ser Leu Ser Cys Al a Val Tyr Gy Gy Ser Phe Gy Gy Tyr 20 25 30 Tyr Tr p Ser Tr p I I e Arg G n Pr o Pr o Gy Lys Gy Leu G u Tr p I I e 35 40 45 Gy G u I I e Asn Hi s Ser Gy Gy Thr Lys Tyr Asn Pr o Ser Leu Lys 50 55 60 Ser Arg Val Thr I I e Ser Val Asp Thr Ser Lys Asn G n Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Al a Al a Asp Thr Al a Val Tyr Phe Cys Al a 85 90 95 Arg Gy Asp Val Val Gy Phe Phe Asp Tyr Tr p Gy G n Gy Thr Leu 100 105 110 Val Thr Val Ser Ser

115 <210> 173 <211> 120 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 173

G n Val G n Leu Val Q n Ser G y Al a G u Val Lys Lys Ser G y Al a

15 10 15

Ser Val Lys Val Ser Cys Lys Al a Ser Q y Tyr Thr Phe Thr Q y Tyr Page 117

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2016244220 11 Oct 2016

Tyr IVbt Hi s Tr p Val Arg G n Al a Pr o Gy G n Gy Leu G u Tr p IVbt 35 40 45 Qy Tr p I I e Asn Pr o Asn Ser Gy Gy Thr Asn Tyr Val G n Lys Phe 50 55 60 G n Gy Arg Val Thr IVbt Thr Arg Asp Thr Ser I I e Ser Thr Al a Tyr 65 70 75 80 IVbt G u Leu Ser Arg Leu Arg Ser Asp Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Arg Asn G u Tyr Ser Ser Al a Tr p Pr o Leu Gy Tyr Tr p Gy G n 100 105 110 Gy Thr Leu Val Thr Val Ser Ser

115 120 <210> 174 <211> 118 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 174

G n 1 I I e Thr Leu Lys Q u Ser 5 Gy Pr o Thr 10 Leu Val Lys Pr o Thr 15 G n Thr Leu Thr Leu Thr Cys Thr Phe Ser Gy Phe Ser Leu Ser Thr Ser 20 25 30 Gy Val Gy Val Al a Tr p I I e Arg G n Pr o Pr o Gy Lys Al a Leu G u 35 40 45 Tr p Leu Al a Leu I I e Tyr Tr p Thr Asp Asp Lys Arg Tyr Ser Pr o Ser 50 55 60 Leu Lys Ser Arg Leu Thr I I e Thr Lys Asp Thr Ser Lys Asn G n Val 65 70 75 80 Val Leu Arg K/bt Thr Asn IVfet Asp Pr o Leu Asp Thr Al a Thr Tyr Phe 85 90 95 Cys Al a Hi s Arg Pr o Gy Gy Tr p Phe Asp Pr o Tr p Gy G n Gy Thr 100 105 110

Leu Val Thr Val Ser Ser 115

Page 118

A1472PCT. t xt

2016244220 11 Oct 2016 <210> 175 <211> 321 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 175

gacat ccaga t gacccagt c t ccat cct cc ct gt ct gcat ct gt aggaga cagagt cacc 60 at cact t gcc gggcaagt ca gggcat t aga aat gat 11 ag get ggt 11 ca gcagaaacca 120 gggaaagccc ct aagcgcct gat ct at get gcat ccagt t t gcaaagt gg ggt cccat ca 180 aggt t cagcg gcagt ggat c t gggacagaa 11 cact ct ca caat cagcag cct gcagcct 240 gaagat 11 ag caact t at t a ct gt ct acag t at aat at 11 acccgt ggac gt t cggccaa 300 gggaccaagg t ggaaat caa a 321

<210> 176 <211> 321 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 176

gacat ccaga t gacccagt c t ccat cct cc ct gt ct gcat ct gt aggaga cagagt cacc 60 at cact t gcc gggcaagt ca gggcat t aga aaggat 11 ag get ggt at ca gcagaaacca 120 gggaaagccc ct aagcgcct gat ct at gga gcat ccagt t t gcaaagt gg ggt cccat ca 180 aggt t cagcg gcagt ggat c t gggacagaa 11 cact ct ca caat cagcag cct gcagcct 240 gaagat 111 g caact t at t a ct gt ct acag t at aat agt t t cccgt ggac gt t cggccaa 300 gggaccaagg t ggaaat caa a 321

<210> 177 <211> 359 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 177 aggt gcagct ggt gcagt ct ggggct gagg t gaagaagt c t ggggcct ca gt gaaggt ct 60 cct gcaaggc 11 ct ggat ac acct t caccg get act at at gcact gggt g cgacaggccc 120 ctggacaagg gettgagtgg atgggatgga tcaaccctaa cagtggtggc acaaactatg 180 tacagaagtt tcagggcagg gtcaccatga ccagggacac gtccatcage acagcctaca 240

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A1472PCT. t xt

2016244220 11 Oct 2016 t ggagct gag caggct gaga t ct gacgaca cggccgt gt a 11 act gt gcg agaaat gagt at agcagt gc ct ggccct t g gggt at t ggg gccagggaac cct ggt cacc gt ct ct agt <210> 178 <211> 336 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 178 gat at t gt ga at ct cct gca t acct gcaga t ccggggt cc agcagagt gg 11 cact 11 eg t gact cagt c ggt ct agt ca agccagggca ct gacaggt t agget gagga gccct gggac t ccact ct cc gagcct cct g gt ct ccacag cagt ggcagt tgt t ggggt t caaagt ggat ct gcccgt ca cat agt 111 g ct cct gat ct ggat caggca t at t act gca at caaa cccct ggaga ggt acaact a at 11 gggt t c cagat 111 ac t gcaagct ct gccggcct cc 111 ggat t gg t aat egggee act gaaaat c acaaact cca

300

359

120

180

240

300

336 <210> 179 <211> 336 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Arti pol ynucl eot i de <400> 179 gat at t at ac at ct cct gca t acct gcaga t ct ggagt gc agccgggt gg ct cact 11 eg t ggcccagac agt ct agt ca agccaggcca cagat aggt t agget gagga gcggagggac t ccact 11 ct gagcct cct g gcct ccacag cagt ggcagc t gt t gggat t caaggt ggag f i ci al ct gt ccgt ca cacagt get g ct cct gat ct gggt caggga t at t act gca at caaa

Sequence:

Synt het i cccct ggaca gaaagacct a at gaagt 11 c cagat 11 cac t gcaaagt 11 c

gccggcct cc 111 gt at t gg caaccggt t c act gaaaat c t ccgct t ccg

120

180

240

300

336 <210> 180 <211> 336 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 180 gat at t at t c tgacccagac t ccact 11 ct ct gt ccgt ca cccct ggaca gccggcct cc at ct cct gca agt ct agt ca gagcct cct g cacagt gat g gaaagacct a 111 gt at t gg Page 120

120

A1472PCT. t xt

2016244220 11 Oct 2016 t acct gcaga t ct ggagagc agccgggt gg ct cact 11 eg agcccggcca cagat aggt t agget gagga gcggagggac gcct ccacag cagt ggcagc t gt t gggact caaggt ggag ct cct gat ct gggt caggga t at t at t gca at caaa at gaagt 11 c cagat 11 cac t gcaaagt 11 caaccggt t c act gaaaat c t ccgct t ccg <210> 181 <211> 336 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

180

240

300

336

<400> 181 gat at t acac t gacccagac t ccact 11 ct ct gt ccgt ct cccct ggaca gccggcct cc 60 at ct cct gca agt ct agt ca gagcct cct g cacagt gat g gaaggaact a t ct gt at t gg 120 t acct gcaga agccaggcca gcct ccacag ct cct gat ct at gaagt gt c caaccggt t c 180 t ct ggact gc cagat aggt t cagt ggcagc gggt caggga cagat 11 cac act gaaaat c 240 agccgggt gg agget gagga t gt t gggat t t at t act gca t gcaaagt 11 t ccgct t ccg 300 ct cact 11 eg gcggagggac caaggt ggag at caaa 336 <210> 182 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> source <223> 1 not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 182 gaaat t gt gt t gacgcagt c t ccaggcacc ct gt ct 11 gt ct ccagggga aagagccacc 60 ct ct cct gca gggccagt ca gagt gt t age agegget act t aacct ggt a ccagcagaaa 120 cct ggccagg ct cccaggct cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 180 gacaggt t ca gt ggcagt gg gt ct gggaca gact t cact c t caccat cag cagact ggag 240 cct gaagat t 11 gcagt gt a 11 act gt cag cagt at ggt a act cact gt g caggt 11 ggc 300

caggggacca aget ggagat caaa

324 <210> 183 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

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2016244220 11 Oct 2016

<400> 183 gaaat t gt gt t gacgcagt c A1472PCT. t xt aagagccacc 60 t ccaggcacc ct gt ct 11 gt ct ccagggga ct ct cct gca gggccagt ca gagt gt t age agegget act t aacct ggt a ccagcagaaa 120 cct ggccagg ct cccagact cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 180 gacaggt t ca gt ggcagt gg gt ct gggacg gact t cact c t caccat cag cagact ggag 240 cct gaagat t 11 gcagt gt a 11 act gt cag cagt at ggt a act cact gag caggt 11 ggc 300 caggggacca agct ggagat caaa 324

<210> 184 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 184

gaaat agt ga t gacgcagt c t ccagccacc ct gt ct gt gt ct ccagggga aagagccacc 60 ct ct cct gt a gggccagt ca gagt gt t ege agcaat 11 ag cct ggt acca gcagaaacct 120 ggccaggct c ccaggct cct cat t cat gat gcat ccccca ggaccgct gg t at cccagcc 180 aggt t cagt g gcagt ggat c t gggacagaa 11 cact ct ca ccat caacag cct gcagt ct 240 gaagat 111 g cagt 11 at t a ct gt cagcag t at aat t act ggact ccgat cacct t egge 300 caagggacac gact ggagat t aaa 324

<210> 185 <211> 339 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 185 gacat cgt ga tgacccagtc t ccagact cc ct gget gt gt ct ct gggega gagggccacc 60 at caact gca agt ccagcca gagt at 111 a gacagct cca acaat gat aa ct act t agct 120 tggtaccagc agaaaccagg acagcct cct aaact get ca 111 act gggc at ct acccgg 180 gaat ccgggg t ccct gaccg at t cagt ggc agcgggt ct g ggacagat 11 cact ct cacc 240 at cagcagcc t gcaggct ga agat gt ggca gt 11 at t act gt cagcaat a 11 at aat act 300 ccat t cact t t cggccct gg gaccaaagt g gat at caaa 339

<210> 186 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220>

Page 122

A1472PCT. t xt

2016244220 11 Oct 2016 <221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 186

cagt ct gt gt t gacgcagcc gccct cagt g t ct gaggccc caggacagaa ggt caccat c 60 t cct get ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagct c 120 ccaggaacag cccccaaact cct cat 11 at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t cagccaccc t gggcat cac cggact ccag 240 act ggggacg aggeegat t a 11 act gegga acat gggat a gccgcct gag t get gt ggt t 300 11 eggeggag ggaccaagct gaccgt cct a 330

<210> 187 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 187 cagtctgtgt tgacgcagcc gccct cagt g t ct gcggccc caggacagaa ggt caccat c 60 t cct get ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagct c 120 ccaggaacag cccccaaact cct cat 11 at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t caaccaccc t gggcat cac cggact ccag 240 act ggggacg aggeegat t a 11 act gegga acat gggat a gccgcct gag t get gt ggt t 300 tteggeggag ggaccaagct gaccgt cct a 330

<210> 188 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 188 cagtctgtgt tgacgcagcc gccct cagt g t ct gcggccc caggacagaa ggt caccat c 60 t cct get ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagt t c 120 ccaggaacag cccccaaact cct cat 11 at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t cagccaccc t gggcat cac cggact ccag 240 act ggggacg aggeegat t a 11 act gegga acat gggat a gccgcct gag t get gt ggt t 300 tteggeggag ggaccaagct gaccgt cct a 330

<210> 189 <211> 330

Page 123

A1472PCT. t xt

2016244220 11 Oct 2016 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 189

cagt ct gt gt t gacgcagcc gccct cagt g t ct gcggccc caggacagaa ggt caccat c 60 t cct get ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagct c 120 ccaggaacag cccccaaact cct cat 11 at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t cagccaccc t gggcat cac cggact ccag 240 act ggggacg aggeegat t a 11 act gegga acat gggat a gccgcct gag t get gt ggt t 300 11 eggeggag ggaccaagct gaccgt cct a 330

<210> 190 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 190 cagtctgtgt tgacgcagcc gccct caat g t ct gcggccc caggacagaa ggt caccat c 60 t cct get ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagct c 120 ccaggaacag cccccaaact cct cat 11 at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t cagccaccc t gggcat cac cggact ccag 240 act ggggacg aggccaat t a ct get gegga acat gggat a t cggcct gag t gt 11 gggt g 300 tteggeggag ggaccaaact gaccgt cct a 330

<210> 191 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 191 cagt ct gt gc tgactcagcc accct cagcg t ct gggaccc ccgggcagag ggt caccat c 60 t ct t gt t ct g gaagcagt t c caat at egga agt aat act g t gaact ggt a ccagcagct c 120 ccaggaacgg cccccaaact cct cat ct at act aat aat c agcggccct c aggggt ccct 180 gaccgat t ct ct ggct ccaa gt ct ggcacc t cagcct ccc t ggccat cag t ggact ccag 240 t ct gaggat g agget gat 11 11 act gt gca gegegggat g agagcct gaa tggt gt ggt a 300 tteggeggag ggaccaagct gaccgt cct a 330

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A1472PCT. t xt

2016244220 11 Oct 2016 <210> 192 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 192

cagt ct gt gc t gact cagcc accct cagcg t ct gggaccc ccgggcagag agt caccat c 60 t ct t gt t ct g gaagcagct c caacat cggc agt aat t at g t at act ggt a ccagcagct c 120 ccaggagcgg cccccaaact cct cat ct 11 aggaat aat c agcggccct c aggggt ccct 180 gaccgct t ct ct ggct ccaa gt ct ggcacc t cagcct ccc t ggccat cag t ggget ccgg 240 t ccgaggat g aggct gat t a 11 act gt gca gcat gggat g acagcct gag tggttgggtg 300 11 cggcggag ggaccaagct gaccgt cct a 330

<210> 193 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 193

cagt ct gt gc t gact cagcc accct cagcg t ct gggaccc ccgggcagag agt caccat c 60 t ct t gt t ct g gaagcagct c caacat cggc agt aat t at g t at act ggt a ccagcagct c 120 ccaggagcgg cccccaaact cct cat ct 11 aggagt aat c agcggccct c aggggt ccct 180 gaccgat t ct ct ggct ccaa gt ct ggcacc t cagcct ccc t ggccat cag t ggget ccgg 240 t ccgaggat g aggct gat t a 11 act gt gca gcat gggat g acagcct gag tggttgggtg 300 11 cggcggag ggaccaagct gaccgt cct a 330

<210> 194 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 194 cagtctgtgc tgactcagtc accctcagcg tctgggaccc ccgggcagag agtcaccatc 60 t ct t gt t ct g gaagcagct c caacat cggc agt aat t at g t at act ggt a ccagcagct c 120 ccaggagcgg cccccaaact cctcatcctt aggaataatc agcggccctc aggggtccct 180 gaccgat t ct ct ggct ccaa gt ct ggcacc t cagcct ccc t gaccat cag t ggget ccgg 240

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A1472PCT. t xt

2016244220 11 Oct 2016 t ccgaggat g aggct gact a 11 at t gt gca gcat gggat g acagcct gag t ggt t gggt g 300 ttcggcggag ggaccaagct gaccgtccta 330 <210> 195 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

<400> 195 t ct t ct gage t gact cagga ccct act gt g t ct gt ggcct t gggacagac agt caaaat c 60 acat gccaag gagacagcct cagaagt 111 t at gcaagct ggt accagca gaagccagga 120 caggcccct g t act t gt ct t ct at ggt aaa aacaaccggc cct cagggat cccagaccga 180 11 ct ct gget ccagct cagg aaacacagct t cct t gacca t cact ggggc t caggcggaa 240 gat gagget g act at t at t g t aat t cccgg gacagcagt g 111 accat ct ggt act egge 300 ggagggacca aget gaccgt cct a 324

<210> 196 <211> 390 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 196

caggt gcagt t ggt gcagt c t ggggct gag gt gaagaagc ct ggggcct c agt gaaggt c 60 t cct gcaagg ct t ct ggat a cacct t cacc gget act at a t gcact gggt gcgacaggcc 120 cct ggacaag gget t gagt g gat gggat gg at caaccct a acagt ggt gg cacaaact at 180 gcacagaagt 11 cagggcag ggt caccat g accagggaca cgt ccat cag cacagcct ac 240 at ggaget ga gcaggct gag at ct gacgac aeggeegt gt at 11 ct gt gc gagagat caa 300 at gagt at t a 11 at get t eg gggagt 1111 ccccct t act at t aeggt at ggacgt ct gg 360 ggccaaggga ccacggt cac cgt ct ct agt 390

<210> 197 <211> 381 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 197 caggt gcagc t ggt gcagt c t ggggct gag gt gaagaagc ct ggggcct c agt gaaggt c 60

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2016244220 11 Oct 2016

t cct gcaagg ct t ct ggat a cacct t cacc gact act at a t gt act gggt gcgacaggcc 120 cct ggacaag ggct t gagt g gat gggat gg at cagccct a at agt ggt gg cacaaact at 180 gcccagaagt 11 cagggcag ggt caccat g accagggaca cgt ct at cag cacagcct ac 240 at ggagct ga gt aggct gag at ct gacgac acggccgt gt at t act gt gt gagaggagga 300 t at agt ggct acgct gggct ct act cccac t act acggt a t ggacgt ct g gggccaaggg 360 accacggt ca ccgt ct ct ag t 381

<210> 198 <211> 354 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

<400> 198 caggt gcagc t ggt gcagt c t ggggct gag gt gaagaagc ct ggggcct c agt gaaggt c 60 t cct gcaagg ct t ct ggat a cacct t cacc gcct act at t t acact gggt gcgacaggcc 120 cct ggacaag ggct t gagt g gat gggat gg at caaccct c acagt ggt gg cacaaact at 180 gcacagaagt 11 cagggcag ggt caccat g accagggaca cgt ccat cag cacagcct ac 240 at ggagct ga gcaggct gag at ct gacgac acggccgt gt t ct act gt gc gagaggaagg 300 cagt ggct gg get 11 gact a ct ggggccag ggaaccct gg t caccgt ct c t agt 354

<210> 199 <211> 321 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 199

gacat ccaga t gacccagt c t ccat cct cc ct gt ct gcat ct gt aggaga cagagt t acc 60 at t act t gcc gggcaagt ca gggcat t aga aat gat 11 ag get ggt at ca gcagaaacca 120 gggaaagccc ct aagcgcct gat ct at gt t gcat ccagt t t gcaaagt gg ggt cccat ca 180 aggt t cagcg gcagt ggat c t gggacagaa 11 cact ct ca caat cagcag cct gcagcct 240 gaagat 111 g caact t at t a ct gt ct acag t at aacact t acccgct cac 111 eggegga 300 gggaccaagg t ggagat caa g 321

<210> 200 <211> 393 <212> DNA <213> Ar t i f i ci al Sequence <220>

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A1472PCT. t xt

2016244220 11 Oct 2016 <221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 200

gaggt acagc tggtggagtc tgggggaggc 11 ggt aaagc ct ggggggt c cct cagact c 60 t cct gt gcag cct ct ggat t cact 11 cggt aacgcct gga t gagct gggt ccgccaggct 120 ccagggaagg ggct ggagt g ggt t ggccgt at t aaaagca aaact gat gg t gggacaaca 180 gact acgct g cacccgt gaa aggcagat t c accat ct caa gagat gat t c aaaaaacacg 240 ct gt at ct gc aaat gaacag cct gaaaacc gaggacacag ccgt gt at 11 ct gt accaca 300 gat cggaccg ggt at agcat cagct ggt ct agt t act act act act acgg t at ggacgt c 360 t ggggccaag ggaccacggt caccgt ct ct agt 393

<210> 201 <211> 393 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 201

gaggt gcagc t ggt ggagt c tgggggaggc 11 ggt aaagc ct ggggggt c cct t agact c 60 t cct gt gcag cct ct ggat t cact 11 cagt aacgcct gga t gagct gggt ccgccaggct 120 ccagggaagg ggct ggagt g ggt t ggccgt at t aaaagca aaact gat gg t gggacaaca 180 gact acact g cacccgt gaa aggcagat t c accat ct caa gagat gat t c aaaaaacacg 240 ct gt at ct gc aaat gaat ag cct gaaagcc gaggacacag ccgt gt at t a ct gt accaca 300 gat cggaccg ggt at agcat cagct ggt ct agt t act act act act acgg t at ggacgt c 360 t ggggccaag ggaccacggt caccgt ct ct agt 393

<210> 202 <211> 393 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Arti pol ynucl eot i de <400> 202 gaggt acagc t cct gt gcag ccagggaagg gact acgct g ct gt at ct gc gat cggaccg t ggt ggagt c cct ct ggat t ggct ggagt g cacccgt gaa aaat gaacag ggt at agcat tgggggaggc cact 11 cggt ggt t ggccgt aggcagat t c cct gaaaacc cagct ggt ct f i ci al

11 ggt aaagc aacgcct gga at t aaaagca accat ct caa gaggacacag agt t act act

Page 128

Sequence:

Synt het i ct ggggggt c t gagct gggt aaact gat gg gagat gat t c ccgt gt at t a act act acgg c

cct t agact c ccgccaggct t gggacaaca aaaaaacacg ct gt accaca t at ggacgt c

120

180

240

300

360

A1472PCT. t xt

2016244220 11 Oct 2016 tggggccaag ggaccacggt caccgtctct agt 393 <210> 203 <211> 393 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 203

gaggt gcagc t ggt ggagt c tgggggaggc 11 ggt aaagc ct ggggggt c cct t agact c 60 t cct gt gcag cct ct ggat t cact 11 cagt aacgcct gga t gagct gggt ccgccaggct 120 ccagggaagg ggct ggagt g ggt t ggccgt at t aaaagca caact gat gg t gggacaaca 180 gact acgct g cacccgt gaa aggcagat t c accat ct caa gagat gat t c aaaaaacacg 240 ct gt at ct gc aaat gaacag cct gaaaacc gaggacacag ccgt gt at t a ct gt accaca 300 gat cggaccg gat at agcat cagct ggt ct agt t act act act act acgg t at ggacgt c 360 t ggggccaag ggaccacggt caccgt ct ct agt 393

<210> 204 <211> 393 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 204

gaggt gcagc t ggt ggagt c tgggggaggc ct ggt caagc ct ggggggt c cct gagact c 60 t cct gt gcag cct ct ggat a cacct t cagt acct at agca t gaact gggt ccgccaggct 120 ccagggaagg ggct ggagt g ggt ct cat cc at t agt agt a gt agt agt t a cagat at t ac 180 gcagact cag t gaagggccg at t caccat c t ccagagaca acgccaagaa ct cact gt at 240 ct gcaaat ga gt agcct gag agccgaggac aegget gt gt at t act gt gc gagagaaggg 300 gt gt ct ggca gt t cgccgt a t agcat cage t ggt acgact act at t acgg t at ggacgt c 360 t ggggccaag ggaccacggt caccgt ct ct agt 393

<210> 205 <211> 390 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 205 gaggt gcagc t at t ggagt c t gggggaggc 11 ggt acagc ct ggggagt c cct gagact c 60

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A1472PCT. t xt

2016244220 11 Oct 2016 t cct gt gcag ccagggaagg gcagact ccg ct gcaaat ga agggaggtag ggccaaggga

cct ct gggt t cacct 11 age aget at gcca t gaget gggt ccgccaggct 120 ggct ggagt g ggt ct cagct at t agt ggt a gt ggt ggt eg cacat act ac 180 t gaagggccg gt t caccat c t ccagagaca at t ccaagaa cacgct gt at 240 at agcct gag agccgaggac aeggeegt at at t act gt gc gaaagat caa 300 ggccgt at ag cagt ggct gg t acgact act act aeggt at ggacgt ct gg 360 ccacggt cac cgt ct ct agt 390

<210> 206 <211> 387 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 206

caggt gcagc t ggt ggagt c tgggggaggc gt ggt ccagc ct gggaggt c cct gagact c 60 t cct gt gcag cct ct ggat t cacct t cagt aget at ggca t gcact gggt ccgccaggct 120 ccaggcaagg ggct ggagt g ggt ggcagt t at 11 cat at g at ggaagt ca t gaat cct at 180 gcagact ccg t gaagggccg at t caccat c t ccagagaca 111 ccaagaa cacgct gt at 240 ct gcaaat ga acagcct gag aget gaggac aegget gt gt at 11 ct gt gc gagagagagg 300 aaacgggt t a egat gt ct ac ct t at at t ac t act t ct act aeggt at gga cgt ct ggggc 360 caagggacca eggt caccgt ct ct agt 387

<210> 207 <211> 390 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 207 caggt gcagc t ggt ggaat c tgggggaggc gt ggt ccagc ct gggaggt c cct gagact c 60 t cct gt gcag cct ct ggat t cacct t cagt aget 11 ggca t gcact gggt ccgccaggct 120 ccaggcaagg ggctggagtg ggt ggcagt t at at cat 11 g at ggaagt at t aagt at t ct 180 gtagactccg tgaagggccg at t caccat c t ccagagaca at t caaagaa cacgct gt 11 240 ctgcaaatga acagcctgeg agccgaggac aegget gt gt at t act gt gc gagagat egg 300 ct caat t act at gat agt ag t ggt t at t at cact acaaat act aeggt at ggccgt ct gg 360 ggccaaggga ccacggtcac cgt ct ct agt 390

<210> 208 <211> 390

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A1472PCT. t xt

2016244220 11 Oct 2016 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> 1 not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 208 caggt gcagc t ggt ggaat c tgggggaggc gt ggt ccagc ct gggaggt c cct gagact c 60 t cct gt gcag cct ct ggat t cacct t cagt agct 11 ggca t gcat t gggt ccgccaggct 120 ccaggcaagg ggctggagtg ggt ggcagt t at at cat 11 g at ggaagt at t aagt act ct 180 gtagactccg tgaagggccg at t caccat c t ccagagaca at t caaagaa cacgct gt 11 240 ct gcaaat ga acagcctgcg agccgaggac acggct gt gt at t act gt gc gagagat egg 300 ct caat t act at gat agt ag t ggt t at t at cact acaaat act acggt ct ggccgt ct gg 360 ggccaaggga ccacggtcac cgt ct ct agt 390

<210> 209 <211> 363 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 209

gaggt gcagc t ggt ggagt c tgggggaggc 11 ggt aaagc cagggcggt c cct gagact c 60 t cct gt acag ct t ct ggat t cacct 11 ggt gat t at get a t gaget ggt t ccgccaggct 120 ccagggaagg ggct ggagt g gat aggt 11 c at t agaagca gaget t at gg t gggacacca 180 gaat acgccg cgt ct gt gaa aggcagat t c accat ct caa gagat gat t c caaaaccat c 240 gcct at ct gc aaat gaacag cct gaaaacc gaggacacag ccgt gt at 11 ct gt get aga 300 ggacggggt a 11 gcagct eg 11 gggact ac t ggggccagg gaaccct ggt caccgt ct ct 360 agt 363

<210> 210 <211> 378 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 210 caggt gcagc t cct gt gcag ccaggcaagg gcagact ccg t ggt ggagt c cgt ct ggat t ggct ggagt g t gaagggccg tgggggaggc cacct t cagt ggt ggcagt t at t cat cat c gt ggt ccagc agct at ggca at at ggt at g t ccagagat a Page 131 ct gggaggt c t gcact gggt at ggaagt aa aat ccaagaa cct gagact c ccgccaggct t aaat act at cacgct gt at

120

180

240

A1472PCT. t xt

2016244220 11 Oct 2016

ct gcaaat ga acagcct gag agccgaggac acggct gt gt at t act gt gc gagagcgggg 300 ggt at agcag cagct ggcct ct act act ac t acggt at gg aegt ct gggg ccaagggacc 360 acggt caccg t ct ct agt 378 <210> 211 <211> 351 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> source <223> 1 not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 211 caggt gcagt t acagcagt g gggcgcagga ct gt t gaagc ct t cggagac cct gt ccct c 60 agct gcgct g t ct at ggt gg gt cct t cggt ggt t act act ggaget ggat ccgccagccc 120 ccagggaagg ggct ggagt g gat t ggggaa at caat cat a gt ggaggcac caagt acaac 180 ccgt ccct ca agagt cgagt caccat at ca gt agacacgt ccaagaacca gt t ct ccct g 240 aagct gagct ct gt gaccgc cgcggacacg get gt gt at t t ct gt gegag aggegat gt a 300 gt aggt 11 ct 11 gact at t g gggccaggga accct ggt ca ccgt ct ct ag t 351

<210> 212 <211> 354 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 212

cagat cacct t aaaggagt c t ggt cct aeg ct ggt gaaac ccacacagac cct cacgct g 60 acct gcacct t ct ct gggt t ct cact cage act agt ggt g tgggtgtggc ct ggat ccgt 120 cagccccccg gaaaggccct ggagt ggct t gcact cat 11 at t ggact ga t gat aagege 180 t acagt ccat ct ct gaagag caggct cacc at caccaagg acacct ccaa gaaccaggt g 240 gt cct t agaa t gaccaacat ggaccct 11 g gacacagcca ct t at 11 ct g t gcacacaga 300 ccagggggct ggt t cgaccc ct ggggccag ggaaccct gg t caccgt ct c t agt 354

<210> 213 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 213

Gy Gy Gy Gy Gy Val Asp G y G y G y G y G y Val Page 132

2016244220 11 Oct 2016

A1472PCT. t xt

1 5 10 <210> 214 <211> 148 <212> PRT <213> Rat t us sp.

<400> 214

l\/bt Al a Pr o Qy Leu Arg Qy Leu Pr o Arg Arg Qy Leu Tr p Leu Leu 1 5 10 15 Leu Al a Hi s Hi s Leu Phe IVbt Val Thr Al a Cys Arg Asp Pr o Asp Tyr 20 25 30 Qy Thr Leu I I e Q n Q u Leu Cys Leu Ser Arg Phe Lys Q u Asp IVfet 35 40 45 Q u Thr I I e Qy Lys Thr Leu Tr p Cys Asp Tr p Qy Lys Thr I I e Qy 50 55 60 Ser Tyr Qy Q u Leu Thr Hi s Cys Thr Lys Leu Val Al a Asn Lys I I e 65 70 75 80 Qy Cys Phe Tr p Pr o Asn Pr o Q u Val Asp Lys Phe Phe I I e Al a Val 85 90 95 Hi s Hi s Arg Tyr Phe Ser Lys Cys Pr o Val Ser Qy Arg Al a Leu Arg 100 105 110 Asp Pr o Pr o Asn Ser I I e Leu Cys Pr o Phe I I e Val Leu Pr o I I e Thr 115 120 125 Val Thr Leu Leu IVbt Thr Al a Leu Val Val Tr p Arg Ser Lys Arg Thr 130 135 140 Q u Qy I I e Val

145 <210> 215 <211> 148 <212> PRT

<213> IVhcaca fasciculari <400> 215 s Q n Arg Q y Leu Trp Leu Leu IVbt 1 Al a Ar g Al a Leu 5 Cys Arg Leu Pr o 10 15 Leu Al a Hi s Hi s 20 Leu Phe IVbt Al a Thr 25 Al a Cys Qn Qu Ala Asn 30 Tyr Qy Al a Leu 35 Leu Q n Q u Leu Cys 40 Leu Thr Q n Phe Q n Val Asp 45 IVfet Q u Al a Val Qy Q u Thr Leu Trp Cys AspTrpQyArgThr lie Page 133 Qy

A1472PCT. t xt

2016244220 11 Oct 2016

50 55 60 Ser Tyr Arg G u Leu Al a Asp Cys Thr Tr p Hi s IVfet Al a G u Lys Leu 65 70 75 80 Gy Cys Phe Tr p Pr o Asn Al a G u Val Asp Arg Phe Phe Leu Al a Val 85 90 95 Hi s Gy Hi s Tyr Phe Arg Al a Cys Pr o I I e Ser Gy Arg Al a Val Arg 100 105 110 Asp Pr o Pr o Gy Ser Val Leu Tyr Pr o Phe I I e Val Val Pr o I I e Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p G n Ser Lys Hi s Thr 130 135 140 G u Gy I I e Val

145 <210> 216 <211> 148 <212> PRT

<213> IVfecaca rrulatta Pr o Q n Arg Gy Leu Trp Leu Leu <400> 216 Leu Cys 5 Arg Leu IVfet 1 Al a Ar g Al a 10 15 Leu Al a Hi s Hi s Leu Phe IVfet Al a Thr Al a Cys G n G u Al a Asn Tyr 20 25 30 Gy Al a Leu Leu G n G u Leu Cys Leu Thr G n Phe G n Val Asp IVfet 35 40 45 G u Al a Val Gy G u Thr Leu Tr p Cys Asp Tr p Gy Arg Thr I I e Gy 50 55 60 Ser Tyr Arg G u Leu Al a Asp Cys Thr Tr p Hi s IVfet Al a G u Lys Leu 65 70 75 80 Gy Cys Phe Tr p Pr o Asn Al a G u Val Asp Arg Phe Phe Leu Al a Val 85 90 95 Hi s Gy Hi s Tyr Phe Arg Al a Cys Pr o I I e Ser Gy Arg Al a Val Arg 100 105 110 Asp Pr o Pr o Gy Ser Val Leu Tyr Pr o Phe I I e Val Val Pr o I I e Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p G n Ser Lys Hi s Thr 130 135 140

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G u G y I I e Val 145 <210> 217 <211> 148 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 217

IVbt 1 Al a Arg Ala Leu Cys Arg Leu Pro Arg Arg Gy Leu Trp Leu Leu 5 10 15 Leu Al a Hi s Hi s Leu Phe IVbt Thr Thr Al a Cys Arg Asp Pr o Asp Tyr 20 25 30 Gy Thr Leu Leu Arg G u Leu Cys Leu Thr G n Phe G n Val Asp IVfet 35 40 45 G u Al a Val Gy G u Thr Leu Tr p Cys Asp Tr p Gy Arg Thr I I e Arg 50 55 60 Ser Tyr Arg G u Leu Al a Asp Cys Thr Tr p Hi s IVfet Al a G u Lys Leu 65 70 75 80 Gy Cys Phe Tr p Pr o Asn Al a G u Val Asp Arg Phe Phe Leu Al a Val 85 90 95 Hi s Gy Arg Tyr Phe Arg Ser Cys Pr o I I e Ser Gy Arg Al a Val Arg 100 105 110 Asp Pr o Pr o Gy Ser I I e Leu Tyr Pr o Phe I I e Val Val Pr o I I e Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p G n Ser Lys Arg Thr

130 135 140

G u G y I I e Val 145 <210> 218 <211> 148 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 218

IVbt Al a Arg Al a Leu Cys Arg Leu Pro Arg Arg Gy Leu Trp Leu Leu Page 135

A1472PCT. t xt

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1 5 10 15 Leu Al a Hi s Hi s Leu Phe K/bt Thr Thr Al a Cys Q n Q u Al a Asn Tyr 20 25 30 Q y Al a Leu Leu Ar g Q u Leu Cys Leu Thr Arg Phe Lys Q u Asp IVbt 35 40 45 G u Thr I I e G y Lys Thr Leu Trp Cys Asp Trp Gy Arg Thr lie Ar g 50 55 60 Ser Tyr Arg G u Leu Al a Asp Cys Thr Tr p Hi s IVbt Al a Q u Lys Leu 65 70 75 80 Q y Cys Phe Tr p Pr o Asn Al a Q u Val Asp Arg Phe Phe Leu Al a Val 85 90 95 Hi s Gy Ar g Tyr Phe Arg Ser Cys Pro I I e Ser Gy Arg Al a Val Arg 100 105 110 Asp Pro Pro Gy Ser I I e Leu Tyr Pr o Phe lie Val Val Pro lie Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Q n Ser Lys Ar g Thr 130 135 140 G u G y I I e Val 145 <210> 219 <211> 148 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> source <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence: Synt het i c pol ypept i de <400> 219 IVbt Al a Ar g Al a Leu Cys Arg Leu Pro Ar g Ar g Gy Leu Tr p Leu Leu 1 5 10 15 Leu Al a Hi s Hi s Leu Phe K/bt Thr Thr Al a Cys Q n Q u Al a Asn Tyr 20 25 30 Q y Al a Leu Leu Ar g Q u Leu Cys Leu Thr G n Phe G n Val Asp IVbt 35 40 45 G u Al a Val Gy G u Thr Leu Tr p Cys Asp Trp Gy Arg Thr lie Ar g 50 55 60 Ser Tyr G y Q u Leu Thr Hi s Cys Thr Lys Leu Val Al a Asn Lys Leu 65 70 75 80

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Qy Cys Phe Tr p Pr o Asn Al a Q u Val Asp Arg Phe Phe Leu Al a Val 85 90 95 Hi s Qy Arg Tyr Phe Arg Ser Cys Pr o I I e Ser Qy Arg Al a Val Arg 100 105 110 Asp Pr o Pr o Gy Ser I I e Leu Tyr Pr o Phe I I e Val Val Pr o I I e Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Q n Ser Lys Arg Thr 130 135 140 Q u Gy I I e Val

145 <210> 220 <211> 464 <212> PRT <213> Rat t us sp.

<400> 220

IVbt IVbt Asp Lys Lys Cys Thr Leu Cys Phe Leu Phe Leu Leu Leu Leu 1 5 10 15 Asn IVbt Al a Leu I I e Al a Al a Q u Ser Q u Q u Qy Al a Asn Q n Thr 20 25 30 Asp Leu Qy Val Thr Arg Asn Lys I I e IVbt Thr Al a Q n Tyr Q u Cys 35 40 45 Tyr Q n Lys I I e IVbt Q n Asp Pr o I I e Q n Q n Qy Q u Qy Leu Tyr 50 55 60 Cys Asn Arg Thr Tr p Asp Qy Tr p Leu Cys Tr p Asn Asp Val Al a Al a 65 70 75 80 Qy Thr Q u Ser IVbt Q n Tyr Cys Pr o Asp Tyr Phe Q n Asp Phe Asp 85 90 95 Pr o Ser Q u Lys Val Thr Lys I I e Cys Asp Q n Asp Qy Asn Tr p Phe 100 105 110 Arg Hi s Pr o Asp Ser Asn Arg Thr Tr p Thr Asn Tyr Thr Leu Cys Asn 115 120 125 Asn Ser Thr Hi s Q u Lys Val Lys Thr Al a Leu Asn Leu Phe Tyr Leu 130 135 140 Thr I I e I I e Gy Hi s Q y Leu Ser I I e Al a Ser Leu I I e I I e Ser Leu 145 150 155 160

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2016244220 11 Oct 2016

A1472PCT. t xt I I e I I e Phe Phe Tyr 165 Phe Lys Ser Leu Ser 170 Cys G n Arg I I e Thr 175 Leu Hi s Lys Asn Leu 180 Phe Phe Ser Phe Val 185 Cys Asn Ser I I e Val 190 Thr I I e I I e Hi s Leu 195 Thr Al a Val Al a Asn 200 Asn G n Al a Leu Val 205 Al a Thr Asn Pr o Val 210 Ser Cys Lys Val Ser 215 G n Phe I I e Hi s Leu 220 Tyr Leu l\/bt Gy Cys 225 Asn Tyr Phe Tr p l\/bt 230 Leu Cys G u Gy I I e 235 Tyr Leu Hi s Thr Leu 240 I I e Val Val Al a Val 245 Phe Al a G u Lys G n 250 Hi s Leu l\/bt Tr p Tyr 255 Tyr Phe Leu Gy Tr p 260 Gy Phe Pr o Leu Leu 265 Pr o Al a Cys I I e Hi s 270 Al a I I e Al a Arg Ser 275 Leu Tyr Tyr Asn Asp 280 Asn Cys Tr p I I e Ser 285 Ser Asp Thr Hi s Leu 290 Leu Tyr I I e I I e Hi s 295 Gy Pr o I I e Cys Al a 300 Al a Leu Leu Val Asn 305 Leu Phe Phe Leu Leu 310 Asn I I e Val Arg Val 315 Leu I I e Thr Lys Leu 320 Lys Val Thr Hi s G n 325 Al a G u Ser Asn Leu 330 Tyr l\/bt Lys Al a Val 335 Arg Al a Thr Leu I I e 340 Leu Val Pr o Leu Leu 345 Gy I I e G u Phe Val 350 Leu Phe Pr o Tr p Arg 355 Pr o G u Gy Lys Val 360 Al a G u G u Val Tyr 365 Asp Tyr Val l\/bt Hi s 370 I I e Leu IVfet Hi s Tyr 375 G n Gy Leu Leu Val 380 Ser Thr I I e Phe Cys 385 Phe Phe Asn Gy G u 390 Val G n Al a I I e Leu 395 Arg Arg Asn Tr p Asn 400 G n Tyr Lys I I e G n 405 Phe Gy Asn Gy Phe 410 Ser Hi s Ser Asp Al a 415 Leu Arg Ser Al a Ser 420 Tyr Thr Val Ser Thr 425 I I e Ser Asp Val G n 430 Gy Tyr

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2016244220 11 Oct 2016

Ser Hi s Asp 435 A1472PCT. t xt Cys Pr o Thr Q u Hi s 440 Leu Asn Q y Lys Ser 445 I I e G n Asp I I e G u Asn Val Al a Leu Lys Pr o G u Lys IVbt Tyr Asp Leu Val IVbt 450 455 460 <210> 221 <211 > 461 <212> PRT <213> IVhcaca fasciculari s <400> 221 l\/bt G u Lys Lys Cys Thr Leu Tyr Phe Leu Val Leu Leu Pr o Phe Phe 1 5 10 15 l\/bt I I e Phe Val Thr Al a G u Leu G u G u Ser Pr o G u Asp Ser I I e 20 25 30 G n Leu Gy Val Thr Arg Asn Lys I I e IVbt Thr Al a G n Tyr G u Cys 35 40 45 Tyr G n Lys I I e IVbt G n Asp Pr o I I e G n G n Al a G u Gy Val Tyr 50 55 60 Cys Asn Arg Thr Tr p Asp Gy Tr p Leu Cys Tr p Asn Asn Val Al a Al a 65 70 75 80 Gy Thr G u Ser IVbt G n Leu Cys Pr o Asp Tyr Phe G n Asp Phe Asp 85 90 95 Pr o Ser G u Lys Val Thr Lys I I e Cys Asp G n Asp Gy Asn Tr p Phe 100 105 110 Arg Hi s Pr o Al a Ser Asn Arg Thr Tr p Thr Asn Tyr Thr G n Cys Asn 115 120 125 Val Asn Thr Hi s G u Lys Val Lys Thr Al a Leu Asn Leu Phe Tyr Leu 130 135 140 Thr I I e I I e Gy Hi s G y Leu Ser I I e Al a Ser Leu Leu I I e Ser Leu 145 150 155 160 Gy I I e Phe Phe Tyr Phe Lys Ser Leu Ser Cys G n Arg I I e Thr Leu 165 170 175 Hi s Lys Asn Leu Phe Phe Ser Phe Val Cys Asn Ser Val Val Thr I I e 180 185 190 I I e Hi s Leu Thr Al a Val Al a Asn Asn G n Al a Leu Val Al a Thr Asn 195 200 205 Pr o Val Ser Cys Lys Val Ser G n Phe I I e Hi s Leu Tyr Leu IVbt Gy 210 215 220

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Cys 225 Asn Tyr Phe Trp IVbt 230 Leu Cys G u Gy I I e 235 Tyr Leu Hi s Thr Leu 240 I I e Val Val Al a Val Phe Al a G u Lys G n Hi s Leu IVbt Tr p Tyr Tyr 245 250 255 Phe Leu G y Tr p G y Phe Pr o Leu I I e Pr o Al a Cys I I e Hi s Al a I I e 260 265 270 Al a Arg Ser Leu Tyr Tyr Asn Asp Asn Cys Tr p I I e Ser Ser Asp Thr 275 280 285 Hi s Leu Leu Tyr I I e I I e Hi s G y Pr o I I e Cys Al a Al a Leu Leu Val 290 295 300 Asn Leu Phe Phe Leu Leu Asn I I e Val Arg Val Leu I I e Thr Lys Leu 305 310 315 320 Lys Val Thr Hi s G n Al a G u Ser Asn Leu Tyr IVbt Lys Al a Val Arg 325 330 335 Al a Thr Leu I I e Leu Val Pr o Leu Leu G y I I e G u Phe Val Leu I I e 340 345 350 Pr o Tr p Arg Pr o G u Gy Lys I I e Al a G u G u Val Tyr Asp Tyr I I e 355 360 365 IVbt Hi s I I e Leu IVbt Hi s Phe G n G y Leu Leu Val Ser Thr I I e Phe 370 375 380 Cys Phe Phe Asn G y G u Val G n Al a I I e Leu Arg Arg Asn Tr p Asn 385 390 395 400 G n Tyr Lys I I e G n Phe G y Asn Ser Phe Ser Asn Ser G u Al a Leu 405 410 415 Arg Ser Al a Ser Tyr Thr Val Ser Thr I I e Ser Asp G y Pr o G y Tyr 420 425 430 Ser Hi s Asp Cys Pr o Ser G u Hi s Leu Asn Gy Lys Ser I I e Hi s Asp 435 440 445 I I e G u Asn Val Val Leu Lys Pr o G u Asn Leu Tyr Asn 450 455 460 <210> 222 <211 > 461 <212> PRT <213> IVbcaca rrul at t a

<400> 222

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l\/bt 1 Q u Lys Lys Cys 5 Thr Leu Tyr Phe Leu 10 Val Leu Leu Pr o Phe 15 Phe l\/bt I I e Phe Val 20 Thr Al a Q u Leu Q u 25 Q u Ser Pr o Q u Asp 30 Ser I I e Q n Leu Qy 35 Val Thr Arg Asn Lys 40 I I e IVbt Thr Al a Q n 45 Tyr Q u Cys Tyr Q n 50 Lys I I e IVbt Q n Asp 55 Pr o I I e Q n Q n Al a 60 Q u Qy Val Tyr Cys 65 Asn Arg Thr Tr p Asp 70 Qy Tr p Leu Cys Tr p 75 Asn Asn Val Al a Al a 80 Qy Thr Q u Ser IVbt 85 Q n Leu Cys Pr o Asp 90 Tyr Phe Q n Asp Phe 95 Asp Pr o Ser Q u Lys 100 Val Thr Lys I I e Cys 105 Asp Q n Asp Qy Asn 110 Tr p Phe Arg Hi s Pr o 115 Al a Ser Asn Arg Thr 120 Tr p Thr Asn Tyr Thr 125 Q n Cys Asn Val Asn 130 Thr Hi s Q u Lys Val 135 Lys Thr Al a Leu Asn 140 Leu Phe Tyr Leu Thr 145 I I e I I e Qy Hi s Qy 150 Leu Ser I I e Al a Ser 155 Leu Leu I I e Ser Leu 160 Qy I I e Phe Phe Tyr 165 Phe Lys Ser Leu Ser 170 Cys Q n Arg I I e Thr 175 Leu Hi s Lys Asn Leu 180 Phe Phe Ser Phe Val 185 Cys Asn Ser Val Val 190 Thr I I e I I e Hi s Leu 195 Thr Al a Val Al a Asn 200 Asn Q n Al a Leu Val 205 Al a Thr Asn Pr o Val 210 Ser Cys Lys Val Ser 215 Q n Phe I I e Hi s Leu 220 Tyr Leu IVbt Qy Cys 225 Asn Tyr Phe Tr p IVbt 230 Leu Cys Q u Qy I I e 235 Tyr Leu Hi s Thr Leu 240 I I e Val Val Al a Val 245 Phe Al a Q u Lys Q n 250 Hi s Leu IVbt Tr p Tyr 255 Tyr Phe Leu Qy Tr p 260 Qy Phe Pr o Leu I I e 265 Pr o Al a Cys I I e Hi s 270 Al a I I e

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Al a Ar g Ser Leu Tyr Tyr Asn Asp Asn Cys Trp lie Ser Ser Asp Thr 275 280 285 Hi s Leu Leu Tyr I I e I I e Hi s Qy Pr o I I e Cys Al a Al a Leu Leu Val 290 295 300 Asn Leu Phe Phe Leu Leu Asn I I e Val Arg Val Leu I I e Thr Lys Leu 305 310 315 320 Lys Val Thr Hi s Q n Al a Q u Ser Asn Leu Tyr IVfet Lys Al a Val Arg 325 330 335 Al a Thr Leu I I e Leu Val Pr o Leu Leu Qy I I e Q u Phe Val Leu I I e 340 345 350 Pr o Tr p Arg Pr o Q u Qy Lys I I e Al a Q u Q u Val Tyr Asp Tyr I I e 355 360 365 IVfet Hi s I I e Leu IVfet Hi s Phe Q n Qy Leu Leu Val Ser Thr I I e Phe 370 375 380 Cys Phe Phe Asn Qy Q u Val Q n Al a I I e Leu Arg Arg Asn Tr p Asn 385 390 395 400 Q n Tyr Lys I I e Q n Phe Qy Asn Ser Phe Ser Asn Ser Q u Al a Leu 405 410 415 Arg Ser Al a Ser Tyr Thr Val Ser Thr I I e Ser Asp Qy Pr o Qy Tyr 420 425 430 Ser Hi s Asp Cys Pr o Ser Q u Hi s Leu Asn Qy Lys Ser I I e Hi s Asp 435 440 445 I I e Q u Asn Val Val Leu Lys Pr o Q u Asn Leu Tyr Asn 450 455 460

<210> 223 <211> 460 <212> PRT <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 223

K/bt Q u Lys Lys Cys Thr Leu Tyr Phe Leu Val Leu Leu Pro Phe Phe 15 10 15

IVfet I I e Leu Val Thr Ala Q u Ser Gu G u Gy Ala Asn Q n Thr Asp 20 25 30

Leu Qy Val Thr Arg Asn Lys

I I e IVfet Thr Ala G n Tyr Q u Cys Tyr Page 142

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35 40 45

G n Lys 50 I I e IVbt G n Asp Pr o 55 I I e G n G n Al a G u 60 Gy Val Tyr Cys Asn 65 Arg Thr Tr p Asp Gy 70 Tr p Leu Cys Tr p Asn 75 Asp Val Al a Al a Gy 80 Thr G u Ser IVbt G n 85 Leu Cys Pr o Asp Tyr 90 Phe G n Asp Phe Asp 95 Pr o Ser G u Lys Val 100 Thr Lys I I e Cys Asp 105 G n Asp Gy Asn Tr p 110 Phe Arg Hi s Pr o Al a 115 Ser Asn Arg Thr Tr p 120 Thr Asn Tyr Thr G n 125 Cys Asn Val Asn Thr 130 Hi s G u Lys Val Lys 135 Thr Al a Leu Asn Leu 140 Phe Tyr Leu Thr I I e 145 I I e Gy Hi s Gy Leu 150 Ser I I e Al a Ser Leu 155 Leu I I e Ser Leu Gy 160 I I e Phe Phe Tyr Phe 165 Lys Ser Leu Ser Cys 170 G n Arg I I e Thr Leu 175 Hi s Lys Asn Leu Phe 180 Phe Ser Phe Val Cys 185 Asn Ser Val Val Thr 190 I I e I I e Hi s Leu Thr 195 Al a Val Al a Asn Asn 200 G n Al a Leu Val Al a 205 Thr Asn Pr o Val Ser 210 Cys Lys Val Ser G n 215 Phe I I e Hi s Leu Tyr 220 Leu IVbt Gy Cys Asn 225 Tyr Phe Tr p IVbt Leu 230 Cys G u Gy I I e Tyr 235 Leu Hi s Thr Leu I I e 240 Val Val Al a Val Phe 245 Al a G u Lys G n Hi s 250 Leu IVbt Tr p Tyr Tyr 255 Phe Leu Gy Tr p Gy 260 Phe Pr o Leu I I e Pr o 265 Al a Cys I I e Hi s Al a 270 I I e Al a Arg Ser Leu 275 Tyr Tyr Asn Asp Asn 280 Cys Tr p I I e Ser Ser 285 Asp Thr Hi s Leu Leu 290 Tyr I I e I I e Hi s Gy 295 Pr o I I e Cys Al a Al a 300 Leu Leu Val Asn

Leu Phe Phe Leu Leu Asn lie Val

Ar g Val Leu I I e Page 143

Thr Lys Leu Lys

2016244220 11 Oct 2016

A1472PCT. t xt

305 310 315 320

Val Thr Hi s G n Al a G u 325 Ser Asn Leu Tyr 330 IVbt Lys Al a Val Arg 335 Al a Thr Leu I I e Leu Val Pr o Leu Leu G y I I e G u Phe Val Leu I I e Pr o 340 345 350 Tr p Arg Pr o G u G y Lys I I e Al a G u G u Val Tyr Asp Tyr I I e IVbt 355 360 365 Hi s I I e Leu IVfet Hi s Phe G n G y Leu Leu Val Ser Thr I I e Phe Cys 370 375 380 Phe Phe Asn G y G u Val G n Al a I I e Leu Arg Arg Asn Tr p Asn G n 385 390 395 400 Tyr Lys I I e G n Phe G y Asn Ser Phe Ser Asn Ser G u Al a Leu Arg 405 410 415 Ser Al a Ser Tyr Thr Val Ser Thr I I e Ser Asp G y Pr o G y Tyr Ser 420 425 430 Hi s Asp Cys Pr o Ser G u Hi s Leu Asn G y Lys Ser I I e Hi s Asp I I e 435 440 445 G u Asn Val Leu Leu Lys Pr o G u Asn Leu Tyr Asn 450 455 460

<210> 224 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 224 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t get gt gget gagaggt geg 60 eget gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g aggccccagg acagaaggt c 120 accat ct cct get ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagct cccag gaacagcccc caaact cct c at 11 at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt cag ccaccct ggg catcaccgga 300 ct ccagact g gggaegagge egat t at t ac t gcggaacat gggat agccg cct gagt get 360 gt ggt 111 eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540

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2016244220 11 Oct 2016 gt caaggcgg agcagct acc gt cacgcat g gagt ggagac t gagcct gac aagggagcac caccaaaccc gcccgagcag cgt ggagaag

A1472PCT. t xt t ccaaacaga gcaacaacaa t ggaagt ccc acagaagct a acagt ggccc ct acagaat g gt acgcggcc cagct gccag

11 ca <210> 225 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 225

600

660

714

at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t get gt ggct gagaggt geg 60 cgct gt cagt ct gt get gac t cagccaccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at ct 11 agga gt aat cagcg gccct caggg 240 gt ccct gacc gat t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt ggg 300 ct ccggt ccg aggat gaggc t gat t at t ac t gt gcagcat gggat gacag cct gagt ggt 360 t gggt gt t eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

<210> 226 <211> 708 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 226 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t get gt ggct gagaggt geg 60 cgct gt gaca t ccagat gac ccagt ct cca t cct ccct gt ct gcat ct gt aggagacaga 120 gt caccat ca ct t geeggge aagt cagggc at t agaaat g at 11 aggct g gt 11 cagcag 180 aaaccaggga aagcccct aa gcgcct gat c t at get gcat ccagt 11 gca aagt ggggt c 240 ccat caaggt t cagcggcag t ggat ct ggg acagaat t ca ct ct cacaat cagcagcct g 300 cagcct gaag at 11 agcaac 11 at t act gt ct acagt at a at at 11 accc gt ggacgt t c 360 ggccaaggga ccaaggt gga aat caaacgt acggt ggct g caccat ct gt ct t cat ct t c 420

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2016244220 11 Oct 2016 ccgccat ct g

11 ct at ccca t cccaggaga ct gacgct ga cagggcct ga at gagcagt t gagaggccaa gt gt cacaga gcaaagcaga get cgcccgt gaaat ct gga agt acagt gg gcaggacagc ct aegagaaa cacaaagagc

A1472PCT. t xt act gcct ct g aaggt ggat a aaggacagca cacaaagt ct 11 caacaggg

11 gt gt gcct acgccct cca cct acagcct acgcct gega gagagt gt get gaat aac at cgggt aac cagcagcacc agt cacccat <210> 227 <211> 708 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 227

480

540

600

660

708

at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt t ct t ct gagct gac t caggaccct act gt gt ct g t ggcct t ggg acagacagt c 120 aaaat cacat gccaaggaga cagcct caga agt 1111 at g caagct ggt a ccagcagaag 180 ccaggacagg cccct gt act t gt ct t ct at ggt aaaaaca accggccct c agggat ccca 240 gaccgat t ct ct ggct ccag ct caggaaac acagct t cct t gaccat cac t ggggct cag 300 geggaagat g agget gact a 11 at t gt aat t cccgggaca gcagt gt 11 a ccat ct ggt a 360 ct eggeggag ggaccaagct gaccgt cct a ggt cagccca aggccaaccc cact gt cact 420 ct gt t cccgc cct cct ct ga ggaget ccaa gccaacaagg ccacact agt gt gt ct gat c 480 agt gact t ct acccgggagc t gt gacagt g gcct ggaagg cagat ggcag ccccgt caag 540 gcgggagtgg agaccaccaa accct ccaaa cagagcaaca acaagt aege ggccagcagc 600 t acct gagee t gacgcccga gcagt ggaag t cccacagaa get acagct g ccaggt cacg 660 cat gaaggga gcaccgt gga gaagacagt g gcccct acag aat gt t ca 708

<210> 228 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 228 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt gat a 11 at act ggc ccagact cca ct 11 ct ct gt ccgt cacccc t ggacagccg 120 gcct ccat ct cct gcaagt c t agt cagagc ct cct gcaca gt get ggaaa gacct at 11 g 180 t at t ggt acc t gcagaagcc aggccagcct ccacagct cc t gat ct at ga agt 11 ccaac 240 cggt t ct ct g gagt gccaga t aggt t cagt ggcagcgggt cagggacaga 111 cacact g 300

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2016244220 11 Oct 2016 aaaat cagcc ct t ccgct ca t ct gt ct t ca t gcct get ga ct ccaat egg agcct cagca t gegaagt ca t gt

A1472PCT. t xt

gggtggaggc t gaggat gt t gggat 11 at t act gcat gca aagt 111 ccg 360 ct 11 eggegg agggaccaag gt ggagat ca aacgt aeggt ggct gcacca 420 t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aaegee 540 gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600 gcaccct gac get gagcaaa gcagact aeg agaaacacaa agt ct aegee 660 cccat caggg cct gagct eg cccgt cacaa agaget t caa caggggagag 720 723

<210> 229 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 229

at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g cggccccagg acagaaggt c 120 accat ct cct get ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagct cccag gaacagcccc caaact cct c at 11 at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt caa ccaccct ggg cat caccgga 300 ct ccagact g gggaegagge egat t at t ac t gcggaacat gggat agccg cct gagt get 360 gt ggt 111 eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 ageaget acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

<210> 230 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 230 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt gat a 11 gt gat gac t cagt ct cca ct ct ccct gc ccgt cacccc t ggagagccg 120

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2016244220 11 Oct 2016

gcct ccat ct cct gcaggt c t agt cagagc A1472PCT. t xt ct cct gcat a gt 111 gggt a caact at 11 g 180 gat t ggt acc t gcagaagcc agggcagt ct ccacagct cc t gat ct at 11 gggt t ct aat 240 cgggcct ccg gggt ccct ga caggt t cagt ggcagt ggat caggcacaga 1111 acact g 300 aaaat cagca gagt ggaggc t gaggat gt t ggggt 11 at t act gcat gca aget ct acaa 360 act ccat t ca ct 11 cggccc t gggaccaaa gt ggat at ca aacgt aeggt ggct gcacca 420 t ct gt ct t ca t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 t gcct get ga at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aaegee 540 ct ccaat egg gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600 agcct cagca gcaccct gac get gagcaaa gcagact aeg agaaacacaa agt ct aegee 660 t gegaagt ca cccat caggg cct gaget eg cccgt cacaa agaget t caa caggggagag 720

t gt 723 <210> 231 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 231 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt gat a 11 at t ct gac ccagact cca ct 11 ct ct gt ccgt cacccc t ggacagccg 120 gcct ccat ct cct gcaagt c t agt cagagc ct cct gcaca gt gat ggaaa gacct at 11 g 180 t at t ggt acc t gcagaagcc cggccagcct ccacagct cc t gat ct at ga agt 11 ccaac 240 eggt t ct ct g gagagccaga t aggt t cagt ggcagcgggt cagggacaga 111 cacact g 300 aaaat cagcc gggtggaggc t gaggat gt t gggact t at t at t gcat gca aagt 111 ccg 360 ct t ccgct ca ct 11 eggegg agggaccaag gt ggagat ca aacgt aeggt ggct gcacca 420 t ct gt ct t ca t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 t gcct get ga at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aaegee 540 ct ccaat egg gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600 agcct cagca gcaccct gac get gagcaaa gcagact aeg agaaacacaa agt ct aegee 660 t gegaagt ca cccat caggg cct gaget eg cccgt cacaa agaget t caa caggggagag 720 t gt 723

<210> 232 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source

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2016244220 11 Oct 2016

A1472PCT. t xt <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

<400> 232 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt gcg 60 cgct gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g cggccccagg acagaaggt c 120 accat ct cct get ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagt t cccag gaacagcccc caaact cct c at 11 at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt cag ccaccct ggg cat caccgga 300 ct ccagact g gggaegagge egat t at t ac t gcggaacat gggat agccg cct gagt get 360 gt ggt 111 eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 ageaget acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

<210> 233 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 233 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt gcg 60 cgct gt cagt ct gt get gac t cagt caccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at cct t agga at aat cagcg gccct caggg 240 gt ccct gacc gat t ct ct gg ct ccaagt ct ggcacct cag cct ccct gac cat cagt ggg 300 ct ccggt ccg aggat gaggc t gact at t at t gt gcagcat gggat gacag cct gagt ggt 360 t gggt gt t eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 ageaget acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

<210> 234 <211> 714 <212> DNA

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2016244220 11 Oct 2016

A1472PCT. t xt <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 234

at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt gget gagaggt geg 60 cgct gt cagt ct gt get gac t cagccaccc t cagcgt ct g ggacccccgg gcagagggt c 120 accat ct ct t gt t ct ggaag cagt t ccaat at eggaagt a at act gt gaa ct ggt accag 180 cagct cccag gaacggcccc caaact cct c at ct at act a at aat cagcg gccct caggg 240 gt ccct gacc gat t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt gga 300 ct ccagt ct g aggat gaggc t gat 1111 ac t gt gcagcgc gggat gagag cct gaat ggt 360 gt ggt at t eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 ageaget acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

<210> 235 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 235 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt gget gagaggt geg 60 cgct gt cagt ct gt get gac t cagccaccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at ct 11 agga at aat cagcg gccct caggg 240 gt ccct gacc get t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt ggg 300 ct ccggt ccg aggat gaggc t gat t at t ac t gt gcagcat gggat gacag cct gagt ggt 360 t gggt gt t eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 ageaget acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

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2016244220 11 Oct 2016

A1472PCT. t xt <210> 236 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

<400> 236 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 cgct gt cagt ct gt get gac t cagccaccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at ct 11 agga at aat cagcg gccct caggg 240 gt ccct gacc get t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt ggg 300 ct ccggt ccg aggat gaggc t gat t at t ac t gt gcagcat gggat gacag cct gagt ggt 360 t gggt gt t eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 ageaget acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

<210> 237 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 237 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 cgct gt gat a 11 acact gac ccagact cca ct 11 ct ct gt ccgt ct cccc t ggacagccg 120 gcct ccat ct cct gcaagt c t agt cagagc ct cct gcaca gt gat ggaag gaact at ct g 180 t at t ggt acc t gcagaagcc aggccagcct ccacagct cc t gat ct at ga agt gt ccaac 240 eggt t ct ct g gact gccaga t aggt t cagt ggcagcgggt cagggacaga 111 cacact g 300 aaaat cagcc gggtggaggc t gaggat gt t gggat 11 at t act gcat gca aagt 111 ccg 360 ct t ccgct ca ct 11 eggegg agggaccaag gt ggagat ca aacgt aeggt ggct gcacca 420 t ct gt ct t ca t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 t gcct get ga at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aaegee 540 ct ccaat egg gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600

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2016244220 11 Oct 2016

A1472PCT. t xt agcctcagca gcaccctgac getgagcaaa gcagactaeg agaaacacaa agtctaegee 660 t gegaagt ca cccat caggg cct gagct eg cccgt cacaa agaget t caa caggggagag 720 t gt 723 <210> 238 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 238

at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g cggccccagg acagaaggt c 120 accat ct cct get ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagct cccag gaacagcccc caaact cct c at 11 at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt cag ccaccct ggg cat caccgga 300 ct ccagact g gggaegagge egat t at t ac t gcggaacat gggat agccg cct gagt get 360 gt ggt 111 eg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggaget gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 ageaget acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g 11 ca 714

<210> 239 <211> 708 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 239 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt gaca t ccagat gac ccagt ct cca t cct ccct gt ct gcat ct gt aggagacaga 120 gt caccat ca ct t geeggge aagt cagggc at t agaaagg at 11 agget g gt at cagcag 180 aaaccaggga aagcccct aa gcgcct gat c t at ggagcat ccagt 11 gca aagt ggggt c 240 ccat caaggt t cagcggcag t ggat ct ggg acagaat t ca ct ct cacaat cagcagcct g 300 cagcct gaag at 111 gcaac 11 at t act gt ct acagt at a at agt 11 ccc gt ggacgt t c 360 ggccaaggga ccaaggt gga aat caaacgt acggt ggct g caccat ct gt ct t cat ct t c 420

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2016244220 11 Oct 2016 ccgccat ct g

11 ct at ccca t cccaggaga ct gacgct ga cagggcct ga at gagcagt t gagaggccaa gt gt cacaga gcaaagcaga get cgcccgt gaaat ct gga agt acagt gg gcaggacagc ct aegagaaa cacaaagagc

A1472PCT. t xt act gcct ct g aaggt ggat a aaggacagca cacaaagt ct 11 caacaggg

11 gt gt gcct acgccct cca cct acagcct acgcct gega gagagt gt get gaat aac at cgggt aac cagcagcacc agt cacccat <210> 240 <211> 705 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 240

480

540

600

660

708

at ggaaaccc cagct cagct t ct ct t cct c ct get act ct gget cccaga t accaccgga 60 gaaat t gt gt t gacgcagt c t ccaggcacc ct gt ct 11 gt ct ccagggga aagagccacc 120 ct ct cct gca gggccagt ca gagt gt t age agegget act t aacct ggt a ccagcagaaa 180 cct ggccagg ct cccaggct cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 240 gacaggt t ca gt ggcagt gg gt ct gggaca gact t cact c t caccat cag cagact ggag 300 cct gaagat t 11 gcagt gt a 11 act gt cag cagt at ggt a act cact gt g caggt 11 ggc 360 caggggacca aget ggagat caaacgt aeg gt gget gcac cat ct gt ct t cat ct t cccg 420 ccat ct gat g agcagt t gaa at ct ggaact gcct ct gt t g t gt gcct get gaat aact t c 480 t at cccagag aggccaaagt acagt ggaag gt ggat aacg ccct ccaat c gggt aact cc 540 caggagagt g t cacagagca ggacagcaag gacagcacct acagcct cag cagcaccct g 600 aeget gagca aagcagact a cgagaaacac aaagt ct aeg cct gegaagt cacccat cag 660 ggcct gaget cgcccgt cac aaagaget t c aacaggggag agt gt 705

<210> 241 <211> 705 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 241 at ggaaaccc cagct cagct t ct ct t cct c ct get act ct gget cccaga t accaccgga 60 gaaat t gt gt t gacgcagt c t ccaggcacc ct gt ct 11 gt ct ccagggga aagagccacc 120 ct ct cct gca gggccagt ca gagt gt t age agegget act t aacct ggt a ccagcagaaa 180 cct ggccagg ct cccagact cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 240 gacaggt t ca gt ggcagt gg gt ct gggacg gact t cact c t caccat cag cagact ggag 300

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2016244220 11 Oct 2016

cct gaagat t 11 gcagt gt a 11 act gt cag A1472PCT. t xt cagt at ggt a act cact gag caggt 11 ggc 360 caggggacca agct ggagat caaacgt acg gt ggct gcac cat ct gt ct t cat ct t cccg 420 ccat ct gat g agcagt t gaa at ct ggaact gcct ct gt t g t gt gcct get gaat aact t c 480 t at cccagag aggccaaagt acagt ggaag gt ggat aacg ccct ccaat c gggt aact cc 540 caggagagt g t cacagagca ggacagcaag gacagcacct acagcct cag cagcaccct g 600 acgct gagca aagcagact a cgagaaacac aaagt ct acg cct gegaagt cacccat cag 660 ggcct gagct cgcccgt cac aaagagct t c aacaggggag agt gt 705

<210> 242 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 242 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt cagg t gcagct ggt ggaat ct ggg ggaggcgtgg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc 11 cagt agct 11 ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagtgggtg gcagt t at at cat 11 gat gg aagt at t aag 240 t at t ct gt ag act ccgt gaa gggeegat t c accat ct cca gagacaat t c aaagaacacg 300 ct gt 11 ct gc aaat gaacag cct gegagee gaggacacgg ct gt gt at t a ct gt gegaga 360 gat egget ca at t act at ga t agt agt ggt t at t at cact acaaat act a eggt at ggee 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat eggt c 480 11 ccccct gg cgccct get c caggagcacc t ccgagagca cagcggccct ggget gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt ega gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c aegt gegt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt aegt g gaeggegt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg 11 ccgt gt gg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaaegg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat eg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaagget t ct accccagcga cat egeegt g gagt gggaga gcaat gggca gccggagaac 1260

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2016244220 11 Oct 2016 aact acaaga ct caccgt gg gaggct ct gc ccacacct cc acaagagcag acaaccact a cat get ggac gt ggcagcag cacgcagaag

A1472 PCT. t ccgacggct gggaacgt ct agcct ct ccc xt cct t ct t cct t ct cat get c t gt ct ccggg ct acagcaag cgt gat gcat t aaa <210> 243 <211> 1437 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

1320

1380

1434

<400> 243 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt gget gagaggt geg 60 eget gt gagg t gcagct ggt ggagt ct ggg ggagget t gg t aaagcct gg ggggt ccct t 120 agact ct cct gt gcagcct c t ggat t cact 11 cagt aacg cct ggat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagtgggtt ggccgt at t a aaagcacaac t gat ggt ggg 240 acaacagact aeget gcacc cgt gaaaggc agat t caeca t ct caagaga t gat t caaaa 300 aacacgct gt at ct gcaaat gaacagcct g aaaaccgagg acacagccgt gt at t act gt 360 accacagat c ggaccggat a t agcat cage t ggt ct agt t act act act a ct aeggt at g 420 gaegt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat eg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct ggget gc 540 ct ggt caagg act act t ccc cgaaccggt g aeggt gt cgt ggaact cagg eget ct gacc 600 ageggegt gc acacct t ccc aget gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t egge acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagegea aat gt t gt gt egagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t cc t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt geg tggtggtgga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc aegt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act gget gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat egee gtggagtggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat get g gact ccgacg get cct t ct t cct ct acagc 1320 aaget caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380 cat gaggct c t gcacaacca ct acacgcag aagagcct ct ccct gt ct cc gggt aaa 1437

<210> 244

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2016244220 11 Oct 2016

A1472PCT. t xt <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 244

at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt gget gagaggt geg 60 cgct gt gagg t gcagct at t ggagt ct ggg ggagget t gg t acagcct gg ggagt ccct g 120 agact ct cct gt gcagcct c t gggt t cacc 111 ageaget at gccat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagt gggt c t cagct at t a gtggtagtgg t ggt cgcaca 240 t act acgcag act ccgt gaa gggccggt t c accat ct cca gagacaat t c caagaacacg 300 ct gt at ct gc aaat gaat ag cct gagagee gaggacacgg ccgt at at t a ct gt gegaaa 360 gat caaaggg aggt agggee gt at agcagt gget ggt aeg act act act a eggt at ggac 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat eggt c 480 11 ccccct gg cgccct get c caggagcacc t ccgagagca cagcggccct ggget gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt ega gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c aegt gegt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt aegt g gaeggegt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg 11 ccgt gt gg t cagcgt cct caccgt t gt g 1020 caccaggact gget gaaegg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat eg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaagget t ct accccagcga cat egeegt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat get ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat get c cgt gat gcat 1380 gagget ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

<210> 245 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

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2016244220 11 Oct 2016

A1472PCT. t xt

<400> 245 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t get gt gget gagaggt gcg 60 cgct gt cagg t gcagt t ggt gcagt ct ggg get gaggt ga agaagcct gg ggcct cagt g 120 aaggt ct cct gcaaggct t c t ggat acacc 11 caccggct act at at gca ct gggt gega 180 caggcccct g gacaagggct t gagt ggat g ggat ggat ca accct aacag t ggt ggcaca 240 aact at gcac agaagt 11 ca gggcagggt c accat gacca gggacacgt c cat cagcaca 300 gcct acat gg agct gagcag get gagat ct gacgacacgg ccgt gt at 11 ct gt gegaga 360 gat caaat ga gt at t at t at get t cgggga gt 1111 cccc ct t act at t a eggt at ggac 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat eggt c 480 11 ccccct gg cgccct get c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt ega gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c aegt gegt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt aegt g gaeggegt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg 11 ccgt gt gg t cagcgt cct caccgt t gt g 1020 caccaggact gget gaaegg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat eg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaagget t ct accccagcga cat egeegt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat get ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat get c cgt gat gcat 1380 gagget ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

<210> 246 <211> 1431 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 246 at ggacat ga cgct gt cagg agact ct cct gggt gcccgc t gcagct ggt gt gcagcct c t cagct cct g ggagt ct ggg t ggat t cacc gggct cct gc ggaggcgtgg 11 cagt agct t get gt gget t ccagcct gg at ggcat gca gagaggt gcg gaggt ccct g ct gggt ccgc

120

180

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2016244220 11 Oct 2016

caggctccag gcaaggggct ggagtgggtg A1472PCT. t xt 240 gcagt t at 11 cat at gat gg aagt cat gaa t cct at gcag act ccgt gaa gggeegat t c accat ct cca gagacat 11 c caagaacacg 300 ct gt at ct gc aaat gaacag cct gagaget gaggacacgg ct gt gt at 11 ct gt gegaga 360 gagaggaaac gggt t aegat gt ct acct t a t at t act act t ct act aegg t at ggacgt c 420 t ggggccaag ggaccacggt caccgt ct ct agt gcct cca ccaagggccc at eggt ct t c 480 cccct ggcgc cct get ccag gagcacct cc gagagcacag cggccct ggg ct gcct ggt c 540 aaggact act t ccccgaacc ggt gaeggt g t cgt ggaact caggcgct ct gaccagcggc 600 gt gcacacct t cccagct gt cct acagt cc t caggact ct act ccct cag cagcgt ggt g 660 accgt gccct ccagcaact t cggcacccag acct acacct gcaacgt aga t cacaagccc 720 agcaacacca aggt ggacaa gacagt t gag egeaaat gt t gt gt egagt g cccaccgt gc 780 ccagcaccac ct gt ggcagg accgt cagt c 11 cct ct t cc ccccaaaacc caaggacacc 840 ct cat gat ct cccggacccc t gaggt cacg tgcgtggtgg t ggacgt gag ccacgaagac 900 cccgaggt cc agt t caact g gt aegt ggac ggcgtggagg t gcat aat gc caagacaaag 960 ccacgggagg agcagt t caa cagcacgt t c cgt gt ggt ca gegt cct cac cgt t gt gcac 1020 caggact ggc t gaacggcaa ggagt acaag t gcaaggt ct ccaacaaagg cct cccagcc 1080 cccat cgaga aaaccat ct c caaaaccaaa gggcagcccc gagaaccaca ggt gt acacc 1140 ct gcccccat cccgggagga gat gaccaag aaccaggt ca gcct gacct g cct ggt caaa 1200 ggct t ct acc ccagcgacat egeegt ggag t gggagagca at gggcagcc ggagaacaac 1260 t acaagacca cacct cccat get ggact cc gaegget cct t ct t cct ct a cagcaagct c 1320 accgt ggaca agagcaggt g gcagcagggg aacgt ct t ct cat get ccgt gat gcat gag 1380 get ct gcaca accact acac gcagaagagc ct ct ccct gt ct ccgggt aa a 1431

<210> 247 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 247 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt cagg t gcagct ggt ggaat ct ggg ggaggcgtgg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc 11 cagt aget 11 ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagtgggtg gcagt t at at cat 11 gat gg aagt at t aag 240 t at t ct gt ag act ccgt gaa gggeegat t c accat ct cca gagacaat t c aaagaacacg 300 ct gt 11 ct gc aaat gaacag cct gegagee gaggacacgg ct gt gt at t a ct gt gegaga 360 gat egget ca at t act at ga t agt agt ggt t at t at cact acaaat act a eggt at ggee 420

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gt ct ggggcc aagggaccac ggt caccgt c A1472PCT. t xt t ct agt gcct ccaccaaggg cccat eggt c 480 11 ccccct gg cgccct get c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt ega gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c aegt gegt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt aegt g gaeggegt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg 11 ccgt gt gg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaaegg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat eg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaagget t ct accccagcga cat egeegt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat get ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat get c cgt gat gcat 1380 gagget ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

<210> 248 <211> 1407 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 248 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t get gt ggct gagaggt geg 60 cgct gt gagg t gcagct ggt ggagt ct ggg ggagget t gg t aaagccagg geggt ccct g 120 agact ct cct gt acagct t c t ggat t cacc 111 ggt gat t at get at gag ct ggt t ccgc 180 caggct ccag ggaaggggct ggagt ggat a ggt 11 cat t a gaagcagagc 11 at ggt ggg 240 acaccagaat acgccgcgt c t gt gaaaggc agat t caeca t ct caagaga t gat t ccaaa 300 accat cgcct at ct gcaaat gaacagcct g aaaaccgagg acacagccgt gt at 11 ct gt 360 get agaggac ggggt at t gc aget cgt t gg gact act ggg gccagggaac cct ggt cacc 420 gt ct ct agt g cct ccaccaa gggcccat eg gt ct t ccccc t ggcgccct g ct ccaggagc 480 acct ccgaga gcacagcggc cct gggct gc ct ggt caagg act act t ccc cgaaccggt g 540 acggt gt cgt ggaact cagg cgct ct gacc ageggegt gc acacct t ccc aget gt cct a 600 cagt cct cag gact ct act c cct cagcagc gt ggt gaccg t gccct ccag caact t egge 660

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acccagacct acacct gcaa cgt agat cac A1472PCT. t xt aagcccagca acaccaaggt ggacaagaca 720 gt t gagcgca aat gt t gt gt egagt gccca ccgt gcccag caccacct gt ggcaggaccg 780 t cagt ct t cc t ct t cccccc aaaacccaag gacaccct ca t gat ct cccg gacccct gag 840 gt cacgt gcg tggtggtgga cgt gagccac gaagaccccg aggt ccagt t caact ggt ac 900 gt ggacggcg t ggaggt gca t aat gccaag acaaagccac gggaggagca gt t caacagc 960 acgt t ccgt g t ggt cagcgt cct caccgt t gt gcaccagg act ggct gaa cggcaaggag 1020 t acaagt gca aggt ct ccaa caaaggcct c ccagccccca t cgagaaaac cat ct ccaaa 1080 accaaagggc agccccgaga accacaggt g t acaccct gc ccccat cccg ggaggagat g 1140 accaagaacc aggt cagcct gacct gcct g gt caaaggct t ct accccag cgacat egee 1200 gtggagtggg agagcaat gg gcagccggag aacaact aca agaccacacc t cccat get g 1260 gact ccgacg get cct t ct t cct ct acagc aaget caccg t ggacaagag caggt ggcag 1320 caggggaacg t ct t ct cat g ct ccgt gat g cat gagget c t gcacaacca ct acacgcag 1380 aagagcct ct ccct gt ct cc gggt aaa 1407

<210> 249 <211> 1431 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 249 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt gcg 60 eget gt cagg t gcagct ggt ggagt ct ggg ggaggcgtgg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc 11 cagt aget at ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagtgggtg gcagt t at 11 cat at gat gg aagt cat gaa 240 t cct at gcag act ccgt gaa gggeegat t c accat ct cca gagacat 11 c caagaacacg 300 ct gt at ct gc aaat gaacag cct gagaget gaggacacgg ct gt gt at 11 ct gt gegaga 360 gagaggaaac gggt t aegat gt ct acct t a t at t act act t ct act aegg t at ggacgt c 420 t ggggccaag ggaccacggt caccgt ct ct agt gcct cca ccaagggccc at eggt ct t c 480 cccct ggege cct get ccag gagcacct cc gagagcacag cggccct ggg ct gcct ggt c 540 aaggact act t ccccgaacc ggt gaeggt g t cgt ggaact caggcgct ct gaccagcggc 600 gt gcacacct t cccagct gt cct acagt cc t caggact ct act ccct cag cagcgt ggt g 660 accgt gccct ccagcaact t cggcacccag acct acacct gcaacgt aga t cacaagccc 720 agcaacacca aggt ggacaa gacagt t gag egeaaat gt t gt gt egagt g cccaccgt gc 780 ccagcaccac ct gt ggcagg accgt cagt c 11 cct ct t cc ccccaaaacc caaggacacc 840 ct cat gat ct cccggacccc t gaggt cacg tgcgtggtgg t ggacgt gag ccacgaagac 900

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cccgaggt cc agt t caact g gt aegt ggac A1472PCT. t xt caagacaaag 960 ggcgtggagg t gcat aat gc ccacgggagg agcagt t caa cagcacgt t c cgt gt ggt ca gegt cct cac cgt t gt gcac 1020 caggact ggc t gaacggcaa ggagt acaag t gcaaggt ct ccaacaaagg cct cccagcc 1080 cccat cgaga aaaccat ct c caaaaccaaa gggcagcccc gagaaccaca ggt gt acacc 1140 ct gcccccat cccgggagga gat gaccaag aaccaggt ca gcct gacct g cct ggt caaa 1200 ggct t ct acc ccagcgacat egeegt ggag t gggagagca at gggcagcc ggagaacaac 1260 t acaagacca cacct cccat get ggact cc gaegget cct t ct t cct ct a cagcaagct c 1320 accgt ggaca agagcaggt g gcagcagggg aacgt ct t ct cat get ccgt gat gcat gag 1380 get ct gcaca accact acac gcagaagagc ct ct ccct gt ct ccgggt aa a 1431

<210> 250 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 250 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt cagg t gcagct ggt ggaat ct ggg ggaggcgtgg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc 11 cagt aget 11 ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagtgggtg gcagt t at at cat 11 gat gg aagt at t aag 240 t at t ct gt ag act ccgt gaa gggeegat t c accat ct cca gagacaat t c aaagaacacg 300 ct gt 11 ct gc aaat gaacag cct gegagee gaggacacgg ct gt gt at t a ct gt gegaga 360 gat egget ca at t act at ga t agt agt ggt t at t at cact acaaat act a eggt at ggee 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat eggt c 480 11 ccccct gg cgccct get c caggagcacc t ccgagagca cagcggccct ggget gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt ega gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c aegt gegt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt aegt g gaeggegt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg 11 ccgt gt gg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaaegg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat eg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140

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2016244220 11 Oct 2016 accct gcccc aaaggct t ct aact acaaga ct caccgt gg gaggct ct gc

A1472PCT. t xt

cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 ccacacct cc cat get ggac t ccgacggct cct t ct t cct ct acagcaag 1320 acaagagcag gt ggcagcag gggaacgt ct t ct cat get c cgt gat gcat 1380 acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

<210> 251 <211> 1437 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

<400> 251 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt gget gagaggt geg 60 cgct gt gagg t gcagct ggt ggagt ct ggg ggagget t gg t aaagcct gg ggggt ccct t 120 agact ct cct gt gcagcct c t ggat t cact 11 cagt aacg cct ggat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagtgggtt ggccgt at t a aaagcaaaac t gat ggt ggg 240 acaacagact acact gcacc cgt gaaaggc agat t caeca t ct caagaga t gat t caaaa 300 aacacgct gt at ct gcaaat gaat agcct g aaageegagg acacagccgt gt at t act gt 360 accacagat c ggaccgggt a t agcat cage t ggt ct agt t act act act a ct aeggt at g 420 gaegt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat eg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct ggget gc 540 ct ggt caagg act act t ccc cgaaccggt g aeggt gt cgt ggaact cagg cgct ct gacc 600 ageggegt gc acacct t ccc aget gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t egge acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagegea aat gt t gt gt egagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t cc t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt geg t ggt ggt gga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc aegt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act gget gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat egee gtggagtggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat get g gact ccgacg get cct t ct t cct ct acagc 1320 aaget caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380

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A1472PCT. t xt cat gaggct c tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1437 <210> 252 <211> 1425 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 252

at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt gget gagaggt geg 60 cgct gt cagg t gcagct ggt gcagt ct ggg get gaggt ga agaagcct gg ggcct cagt g 120 aaggt ct cct gcaaggct t c t ggat acacc 11 caccgact act at at gt a ct gggt gega 180 caggcccct g gacaagggct t gagt ggat g ggat ggat ca gccct aat ag t ggt ggcaca 240 aact at gccc agaagt 11 ca gggcagggt c accat gacca gggacacgt c t at cagcaca 300 gcct acat gg agct gagt ag get gagat ct gacgacacgg ccgt gt at t a ct gt gt gaga 360 ggaggat at a gt gget aege t ggget ct ac t cccact act aeggt at gga cgt ct ggggc 420 caagggacca eggt caccgt ct ct agt gee t ccaccaagg gcccat eggt ct t ccccct g 480 gcgccct get ccaggagcac ct ccgagagc acagcggccc t ggget gcct ggt caaggac 540 t act t ccccg aaccggt gac ggtgtcgtgg aact caggcg ct ct gaccag eggegt gcac 600 acct t cccag ct gt cct aca gt cct cagga ct ct act ccc t cagcagcgt ggt gaccgt g 660 ccct ccagca act t cggcac ccagacct ac acct gcaacg t agat cacaa gcccagcaac 720 accaaggt gg acaagacagt t gagcgcaaa t gt t gt gt eg agt gcccacc gt gcccagca 780 ccacct gt gg caggaccgt c agt ct t cct c 11 ccccccaa aacccaagga caccct cat g 840 at ct cccgga cccct gaggt cacgt gegt g gt ggt ggacg t gagccacga agaccccgag 900 gt ccagt t ca act ggt aegt ggacggcgt g gaggt gcat a at gccaagac aaagccacgg 960 gaggagcagt t caacagcac gt t ccgt gt g gt cagcgt cc t caccgt t gt gcaccaggac 1020 t gget gaacg gcaaggagt a caagt gcaag gt ct ccaaca aaggcct ccc agcccccat c 1080 gagaaaacca t ct ccaaaac caaagggcag ccccgagaac cacaggt gt a caccct gccc 1140 ccat cccggg aggagat gac caagaaccag gt cagcct ga cct gcct ggt caaaggct t c 1200 t accccagcg acat egeegt ggagtgggag agcaat gggc ageeggagaa caact acaag 1260 accacacct c ccat get gga ct ccgacggc t cct t ct t cc t ct acagcaa get caccgt g 1320 gacaagagca ggt ggcagca ggggaacgt c 11 ct cat get ccgt gat gca t gaggct ct g 1380 cacaaccact acacgcagaa gagcct ct cc ct gt ct ccgg gt aaa 1425

<210> 253 <211> 1437 <212> DNA <213> Ar t i f i ci al Sequence

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2016244220 11 Oct 2016

A1472PCT. t xt <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 253

at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt gagg t acagct ggt ggagt ct ggg ggagget t gg t aaagcct gg ggggt ccct c 120 agact ct cct gt gcagcct c t ggat t cact 11 eggt aacg cct ggat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagtgggtt ggccgt at t a aaagcaaaac t gat ggt ggg 240 acaacagact aeget gcacc cgt gaaaggc agat t caeca t ct caagaga t gat t caaaa 300 aacacgct gt at ct gcaaat gaacagcct g aaaaccgagg acacagccgt gt at 11 ct gt 360 accacagat c ggaccgggt a t agcat cage t ggt ct agt t act act act a ct aeggt at g 420 gaegt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat eg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct ggget gc 540 ct ggt caagg act act t ccc cgaaccggt g aeggt gt cgt ggaact cagg eget ct gacc 600 ageggegt gc acacct t ccc aget gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t cggc acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagegea aat gt t gt gt egagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t ee t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt geg t ggt ggt gga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc aegt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act ggct gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat egee gtggagtggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat get g gact ccgacg get cct t ct t cct ct acagc 1320 aaget caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380 cat gagget c t gcacaacca ct acacgcag aagagcct ct ccct gt ct ee gggt aaa 1437

<210> 254 <211> 1437 <212> DNA <213> Ar t i f i ci al Sequence <220>

<221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 254 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60

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cgct gt gagg t acagct ggt A1472PCT. t xt ggggt ccct t 120 ggagt ct ggg ggagget t gg t aaagcct gg agact ct cct gt gcagcct c t ggat t cact 11 cggt aacg cct ggat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagtgggtt ggccgt at t a aaagcaaaac t gat ggt ggg 240 acaacagact acgct gcacc cgt gaaaggc agat t caeca t ct caagaga t gat t caaaa 300 aacacgct gt at ct gcaaat gaacagcct g aaaaccgagg acacagccgt gt at t act gt 360 accacagat c ggaccgggt a t agcat cage t ggt ct agt t act act act a ct aeggt at g 420 gacgt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat eg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct ggget gc 540 ct ggt caagg act act t ccc cgaaccggt g aeggt gt cgt ggaact cagg eget ct gacc 600 agcggcgt gc acacct t ccc aget gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t egge acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagegea aat gt t gt gt egagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t cc t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt geg t ggt ggt gga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc aegt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act ggct gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat egee gtggagtggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat get g gact ccgacg get cct t ct t cct ct acagc 1320 aagct caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380 cat gaggct c t gcacaacca ct acacgcag aagagcct ct ccct gt ct cc gggt aaa 1437

<210> 255 <211> 1431 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 255 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 egetgtcagg tgcagctggt ggagt ct ggg ggaggcgtgg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc 11 cagt aget at ggcat gca ct gggt ccgc 180 caggctccag gcaaggggct ggagtgggtg gcagt t at 11 cat at gat gg aagt cat gaa 240 t cct at gcag act ccgt gaa gggeegat t c accat ct cca gagacat 11 c caagaacacg 300

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ct gt at ct gc aaat gaacag cct gagaget A1472PCT. t xt gaggacacgg ct gt gt at 11 ct gt gegaga 360 gagaggaaac gggt t aegat gt ct acct t a t at t act act t ct act aegg t at ggacgt c 420 t ggggccaag ggaccacggt caccgt ct ct agt gcct cca ccaagggccc at eggt ct t c 480 cccct ggcgc cct get ccag gagcacct cc gagagcacag cggccct ggg ct gcct ggt c 540 aaggact act t ccccgaacc ggt gaeggt g t cgt ggaact caggcgct ct gaccagcggc 600 gt gcacacct t cccagct gt cct acagt cc t caggact ct act ccct cag cagcgt ggt g 660 accgt gccct ccagcaact t cggcacccag acct acacct gcaacgt aga t cacaagccc 720 agcaacacca aggt ggacaa gacagt t gag egeaaat gt t gt gt egagt g cccaccgt gc 780 ccagcaccac ct gt ggcagg accgt cagt c 11 cct ct t cc ccccaaaacc caaggacacc 840 ct cat gat ct cccggacccc t gaggt cacg tgcgtggtgg t ggacgt gag ccacgaagac 900 cccgaggt cc agt t caact g gt aegt ggac ggcgtggagg t gcat aat gc caagacaaag 960 ccacgggagg agcagt t caa cagcacgt t c cgt gt ggt ca gegt cct cac cgt t gt gcac 1020 caggact ggc t gaacggcaa ggagt acaag t gcaaggt ct ccaacaaagg cct cccagcc 1080 cccat cgaga aaaccat ct c caaaaccaaa gggcagcccc gagaaccaca ggt gt acacc 1140 ct gcccccat cccgggagga gat gaccaag aaccaggt ca gcct gacct g cct ggt caaa 1200 gget t ct acc ccagcgacat egeegt ggag t gggagagca at gggcagcc ggagaacaac 1260 t acaagacca cacct cccat get ggact cc gaegget cct t ct t cct ct a cagcaagct c 1320 accgt ggaca agagcaggt g gcagcagggg aacgt ct t ct cat get ccgt gat gcat gag 1380 get ct gcaca accact acac gcagaagagc ct ct ccct gt ct ccgggt aa a 1431

<210> 256 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 256 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t get gt gget gagaggt geg 60 eget gt cagg t gcagct ggt ggaat ct ggg ggaggcgtgg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc 11 cagt aget 11 ggcat gca 11 gggt ccgc 180 caggct ccag gcaaggggct ggagtgggtg gcagt t at at cat 11 gat gg aagt at t aag 240 t act ct gt ag act ccgt gaa gggeegat t c accat ct cca gagacaat t c aaagaacacg 300 ct gt 11 ct gc aaat gaacag cct gegagee gaggacacgg ct gt gt at t a ct gt gegaga 360 gat egget ca at t act at ga t agt agt ggt t at t at cact acaaat act a eggt ct ggee 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat eggt c 480 11 ccccct gg cgccct get c caggagcacc t ccgagagca cagcggccct gggct gcct g 540

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A1472PCT. t xt gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt ega gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c aegt gegt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt aegt g gaeggegt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg 11 ccgt gt gg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaaegg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat eg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaagget t ct accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat get ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat get c cgt gat gcat 1380 gagget ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

<210> 257 <211> 1437 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 257 at ggacat ga gggt gcccgc t cagct cct g ggget cct gc t get gt ggct gagaggt geg 60 eget gt gagg t gcagct ggt ggagt ct ggg ggaggcct gg t caagcct gg ggggt ccct g 120 agact ct cct gt gcagcct c t ggat acacc 11 cagt acct at agcat gaa ct gggt ccgc 180 caggct ccag ggaaggggct ggagt gggt c t cat ccat t a gt agt agt ag t agt t acaga 240 t at t acgcag act cagt gaa gggeegat t c accat ct cca gagacaacgc caagaact ca 300 ct gt at ct gc aaat gagt ag cct gagagee gaggacacgg ct gt gt at t a ct gt gegaga 360 gaaggggt gt ct ggcagt t c geegt at age at cagct ggt acgact act a 11 aeggt at g 420 gaegt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat eg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct ggget gc 540 ct ggt caagg act act t ccc cgaaccggt g aeggt gt cgt ggaact cagg eget ct gacc 600 ageggegt gc acacct t ccc aget gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t egge acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagegea aat gt t gt gt egagt gccca 780

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ccgt gcccag caccacct gt A1472PCT. t xt aaaacccaag 840 ggcaggaccg t cagt ct t cc t ct t cccccc gacaccct ca t gat ct cccg gacccct gag gt cacgt geg tggtggtgga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc aegt t ccgt g t ggt cagcgt eet caccgt t 1020 gt gcaccagg act ggct gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat cgcc gtggagtggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat get g gact ccgacg get eet t ct t eet ct acagc 1320 aagct caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380 cat gaggct c t gcacaacca ct acacgcag aagagcct ct ccct gt ct cc gggt aaa 1437

<210> 258 <211> 1422 <212> DNA <213> Ar t i f i ci al Sequence

<220> <221> source <223> I not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 258 at ggacat ga gggt gcccgc t cagct eet g ggget eet gc t get gt ggct gagaggt geg 60 eget gt cagg t gcagct ggt ggagt ct ggg ggaggcgtgg t ccagcct gg gaggt ccct g 120 agact ct eet gt gcagcgt c t ggat t cacc 11 cagt aget at ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagtgggtg gcagt t at at ggt at gat gg aagt aat aaa 240 t act at gcag act ccgt gaa gggeegat t c at cat ct cca gagat aaat c caagaacacg 300 ct gt at ct gc aaat gaacag eet gagagee gaggacacgg ct gt gt at t a ct gt gegaga 360 gcggggggt a t agcagcagc t ggcct ct ac t act act aeg gt at ggacgt ct ggggccaa 420 gggaccacgg t caccgt ct c t agt gcct cc accaagggcc cat eggt ct t ccccct ggcg 480 ccct get cca ggagcacct c cgagagcaca gcggccct gg get gcct ggt caaggact ac 540 11 ccccgaac eggt gaeggt gt cgt ggaac t caggcgct c t gaccagcgg cgt gcacacc 600 11 cccagct g t eet acagt c ct caggact c t act ccct ca gcagcgt ggt gaccgt gccc 660 t ccagcaact t cggcaccca gacct acacc t gcaacgt ag at cacaagcc cagcaacacc 720 aaggt ggaca agacagt t ga gcgcaaat gt t gt gt egagt gcccaccgt g cccagcacca 780 eet gt ggcag gaccgt cagt ct t eet ct t c cccccaaaac ccaaggacac eet cat gat c 840 t cccggaccc ct gaggt cac gtgcgtggtg gt ggacgt ga gccacgaaga ccccgaggt c 900 cagt t caact ggt aegt gga eggegt ggag gt gcat aat g ccaagacaaa gccacgggag 960 gagcagt t ca acagcacgt t ccgt gt ggt c agegt eet ca ccgt t gt gca ccaggact gg 1020

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A1472PCT. t xt

ct gaacggca aggagt acaa gt gcaaggt c t ccaacaaag gcct cccagc ccccat egag 1080 aaaaccat ct ccaaaaccaa agggcagccc cgagaaccac aggt gt acac cct gccccca 1140 t cccgggagg agat gaccaa gaaccaggt c agcct gacct gcct ggt caa agget t ct ac 1200 cccagcgaca t egeegt gga gt gggagagc aat gggcagc cggagaacaa ct acaagacc 1260 acacct ccca t get ggact c egaegget ee 11 ct t cct ct acagcaagct caccgt ggac 1320 aagagcaggt ggcagcaggg gaaegt ct t c t cat get ccg t gat gcat ga ggct ct gcac 1380 aaccact aca egeagaagag cct ct ccct g t ct ccgggt a aa 1422 <210> 259 <211> 981 <212> DNA <213> Homo sapi ens <400> 259 get agcacca agggcccat c ggt ct t cccc ct ggcgccct get ccaggag cacct ccgag 60 agcacagcgg ccct ggget g cct ggt caag gact act t ee ccgaaccggt gaeggt gt eg 120 t ggaact cag gcgct ct gac cagcggcgt g cacacct t ee cagct gt cct acagt cct ca 180 ggact ct act ccct cagcag cgt ggt gacc gt gccct cca gcaact t egg cacccagacc 240 t acacct gca aegt agat ca caagcccagc aacaccaagg t ggacaagac agt t gagege 300 aaat gt t gt g t cgagt gccc accgt gccca gcaccacct g t ggcaggacc gt cagt ct t c 360 ct ct t ccccc caaaacccaa ggacaccct c at gat ct ccc ggacccct ga ggt cacgt gc 420 gtggtggtgg aegt gagcca cgaagacccc gaggt ccagt t caact ggt a cgt ggaegge 480 gt ggaggt gc at aat gccaa gacaaagcca egggaggage agt t caacag cacgt t ccgt 540 gt ggt cagcg t cct caccgt t gt gcaccag gact ggct ga acggcaagga gt acaagt gc 600 aaggt ct cca acaaaggcct cccagccccc at egagaaaa ccat ct ccaa aaccaaaggg 660 cagccccgag aaccacaggt gt acaccct g cccccat ccc gggaggagat gaccaagaac 720 caggt cagcc t gacct gcct ggt caaaggc 11 ct acccca gcgacat ege cgt ggagt gg 780 gagagcaat g ggcagccgga gaacaact ac aagaccacac ct cccat get ggact ccgac 840 ggct cct t ct t cct ct acag caagct cacc gt ggacaaga gcaggt ggca gcaggggaac 900 gt ct t ct cat get ccgt gat gcat gagget ct gcacaacc act acacgca gaagagcct c 960 t ccct gt ct c cgggt aaat g a 981 <210> 260 <211> 324 <212> DNA <213> Homo sapi ens <400> 260 cgt acggt gg ct gcaccat c t gt ct t cat c 11 cccgccat ct gat gagca gt t gaaat ct 60 ggaact gcct ct gt t gt gt g cct get gaat aact t ct at c ccagagaggc caaagt acag 120 t ggaaggt gg at aacgccct ccaat cgggt aact cccagg agagt gt cac agagcaggac 180

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A1472PCT. t xt

agcaaggaca gcacct acag cct cagcagc accct gaege t gagcaaagc agact aegag 240 aaacacaaag t ct acgcct g egaagt cacc cat cagggcc t gaget egee cgt cacaaag 300 aget t caaca ggggagagtg 11 ag 324 <210> 261 <211> 321 <212> DNA <213> Homo sapi ens <400> 261 ggt cagccca aggccaaccc cact gt cact ct gt t cccgc cct cct ct ga ggaget ccaa 60 gccaacaagg ccacact agt gt gt ct gat c agt gact t ct acccgggagc t gt gacagt g 120 gcct ggaagg cagat ggcag ccccgt caag gcgggagtgg agaccaccaa accct ccaaa 180 cagagcaaca acaagt aege ggccagcagc t acct gagee t gacgcccga gcagt ggaag 240 t cccacagaa get acagct g ccaggt cacg cat gaaggga gcaccgt gga gaagacagt g 300 gcccct acag aat gt t cat a g 321

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