AU2016244220A1 - 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

HUMAN CGRP RECEPTOR BINDING PROTEINS 2016244220 11 Oct 2016

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

BACKGROUND 5 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”), 10 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 15 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 20 ischemia. (Zimmermann, et al., Identification of adrenomedullin receptors in cultured rat astrocytes and in neuroblastoma glioma hybrid cells (NG108-15), Brain Res., 724:238-245 (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)). 25 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 30 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 1 the CGRP family. (Katafuchi, T and Minamino, N, Structure and biological properties of three calcitonin receptor-stimulating peptides, novel members of the calcitonin gene-related peptide family, Peptides, 25(11):2039-2045 (2004)). ___ 2016244220 11 Oct 2016 la

The peptides get through se\en~rrjuMnembnine~d0Td«i4'|!|4 2016244220 11 Oct 2016 proicm-uoupled receptor.-' (OPCRsf The calcitonin receptor f(1", ”C! R" or 'V7 receptor") and COR Preceptor are typo II C,sirtpily Β":|:ΟΡθΙ^5 which famiK* includoN other GFCRs that recoerne.e regulatory peptides such m secretitts glucagon and vasoactive intestinal polypepudc 5 i v IF). The bpst: d'daracterltsed splice variants of human calcitOnln receptor diner depending on da- pwsvnee IMnnarh ι Ί Rj. m CTR!, now knm%n as iT»*A or absence fthe major spin. a variant, femerfy €T%. or €31¾¾ now hoowtfas €1¾) of i h dmlnp acids in the first intracellular loop «Jons et a!., Expression of two human skeletal calcitoni«vm%t0rii0ifotta^ cloned rrom a giant call tumor of bone: the first immeelhilabdonmin modulates 10 <uhI Όίτχίΐ mmsouetrou, J t hn Invest, 05 2680-2<>υΐ Hay et al* Arnylw teetptoitf molecular composition .’S^v Trand., 52.303-80-7 (20O4p Foyner ct al. 2002). CORFproposeddlsm differential antagonist aifipltids and agonist potencies in a variety of in vivo and in vitro bioassays. (Dennis et at, CORP8-D7, Λ 1.S calcitonin gene-feiated peptide rece|dor Iteterogejigity in brain and periphery, A Rkarminroi; Exp. Then, 254::1.23-.13:§ (i 000); Dennis et: aleSintoru^activity profile of calcitonin gene-re)ated peptide ih peripheral and brain tissiies. MattnaeoL Exp, ( her,, 25 J ;718- 725 i 1 989): Dumont et aL A potent and aoloetive (XIRF2 agonlsl iCysiBf)2;7]hCQRP: comparison in prototypical CGRFi and GGRP2 ε&amp;&amp;::£' 20 Physiol Pharmacol, ~5:67i-n7oi 1007)).

The CCiRP r mceptof subtype was found to he sensitive id the antagonist fi'agrnunt lsGRPiS-37). (Chiba et stfi. Calcitonin gend^laud peptide receptor antagonist Inman CORF» fg,37l Am, J. Physiol, 2S6:E33M535 (1989); Dennis cud. (1900): Mimeault et nL -. Comparative affinities» and antagonistic potencies of various human calcitonin gene-related 25 peptide fragments on calcitonin gene-related peptide receptors in brain and periphery, j.

Fbdrrraod Exp. Thor, 258:1084« I()90By contrast, theCGRPa receptor was sensin'w to liociSi humun CGRP ihCGRP) analogs, in wfeioh the cysteine residues at positions 2 and 7 were derivaii'/ed {c.g,, with seerouminorrscthyl [Cy.UACMf | or ethylarnide (Cyst Ft}" j; inn CGRPj receptor was insensiti ve to fragment <:,GRP(3-37). (Dermis et al. (! 789); Downs et al. 30 (1990); Duthottf otai/(19971).

Ligand speotfielty :pf C3ldt.hMj;n.'t?^^>T^hd· ca!ciiooln~itkc recoptot T'G|2!,S;>GLR!'! or TCIiLR') depend on the compression ofmdrnbers of a family of abeepotypmtcius called the lOeeptOriCtiyiiyanodriying ^ttleina IRAMFs), The RAMP family Includes three potynepltdes, (RAMFL RAMF2 and RAMP3) that act as receptor modulators that determine the ligand: 0)¾ calcitonin family Merohets. RAMP» are type I trausmemhraue ptntems that sharp about 30¾ amino acrid segueneeidentity ap&amp;a cmamiott predicted topology, 2016244220 11 Oct 2016

Coerntine one trans-membrane domain arid large extraeoilnlar N~ termun that are mapoisaiMe lor the spceilxeity* {McLatcHIe et al, (1998} RAMPs regulate the transport and ligand specificity of the calcitonin -rec^tmyllie receptor* Nature* 393:333-339: Pkpr at al.* (1999) The arnino^terminus of uxeptor^actikty modifying pststelpa la a eAtic&amp;i determinant of glycesytafion state and ligand bind in g o f calci ton i n receptor! ike receptor, Molecular Phamnieohgy* 55:1054-1059). 1.5 20 in 19¾ the CClEBi reeeptor wa$ MemiOed as a b^rodimer eokpoapl of a novel sing le transm.embrane domain accessory protein,, receptor activity-modifyl.ng protein 1 (RAMPl^ and CELE. (McLatehie etal*, atyjm). fStnas-ltnktng experikenta anggsitted fire CJCJRP receptor consisted of a Oue^to-OOe akicbiOinotrie arrangement: of CRLR and RAMP I (Milairet et al. JBC 2¾ 4:2182-42190 (2001)), more recent studies using several methodologics such as BRET and BtFC repealed that the fhnetiomd CGEfi receptor complete may be composed of asymmetric homo-oll^mer of f ;E'LR and monomer of RAMP1 (Bemus cs al. JBC 282* 310! 0-31620 (2007)),

Apurified CREE N-tennioal domain baa been shown to aped Really bind l-CORP : (Chau ban et el Btoencnnstry 34* 7821:2005)). confirming the important and direct interaction between die CR.LR. with CGBP ligand. In particular, f eu 24 and ten 34 of CR1..R are believed to constitute dm docking site of CGRP (Banetjtee et al* BMG

Pharmacol, 6, 4 12006)). Furthermore, Rnller et a!* (EBBS Lsit. 531.1»; ..evidencethat i hat the N-terminal 18 amino acid residues of CRI.R contributes the selective interaction :%ilh OJRP Inner et a! (Bi0ebemi^:v4ll*. $749-::1^54 :(200:5)): suggeated that the N-icrmtua! arulno aetd residue. 23- 60 of CRLR mediate association with RAMP). A sirnetusn-fenotion analysis of RAMP i identified residues 91-103, which correlate lo '“helix 3*! (Simms et al. Biophys. i. 91,66:2 - 669 (2006))* as potentially significant in interaetionogitb CRLR, androsidrtesTrp74 arid Pbo92 as potentially interacting with the CGliP ligand in connection with its binding to dm OGtlR receptor complex, Ligand binding: stndies using a humau/rat RAMP! chimera suggest that the hiadmg site lor certain small molecule inhibitors of CGRP R (c.g., BiBN4006BS), is located within a region which includes amino acids 66-402 of RAMP! (Malice et al JBC 277,14294- 14298 {2002})* CRLR has 553¾ overall amino aurd·CTR* although the trausmembrane domains are almost 805¾ identical. (MeLatdue et al, (1998); Poyncr at al,f --¾ Λ &amp; 2016244220 11 Oct 2016 tj··,

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M 2016244220 11 Oct 2016 SUMMARV isolated antibodies aniieae-binding tYayinenis thereof and other Lsoiaicd anbecn-binding proieina diet Mnd CORF R, particularly primate CGPP R„ c.c., human CGRP R, arc viesc! dad heroin. Such holmed mUigondnndmu protein·' may aehmiivciy inhibit primate ('GRP K inA compared vodt primate AML -VvLL Cl or »mylin teeepxom) and may bind body o r «; S' S /. u -%r ft a;· O O.£ ro cx' o I 1. i o

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ft B ft' rz cr Q2 ft'· a' ft. m 7 s 'ft % te. <ϊϊ ft ft ft' <,s* o T, ft ft z 7tf ft3 5 the CRLR and RAM p ! components ofCGRP R. The CGRP R. binding proteins were found to inhibit, elated' to GGRF R.. 2016244220 11 Oct 2016 3^&amp;-ϊ&amp;ςί&amp;£3&amp; tBefutfN^meUoiMxRg Urn eRecis of CGRR RTfelated diseases of disoixlefs. Biadiog of certain aatigGf-Bjadmg proteins te CORE have one or mote of tie f s isllowiag aeriviiies: InMhi&amp;g, intertermgwpb Of rnodjl?ai;logCGRP % ibMbmt% vssOdGiatloh, ami alleviating, apteliomriog, treating, pro venting, of redlining symptoms of chron ic pain or migraine.

In one exemplary aspect, the isolated atingen-binding proteins selecti vely inhibit human CGRF nmepar |as compared with the Inman AMI, Α'Μ^^:Ι^Ι.ΐ».·'^οί6ο^ I» some SO <.:\obodimeiUs, the isolated antigen binding protein selectively inhibits tie human CGRP receptor with a selectivity ratio of 50 or mom, 75 or mom,. 100 of more, ISO or more, 200 or more, 250 or mom, 300 or mom, 400 or more, 500 of mom, 750 or moteiof 1,000 Or more. Thd-degree of .udeatve inhibition may be determined nsing any snifalde metlod, c,g., nsinga:OAMFasaa.y as described in the Examples herein. In some embodiments, theri^lat^::piig0a:.^»®tg pmteib 1:5. specifically hinds to both human CRBRand human RAMFI, .atxd.bindto hitman AM 1, human A M2 or a die isolated antigen binding protein may specifically bind human CGRP R with a Kof i nM, :5100 nM, <10 rtM, or <3 nM, in some embodiments, the isolated antigen binding protein specifically hinds to human 03.RP R with a Ko<100 nVI, <10 nM, or <5 nM as detemnuod 20 using a 1- AC'S binding assay and analyzed, for example, using mmhods described in :

iRhthhnaswami, ei at, 8i</chemical C2005;F 1004 1013. in some embodiments, rite isolated antigen binding protein has a Ki of <100 nM, <10 nM, <1 nM> GO-5 dM pr M)J nM In a CORF binding eornpetltimt asiay, In. some embodiments, the isolated antigen bidding protein has a Ri of <100 nM, <50 nM, <20 nM, <10 25 nM, <1 nM, <0.3 nM or <0.1 nM in a radiolabeled UT'€GRP binding competition assay to membranes from cells expressiag human CORF R, for example, the assay described in Example 5 herein.

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Td^y-'OtfMiboA’e-rrujntioned embodiments, the isolated antRbbtedi that lor bmdmgio human GQtlP feinay be, {br fexampleoa BM>aoebHalmo0bodyfa polyclonal tmtibody. amcomhiuant antibody, a human, (e.g, fully human) antibody? a hunmuDed antibody, a eliimenc aubbody, u muin-'Spccihc antibody, or an antigen binding .fragment thereof, FonhorgOie astiisody fiatgmem of the isolated andgeo-bmdmg prutem One compete,' for binding to human CQRR Roaa-M^F^ IMg^igptynnd hub! fingmenE a didhody or a singb be, for example* a human monoclonal antibody, e.g., an !gGl~, lgG2-, IgG.V, or 1 gQ4~type antibody, in certain embodiments, the isolated antigen binding proteins that compete for binding to human CGEP It may be neinratixmg antigen binding proteins.

In certain exemplary aspects, the isolated antigen-binding proteins described, e.g.? isolated antibodies or fragments thereof, comprise (A) one or more heavy citron complementary determiningregiortp(€DRMs) selected from the group consisting of (i> a CDRHI having SEQ ID NO:134; (iff a CDRH2 bavingJEQ ID NO: 13.5; Cm) a QDRM3 having SEQ ID hRBlJb; and ogtionMiy (iv)aGQRB 0l):ajHl:{M)ihaf edntamsone or more ammo acid substitutions (c.g., emtservatfvc amino rod snbsntniipns)s deletions or insertions that eolfeefivciy totsl no more than tour amino acids; chain complementary determining r^on|i'lPDRy^iielocted:%m the group consisting of: (i)a ('DR I 1 .selected from the group cott^stjhg'ofS.B^;ID:;M0st|,OI, 1 1 1 mid i lRt^liia CDRE* seieeved from the group consisting of SEQ ID NOs: .! 08, 112 and 1 1S>; (in) a CDR.1..3 selected from the group consisting of SBQ IDMDs: 109, 113 and 120; and optionally (iv) a CORE of (if fir) and (Ml that contains one or more, e.g„ one, two, three, lour or more, amino acid substitutions (c.g., conservative amino acid substitutions), deletions or Insertions t hat collectively total no more than feur amino acids;· or (C) otte or more heavy chain CORED of (A) and one or more light chain CDRts of (B).

In some embodiment the CDRHs· am (briber selected Som the group consisting of: (t) a QDRH I having SEQ IQ HO·: 13 f; (ii) a CDRH2 having SBQ ID NO: 132; Cm) a CDRH3 having SEQ ID NO: 1 33; and optionally 1 iv j a CDRI1 of it). lh) and. (.in.) that contains One Or • mote, e.g>, one, two, three, tour or mom amino acid substitutions {c.g, conservative amino acid substitutions), deletions or inaerrions that collectivelytotal no mom than three amino acids In ;related embodiments, the CDRHs are further selected ftpm the croup consisting of us a : CDRHI selected from the group consisting of SEQ 1Q1SD: "0, xs·, 100. 12rt Crand \2K (ii>a CDRH2 selected ffdm the grriup couNcsdng of SEQ JI) HO SR 101, 122, 124, 1.)6. and 120; <nt)a( DRD.i selected from mogmeo consist, ng of SI Q ID \Q 'buR), 102, 12' id”,and 130; andoptionally (lyj aCDRI1 of i'i)> (it) and <ni t that columns on..: or mom,«g one, bvo, thmc, tour or mom amino acid sabsiitiitipns |&amp;g., conseitotive amino acid aalbdtimtioa^, deletions or insertions. ihcii col I con \ cly total no more than two amino mods. In ©the* n dated embodiments, the CDRHs are further selected tom the group conststoy of. (i 1 a COR 111 sei^^;:;iR0m'lhiegroup οόο^$ί!»ι;of SE^ ID HO: 1¾ '?(>* 7¾82,:85,:88,92,97, and 100; |u):¾ CDR.H2 selected tom the group consisting of SEQ ID NO: 74, 77,31), 83, 86, 89,91,93, 95. 98.. 101, and 129; (Hi) a CDRB3 selected from the group consisting of SEQ ID NO: 75, 78, 81, 84, 87, 90, 96,99, i02, and 1.23; and optionally f iv) a CORE! of (1), (is) and (iii) that contains one or more, e.g., one, two, throe, four or more amino acid substitutions, (e.g., conservative amino acid substitutions), deletions or insertions shat collectively lotal no more than two amino acids. 2016244220 11 Oct 2016 in some embodiments, the CDRLs are further selected from the group consisting of; (i) a CDR \ 1 \oieeted ifom the group consist utg of SEQ ID NOs- i 07,111 and 115, (ii> a ί 'PRI .2 selected tom the group consistiogof SEQ ID NOs: 108, 112 and i 16; (in} a CDRL3 selected 15 front Ibo group cons isting of SEQ ID NOs: 109, 15 3 and ! 17; and optionally (tv) a CORE of pi, <h* and tail thateoniaito0ueOrnioref e.g,, G8e,.t^stoteei,toto'^ tcM': ^substitutions to g. eousetortoe amind aeid sttbsdtette^ In some embodiments, the amino acid substitutions (.e.g., e<mscrvatsve atohiy acid bnb,touttOMh: deletions or insertions colk·. lively total no more than three alit some 20 embodiments, the amino acid substitutions, deletions or toctiioussolleeife fbatytoo amlto acids perQDRl,;, in related emhoditmihtsf ihe CDRtoure tether selected· tom site group corset· eg of. <3 » a CDRI.l selected from the gtonp consisting of SEQ ID NOs: 42, 15, 51, 57. 62- 69, 105, and i 10; tit; ; C DRL2 selected trout the group consisting of ShQ ID NOst 43, 52, 55, 58. 63, 70, 104, ION ami 114; tm) a CDP: 1 selected Eom the group 2.5 consisting of SEQ ID NOs. 44. 47, 53.5b. 59, M, 105, and 10b; and optionally of (1), (it s and,(ui> that contains one 01 more, o g , one, mo, three, four or mem.- amino acid substitutions ie,g„ conservative amino acid substitutions), deletions or insertions that 'collectively total no more than two amino acids. In additional related embodiments, the CDllLs ate forms 5 .selected Horn the group consisting of: fi) a CDRL1 selected torn the group consisting of SEQ ID NOs; 42, 45, 48, 51, 5-h 5'?, 62,65, 66, and 69; («} a CDRE2 selected tom the group consisting of SEQ ID NOs: 43. 46,49, 52, 55, 58, 6.1, 63:, 67, and /0; (iii) a CDR 13 selected tom the group consisting of SEQ ID NOs: 44,47, 50, 53, 56, 59, 64,68.71, and 72. -md onOonally tis > a CDRL ot (0. ;n) and (iii) that contains*one0¾¾. two, three, tour or more amino acid substttutiomto,g,? tonser\ratiyu gmind ucidNubstituilogsh 11 deletions or insertions. In one embodiment, Ihq total uumhet of ammo^agidrShbsbmtfons,, delations or insertions is no more than two am iso acids per CDIL In Mother1 embodiment, dtp amino acid substitutions are cousavarive substitutions. 2016244220 11 Oct 2016 in another embodiment the isolated antigenmindum protein comprises at least ope; dr 5 two CDRH of any ol the above-mentioned (A) and at least one or two CDKJL of any of the above-mentioned (B), In yet another embodiment, the isolated aruigombrnding protein comprises <h at leaser three CDRH of any of the ahove-mermoned (A), where the three CDRHs include CDRH 1 , a CDRH2 and a CDKIB, and {ii) at least three CDRI. of apyq? the above-mentioned (B), where the three CDRLs include CDRL1 * a CDR12 and a CDRL3. In 10 iddiddhaleinfeddimoMs, the isolated antipn,binding proteins described above coruprise a feat amino acid sequence comprising at least one: QBE.B and a-.'second mMO acid sequence Comprising St least one CDR I. In one 4hd the second amino acid sequences are covalently bonded to each other.

In another aspect, the isolated antigen -binding protein includes a CDRH I, a CDRB2 15 arid a (‘DR H3. hr one embodintent, CDRI II comprises SEQ ID NO:73, CDRHS comprises SEQ ID NO:" I and CORH3 comprises SEQ ID NO:73. In another embodiment, CORD 1 comprises SEQ ID NO:~6, CDR.H2 corn prises SEQ ID NO :77 and CDRB3 comprises SEQ ID NQ:38. In another embodiment, CDRH! comprisies-SIQ ID NO;705 CDRI-I2 comprises SBQ ID NO;R0 and CDRH 3 comprises SEQ IDNQtRI · In another embodiment, GDRIdrpOPtpshaes 20 ;|EQ ID NO;82. CD R.H2 comprises SEQ ID NO;B3 and CORED comprises SEQ ID HO:$4r M another embodiment, CDRHI comprises SEQ ID NQ:s5, CDRH.? comprises SEQ ID NQ:SC and CDRI D comprises SEQ 1(5 NO:K7. in another embodiment, CDRH I comprises SEQ ID NQ:BS, CDRHS comprises SEQ ID NQk0and €:DRII3 cbptprisos SEQ ID NO:90. In another ernhodtraeni. C'DKEII comprises SEQ ID NO:76, CDRI 12 comprises SEQ ID NO:9l and 25 CDBEB compnscs SEQ ID NO:'';8. In another embodiment, CDRH! comprises SEQ ID .190:92, CDRII2 comprises SEQ ID NON3 and CDREB comprises SEQ ID NO:94. In audited Embodiment, CDRH1 comprises SEQ ΙΠ NO:76, CDRH2 comprises SEQ ID NO;95 and CDR i (3 composes SFQ ID NO N Ir a: oduu crohn hovnt, CDRH' composes SEQ ID NQ:73. CDRH2 comprises SEQ ID NO:”;4 and CDRH3 comprise* SEQ) ID N096, In another 30 embodiment, CDREII comprises SEQ ID NO:9Q CDRH3 comprises SEQ ID NO:98 and CDRI13 comprises SEQ ID NO.99. hr another embodiment, CDRHi comprNo.v SEQ ID NO: 190, CDIIH2 comprises SEQ ID NO: 101 and CDR He comprises SEQ ID NO: 102c

in another aspect, the isolated mtrigimrismdlhg prqipfh Includes a ODRLI sequence, a CElEL2 sequqace Md a OpRL3 sequence. In one embodiment, CDRI, i comprises SEQ ID

NO:42, CDRE2 comprise* SEQ ID NO:43 and CDR1..3 comprises SEQ ID MO:44. In another embodiment, CORE! e^pti^SEQ. ID' M0$JQ€QRL2 comprises SBQ ID NO;46 end CDR 13 comprises SEQ ID CDRE1 comprises SEQ; ID 2016244220 11 Oct 2016 "N0:48, CDRL2 comprise SEQ iD N<);49 and CORL3 comprises SEQ ID NO;S(). In another S embodiment, CDRL! composes SE0 ID N0:52 and

CDRL 3 comprises SEQ ID \u 53. in another embodiment, CDRI I comprises SEQ ID • NO:$4, CDRL2 comprises SEQ ID NO:55 and C DRE3comprises SEQIU N0:56, la another embodiment, CDRI l composes SHQ ID Ml 5\ CDRL2 comprEsus NFQ ID NQ:58 and : CORO comprises SLQ ID SO:39, In another embodiment CDRLI comprises SEQ ID ία NO:60, CDRE2 comprises SEQ ID NO:S5 and ('DRU cmapriSdS:SE0 ID

embodiment, CDRLI comprises SEQ ID NO/41 CDRLS comprisesSBQ ID NO;61 and CDRI 5 comprises SEQ 5Π \i) 47. in and hoi .mk»dimonhCDltt^.^mpri^:$-R(i:ID' NO;62, CDR.L2 comprises SEQ ID NO:63 arid CDRL3 comprises SEQ ID NOtM, In another embodtmem* CDRLI comprises SEQ ID NOdid, CDRL2 comprises SEQ ID N0:55 and i 5 CURESoomprisps SEQ ID NO:56. 1« anOthot embodiment, ( DRII comprises SEQ ID NO:66i: Ed^RI^bomprNds SEQ ID N:0;:67 and CURES comprises SEQ ID NQtbE In another embodiment, CDRLI comprsse.s.'^jp^:I^-NO'.6a, CDRL2 conmride* SEQ ID tiiOiDahtid; CDRL3 comprises SEQ ID N():ti, Id another embodiment, CDRLI comprises SEQ ID-NO:6b, CDRI 2 compiles SEQ;::l6K0tlb.^i€PRi3 eotnprises SEQ ID»71. 2Θ hi another aspect, the Isolated antigenobidding : a CDRL2 scqaence, a CDR.L3 sequence, a CDR0I sequence, a. CORDS sequence and aCDRH3 •sequence Itj'one embodimcaQ J$D&amp;LI comprises SEQ ID N0.42, ODRL2 comprises SEQ ID NO; 13, CDRL3 comprises SEQ ID NO:44, CDRHi comprises SEQ ID NO:73, CDRH2 :: com prises S EQ ((> NO.74 and C'DRI 13 compri^:''$^QtQ'-N0:75. in anottmr embodiment, 25 CDR LI comprises SEQ ID N0.45, CDRL2 comprises SEQ ID N0:46. CURES comprises SEQ ID NO;47, CDRHi comprises SEQ ID NO:76, CDRII2 comprise* SEQ ID N0;77 and CDRH3 comprises SEQ ID N0:78. In another embodiment, C'DRI.. I comprises SBQ ID NQ:4S, 0DRE2 comprises SEQ) ID NO:49, CDR 1,3 comprises SEQ ID HQDdECDRDi comprises SEQ ID NOME C'DRI 12 composes SEQ ID NO;bO and CDRI 15 comprises SEQ ID M; mm. In another entbodlmenE CDREI comprises SEQ ID N0:5;L C'DREl comprises SEQ IDNO',57, CDRL3 comprises SEQ ID NONE CORE!I comprises SEQ ID NON2, {'DRI 12 comprises SEQ ID NO:83 and CDRFI3 comprises SEQ ID NO:84, In dnotbpr embodiment, CDRLI comprises SEQ ID ME54, CDRLI comprises SEQ ID NCE.55, CDR 1.,3 comprises SEQ;IDNO:56, CDRHI comprises SEQ ID NO;85, CDREI2 eontpriaep SEQ ID MOM and 13 Μ 2016244220 11 Oct 2016

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'snuHaid Sptpinq odipqn du:xs;e.sjntm eq seat smeio.kl duiptuq uoSum?pmofost sept 'jetg.tn.3 'Apo£|ntin od-st-pD^I ·!0 'ΌΙΕΟ ΓΟ“Ι ns1' O 0 *oq rorui pen '.fpoqssnsi psuopx'iuom urunsq n ocj Asses otojood ihuputq sLoihua: pmajOS; sxq COR.3 ^Q¥€INSLXrK (SB<Jp M6;:I06), w consisting of S and C-. 2016244220 11 Oct 2016 K.L4 Consensus 54 CDR1 RASQXiX>X3XjOXjiiX6 (SEQ ID NO: 1§7)? wfeeih X* % seieeied tom the group consist mg ot S and G, X? is selected from the group consisting of V and i, X* is selected from the group consisting of S the group cmsmmg-pf K* X<, w selected Pom the group consisting of V mu! D, urn I X·, is selected from the mo up con rising of 1 unci G, ICi CDR2 X,AS5Xpi X.; {SEQ ID I^G:10X)g wherein X* is selected front the ;.roup epnslMiog of<l and A, %? is selected torn the group consisting of R. and 1.. X» >. v Icctccl tom fhe group oopsisung of A and Q, and Xlj is selected from the group consisting of'T hnd Ei CDR3 XiQXXcXiX'XjXsX’ (SEQ ID: NO; 109), wherein X, is selected ffopntlte ggpup Jooabdngof Q and L> Xt is selected from the group consisting of G and N. X.< is selected from 15 ; fhe gtOop consisting of N and T, Xa is selected from the group consisting of $. Y and: F:,)X« m :selected:tom ;the gmitp consistlog of ih and ili Xp,Is selected from the group consisting of C, W end S^ andfX? is selected tom fhe group consisting of E and T. tj3,,;C;0;tionsus CDR;} RS$QSLLH$X*G.X>X-«YTY (SEQ ID NO: 110); wherein Xr Is selected ikon the 20 gp>up consisting of 0 aud A, 3G Is selected front the group coaststing of R and R, and X* is selected from the group consisting of N and 1.,

ElJiAhMlMiG COR i :¾ SSQSLMSX^GXtXtYlX s (SEQ ID NO: 1U X whetoft Xi is selected from the group consisting of R and K, X-; is selected front the group consisting off, D and .4, X* us 25 selected from the group consisting of Y, R and $G X^is selected tom tlte group coni sting of M and T; and X* is selected tom the group consisting of D and Y. CDR2 XiX.'SNRXsis (SEQ ID NO;l 12 h wherein X> is selected tom the groop consisting οΠ and E. X’ 's sole mod ton' 'he group eonsis'iug oi ft and V. and X; is vN ecn.nl tom the sunup consisting of A and F. M CDR 3 MQX sX.sX/X4PX3T (SEQ ID NO; I S 3), wherein X: is selected front the group consisting of A and S, X,; is selected from the group consisting oil, and F, X< ts selected torn the group consisting of Q and P, Xd b selected from the group consisting of T and L. nud X) is selected fact! the group consisting of F and L.

LmMtotscnsus K> 2016244220 11 Oct 2016 CPR2 R.XiNQRPS (SEQ iD NO: 114), Adteroin. Χλ from the group consisting of N and S, CORi iaaSSMlGXiNXiVXi (SEQ ID NO rfri 5), wherein X, is selected from the 5 grmif ix^nsisliiig ©FX and S« X? is selected froift the group consisting of V and T. and X* is selected fern the group consisting of S, N and Y, CDR2 XjXxXXsRPS (SEQ ID NO: 1 Jfr), whereto Xj is seleeicd Item the gamp consisting ofi'XT and R, \„· as selected from the group ronsiaisng of X and X and X* ts selected from the group consisting of K and Q. m CDR3 X,X>KdDXwX?i ΧΥΧΛΎ tSRQ IP MO'l 17), w heroin X, is fleeted from the group coitsistmgdf p the group consisting off and A, %.$ Is

selected.- item the group consisEng oF W and % &amp; k of S and IX X -*« adeemed from the group consisting of R and S, X* is selected from the group con-asting of 5 and N. andftoni:j#::|pnp eomstmgof A and G, 15 im Λ j.j. Comchmis COR! :g6X?X AMS:X*^ (SEQ ID NON 1H}? wherein Xs is selected from the group consisting of S and Q, X,> is present or absent, and if present, is $, X ; is selected from the group eoMtelfng of S and D. Xa is present or absent, and if proseni, is N« Ns is selected from the group eotntesdac of I sad 1., X* is selected from the |3|tep€0bsisfing rd'Q 0 and R, \- is selected tvro Γ s v, oup co >ust>ng of X and b> Xs is seLxmd Rom the group consisting ofN and F, Xs is selected from the group the group consisting of V and A, and X t; is selected ft^i;fe-0#iitp-p0p^ipg.pf $, N and Yc CDR2 Xh X NX R PR (SEQ ID Κί κ 119), w herein X; is selected from the group consisting of D, Cl, T, and IE X> is selected Iropithc group eonsiroogoi N, K and S„ and X» is 25 selected from the group consisting of K., N and Q, ( DR3 XfXsX.ddX,:;XfX;,X :XsX\iV (SEC) ID NO: 120), wherein X* is selected from the group eoti-istmg of G„ N and A, X? is selected from the group consisting ofT, $ and A, X>. is selected from the group consisting·-.of W and Rf Xs Irsdlectcd RwiAtho group temsitPing of S and D, X< ts selected from the group consisting of R. and B, X&amp; the group M eonsiMiug of :L group consisting opg, γ and X, Xros selected from the group consisting of A, O and G, and .¾ is selected. from the group consisting of V and t. 2016244220 11 Oct 2016 K5- KS o K 03 a qg' s s V. <*-r, i 8 ί pi a X·/, Φ- :L r*> 3 3 9 X; C5 P % £2 vz S &amp;: Z L· m X a 3. s* r/Q Cci X V< B 1 S c? X; a z S' m c o o '/: ?v o S'; o Jv c c V X'-v. P 'f, c‘ f'-; c :Si: ‘•J’' 72 £2 'Ϊ, O a 3 >r, ".'J s SJ X £ 0 S‘ yc •G ij5? O ·"" · £ ijy r?2 X L· rL· o A % .·**ΐ o X X £ a, X a 3* d Λ >;a 3 r.i v.; z 5' 'Ji M ’X ? X 8' C/5 X yVV •V:; 3 3 -3 w. X ii<! P Xii a CL· L· s- 8 X a a ·->·, Ϊ5 o V: '/: P x*·. £L •o '£3 .jf·. if S Ϊ3 m X X Ci &amp; £2 a, X -w:->· X •,q S« o’ λ £ \S £ o ys; L·.·’ m X -.{ X X c £2 X·; 0 di. » 3 SK5 o L· ΪΖ CL· > X \/<. - W <**. X > 1 ΪΛ 9 a Is % -W· 3 γ w X 3 ί,Ρ: Ό 3 £ i# /•J % &amp; X· >v· ?;· X 'St v. ip 3 a a> •xX* § zi £L· r. Vi X X rr s i^j· /<<. a S 0 r". £» 1 rr. 8 £2 ίΓί T-2 X ii; b •X w· vs^ o X X :r; O X 0; c. b 7.' 9. 1 X V · O: Xp pi O <?2 c £2 ^5. S S' V} 35 p. V; CP CL· P· ϊλ <v C; <./ a.. ?cs ('L· £2 O 3 P V i w P X i£ il V' /X § 2. s. ir- n Dm X o dS c '•'j Si o •K V a. 8 iJ o wX. s*··. £ ?»>< ·**/ £ 8' u. X: •D £2 y£2 •:M\ v; δ 4fc '/ £2 B CL· a r c ν α S' Γ2 O 8 s 3 Ci, V- X a 'X «5 L· fir: > B r~ y .^- ^ φ. o O S' -> o X y; :¾/ X 7?' i £2 -£2- i ^ . ---4 <"’/ ?* ££. 2£2 8 S' ti£i O X pi... X &amp; £2 ·;<; V % a 3 ·χ; '/'Τ' ,s 3 <X: :/: •Vft ’ ·/ '·✓> a· a, P 1 a f a. A .V £2 £2 ‘J ;2? C&amp;- u 3 /"/ £T <2 -¾ X'- 8 S' 1 s, P {; Vi V 1.. 1 1 3' S 3' 1 o X ]'£*? X X a

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I s, a X Λ l>iir U X iun^Nuo;: dfuud oui iuou poppj^ >-> ·. v (j pur r)jn ip|msuao dnoiS mp moj) p^pcq.M tit tuojoqw'(; ~\ ;qn 01 u'!S> Xi\ ^A:X ΠΚ’,ΙΑ SKupAkV} f )| > C'DIU SXjGMH (Nl Q ΓΟ NO 128k therein At ts selected from the group consisting 2016244220 11 Oct 2016 of F and Y, 5 CDR2 Vf SXiOGSX>KYX.nX^DSVKG (SEQ ID NO: 12¾ wherem X j is selected from, of E and V, A,» selected from the group consisting of ϊ and Η, X ? is selected from the group consisting of S ami Y, and X* is .selected from the group consisting of V and A, GDR3 XjRV.XAtXAVSX-XsYVXeXuAnYVCiXK.XuiV (SFQ ID MUiO). wherow Xs is selected from the ^α^.οο^^ίία^ο^-Ο,^ι^,β,.Χ^ is selected from the group: consisting of ! and K, is selected from the group consisting of X <md R, XX is selected from the group consisting of Y and V, Xs is selected from the group eoadstmg of Y and t\ X<; is selected fropi the group consisting of D and Μ, X ?s selected trotn the group consisting of S and T, X* is .selected from the group consist tog of G end I. X>· ts selected from the group cottsistittg off! and Y, Xus is present or absent, and if present, is Y, X; < is selected from the group consisting of X and I, Xj: Is selected from the group consisting ofYI and. Lgand X\* itM^lesclod -from, the.. group consisting of A and D, MCA Concensus (3DR I X; X 8AM X,! t SEQ ID NO: 13 i). xv herein Xir is selected Rom the group ,consist.m of\aitd N, Xs is selected from the

flop* the group consisting of W, A and G. and X , is selected fern: lie group constating gfS

GDR2 XdX,An\iX.XXIX-\, VXvX \RX' Λ Λ KG I SFQ ID NO 1 12), wherein Xi is selected from the group consisting of R, A and V, X: is selected from the group consisting of K. S and W, Xs is selected from the group consisting ofS* G. Γ and Y.-Xiis 25 present or absent, and if present, is selected from the group "consisting of K and T. Xs is present or absent, and if present, is T, XV, is sof a ted from the group ronvroiro· of Π and N, X·’ is selected from the group consisting ofG and$, Xs is sclocfed from the group eomtsdngoEiV IX h N and H, No is selected front the group consisting «ΓΤ and K< X)t'· is selected trotti dfe group consisting of D and Y„ X} is selected from the croup· consisting of Y and S, X;? is spleetod fen* this group consisfing of Yi A and V* Xan sdectedtfrom the group POPsistmgoFA and Dp and Xu is selected from the group eoitsIslmgofFand :S·

Cl>R3 X ΥΛΛ,Χ-Χ(,Χ ΥΛ Λ,,,Χ. \ >χ5 X Λ,Λ,Λ ΌΛιχΧόΥ (MiQ ID NO:I33k wherein X; ts selected from the group ,,ot!-ihiiogof DVA and #0¾ the group consisting of R, Q and G. At ts selected fro® tieT^R,· k Q and Κ X ;<s \ ο«ν<ΐ ί^Η ,Μ,χιρ ' <ms - η ,, 0 Υ, landR Υ .s vA'Cted om the group 2016244220 11 Oct 2016 consisting ofY, V and A. X<. is selected from tl>-„ group consisting o|%'0,'ViAlpd T, X? Is selected from the group consisting oH, P, D, \ and M. \s is presmb or absent, and if present, is selected Irom the group consisting ufS and Y, X·.- ^ present or ai'seef* and if present, is· S selected from die group consisting of W„ S and T. Xn. >-> -«elected from die 5, G and I \m is s.\.\toe r om the ijoup cimsisung id S, G, L >nd Y. Xo is pi escm m absent, and if present, is selected Ikunthc groop consisting of \V and Y, Xois selected fern rite group consisting of Y and !.L X..;. is present or ab*cm, and if present, us selected ftom^fe-^toiip·. consisting of Y and D. Xi ' is selected from the group consisting of Y, K. and F, Xicis present IQ -or absent, and if present, is Y, Xp- t^jftesom t»r absent, and if pa*^tjil:Yp|C.ia is selecteddMte the group eousistmg of hi and 1,, aid Xj»is selected from the gmnp esnsisfing ofi> and A. παπ; onsensus CDR I X3 XAXX.jX, ISHQ ID XΟ j34¾ Xherem X i is selec ted fpM the gt^dp ConiisPng of N, G, D, S and A. X? is scioctid fetm the group consisting of A,F and Y, Xi?s 1.5 selected iron·; the group consisting of W, Y, A and G, X<j is selected from th0:;p0tip:.edtmihtih'g of XI and L, and X- is selected from the group consisting of S and FI. t DP" X '\ \ ΧΛ,Χ,ΛΛ XA Λ iXlsX AhX{A ,ArGtSI Q ID NO B5), wherein Xi is selected Shorn the grmip consisting ofR, W* A, V. S and f, X? is selected fern the group consisting of E, .¾ S, W and RdXjisseteeted %pib4.|ptp':o«^feti»g'ofS, F, G* F 20 and \ , X,: is present or absent, and if present, is selected from the group consisting of FL T and R, X> is present or absent and if present, is-selected from the group consisting of "f and A. X<, is selected tern the poop consisting of D, X, B, $ end Y,:¾ is selected Rom the group consisting of G and S, Xs is selected bom the group consisting of G and S, Xf is selected from fbo group consisting of T, 6, II, 1, X, H and Y, Xl0 Is selected from the group consisting of T, 25 FG E and F, X; ;> is selected from the group eonsisting of D, X, Y and E, X n is selected tmtn the group consisting ofY and $, Xp is selected from the group consisting of T, A and V, Xp is detected from the group eonsisttng of A, (3 andD, eonsistmg of P, R and S, Xjtc is selected from the group consisting of V and P, and Xr; is selected from the group consisting of K and Q, 30 CDR3 Xi^XMsSXsXiXsX^Xii®

wherein Xi is selected horn the group consist mg of O, Ch A ami h, X; is selected boot the group eonsistingof R, G and Q, X? is selected fern. the group consisting ofL Μ, Y, R, L, G and K, X4 is selected Root the group coresisting of th S, E, ?Ί, I and R, Xs is selected from die group consisting of Y, L G, V and A, MM I, %is, A 20 2016244220 11 Oct 2016 ij·-5 suuablc method, c g„ usmg a cAMP assay as described in the Examples herein. In any of the alx>\ o-momioacd consensus sequence defined embodiments, the isolated antigen-binding nroteht may ha vs' a Ki ot £ 100 nM <i 0 nM <1 nM £0.5 nM or <0.1 nM in &amp; C'GRP binding ernnpeiihroi assay, e.g.. m a radiolabeled "i-CGRP binding competition assay k> mesnbraitss irons ceils expressing human CGRP R, c.g,„ the assay described in Example 5 herein, 21 C» B S' ff i M Ki ’ /> 2 cp ... o c ~i. a A o

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I -Ϊ < w ' £ ^ P 3 Λ’ί !/ £ o os ^ s r O'·· 0dl“8t S ;^ON. Of OHS cO;posox ilncuS ο·ρ usoij. poy.TOps o^usnbo** ouaur to; qji.w Οηίί?(}:. twu'inb^ <:.1pq ao «;;i06 P’n? N; cSS .i^cq yr> >:m| pip .^HOfitw«οΛ> uoiHo op.ps m s ϋίίϋρ AAPOq r ^Siadoao.·» poqu^op suiojoad ??uipu[q~un«i[u>{> jX'nqoss rnp p> Ptlldg amino acid substitutions), deletions or ingenious, 1» another embodiment, she tNoUitcd antigen-binding protein comprises a V,5 comprising an amino acid sequence veered troto the group eomrisring of (i1 SEQ IDNOrti,riu a sequence that is at least. 90% or 95¾. identical to the sequence defined by (ih and (id) a sequMce as defined by (1) containing up to 5 ten ..mine acid subnhiuikjns acid aitbstiditions}, deletions or 2016244220 11 Oct 2016 insertions. in another embodiment; the isolated antigen-binding protein comprises a comprising an ammo acid aeqaeftce selected from the group consisting of (t) SEQ ID NO: 162, (tri a sequence that is at leant 90% or ^5% identical to the sequence defmeri by < t>, and (in) a sequence as defined by (i) containing up to ten amino acid substitutions (e,g,, coiisstyMmt ΙΟ amino acid in, 800:1110(- embodiment, the isolated autigep- binding protein comprises a Vn comprising· an amino acid sequence selected from the group consisting of {.o ShQ iD NO i 63, (ii)a sctplence that is at least 905« or 95% identical to the sequence defined by (i), and ri.it) a sequence as defmed by (i) contammg up to ten amino acid substitution^. te.g., conservative amino acid substitution^}, deletions or insertions. In another 1.5 embodiment, the isolated antigen-binding protein cm apt iscs a Vn comprising an amino acid sequence selected(from:the: group ponristmgof (i) SEQ 10 NO; 164., leasd;90% <3^·: by (i};,aud0ii) a containing up to ten amnio acid substitutions t c,a.. conservative ammo acid substitutions), deletions or ingenious. Ip another embodiment, the isolatedMriien-hinding pputelnVOmprities 20 a V comp! ,*mm at ammo acid sequence fleeted iron the group eooMNttnu, of $ t) SEQ ID NO; 165, (in a sequence that Is at ©Ε95*%·identical,iSeqaqhce defined by (i), and (Hi) a sequence as defined by (i) oontainlng up to ten amino· acid substiintibns (e,g,? conscrv ative amino acid subahduiionsl, deletions or insertions. In another embodiment, the isolated cumgen-bindingpffitein comprises aacid sequence selected 25 irom the group consisting of(i) SEQ ID ΝΟ;Μ6, (it) a sequent that is at least 96%ογ95% identical to the sequence defined by (i>, and fib) asequence asdofitied by (i> containing npto ten ammo acid subsntutmns (c.g,. conservative deletions or insertion*.. In another embodiment, the Isolated antigen-binding protein comprises a V» comprising an amino acid sequence selected from the grout» consisting of (t) SEQ ID NQ: 167, .30 (in a sequence that sc* at lease 9tt .. e<- u5y»ldvrtn αί to die - .queme defmed by and rid s a sequence a»* defined bs (!) eoet unun> en to ten «mono aeid substitutions ·> g„ censor* at!v„ :::ramj0^id-3^bstitution&amp;). deletions or insertions. In another embodiment, the isolated antigen-binding protriin eoinprises a V« composing «η amino acid sequence selected from the group consisting of ft) SEQ ID NO; 168, (it) a sequence that is at least 90% or 95% identical tpfhe: sequence defi ned by (0* and («0 &amp; sequence as beioed hy (i) conkming op to ten tmdndnfenl substitutions (ey- cotucrvutbc amino acid substitutions),fictions or mser&amp;ns. In another embodiment. the isolated ^migon-binding protein comprise#^ VH compiling an amino acid sequence seketed:front the group consisting ofti) SEQ ID NO: 169, fiO a sequencethat N at 5 least 90% or 95% idemiCaftb the seqnORce dbfipy by (1), and nil) a sequence as defined by (i) containing up to ten amino acid substitutions te.g., conserv stive amino acid substitutions), 2016244220 11 Oct 2016 deletions: or iMertiOMeia^fc· efi^dtn^felfe· iankfed antiien-bmdingpmiOT emprises a V's? comprising an amino acid sequence selected from the group consisting of us SEQ ID MO: 170, fit ) a sequence that is at least 90% or 95*« identical to the sequence de fined by (i), 10 art ,m) a se punk* >n iefm> e St fit tonuunr g up ,*> ten amino· acid subsbtutibiQ (e.g., :conservative amino acid substitution'·;), deletions or insertion#)

Ip qtteembodiment, the isolated antigen-binding protein comprises a light chain ’variable region (VQ comprising an ammo add sequence selected hem the group consisting of (i) SEQ IP NO: 137, (ii) a sequence that is at least 90% or95% identical to the .sequcqeo 15 defined by frlpead :(1 iff a «eqp0nee::as,de:Enedife| (1) containing up to ten ansi.no acid Substitutions (e,g„ eonservabye amino acid lubstimbsus), delettonabrim embodiment, the isolnW autigen~b(ndipg protein comprises a ; sequence selected from the group consisting of (h SEQ ID NO :118. fit) a sequence thai ts at least 90% or 9$% identical to the sequence defined by (n, and tni) a sequence as definedby (f) /containing up io ten gmiqo acid Mibstiiimcus (o,g,? conservative amiuoiacld substiturioas); deletions or insertions:. In another edibodiment, the isolated,antigembinding protein comprises a V; comps ;smg an ammo acid sequence selected Dorn the group consisting of (1) SEQ .ID NO: 139, (it) a sequence that D at least 90% or 95% identical to the sequence defined by u ), and tni) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g.. 2$ conservative ptfco aeti yuhstitudopsh: deletions or inseroons in another embodiment the pfot^bompriiiig# n^i.'p0ip^ns>og .in umino acid:sequence detected: bom the grotip consistingof u) SEQ ID NO.140. in) a sequence that is at least o{!%o( 93% defined by (if and fib) a sequence as defined by ft) eomatumg up ίο -(erg,. conservative amino acid substitutions), deletions or 3:0) insesfions. In another embodiment, the isolated antigen-binding protein comprises 0¥);, comp si u ,» ' n to < i 1 sequence \de to.' horn the ^ ί ί o tssst sp ot (Ί s m ID \Q %1 5(«):.n.^nqd(^’that\is at least 90% or 950¾. identical to the sequence defined hr fi), and (Hi) a sequence as defined by (i> containing up to: ten amino acid substitutions fe,g„ conservative amino acid Substitutions), deletions or insertions. In asmther embodiment, the isolated antigen- 04 Η 3 ο 3 2. ίΛ 3* m ip rjs s&amp;. 3 &amp; αΰ '3 I £3 Ο Ο $ ij: χχ ί>

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Us s 'f. ,.o XV 3 £ Sr A ‘Ό % XV I 1/: —i- XV V S’" XV XV 3 XV O Q :iv CV5 *T5 P· •Γ" Xr sD a F a . >xiv <p itL V^·' 1' XC: ύ o P \C λ; <'·/ &amp; a 1 fie i» y." x£ < 'm/ 3 tie' £r c: rs ί:ί< XV "P ί» X?:: XV Sf s &amp; O XV S' S' >12 ’/- a. o S 7/ S' Q rr. SC D. • XV o* a m rs p; a, /. XV o E zz w 3. % ct> 3' fv rt X2* %·^ 5« ro ό 3 zz —ί- Ο /.Q XV :P δ •7/ y> 'P ss z XL· XV CP, p te ·< a ZZ' sXs<> o ’-./J XV O /'. f'w <Z:. 3 o L·, Δ a r\ ‘XV 2. '£ zz h P XV &amp; π ζη 3-. XV τϊ. •?v-> O *£·. Q 3 CCS s. i/ ?b £ 2i: 3 AAA/ r,i-< 5—;. AA/ Ss- s X·: a. w 1 w o cr y>y ·, d* *< Cv CL· f'/ 'Zs binding protein comprises a Vj comprisim: an arnino an id sequence selected Horn the group consisting of(i) SI::Q ID NO.!42, (ii) a sequence that is at least 99%or 95% identical to the* sequence dub nod by {is. and tin} a sequence as denned by (I) containing up to lest am; no acid o isolated antigen-binding protein comprises n Vh eomprising an amino acid sequence selected front the group consisting off!) SIIIQ ID NO. 145, (ii) u sequence that is at least 90% or 95% identical to the sequence defined by (if and {lit} a sequence as defined by (i) containing up to ten amino acid .substitutions bog., conservative amino acid substitutions}, delations or insertions. In another embodiment, the isolated anti gen-binding proton comprises a V l

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XV P XX. s P Xa r s xr g a Ci. acid substitution# deletions' or Insertion* In another embodiment, the eompirisa a % conspiring an atprto acid sequence selected: fedtlbe group Stopping of in SKQ ID NO-150, «in a ocqnenoe that is &amp;r. least. 90% Of 95¾ identical tsdho^itenco defined bs· (if and lid) a sequence as defined by«; j) containing φ ter 5 ten amino aeMshbsitoitons#,^ eeidptbstiiutians), deletibios dr 2016244220 11 Oct 2016 tosertlona InmindM eotl>odloiddtrtbe ||^i.^edafttigeo^bio4log ptotein. comprises a %:: comprising an: smlnn aeid;Sec|Uenoe Selected from the groOp consisting of (t) SEQ ID MO: 1511 rip a sequence that is at least 90% or CG% identical to the ^equena: dellncd by ft), and (hi) a sequence ,is defined by (I) containing un to ten ammo acid suhsiituiioos (e.g,, conservative Kl amino acid substitutions), deletions or mserriom·. ht another embodiment, the isolated antigon-bmding protein comprises a Vj comprising an umitto acid sequence selected irornthe group-consisting ot\i> SbQ ID NO· 152., (ilia sequence that is at least 90° <· or 95% idobdiud to the sequence detlnedbv or and tints sequence as defined h> ft)containingup to ten tnnimyaeid subslimuous (e.g., conservative amino acid substitutions*, deletions or insertions. Inartothcr 1.5 embodiment, the isolated anuge-uhiuding prttiem cot opt kc.s a V} comprising an urMdoncId i sequence soicctedifroni fhc group conrisfibg of(i)"S:EQ ID M>:151, {ΙΙ|«'·^βφφ.ίδ^Ιί%όί. least 9Q% or 9.5%;idqnitcal to die seqdsncqidofinbd by Ci),.'^hd;|(i«)%-S0qucftce : edniainibg up to top airitoqaeid sidiatitutionis (c.g., conservative arnino add substitutions), deletions or irussrtiona. 20 In any of die above-unentipnod¥h and ¥p sequence defined embodiments, the i^slufed,: antigen-blading protein may be, lor example, a monoclonal antibody, a polyclonal antibody, a rocontbioiunnnliimdy, a human a hntnaniged antibody, a eMnteric ; dntibotfvg «.'ttoi^^eqrfefAptibodyv or an amifpiblMlng fragment thereofl Further, the; antibody fragment of the isolated antigersdnodmg proteins may be a bah fragment, and Fab' fragment, an 25 :'ξζφ% ffagmong an Fo Ifagnseni, a diabodyqor a single chain antibody molecule.: f qr example^ the isolated antigen binding protein may be a human e,g;„ an

IgG f--, lgG.2-, fgtIK or fgG4-type antibody. further, the isolated antigen binding proteins may be he utral i z ing antigen binding proteins.,

In any of dtp abovemiennonod V2, and ¥u sequenco deb nod embodi ments, the isolated. M ^^g6n*bmd^;'prot^B.-m8^· specifically bind so both human CRI.R and toman RAMFf and nor specdkalis bind to AMI, \M2 Ot a human anvylm snoop tor R g„ ΛΝΓΠ), fot example, the isolated antigen bmding pmtein may;specifically bind to human C GRP R with a.%<l μΜ, "'100 nM, <10 nM, or stol e a.., as determined none a FACS bsndmg assay and analyzed, for example, described in Rddi^qawami,etna;, Mocmmkai αηάΜχψΗ0Μΐ

Research Conmunm αίύηκ 334 £3005} 1004-1013. In my-ofthe¥1 and Vi{ sequence doimed embodiments, the Isolated anngemhihdmg;;^^ scleelieelf pbibit :: human t GRP R, s./'UIao m 'ho humanohe VM t. AMP os A M3 1 rceepiots 0 &amp;. with a adeem 0\ ratio of 1¾Ipr xnarc. 250 or more, 500 or more, 750 or more. 1,000 or nmre, 2,500 or mote,, 5,000 5 of mors or 10,000 or more, where the degree 0) sc lecti ve toy 2016244220 11 Oct 2016 suitable method, e.g., usii^qu eAMR asiay u§ 4»ril*2$mf above-mentioned V( sod Yfl ^u#fe^efiaedep^»^nt^:^wk^;pSi^bm|&amp;|v protein may have a Ki of·7100 rdvl <10 nM, <1 nM, <0,5 «Μ or <0.1 nM in a CGRP binding eoropemioa assay, c.g„ in a s ad io labeled U'GRP binding competition assay to membranes |0 from cells expressing iuunnn CORF R, e;gb die assay described ur BMutple 5 befein,

hi one aspect, the isolated atnigen-binding ptoteins comprise a heavy chain sequence that has at least K0! ·», 85%,. C)0% or 9554 sequence identity with an amino acid sequence selected from the group consisting ofSBQ 10 MGs;294l, Some of the isoiated antigen-minding proteins described comprised light chain sequence that fens at!easti0%, 85%, 905¾ or i 5 95% sequence identity 0 nh an ^inO'nnM^^^etoedB^fe.thn groupconMsdngof SBQ ID NOs; 12-28, Some of the isolated antigen binding promitts comprise a heavy chain sequence that has at feast803¾ 85%, 00% or 95% Sequence identify with an aotino acid, sequence selected from rite group eosisistingoFSEf|dD%:C3s: 29-41, and a light chain sequence tbarhas It;leaSi 80%s 85%, 905» or 9$**' sequence acid sequence 2fi .fksm'0f SKO ID M5s:'|2-28, in soorn cotbodfmenta, the isolated: trngen ht Mmq proiesr,\ comprise (A) a hem \ Owm composing a .sequence (i) selected from the group eopsitla^'pf $|i(| li);:NO,s: 29-41, or tu > as defined by (0 and eontaiumgiono or mom (e,gg frveyfen, fifteen or twenty) amino acid substitutions te.g., conservative amino acid substitutions), deletions or imeriiomt '{8} ;t hght chant comprising a sequence (fit) selected 25 front the gtoup consisting of SEQ ID NOs. 12-28, or {iv> as defined by (iii) containing one or morale g, me, ten. fifteen or twenty} ammo :·,:. ;d substitutions (e.g., cons^|tlyjg::j^:aia acid substitution^. deletions or Insertions:. or CO a hoax > cham of (A) and a light ehaio of ρΐ)ό1η some enuxubn-enia, the isolated antigen-binding proteins comprise a heavy chide < ^uprising a sequence selected ttom the group consisting of SEQ ID NOs: 2'MI and a tight chain 230 comprising :¾ sequence selected from die group consisting of SEQ IBBOs; 13- 5S,

In.one embodiment, the isolated antigen-binding protect comprises r A) a heavy cham Jootprfriui an amino acid sequence selected from the grodp consisting of Q) SEQ IB %0:29, , (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i)} and (Ίο) a sequence as defined by (i) containing up to ten ami.no asm! substitutions to g„ couvn ative ammo -icui substitutions),. deletions nr insertions; and (B) a ught chain comprising an amino acid sequence selected from ilia(i) SEQ ID NO;12, («} a sequence that is, at least 90% or 05% identical lo rhe sequence defined by (i), and (Hi) a sequence as defined by |t> containing dp to ted amine acid substitutions (c.g., conservative amino acid substitutions), 2016244220 11 Oct 2016 5 deletions or insertions.

In another embodiment, the isolated and gen-binding protean cosnprises (A) a heavy chain comprising an amine acid sequence selected from the group consisting-of fi) SEQ ID NO;30:, (fi) a sequence that is at leaid: 90% or 95% Identical to the sequence defined byfi), and (in) a sequence as defined by fl|cdntaieidg np,lbisubstlt«to§;{§φ 1(1 eonsenabxu ammo acid substitutions!, deletions m insertions, and (B) a light chain composing an amino acid sequence sclcctcd fiem the group ksnSistiug efbQ SEQ ID NO: 13, p) a sequence that is at least 90% or 95% identical to the sequence defined by fi), and pi) a sequence as defined by (i) containing up to ten arnmo acid substitutions fe.g., conservative amino acid substitutions), delctions cufinacOtons, 15 la another;: ei-hhedhnenfi the Isolated antigendiiodi ng protein cotnpdaes (A) a heavy chain comprising an amino add sequence selected from the group consisting of (i) SEC) ID N0 3 i. fd) a sequence that is at least or 9S% identical to the sequence defined by (¾ and fits' a -cqucncc as define',) b\ (i) containing up to tea annuo acid substitutions t;e,g,„ couscrvadx e and no acid substitutions!. deletions· or lusefiions; and (B| a fight chain oompfiSing 211 fin amins * act d sequence selected from the group consisting of ft) SEQ ID NO: 14, III) a sequence that is at least 90% or 95% Identical to the sequence defined by (ifi and pi) #: mspruce as defined K in em\annrsg up to ten avid substitutions (e g, convex afne amino acid substitutions), deletions or insertion#

In another embodiment, titc isoIa;t^d';uptige«-I«ndl.ng protein eornpmes (A) a heavy-25 chqin eomppislni;iOi: amino: neid sequence selected li-om the group consisting of (i) SEQ ID NQ'32, lul a sequence fi" n is at Ka^t nq«v> or o '<>'« ,q mood to the sequence defined by ft), and iiia sequence as defined by (fi containing up to ten aminoacid substitutions (e,g,, conservative arnino acid substifyfions), deletions Ot-ipettidP^.#d;(B)« fightofiam'OdmpfiMng an amino acid sequence selected from the group consisting off!) SEQ ID NO: 15, (il) a 30 sequence that is at least 90% or 95% identical to the sequence defined by (i), and (fit) a sequence as defined by (I) containing up to ten arnino add substitutions (e.g,, conservative amino deletionsor Insertions,

In another embodiment, the isolated an ngcu-binding protean compiles (A) a hear s chain comprising an amino acid sequence selected fifirn the group consisting of fi) SEQ ID : ov

sS.-sP NO: 33, (if) a ysqusgee that is at least 90% or 95% identical to the sequence defined by (i), am! (iii} a sequence as defined by 11} containing up to ten ammo acid substitutions (c,g., conservative aniino add substitutions), deletions or insertions, and {B) a light chain comprising an amino acid sequence selected from the group consisting.of (i) SEQ ID NO; 16, {11} a 5 ? sequence that Is at least 9031» or 95% identical to the sequence defined by (i), and (id) a sequence as defined by (i) eontaiqmg α|ϊ::·.ΐο:·^tritrso:^ubstiiutioiis ίο g.. conservative «‘m ,tc*d substitutions), deletions or iaseriious,: 2016244220 11 Oct 2016

In at,other embodiment, the is«M|^.'a|ilig^j4'3iindtng pioicus composes f \) a heavy chain conrnising anarmno acid sequence .selected from the gtoug* consisting of (it SEQ ID ICE 'NQ::29sthatsequenced> finod by fi), ,etd (Hi) a sequence m defined by (it containing up to ten amino acid substitutions (e,g., conservative ammo acid SnbsOmrion.,) deletions or insertions, arid t Ist a light chain < ornpriMHg an jttnno acid sequence selected (tom the group consisting of (i) Slu'd ID NO 17, (ii) a aequcncc that Is at least 90% or 95% identical to the sequence defined by (% und tin? a i 5 sequence as defined by (i) contain mg up to teniminct acid substitutions to g„ conservative amino acid sufisdfiifiohs), delations or Inseftlhns,

:In anqfher exnbodlmont., the isolated anfigeo-bindtdf protein comprises (A) a heavy chain comprising an amino acid sequence yef acted of (i) SEQ ID NO:34, (Is) a sequence that is at least 90% Of 95% tdonn*..a! to the $equdbc'e defined.byiCQciadl' 20 (iii) a sequence as defined by (t) containing up itr^. amino #Mmb.«tituttOM· conservative atpldq: acid bdbsfiidfi^ or insertions;; and (B) a. light chain comprising an amino acid sequence selected Horn the group epnsMmgof(i) $BQ ID NO: 18, (It) a sequence that is at least 905,, or 95% identical to the sequence defined by (i), and (id) a sequence as defined by (I) contfcmmg tip to tern amino acid substitutions (e.g., eomerva||yb 25 amino add substitutions), deletions or insertions.

In another emhodir ore the iwhiten antigen- un<or; pso m comps ,,cs q/Vs st heavy chain comprising an urmao acid sequence seieetM from the group consisting of (it SEQ ID NO:33, (Is) a sequence that is at least 9056 or 955¾ identical to the sequence defined by is), nod tin) a sequence as defined by it) containing up to ten amino acid substitutions u:.g , 30 conservative amino acid substitutions), deletions or insertions, and (B) a light chain comprising an umino acid sequence selected from thegroup consisting oft i s SEQifD NO. 19, (!i| a sequohec that isat least 995« or 935:, Identical to the sequence defined by (I), und-fni) a •sequence as defined bv ft) containing up to ten amino acid suhshtutbas (c g., cottscnative ami.no acid substitutions), deletions or insertions. % F" ε; Π X, § ft D. I 0 B n f Ο $ri η. ,-. o Ul c; o <ζ £Χ f 3 tgg Ο ζ: 'Ή rr o ?; δ 2 η cx ο y«>, 2Γ <'ν ρ, CT < Μ ο r? sx Ζ Χ2 8 Ζ /**, W' L· S3 ι ο £? ? ·;·;; &amp;* α 5 3 ί f Ξί './·. π. <τ Ο: &amp; '/ £Χ >r: 'W Z .***, ''~S 8 X; δ. 1 r W S £ n f. ‘‘.JS o # 8 XX 2;. 5 ο .o. rz % ίχ "2 &amp; x cL ί#5· :CH ΪΪ5 Cy frf £? % r, ir •S!5.· fiS O Br g r <r * 8' cr< r &amp; Ci n 3 n ή B' -X· 2 Ξ7 I 1 C3 o' 8 a. cr %i5 a' T/z &amp; c- 1. :**{ 1 C-. ;2.. O* c 2 c-· &amp; -w δ’ 2 ry O % | •b“ ro a as rz B’ 2 F S' r O ra m "B <ίί £' O P c a ίί :α o ex y* ί— ;£C· δ « ·£> -S 53. &amp; o~y i.S’ >. >:> %:'· if a ΐ?ς·· xs f. 3 r> Vy. . :C2' tZJ' Ώ CX 3' ,ί,Λ r P 3 rs Λ\ 2 ia rj g 8 y*.· XZ“ ίίδ· s r:: 1 s; 2 <5 o rr S iT s is: ex s d S' rs <5 '+*, X 13, 2. &amp;: U %. P; o r; Z S' 0 jr >v-5 f;i '•O ^ j·· :;i? S5 C- 2. B Έί, B 1 sP' 1 o rr δ Έ s Γ; O £i. O 2' a iT < ¢5 o ' 5 ’ 3Γ ξ? r; yv 3“ r> ~. a® ώ ·; r> o: 3. S' 08 m id ,C 6 > rr i «ί =·<? 8 ZS £1.

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In another emboditnem, the isolated untiucnHiiuditsg protein comprises (A) a heavy chain eornpristhg an amino acid sequence selected from the group consisting of (i) SEQ ID MOdid, lit) a sequence that is at least 90V·» or 95% identical to the sequence delated by (i). and 2016244220 11 Oct 2016 15 25 sequence as defined by (i) containing up to ten amino acid substituting (e g., conservative amino acid stdistimrionsh deletions or insertions, l?t Mtigqn-binding pn^leirf comprises (¾¾ a Imayy chain comprising an amino acid sequence selected iron* the group; cons isting of (Q SBC) ID :%Q:3$, 111) ashquenee^ihatisai Icaai;90|it Or 95% identical to the sequence defined by ii). and :<Hi) a sequence as defined by lit cuatainlhinp to m\ amfno (Ogs :eonseryadtie :athino or chain comprising: an ammo acid .sequence a?.leered from the group consisting of *J j SEQ ID SO, 23, (is '> a sequence that k at least 90% or 95¾¾ identical: to the sequence defined by (i:b and (m| a sequence as defined by (i) containing up to ten amino acid substitutions fc,g., conservative amino acid .substitutions}, deletions or insertions.

In another embodiment,: the isolated Mdgen-bihding ptolein comprises (A| a heady chum comprising an amino acid sequence sefected trom the group consisting of (i) SEQ iip 190:33, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by 1:¾ and (hi) a sequence as defined by iiieotuamhgup to ten amino acid .substitutions fo g., conservative or insertions:; and (B) a light chain comprising an amino stud sequence selected horn the group consihtingoftt) SEQ I D NO :24, (11) a sequence that is at least 90% or 95% identical to the ssquonpe defined by (¾ and iillja sequence as demrud by (i) containing up to ten arruno acid Suhsdtufipna (e.g.s ctm^rvatiye amino acid substitutions), deletions or insefdqas. M. another embodiment, :the:isole.ted:8ntigeo-»bindi!}g pnnein e^ d K on i *\ >i f 51 f no us u scqi u\ sekxted uom the gmup consisting oi U1 SI Q ID NO ^κν\'>Λ (iiu rvo that is at least 90% or 95% identldai fbtbe sequence defined by 1¾ and (hi) a sequence as defined by ii) containing up to ten amino acid substitutions (c.g,, conservative amino acid substitutions), deletions or insertions; and (B) &amp; light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID 190:25, (u) a sequence that la at least 90% or 95% identical to the sequence defined by (i), and ( hi) a sequence as defined by (I) eodtainmg tip to ten annnd aeld suhsti tufions (e,g-i consetyati ve amino acid substitutions), deletions or insertions, fn another embodiment, the isolated antigen-binding protein comprises (A) a heavy eham *.ompiiNi«g an emmo m id sequence selected Stem tnc comp consisting ot r l SEQ if? 990:90, fu) aydqttence that;is at icasr90%,or 95%ideniicai to the sequence defined by (i), and: (•Hi) a sequende an defined by o t containing up te ι> u enunn .mm «ubMiintuii* l·. g, conservative amino acid substitutions), deletions pr insertions; and (B) a light chain comprising an ®ή1ϊίθ selected from the group consisiihgbf (i) 8Β^1ίϊ3'1Sl6>26:, (it) a 2016244220 11 Oct 2016

Seqaence that .is at least 0010or 95*0, identical to thesequenceHelmed by ;{)),and (hi) a Sequcneb as dbfiheci by i i) comatitmfup to text amino amino acid subaiitudons), deletions or insertions.

In another embodiment th|1soktcd antigen-binding (A) alheavy ίο 15 20 : chain cotmuising an amino acid sequence selected irons the group cbqaMdgof(i) SKQ ID NQ;41, (it s a soqtamee shat is at least 90%or 95% tdenneul to the seqgMCb defined by (i) and hii) a sequence as defined b\ (u containing up to ten amino acid substitutions (e.g., conservativeammo acid substitutions), deletions or insert ions; and;(Β)η light chaimcompi tsmg an amino acid(ΐ)Βίίϊ^ΙΡHO;27:, (is) a sequence that is: atlbast 99¾) or fS|shiiettt;ieaI io the sequence dedned'by (i),:and (Hi): a seem m e as defmed by tit containing up to test amino acid subvbunious sc g , -..onx-nsth ammo acid Mibstitudons), deletions, or insert ίο 1¾.

Inanhiher embodiment thgisolatcd Mhgeu(binding)prot^ heavy ichain .cempHsmg an atnino acid seqbestceipiqcted' fern the group cdbstMt ttg of (I) S1Q ID). NO:41, (si) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (id) a sequence as defined by (is containing up to sets amino .acid substityfoiis (e.g., conservative ammo acid substitutions), deletions or insertions:; and (B) a light chain compnirng an .mono acid sequence seiccledfeun the gsmipconsistlssgoffi) SBQ iDNO:2h, (h)a Seqstenee that is ist least 9(1% or 95% identical to the sequence defined by (i), and (hi) a Sequence as defined by ft) amino acid subabttstiona (c,g,, eonSetVtdive ammo sssnd s

In. My of the abdyehlieubdndd light: and heavy chain sequence defined emhddishenhv the lMkt^;M%^nbted|3^:^^b'M&amp;f:';eoh8^riM'the specified ii&amp;Vy hnd/or light: chain 25 sequence, hut with a different signal peptide or with no signal peptide. In any of the above-men tj os icd light and heavy chain sequence defined embodiments, the Isolated antigen'binding pmtikt may he, polyclonal antibody, a s^edmhiitanf antibody, a human (e,g,, fully human) antibody, a hitrnanixed antibody, a chimeric antibody, a multi-specilk antibody, or an. antigen binding fhsggsent thereof Fsather, the antibody tmgment of 30 the isolated antigen'•binding proteins may be a fab fragment, and fW fragment, an Ftab’h fragment, an Fv fragment, a diabody, or a single chant antibody molecule.. For example, the isolated antigen bitting pmtein may he a humirn monoclonal antiM>dy, and may h% e.g>, an IgG !·> , lgG2-, IgC13~, or IgCM^typenntibody, Further, tjeutralixing aplgen binding proteins. 32 2016244220 11 Oct 2016 ίπ any ni the ilis isp lafcecl anti gen-binding protein oiay specifically fcoid:t0: Bgili hutBan CRLR anddiutoan RAMP1 .and not spo-dlmd!·, bind to AMI, AM2 or a human amy lin receptor {e,g., AMY I), for example, the isolated-antigen binding ptoielo may specifically bind .&amp;> human CIQRP R with a $ K;o<l pM, 4M, er;g<, asdetcrnfined using aEACS binding assay and analysed, lor example, using methods described in Rutharawwarm, w a 1., Biochemical and : Bhpkymcal Resmrek Communications 334 (20(15! 1004-1013, In any of fife ahoye-menhooed light and heavy eham sequence defined onibodtmoms. the isolated amigembimlingprourin mas selectively inhibit human CGKJ* R, relative to the hmnan the AM h AM2 or AMY 3 receptor. 10 ivg,, whh a eeleehvity :ί·ήίΐο of 1.003:01 more* 250 Or mote, 500 or traite* 750 1,000 or

more, 2,300 or more, 5,000 or more or 10,03)0 or more, where die degree orsdeenve inhibition may be determined riamg anyisOitable method, e.g<5Ming a eAMP axsay as described in the Example^ herein. In any of the above-mentioned light and heavy chain sequence-defined· embodiments, the isolated aa»gavhmdi%p?0tieih may h4ve a Hi of <100 aM, <10 hM, <1 nM, 15 5:0.5 nM or <0, I nM in a CGRP binding competition assay, e.g., in a radlolabeled ! ; S 1410)11 P binding hdmpetitiodiassay m :mem&amp;^ expressing human CORF R, e.g., the assay described in Example 5 herein. in a further aspect, also provided am isolated nucleic acid polynucleot ides that encode any of fh$ pt^hhis sumnrafiaed:#ove:. lit mieomhodimeht, the 2D isolated polynucleotide comprises a sequence selected from the group consisting of SBQ ID : NOs: 3 75, 176, 178, 179, ll| 111, 1423¾ 186, 1 8 if j 88,189,191,192, 193,194,19¾ 3 96, 197,200,203,202.203,204,205,206.207,20% 209 and 210. In another embodiment, the isolated polynucleotide edmprises a sequence selected:fi-oth the group Portsistmg ofiSfeQ ID 190^ .224-258. In another emhodirneni, the isolated polynucleotide comprises u sequence 25 capable of hybridizing under stringent hybridisation conditions with a sequence selected from the group consisting of SBQ 10 1408:224-258. in another embodiment, the isolated polynucleotide comprises tt wpnonce that is about X0%, 85Ά, o 0¾ u5% or more identical to a sequence selected from the group consisting of SFQ ID NOs;224~258 III .some instances, the Isolated nucleic acid molecules are opembly-llnbed to a control sequence. 10 related 30 embodiments, the isolated polynucleotides am incorporated into an expression vector,:

Also [«eluded are cell tines tranx formed with expression vectors comprising iso I med poiynnclebbdes as described alotiei In a ml aied aspec k also 'prbyided are: expressiohb’ectomi and host colls traitstopned-brtransfected 0 nh the exoTcssion yeetors dtat:pontprixethy

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The# sid other aspects wil the desodhed Id greater debdl. herefa..:; Each pFtbe aspects:; provided can encompass various eoibpdimdKts provided herein. It is therefore anticipated than each of ihe emlxxliments involving one element or conihipadops of efemmrts can he included 2016244220 11 Oct 2016 such obmhinadonsbf the above aspqeiFandembp^^ "$. bxpreskly |onsidered, Other festums,- objects, and advadtages of the invention u#: apparent; in ;'%0ij|etifligi4.-descnp{i<)n that follows.. BRIEF DESCRIPTION OF THE DRAWINGS Fig. .1 shows ao alignmeptof R^ cynonupgus monkey and rat 10 fig. 2 shows ah. alignment of CRI..R sequences from human, cynomoigus monkey and rat.

FijpAA and BB "$hd# seddduee dUjpfi&amp;bfls of

Fom the Indicated ann-C.'GRP receptor antibody clones has mg kappa light chums, and certain Corresponding consensus sequences, 1.5 Frgi 4 shows pbylpgenedsallyi^a^ 'cha.i«."G0ife 'SoPi-the indicated antt-C ORE receptor antibody clones has mg lambda light chains, and certain sequences.

Ftp, ΙΑ, 5B, 5Cv 5D and 5fc show phytogcnetieaily-base-d sequence aliisirpentsoF heavy chtdd CDRs don·! the Indicated aqtt-UjiRP receptor antibody clones, ;md pertain 20 ;cpn®spo:nding coasdhsus sequences.

Fig rf shows consensus sequences of exemplary - chain CDR§ disclosed herein.

Hg. 0 is a plot oi data from ova experiments shelving percent Ihhlhttiop of labeled: ligaiul binding to CGRP R by 1092 arsti-CGRP R Uybridomasupemiat|^^.{dl.atnPhds>) and bfv 25 negative control supernatants (squaresr

Fip.|2A-D show' exemplary cAMP assay 1C50 dadf'ftotp ediihnkpressing ItGSRF receptor {fig, 7A>, hAM I (Fig. ?B>, hAM2 (Fig. 1C.) and human amylin receptors (Fig. TD) fbr three Indicated antiAAIRF E mAbs.

Fig, E-shows an example of ^i-CGRF binding dam such as may be used;ίο detOmtlne 30 human CORF receptor,

Flp. 9A-D show Biscore competition date tor ··:

Fig. 10 shows a FACS Kd determination ot snAb 12GR;

Fig. 11 shows an alignowpidfeynomolgns, littninn. liuniureelb iiierus, rat, and rhesus RAMP I sequences. &amp; u

KL 2016244220 11 Oct 2016

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«sequences’* can include leader sequences and·or fusion partner sequences. The term ‘'vector" means any molecule or entity {e.tc. nucleic acid, plasmid, bacteriophage or virus) used to transfer protein coding information into a host cell. The term ''expression vector"' or “expression construct’* refers to a sector that .as suitable for transformation of a host eel! and contains nucleic acid sequences «hut direct and/or so.tti.to,)., eeueitbes oorsmtito.sm uoqdposimn pun Tooositbos jooueutse uofpIue-suc.n. ‘saouny uoitd;.r>su'c.n joj sons uoumdo.'ioj ,to Xu pun id r ao ouo funsudmon Ooiootoud /-pup· π Xtno ce>OA.n;qr:S .so* sonuonbos joatuon '^jdiuexo so^ eouonh.> uunnusuues saopdetosusot t; puu Tuis Suipusq futtsosoqta a ".psotuoad n opngou; Xsttst s-mXtuquad joj swuonbov joitnoo 'S'litsiuxpoqiuo a8|nopied uj uasum&amp;o xsotf φψ. nodrs puodop Xmit soousnbos fOJiuop r; iw vl Z:· is '"‘1 • >rp --RT 3 <% c 3 .8 I. I ZZ ¢2 HZ i .s 3 r/; o n 9 o 6 % '<* - ' ··. n zzr ^ rc

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The term '‘naturally occurring” as tlimugttiii-rt the spee*%atiou In connection with biological rmiotsals sueh as polypeptides, nucleic acids, liosycelky and the iik&amp;profers' to:' 2016244220 11 Oct 2016 , hi nature. a protein that speeiiseally binds a "$. specified target ami gen, such as COUP R, particularly prim.ac, e.g,, htnnan CdRB R. A CGRB K utmen Uud n!i mok ~ < U^aUs hr k s e urn' tr < ( ^Mt^cpoi \r ar u,vr >!( < n'cpmnent to aoeetf <. ilk h nd as ingct v no- be >Vmx anon e*> -lU'iX {KM is a|(k' Μ I he aw Av* speedt. uh\ hm<> ihc target amu a si m>' \n ,ufsn.s' lien the kr w' U ' o' M in one embodiment, the antibodies wilt bind to CGRP it 10 Orb U'RP R xstt ak^'kio" ,.nmue'cmhnmrnent th antibo i > < ^1' bind with a IGyXis Hi . m another embodiment Use antibodies will bind with a Kn 5 5 λ 10s; in another embodiment the antibodies \> ίΠ bmd with a Kf} Mx ! 0s; in another embodiment the antibodies will bind with a K*> -5x 10 2 in another embodiment the antibodo will bind with a K{> <lx H) \ in another embodiment the antibodies will bind with a &amp;o <5* I0!'in another IS ; MU hind with, a K® thi s I O' -* :20 25

An antibody antigen binding :fra|rhent thetnof pdhHieahmdmg protein 'selectively inhibits” a,Speefftc receptor mlatfye to ether meeplors 'When the IC50 of the antibody* antigen binding fragment thereof or antigen binding protein in an inhibition assay of the specific receptor Is at least 50-fold lower than the IC50 in an inhibition assay of another1'reference” receptor- The "selectivity ratio'1 is the IC50 of the reference receptor divided by XC50 ofihe specific receptor. An antibodypahiigeri binding fmgment thereofor antigen binding protein selectively inhibits the hdna«arfe6kF recejRor ΙΙ^-ΪΟδ of tbe.^ibody- antigen binding fragment thereof or antigen binding protein in a eAMF assay. e,g.< the eAMP inhibition assay as described in Exanrpk # het®ittrM at l^st 50-§>!d lower than the K250 of that same andlmdy, antigen binding h'agrnent thereof or antigen binding protein in an inhibition assay of the human AM I v AMl;.^:im::dmylp.|pp«^3r C«.g.} AMY!). By way of ophchtniiihg example, if the IC50 of a ^eeiftc anfiA'GAP R antibody in a eAMP assay of h£6RB R is, sig,, between 0,1 nM and 20 nM, and the IC50 of the sante antibody to ac.A MP assay of the h.AM!, hAM2 or human AMY I receptor is 1000 nM or more, that antibody selectiyely phihits the hCGRP receptor; 30 An antigen binding pitdetn that selectively inhibits a sptshSe:receptor is also understood to be ^Antigen binding region11 means a protein, ora portion of a protein, that specifically binds a specified antigen. For example, thattprtion of an antigen binding protein that eon tarns the amino acid tosidues thatintofadtwddi an antigen and confer on the antigen binding protein its Npccmcily <n».l «iTinity *or the antigen is. (cfenvil ίο as "anugen binding region/' An antig# 2016244220 11 Oct 2016 bindmg region typically includes one or more "complementary binding regions’' {AXd\T'). < eii'uo untig. n 'unding region* also ux aide ore »> ox>v 'Ammowotk" regions A 'ODR" is· an amino acid sequence that contributes manugen binding speeificiry and aiSmty, 5 ?>lnAmoworke legions can lid ip maintaining the proper cotdormstiob of Sd CIDRs id promote binding between the antigen binding region and an antigen. binding proteins that bind OCIUP £ protein, or human CGJIP R, ate provided, in bus context, a ''recombinant protein'’ ns a protect made usmg i.w, through the expression of a recombinant nucleic acid as described 10 herein. Methods and techniques for the production of recombinant proteins am well known in the an.

The term “antibody1” refers to an intact immunoglobulin of any isoiype, or an antigen binding fragment thereof that can compete with the intact antibody lor specific binding to the target antigen, and includes, for instance, chimeric, humanmed, fully hitman, and feispeoifie i .5 antibodies. An "antibody5' as such is a species of an antigen binding protein. Art Intact antibody generally will comprise at least and two fnildengthdiidf

chtiins.: but in some instances may include fewer chains χηόΐι,ηχ infihodies natnraliy Ofeeutying m came lids which may comprise only heavy chains. Antibodies may he derived solely fmtn a single ,>ourc>,.\ or may K- “chimeric,''5 Thai 1¾. diftetpRi-'j^pflOhd of 20 from two dritbrem antilx>dics as described lurthcf beidAe The antigen binding proteit% antibodiea,:or binding fegmentsdnay be produced recombinant: DNA teeifniqnea, or by euayrnatfe or chemical cleavage of Intact antibodies, Unless otlterwtse indicated, the term ''antibody'5 ins. luces, in addition id antibodies comprising two full-length heavy chains and two full-length bght ehams, deri vatives, variants, fragments, and mutations 25 thereof, exampl es of winch arc described below,

Thetenn ’'light chain" includes a full-length light ebaih and fragments thereof haying 'sufficient variable region sequence to confer binding specificity; A hdhlength light chain includes a variable region domain, V\, and a eonsinut regain domain, C; The variable region domain of the light chain is at the amino-terruinys of the polypeptide. Light chains include 30 kappa chains and lambda chains'.

The term 'heavy chant5' includes a full-length heavy chain and fragments thereof having sufftoiem variable region sequence to cottier binding specificity. A full-length heavy eimiu inelndcs a variable region domain, Vy, and three constant region domains, £«!, (3,2, and Cun, Tip Vh; domain is at the ammo-terminus of the polypeptide, and the Cw domains are at : C||3 Being closest to fhg 1¾¾ polypeptide. 2016244220 11 Oct 2016

Beayy class may Be mbluding igCi (inciudi:n|: igl3 3 s %£*%« Jg63 and Jj^34·· |^;.j[to.6tedlittg·'Ig&amp;J apd1.|A2 subtype*)* lg.M and fgh, : The tetsoiNIgmd sequence^ ‘leaderseque«M” or ^signal peptide'* refomip a short (3« 5 60 ammo acids !ong|p#tide oh|m that directs the transport of a protein. Signal peptides may alsp Be::cal3ed::tai^aBgg: signals,: oigoaJ. serpipnces, transitffofitides, or ipcalieabrm slsmdA Some signal peptides are cleayed fipni me protein by signal peptidase after the proteins are. transported, *uch that the Biologically actisc firnn of the protein (e.g , art antigen binding protsm as described herein) t> foe cleaved, shorter form. Accordingly, terms such as "aetthpil !() u up >m\! . s><iM ^in ' an nod > otuff iMrg &amp; mhumu ' i. . νΟκνΙκ t>od\ is chamcieriaed as having a heat \ and or light chain with a particular identified sepitencp, are understood to include antibodies having the specitie identified soquPPCes. antibodies haying·; the specific identified sequences except that the signal sequetfoes ^fep-placed signal sequences, as well as antiBodies having the identified sequences,· 'mimta'4p^>^j|nah 1.5 sequences.

The Icrm "antigen binding fragmenbs |dr simply ''Iq^j^t^fian.. aptiliqdy;:^ - -immubBglobslin: chain (heavy or light c;B$m)y&amp;s used herein, epmptiises a portibn (regardless : Of how that portion is obtained ^-tyhiidsisseilli of ah antibody that ladfca at least gome of the ammo acids present n> a full-length chain But winch is capshkof sppeifipaliy'Bthdihi''1fe'm 20 antigen:. Sudb fragments are biologically acme in that ^bi&amp;aily'td-ffeo fa-bget. antigen and can compete with other antigen bmdmi pro^ins. mdading^tactahtibodids, for specific binding to a given epitope, in one aspect,such a fragment will retain at least oneCDR present in the foil-length light or heavy chain, and in some embodiments will comprise a single heavy chain and/or light chain or portion thereof. Those biologically active fragments may be 25 p'odueed by recombinant ON A techniques, or may be produced By enaymatie or chemical cleayage Of antlgeu binding proteins, ifKl.udihi;:in^ct:^tibqdid^· Itnmahologioally fooctiOpai irnmunoglohu1in fragments inciude. But are not limited to, f ab. Fab’, FCab'B, Fv, domain antibodies arid single-chain antibodies, and may be derived from any mammalian source, including but not. limited to human, mouse, rat, casnetid or rabbit. It is contemplated further 30 that a functional portion of the antigen binding prot eins d isclosed hernia, lor eMmple, one or more CDIis, could Be covalently bound to a second paotem or to a small molecule to create a therapeutic agent directed to a particular target in the body, possessing biiunotiona! therapeutic setum balf-lBB, 43

An “fab fragment"' is comprised of one light chain and the Cs γ ί and variable regions of one hea v y chai n. The hea vy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule. 2016244220 11 Oct 2016

An *TV’ region contains two hea vy chain fragments comprising the Cn I 31¾¾¾¾ 5 ioThaim ofhh antibody:, The two heavy chain fingtnenia are: :he lei together by two or tnorO: disdlfide bonds arid by hydrophobic intoraemms of the Cn3' dhtnains, : An '*FW flagmenf· contains one light chain and a pardon of one heavy chalmthM:; contains the V;i domain and the (10 domain and a ho the region between the (;fi 1 and C'}{2 domains. such.that an imerehain disulfide bond can he termed herween the two heavy chains of 10 two fab* Imgments to form an Pfab’h molecule.

An 'T'Cabfh fragment4’ contains two itght chains and two heavy chains containing a pmtioo of the constant region between the Cg 1 andGg2 dotBuins, suchthat an interchain disulfide bond is fmtned. between the two heavy chains.. A F(a!v >? fragment thus is composed of two Fab4 fragments that are held together by tt disulfide bond between the two heavy chains. 1.5 : The ‘Tv tegsoh” comprises the variable: regions from both the heayy and I Ight: chains^ hut lacks the constant regions. '‘Stngle-ch^pfsitbodi^ihfe Fv molecules in which the heavy and light chain variable regions have been .connected by a flexible linker to form a single polypeptide chain, which fotins an amigerubrndmg region. Single chain antibodies are discussed in detail in 20 international Patent Application Publication No. WO BH D 1649 and United States Patent Km ,Ήο/ S<md\(‘ r H 0,203, tK o s osims ^ s s < m meoipo ato< ^ u ew <, . A.2'dpMain. antibody” is an 1mmunoiogiealiy .ihsmilihoglobulin: frogmen! containing only tire variable region of a heavy drain or the variable region of a light chain. In .some instances, two or more Vn regions arc covalently joined with a peptide linker to create a 25 bivalent domain antibody .: The two; Vg regions of n:bivalent:domain antibody may target the Stone Or differem antigens A “brvaiem antigen bihdihgpmteln’^dr “bivalent ^antibody ” comprises two antigen binding sites, .In. some hwomres, the mo bmdmg sites have the sam° art<o a specificities; Bivalent antigen Hu dim;, proioms ansi H . dent antibodies may be bispm On.-, »r, mho 30 A 'hnultispccifk antigen binding protein” or “muirispeelfk' antibody” is one that targets more than One antigen or epitope, A “bfspecifiey i4dual -specifie” of^‘bifunetionaf ’ antigen binding ρκήόίη or antibody Is: a hybrid sites. Bispecifte antigen binding proteins and antibodies are a species of rnuliispecille antigen lading protein or- '#ijd.:jb«·:^:ί“ρ4ίι·Ρ«^ by a variety of methods : 2016244220 11 Oct 2016 melndingg'hut not limited to;, RtsiodoP)^ Pab* ftagmettis, Sm «%,· : i; Songsiv jlai and l|.aehman«, 1990. Cim Exp, immiwA. 79'31.S~321; Koweiny ,0:M., 199:2, Jp MmmelPlMAS4ltPiM± fie two binding bfspeerfio ap%mOP· 5 * antibody mill bind Id two ditfcehl epitopes, which may reside on the same or diffemnl: protein targets. 1"he term Hieblralizing «nobody"5 refea to an antigen binding protein or antibody, respectively., that binds to a ligand, prevents binding of the itgand to its binding partner and intermpta fne biological response that otherwise would rcauh i 0 rt mt too h un e P tdrug to ri nd;ng oarm·," In ass ss eg i t on di > ^ ί 1 ^peunc4 v oi'a anti|en: fentding pmteibj tegtean:.antibody or inimunologicaliy %nctionaPanti:gen.b;inding fingtnent; thereoC an ahtibody mttegmbht will substaniiallyinltibit binding of a ligand to its binding partner when an excess of antibody reduces the qu&amp;flj^'olli&amp;tdiBg pamter bound to the ligand by llt least about 20%, 30%, 49%, 50%, 605«, 70%, E0%3$%, 00%. 95%,

1:5 99% or more (as measured &amp; an inmim competitive binding assay). In the case of a GGRF R bindingpratein, sucb a ncntrabztng iaapleeule will dimmish the ability of€G|lR Rto bind: CGRP; t‘hc term “compete'", when used in thecontext of Mtigen binding:^proteins that may bind the sanie region on a target antigen, means competition between antigen binding proteins 29 Is deterntitM by ran assay in which the antigen binding protein {£.«., antibody or immunologically functional antigen binding fragment thereof) under test prevents or inhibits spec the binding of a reference antigen binding protein (&amp;&amp;, a 1¾¾¾ or a reference antibody) to a common antigen (e.g„ CGRP R or an tmtigen binding fragrhcsttherco:l). Anyoifirpimifcob oEeornpebtive binding assays can be used, lor example: solid phase direct or indirect 25 radiominntnoa'.sas (RlAg solid phase dneet ot mdnvei emwme norusmxwww ¢1 lAf sandwich competition assay f,ve«, e.g,, Sfahli e.to7, I9K3, Meitmk in Enzymohgy 9:242-253): solid phase direct biotiumvidin EK (yeme.g,> Kirkland et ai, 1986, Jl immmml 137:3614-36.19) sohd phase direct labeled assay, solid phase direct labeled sandwich assay (wm, e.g.( Harlow and 1 .ane, 1988, Arrtii?c>dies, A Lahorap>ry Aianual, Cold Spring Harbor Press}; solid phase 30 direct label RtA: using Wl$ label (dee, e#, Morei mmG: 1988, Moiec. inmwnoL 25:7-35)2 solid phase direct Rg·, Cheung, bi oh, 1990, kiro/ooF i 76:546-352): and dimer labeled 1990, Scami, <Z fmmmal 32:77-:12). Such '0 ass.u *\<v< nuoUe me use of pieced antigen hound to a solid audbee or ceils bearing cither oi tliese, an un.iabe.Ucd test antigen binding protein and a labeled relbroncc antigen bitMing protein. Congtehilvemiobiboo. mayme toured by determining 2016244220 11 Oct 2016 the solid sorllce or cells ra the ps-esettee of the test antigen hindittg protein, 7%tigen binding: : proteins identified by (conspiring .:ittic:iiu<i4S antigen r (byd5»gp-f^!^^:1bmdki'p the same epitope as titeidlerettee aMigeo bicdiag ptofeiul apd: 3 antigen hinding proteins binding to an ad|aeent epitope sutYietently proximal Id dtp epito|>e bound by the reference antigen binding protein lor stearic hindrance to occur. Usually, when a eotnpettog antigen binding: protein is pmsent in excess* it will inhibit specific binding: ttf a a common antigen by at least 40%, 45%, 50%, 55%, 60%, i 65%,: 70% Or 73%, In sdnte insdanoe, binding is inhi biied by at least 10%, .1555,90%, 95 %, or 1:0 97% or «tore. Compobtive iphibition tony also &amp; reference antigen binding portent to a substrate, e.g., a '‘sensor chip”, capturing antigen on the substrate via binding to the reference antibody, and assaying whether a different anisgen binding protein (a competing antigen binding protein) can additionally bind to the antigen, An example of the latter competitive bidding assaysemploys god is described in Example 7 15 herein.

The term ‘'antigen ” or “immunogen” refers to a. molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antigen binding protest! (indudistg, e.g., an anifti^yiofMrto^i^ieal functional antigen binding fragment thereof), and additionally capable of being used in an animal to produop'gntilbo4^:'^l^^'ldt:todlng:tQ'' 20 that antigen,: : A;:ti atnigen/ mgy posssss one or more epitopes that: are capable of interacting with different antigen biading;proteinas eg., antibodies,

Tbe term ftopitopo” is the portion of a. .moiecnle that: Is bound by an antigen binding protein (for evampic, an antibody). I he term includes any detotmmaut capable of sped ties· Ilf binding to ;m antigen binding protein, such a» 'ίΐ^φοάγ orto-a T-Cdl receptor. An epitope 25 :can be contiguous w nonteontiguouS:: (e,g., (i):: in a singlo-c h a|n poly peptide, amino acid results cs that are not eontitu>ms so one aanher sn the polypeptide vquc'nebt' tb.n v-uhm m context of the moleeulo are hound by the antigen binding protons, or fii) in a mulumoric receptor* e,g., CORE R, comprising two or snore indh idtsai components, e.g,, RAMP! and CRLR. amino acid residues present on txvo or more of the individual cotuponotua, but that 30 within the context of the smiltimiiuie sxseeptor are hound by the antigen binding' protein'K hi certain embodiments, epitopes may be immerse in that they comprise a three dimensional structure that is similar to an epitope used to generate the antigen binding protein, yet comprise none pronto some of the amino!acid mslda^^ to gerterate the antigen binding poitem. Most otlenl epm«pv> tcode on proteins, but in some instances rhay reside on 46 .&amp;

Ua 2016244220 11 Oct 2016 tjy, used; the; "άώ&amp;οηυί" is the «core or number assigned to each perfect amiifo'actd'tn«l«h'-by·ihe parucuiar comparison mains) and a gap extension penalty t which is usually 1-10 time*· the gap opening penalty}, as well as u comparison matrix such as ΡΛΜ 550 or BLOSUM 62 are used in-conjunct ion with the aSgonibm. in certain embodiments, a standard comparison matrix (Λί t·, Dayhoff at ul, 1978, Afia> ot'Prau-in Smaena: and Simatura 5:346-362 for the PAM 250 3-ft a <jr> ft r m /*·. % :r; ft rr S <ic rs Q.

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jo/pm? ΛίμοΛΟδΟίρ oDRpoa oi jur-pi^ns lunoiue un .\j[rjoucn si ^lursoiur o.'oiarapx, ογ 'sotti>rpaer| xSupaBuo ιρρ,-ή. penmmxm ιοοκΡιιΑΤ « SuiiBaofioios lo/ptra *yct|onpaop om«.iSim jo a^usaos nip ;Soisrmaop ^epeepnotj; sumiSiitijo : polypeptides into which one or more complementary detefmming regions (i'DRs), as described herein, am embedded anddar jomptl. la some antigen binding proteins, the CDEs are embedded into a ‘vfrernewor!f ’ region, which orients the COR(s) such that the proper antigen binding properties of the CDRis) is achieved. In general, antigen binding proteins that are 5 provided can interfere with, block, reduce or modulate the interaction between CGRF and CGRF R. 2016244220 11 Oct 2016

Cettnia antigen binding pmteins described herein are antibodtea or am derived Rom antibodies, in certain: embodirnfids, the polypeptide structure oh the antigen binding proteins if based on antibodies, indnding, hut imt limned io, monoclonal anlibodieSv biapecide antibodies, 10 Mloshotbex, referred phemln as: Antibody mimetlca''). chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sonivgimcs refeta ed to herein as i-antibody eonlngaias- R: and fragments t hereo f The various ηίρηαυί .>< are further described herein below.

Che antigen binding proieiits pmfidedhe#in have been dernonstpat^ io bind to GGRP ! 5 R, m pm ocular human ('GRP R. As described further in the examplesbefow, certain antigen tested and found Id bind to epitopes different from those hound by a number df other antibodies the components of CGRF R,

The antigen binding protems that are provided eompde with GGRP and; thereby prevent CGRF from binding to its receptor. As a consequence, the antigen binding 20 are capable of inhibiting CG Rif R activity. In parti euhtff unit gen binding proteins bindingto fheae epiitdpcs can hio. e one dr mdm of the following activilies: inhibiting, inter thduetlon pf CXiRR R signal transduction pathways, inhibiting vasodlaiaiion, causing vasoosnstrietlon, decreasing inflammation, e.g„ ncarogenip indarnmatipn, and other physiblogieai effects induced by CT1EP E upon CiGRP binding:. 25 The antigen binding proteins that are disclosed herein have a variety of utilities. Some of the antigen binding proteins, tor instance, are useful in specific binding assays, affinity purification of CGRF E, hi particular hCGEF R or its ligands and in screening assays to idbRlt^:;$thdbahtagdpisia of CGRF R. activity, arp; useful for ihhibitmg binding of CGRF to CORF R, 30 The andgen-hindingproteins can be used in a variety of treatment applications, as explained herein. 1 ot example, certain ('GRP R aim gen-binding proteow ate useful for treating conditions associated with GORE R mediated signaling, Meh m mdnoing, alfevlufittg, or trsafing thc Regneney audfor seventy of migraine headache, reducing, allcyiatiug, or treating cluster headache, reducing, alleviating, or treating chionic pain, alfeviating ortmating 10 K> Cftft ft/* 2016244220 11 Oct 2016 Βϊΐηαμίΐϊίί α| % «ΓΗΟΐ) °l pxqq. pirn (iios;Sax &amp;mpmq usinmnxxx ιρίΜ sspijdsddfod pm* *«.ηοικοΐ]pcounuuut '^ipoquus ipmuop '«oipoquim ump »}8uis ’ .¾} uieiucip vhqpusq usdpus* «0 uqquo;< u:tp 'cupvsojd Sunxuq ικ^ρχη; -^imism .k>j *c*pnjimi 81113¾ OKsqj 'psppcud Si's? -¾ 1» 00)¾ sip $iips|;n^ai jqi |iq.sm 0ssSt §®pu?q sAp3Sps ji> 0spm ^ '^Hti3lDJ^-8aipaiQi0^3S)i <1)10 > "3 "P ft; P> ··/ 8: 3 £ 0 pj. y·.· ft. a ft·. r. P. 7 >y; '+*.· :cs 43 P S Pft ft: P· b P P. <-y; |z P ft; 3' I a 0 ftS P- O s </ /: 0 /*·{. pr ft; CL· v>. >v oc· £&amp; 0 ri. ftr B1 to£$p h CL·8 23 i -Hb* ys: >;r~f n o.¾

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In general, the antigen binding proteins that are provided typically compose one or $ more CDRs as described; herein (eg., !, 2,3, 4,5 or b), in some instances, the antigen binding protein comprises (a) a polypeptide structure and (h) one or more CDRs that are inserted into and/or joined to the polypeptide structure. The polypeptide structure can take a variety of di fferent forms. For example, it can be, or comprise, the framework of a naturally occurring antibody, or fogment or variamihereoE or may be completely synthetic m nature, Examples 10 of various polypeptide structure* am further described below. is certain embodiments, die polypeptide structure of th e antigen binding proiGns is an antibody or is detTCed ftom an antibody, inetndings but not limited to, monoclonal antibodies, bixpedfic antibodies, minibodies, domain antibodies, tdfetted to herein as "antibody mimetics’·')·* chimeric antibodies, humaniacd antibodies, antibody 15 fusions (sometimes teferrod: to as ^antibody conjugates^ and pordotts or Rapreuts of each, respectively. In home instances, the antigen binding protein is an immunological fragment of an antibody p\y , a Fab, a Faff, n.jP(atF};n or a scFy), Thevmious strnciares afc fkrffef described and defined herein.

Certain of d-e amigen binding proteins a* provided herein specifically bind to human 20 CGRP K Jn a specific embodiment, the antigen binding proto^;^p^iieb%%md8· to human CGRP E f roteiu comprising human CRLR having the amino acid sequence of SEQ ID NO;2 and human RAMP1 havingthe amino acid sequenee of SEQ in embodiments where the antigen binding protein is used for ttherapeutic applications, an antigen binding p*pteirt can inhibit, interfere with pr modulate one or more biolf^lea! 25 activities of CGRP R. In this case, an antigen binding protein binds spedftcally andAir lubstantMly mhihlfe binding of human CGRP R to CGRP when art : the goanfity of bdo&amp;n CGRP 1 bound to CGRP, or vfee vm, by at least about 28Ψk 30%, 40%, 50¾¾ 60%,70%, R0%,E5%, 90%, 95%. 97%, 99% ψ measuring binding in an m mm competitive binding assay l 30 ..

Sonic of the antigen binding proteins drat are provided have the sttneture typically associated with natnraily oeeurring antibodies. The structural units of these antibodies /tfpka;ii.y:^mprisb/i^9^'''l®®f9tetramers, each eony>osed of two identicaleoupieis of v spend L ciuni*· <. ougn some Npcvtc>o* mi nnt \a ·><> produce aotibbdicxbavingonls a 2016244220 11 Oct 2016 15 10 25 30 single ofiMv. It? a., typical each pair or couplet includes one full-length "hghf' d&amp;M.ateut 25 lulWbiigfh ‘'heavy'- chain (in certain enhmdinvms, shorn 50-70 KDa). Each individual imsnanoglobuhn chain A amiposod of several sImm·^ eadt:::0®^sti»|'«fr^gMy 90 to 1 ID ammb acids and expmsidrig a charaekrtstie folding patted?, Th#b:4op$iM^^^ wii# · • amiuoAerminai portion of Mph ehai?? typically trie hides a variable domain &amp;at in rcnponniblc for antigen recopifoon,: The carboyydesmtna! : portion fa ntou: conser, cd evokmorsaruy than die other end of the drain and is referred to as the ''constant region*or wO rccioc h Homan; light chains generally ant clarified as kappa mid lambda light chains, and each of these

Heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon chinas, and these

IgD, JgO,IgAs sod IgE, respeclively: Igfl has several subtypes, including, but not limited to, IgGL fgG2- fgG3, and U\G4. mehtde;:

IgM, and JgM2, IgA subtypes include IgA ! and lgA2. In hnmansgith# IgA and kD fovtypes ;]caatum. fehr5hcuyy chains and four light chains: the igG and IgE IsOtypes contain two heavy chathaghd two light chains; and the IgM isdiypucontuics five he&amp;yy chains and Sve: light; chains. Theftesy'V chain C regiot? typldglly comprises: one grmofobornalps that, may he responsible for effector function. The number of heavy chain constant region domains will deppht! Oh the isotype, IgG heavy chains, for syantgle, eaeheonkiu three € mgtott domains known as Cub (1:2 and GgS. The antibodies that are provided can have any of these isotypes and subtypes. In certain embodiments, the OG.RP R antibody is of the IgGl, IgCs2^ or lg<34 subtype. in foli-fertgih light and hoayy chains, the variable and constant regions afe joined by φ S,:F region of about twelve or more amino acids, with the heavy chairs also including a IT' region of about ten more amino acids. Sec, u.g., Futidamental Immunology, 2nd ed., Ch. 7 (Raul, W v ed.) 1985), New York: Raven Press (hereby incorporated by reference in its entirely for all purposes). The variable regions of each i ight/hcavy chain pair typically form the antigen binding site

One example of an igG2 heavy constant domuin of un eaemp! ary CGRP R: moooc|onai antibody ms tt?c ammo acid sequence;

A SI KG PS V F Pi., A PCS RSTSHSTA

PVAGPSVFLFPPKPKlJrLMlSRTPBVTCVVVDVSHHDf^VOPNWYVDGVlVHNAO'K 2016244220 11 Oct 2016 YSKL rVDKSRWQQGWFSCSVMHF^UiNHVFQKSLSLSPGSC {the last 326 residues of the sequence shown ax SKQ. ID \0;29).

One example of aTapps:: tight .Constant ditoaih of a» exemplary €<IEP E j^oooIom! 5 antibody has the amino add sequence' RT\/\APSVfIFPPSde$LES(i rAS\fV(: iJ..NNiTPR£AKVQWKlPNALQSGNS(3 : ES\'TE9DSKDSlTSLS$mrtpAD3;PKHKV'VA(i;vrHQGLSSPVTESFNR(iE<:tthe fast K37 res id-Acs of the sequence shown as KFQ Π) NO: 14)

Variable regions 0ihuhunOgiobidin chains generally exhibit the mme overall 1¾ regions (FR) joined fey f tee hypervariabic regions, .more often called ‘'eompiementarity determining regions'' or CDEs,

The GDRs tom the two ehatna of each pair are aligned by the framework regions to form a structure that binds specifically with a speeito epitope on the target protein (e.g.. OGRP R). From N~ierminal to C-tempnaif tmhiraiiy* 15 occurring 11ght and heavy chain variable regions both typicaliy conform with the following order of these dements: PR \„ CDEE 1¾ GOES, FR3. CD R3 and FR4. A ntrmhefmgaystmn has been devised for assigning in each of these domains. This numbering system is defined in Rabat Sequences of Proteins of Immunological Interest (! 98? and 1991, KIEL Beihesda, NTQ), Or Ghothia &amp;:Tosh. I9E?S T Μ196:9(11 -m 9Π; Chothm or .»/, i 9X9, Aumre 342:8? A XXd

The various heavy chain and':light chain venabibilhiidns: provided:hecdn are ddpided In Table S>: Each of these variable mgldns may heMtaehoi! to the above heavy and light chain ::constunt regions to form a complete antibody he rv> and light chain, respectively Further, each of the so generated heavy and light -Tam sequences may be combined to form ;; complete 2S antibody structure, li should be understood that the heaw cham and bgbt dud \arable': regions provided herein v.m also he anadneO Hi onus con emu domains lav mg different sequences thtu) the exdqplbry sequences listed: above.

Specific example*» of some of die foil length light and heavy chains of the arnibodies that are provided and their corresponding amino acid sequences are summanaod in Tables 2A 39 and 2B. "fable 2A shows exemplary light chain sequences, and Table 2B shoves exernpiafy heasy chain sequences. 2016244220 11 Oct 2016

i pgiign NO: j <itson :S8we,,“ | : 12" 4 11/: OlfilLC KIDMRVRAQILOLLUWLRGA® : I SGSSSNIGNNYVSWYQQlPGTAPKLyYDNNKRPSGlFDRFSGS | :KS6T|ATIG!mQTGP» 1 GQR<ANRTVTLFPPSSEELQANS44YLYGL!SDFYFGAVTyAVVKAD | GSPVRAGvETTKP$KOSNNKMslft0iIPE#KSHRSYSCQ VTHEGSTVEKTVAFTECS 7/^3-1 L2 01H7 LC MOMRVPAQLLGLLtLVVLRGARCQSVltQPPSASGTPGQRVTiSC j SGB$8NlG§W7WYQQLP(^ / KSGTSASLASSGLRSEDEADYYC.AAWDOSLSGWVFGGGTKLTVL GGPKANPTVTLFPPSSEELQANKATLyCUSDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSaPEO^KlHRBYSCQ: VTHEGSTVEKTVAPTECS ^DMRVP^a^.....1 CRASQGfRNDlG’^FQOKPGKAPKRlIYAASSLQBGVPSRFSGS /G8§IEFTt;?jS5FQPEDiATte APSVFiFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDHALQ SGMSQESVllG0SK|B4YSL$STtTLSKADYiKHKWACEVTHG GLSSPVTRSFNRGEC :14 j 13 :026710/: 1δ 1 L4 03B6 LC GGDSLRSFYASWYQQKPGQAPVLVFYGKNNRPSGiPDRFSGSS sgn»titgaqaepeadyy|Nsrossvyhlvigggtkl^ QPKANPTVTLFPPSSEELQANKATLVCliSDFYPGAVTVAWKAPG } SPVKAGVltTRPSRGSNHKYMSSYLS^ THEGSTVEKTYAPTECS T Ιδ 1 L5 030510 MOMRVPAQLLGtLLLWtRGARCDiiLAQTPlSLSVTPGGPASiSC NS8®iAHMGKmYWYtGTC iGSGSGTOFTLNpRYi^ RTYAARSVF»^ naiqsgheqFsweqoskdstysisstltlskad^kNkTOce : WHOGLSIPyTKSFNPEC : 7 " :17:. ':1 β· 045410 MOyRVPAQllGiaiM 2016244220 11 Oct 2016 SGS|SN.!BNN¥¥BW¥QQEPitAFl<LLlYONNKRPSC3l:FDRFSSS | KSGTSmGiTGiBTGi^ GCFRARPBFT LFPPSS||LG^ j GSPVKAG¥iTTi<PSKQSffli0MSSYLSlTPEQVVKS11RSYSGG YTHEGSTVEKTVAPTECS j IB | "" U ; 04H6LC MO MRVPAQLLOEE LLWLROARCi D1¥I1TPSPLBLFVTPGEPAS i$G:: j RSSQSL LpEGYN YLD!W^ SYlSS NRASGVPDRf ^ sgsgbgidftlkssrye^p^gwyc^balqtpftfgpgtkvdi: ! :KM%$VFfPPSD^^ FYPEEAk¥GWK¥ :pNALGSGM8Q£§¥TE€|D$kD8T^ jEVTHQGLSSpyTkSFNRGEC 1 '"""β 1"'" 18 05F5 LC : :i MDMRVPAQttplJCLLWLRGARC01ILTQTFl$PSVT06^^!SC | KSSQSLLH8PpKTVLYWYii5KPGOPPOLLlYEVSRREaGEPPRF SGSGSGTOFtEKlSRVEAEDVGTYYCMQSEPLPLTFGGGTkyiik: RmAPSVTIfPP$i)EQLKSGTASVVCLLNNFYI:YtEAKVQWK\/D KAlQSGHBQESHEGDSkDGim^ | ^rHGGLSIPyikSFMRGHG ! | 1..9 LIDMRVPAGEtGlLllWLRGA^ | SGSSSRlGHRWBWYGqFPGTAPKLLIYPNM KSGT$AiLGnGlQTGPEAPYY(^mDSf^lSAWf::GGGTKLTVL GQP«PWTIFPPSS£ELQAN1<A^ GSPVKAGVETTKPSKQSNNI<YAASSYl.Si.TPI::.QVVKSHRSYSCQ VTHEGBTVEKTVAPTECS | 21 1 Lid 09f 51C iDMRVPAQLLG^ ;SG8$8NIG$?#YWYQQtP KSGISASLTiSGLRSEDEADYYGAAWPSLBGWFGGGTKLTVL GGPKANPlVTLFPPSSEE:LQALlKATi.:\/CySDEYPGAVTVAWKAD ! &amp;$PV}#yETt$BSK^^ VTHEGGTyEKmPTEOS i I 22 | 1.11 : 10E4LG MPMR#»LGLU^ | SGBBBHIGSNTVRMGQLPGtAPkLOYfNNQRPSGVPORPGGB j K$GYSASLAi8GUBEDEADF¥«^ ! GGFPNPimEPFSSEElQANM GBRVI^VETtk^KGSNNKYAAGSYLStTPEeKSLIRSYSCQ S(y 2016244220 11 Oct 2016

$ VTH0GiTVEKmPTE0S 23 1 Li2 k ..........i........... 11D11 Ht 11N9LC MDMRVFAOlLGLlLLWLRGARCQSyiTOPPSASGTPGQHVTISC''' SG$SSN!GSNYWWVGQtPC^FKLUFRNHDRFSGVPDRF$GS KSGTSASLAISGlRSEDEADYm:MWD0BLSGWVFGGGTKLTVL GGI^ANFTVTLFPFSSiELQAN}^lY0y$PFYFGAVTVAWKAO 0#νΚΑ0ΥΕπΚΡ$Ιφ3ΝΝΚ¥Α^ WHEGStVEKYVAPTEGS: m 12E8LC iDif^GLimiLWER^^ ' l<SSGSLLHSDGRRYLYY^LGKFGi^POLUYEVSRFFSGLFDRF: SGlG8GTGFTLKi§RYE® iRmAPSVFW :RAlM#GEl\0E^ %RGGLSBFV7KSFRRGEC 25 | L14 12G8HL SGSSSHlGNNYVSWYQGtPGTAFKLUYDHMKRPSGlFDFFSGB K8GTSAli3!TGia^ G#f<AHPIVTiFPFMELQANKATLYpSDF^ GSPVRAG'v1::T1KPSKQSRNI<YAASSYLSL'TPE0WKSHRSYSOQ VTHEGSTVEKTVAFTECS ,,20 13R2..L0. MDM^PAQLlGLtLLWLRGARGDiGMlGSFSStEASYiSDRYTiT CI7ASQGIRKDI. GWYQQKPGKAFKHPYGASSLGBGVPSRF SGS GSGTEFTLT!SSL|pEDFA^YCLQ^NSFPWTFGC&amp;TKVE!KRTV MFSVFIFPP$DESEKSGTASy\A2..LNNFYFREA|VQWKvDNAL GSGNSOESVTEQPKDSTYSLSSTLTLSKADYEHRKYYAGEVTH QGISSPVTKSFNRGEC : ::27 | L.16 32H7 LC Mi7iPAQijJ:Llii.WLPpTTiY:ilVi.:TQSP0TlSLSPSFRATLSCRA SQSVSSGYLTWYG0|FGGAFRLLIYGA0G^AT6|PDRFSGSGSG !i:}F!i;i16RijFEGFAWYCQ0YGNSLCRFGQGmLEiKRTVAAP SVF!FPF$D6ptKSGtl|SVVCLLNNFYPREAKVDWKVDNALQSG : M§Q:ES?rEGGSKP8TYSi^^ SSFVTKSFNRGEC Μ | LIT::: : 32H7CSLC METPAGLLFLLLPWLpDTTSEiVLTQSPGTLSLSPGERML^^ :! SQSVSSGYLTWYCIQKPGGAFRL t |Y^SSRAT#0R^(^0: TDFTLl'lSRLEFEOFAyYYCQQYGNSLSRFGGGTKLElKRTVMP 2016244220 11 Oct 2016

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SSWTVRSSNFGTQTYtCiiyDHKFSNTIWOiOVERKCC^ECPFC

CAASSFTF

KGRFTiSRDISKNTLYLQ^NSLRAEDTAVYFCARERKRVTMSTLY

WYYGMivVvGGGlTVTVSSASTKGPSVFPLAPGSiRSTSEETAA

LGGiyKD?FPEpVTVSVVNSGALTSG^HtFFAVLQSSGLYSLSSV

VWPSSNPGTQTYTOOT

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1064 HG AKTKPHEEQF^STFRVVSVLTVVHQOV^CNfKEfKCKVSNKGLPA REICTlSKTKGQPREPQVYriPPSREEiyiTKNd^SLTCLVKGFYFS OiAVFWESNGQPENNYKTTPP^LOSDGSFeKO'VDKSRWa

tQGNVFSOSVMHEALHNHYTC

QKC pcrN/'Y/'N.i Λ MDMRVPAQLLGLlLLWLRGARCEVQLVESva^Lx? CAASGFTFSR AWfyl S WVRQAPGKGl EWV QRIKSK PVKGRFTlSRDDSKNTLYLOMNSlKAEDTAVYYCTTORTGYSip SSYYYYYGMOVWGQG1 TVTYSSASTKGPSVfPl APGSRSTlB TMLGCLVKDYF;REpyTVSvVNSGALTSGYHTFPAVL.GSSGL.tSL SSWTVPSSNFqtOTYTCNVDHKPSNTKVDKTVERKCCVPCPPG PAPPVAGPSVFtFPPKPKDTLFilSRTPEVTCVVYDVSHEPPEyQF NWYVOGVEVHNAKYKPREEQFNSTFRVVSVLT ykckvsn kglpApiektiskt kgqpre SLTGL VKGF YPiDlAyEMER^APSKi:

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CPREEGFNSTFRVVSVLTWHQOWLNGKEY LIGlVKGFYPidiAYEWESRGQPENNYKTTPPMLDSDGSFFLYS KlTVRKSRWOQi'NYFSCSVY/IHEAi.HNHYTQKSt.SLSPGK “A devolve;. sggglvkrggslrls

CMSSFTFGllAWSWRQAPGKGLEWVGRiKSKTDGGTTDYA APVRGRBISROdlKNTtYLQMNSL KTE! DTAVYF CTTDRTGYSIS

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CAASGYTFS1 YSMNvVVRSAPGK GLEWYSSI^ 5$SSYRYYADSV KGRFTISRDN pHSLYLQiSSLR ^EOTAVYYCY ^EGVSGSSPYS! SWYDYYYGp WWGQGtI?WSi 5ASTKGPSIf PLAPCSRSTSES TAALGCLVKC YFPEPVTySWNSC IALT8GYHTFS =AVLGSSGLYSL SSWTyPSSNFGT®YTCNyDHF ;psNTKvdKT YERKCCVECPPC

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Contained in Close Designation nmm •NO. Amino Add Sequence 386 Vl4 140 3 SE l Ϊ QD RTVSVAIGQTVF nOQGOSERSEYAS WYGQKPGQ APViyFYGKNNRPSGiPDRFSGSSSGNTA$iTiTGAOAED'EA DY V CN SRDSSVY HLVIGGGTKL'!VI 3CB Vl5 Ml DilLAQTPLSLSVTPGQPASiSCKSSQStLHSAGKTYLYVWLQ KPGQPPQi. L iYEi VSNRFSGVPE)RF SGSGSGTE)FTlKiSRVEA EDVC4YYCMQSFPLPLTFGGGTKYEIK· 4E4 VlS 14:2 WtTQPPSySMPGGKVtiSCSGSSSNlGNNWSWYQ^tF GWKtU^HNKRPSGIPORFSGSKSGTSmGimOTGD^ ADYYCGTWDSRLSAVVFGGGTKLTvl 4H6 yj 143 DiVMTQSPLSLPVTPGEPASiSCRSSQSLLHSFGYNYLOWYL QKPGQSPQLtiYLGSHRASeypDRFBGSGSGTDFTlKiSRVE AEDVGVYYGMGALQIPFTFGPGTKyDiK SF5 VtS: 144 DiiL'KjTPLSLSVTPGQFASiSCKSSOSLLHSDGKTYLYWYLQ KPGGPPQiiJYEVSNRFSGEPDRFSGSGSGTOFTLKiSRVEA EDVGTYYCivIGSFPLPLTFGGGTKVElR 904 y,9 MS QSVtTQPPSVSAAPGQKVTiSCSGSSSNIGNNYVSVVYGGFP GTAPKtLiYDNNKRPSGlPDRFSGSKSGTSATL GiTGIQTGOE · ADYYGGmDSRLSAWFGGGTKLTVL m V?. 10 146 GSVi..TOSPSASGTPGGRVliSCSGSS8NiGSNYVYWyGGLp aAAPKLLiLRNNQRPSGvPORFSGSKSGTSASLTiSGLRSED EADYYGAAWDDSLSGVWFGGGTKLTVL 1064 VlII Ml aSVLTQPPSASGTPGGRVnSCSGSSSNiGSNlfVNWYGGLP GTAPKLLIYTNMQRPSGVFORFSGSKSGTSASLAISGLQSED EAOFYCAAROEaNGyVFGGGTKLTVL 11011 HNS Vl12: 148 QSVU‘QPPSASGTPGGRV11SCSGSSSNiGSNYVYWYQQi.P GAAPKliiFRNMQRPSGVPORFSGSKSGTSASLAiSGLRSED EAOYYCAAVVDDSLSGWVFGGGTKLTVl 2016244220 11 Oct 2016

2016244220 11 Oct 2016

Contained In Clone Designation nmm •NO. Amino Add Sequence 4E4 904 1E11 Vh1 158 QVQLVESGGGVVQPGRSU41SCAASQFT73S9GMHWVRQA PGKGLEVWAViSFDGSiKYSyDSVKGRFTISRONSKNTLFlO MNSlRAEOTAVYVCARDRLNYYDSSGYYi-iYKYYGfvlAVWGQ GTTvTVSB 1H7 Vh2 159 EVQI..VE SGGGLYKPGGSLRLSCAASGFT FSNAWMSWYRQA RGKGlEvWGRIKSTTDGGTTDYAAPVKGRFTiSRDDSKNTLY LailNSLKTEDTAVYYCHDmBVSiSWSSYYYYYGiDWG QGTTVTVSS «? Vh3 ICG EVQLLESGGGLVGPGESLRLSCAASGFTFSSYAMSWVRQA PGKGLEWVSAISGSi3CYYrYYAi)SVKGPFTiSmSKMTLYL QMNSLRAEOTAvTYCAKDOREVGPYSSGWYOYYYGMDW GOGTTVTVSS 388 V::4 161 GVQLVGSGAEvKKPGASVKVSGKASG'v 1FTGYYMHWVRQA PGGGLBVMGWiNPNSGGTNYAQKPQGRVTMTRDTSISTAY MELSRlRSOOTAVYFCARDQMSIlMtRGVFPPYYYGMOVWG QGTTVTVSS 3C8 12E8 5F5 VhS 1® QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGMHWVRQA PGKGtEVWAViSYDGSHESYAOSVKGRFTiSRDiSKNTLYLQ MNSLRAEDTAVYFCARERKRxGMSTLYYYFYYGMOYAYGGG ttvtvss 4H6 M 163: EVQLVESGGGLVRPGRSIRLSCTASGFTFGDYAMSWFRQA PGKGL i:: WIGF iRSRAYGGTPE·YAAS1VKGRFTISRDDSKTIAYL OMNSlKTEOIAVYFCARGRGiAARYvDYWGOGTLVTV'SS SF5 Vh7 184 EVQLVESGGGLVKPGGSlRLSCAASGFTFSNAWMSyvVRGA PGKGii: vWGRi KSK'i OGGTTD YTAPVKGRFTi $ RDDSKMI ί. V LQMNSLKAEDTAVYYCnORTGYSiSWSSYYYYYGMDW.re GGH'VTVSS !κ'> 2016244220 11 Oct 2016

Contained in Close Designation nmm •NO. Amino Add Sepeoee 10E4 VkS 165 QVQLVQSMVIlRPGAGVKySCKASGVTFTDVYMYWyRQA PGQGLE WMGWi S PN EGGTNYAGKF QGRVTK1TRDT 8 STAY MElSRLRSDDTAVWCVRGGYSGYApiySHyYGMOVWGQ GT WIVES 11 Dll Vh9 166 evolve: SGGGLVKPGGSLRLSCAASGFT f: gnawmswvrqa PGKGlEWVGRiKSKIDGGTIDYAAPVKGRFTiSRDQSKNTLY LOIINSLKTE:DTAVyFCWD.RTGYSiSWSSY¥YYYGMDVWG QGTTVTVSS 11H9 VnIO 167 EVQLVESGGGLyKPGGSLRLSCAASGFTFGNAWMSWVRQA PGKGLEWVGRIKSKTOGG TTDYAAPVKGRF TiSRDDSKNT LY LQMNSLKTEDTAVYYCWDRTCAolSWSSYATYYGMDVVVG asTTvivss 12G8 V--11 tea GVQLVESGGGVVQFGRSlRLSCAASGFTFSSFGMI-iVVVRQA PGKGLEYWiSFG.G$!RA^VDSVKGRFTiSRONSKNTLFLQ MNSlKAFDTAV3^''CA.RDRLNyYDSSGYY11Y\KYYGLAVW8:Q: GT WIVES 13H2 Vh12 169 EVOLVESGGGlVKPGGSLRLSGAASGyiFSTYSMNWVRGA PGKGIF: VWSS ^SS 5SS YRYY ADS VKGRR iSRDN AKN SI YIQ MSSLRAEDIAvYYCAREGVSGSSPYSiSWYDYYYGMDVVVG QGTWTVSS 32H7 Vh13 170 QVQLVSSGGGWGPGRSlRLSCAASGFTFSSYGMHWVROA PGKGLEWVAVlWYtlGSNKYYADSVKGRFliSRDKEKNTLYLG. MNSlRAEDTAVYYCARAGGiAAAGLYYYYGMDVWGQGTTV. TVSS 32H8 VhI-4 171 QVOi. VGSGAEVKKPGASVRVSCKASCWTr-TAYYi. HWVROA PGQGLEvVMGYviNPHSGGTNYAQKFGGRVTMTRDTSiSTAY ME! i. ERL RSDDTAVFYCARGROWi GFDYVVGQGTi. VTVSS 2016244220 11 Oct 2016

Each of the-heavy listed in fable 3 may be the light chain variable regions show»: in 'Table 3 to form m antigen binding protein.

Examples oi suclr eonibinatlons ineUide Vyi combined with, any of V*1, V\.2, Vt3,. V;4, Yr$, \\(\ Vf.?,.Y}.8, Vt&amp; Vj to, Vi 1 k Vi-ll ¥| II or VL17; V«2 cmnMnsd with an> of V\ L V; i; Vi.3s Vt4, YKf, V>.bs V, 7, f{Jf¥a,V, 10, Vj i L V{ 12. VrlB, VpM*

Yi 15. V\.16, or \b 17;'Vg3 eppdnnbd with any of V; 1. V-..2, Vr3. V:4, Y«.5> V5.6. V; 7. Yx.tL V· 9, Vi. 10. V;J L V\i2, YiJB, Vi.iY V;..iS: ViM,or VJ7; and so on. m hi mm&amp; Instances, the antigen binding protein includes at least one heavy chain wrriahk region and/or one liaht chain, variable rcaton from those listed in Table 3. in some Itjllif dde^iij0;,anti gen binding protein inemdea at least two different heavy chain vanabie regions and or light chain variable regions from those- -An example of such an antigen binding protein comprises (a)one Vi(i, and: (b) imepfVtfE, '¥$$# ν^.Υ®Ι*:·¥|#5· 15 \ mX 3 tbb YulCL YU1 t, Y,.l 2, m \ .jU Another example comprises pri one \ u2„ and tbr one or Vt ΙΛ ,«3. V - 1 \ (l5, \ .6, Vi( \ \ \ YjPX \ \ l(h Vni I, Yt 13, m Y>ri3 Agam mother

$¢$:¾¾ ¥«%¥»$* W** ViA- YiA YoS, VaY

Yu 10, Viri 1, Vnl2? or VH!3-ete, Again another ekarbplo ©f aneh an antigen binding protein obnipriaos (a;) one Ϋρ,Ι, and (h) Oho of .¾¾ ΥχΑ. YA YrO, Vqds Yt A Vt,8> YsA Vgl:% Vx,l'i,

*W V; 12. YLU, Yj 14. Y, 15/Y}J6, or Vt.17, Vy.S8, V, i 9, V{.20, of Y.;.2L Again another«xappte: of such an antigen bi π dmg protein comprises (a) one Yi.2, and fb) one of Vpl, Yl3, Vf.4, Vp5, Yg6- YiY, V; A Y;.A ν\Κλ V; 11. Vgl 2, Vt.l3, Y'i.1% Vf.15, Vt,14 Ytl% Vi;l>b Vj.19, νΓ20? or VK21, Again another example of such an antigen binding, protein comprises, (a) one VI. 3- 25 2016244220 11 Oct 2016 ami (b) one (1¾¾¾ Vj>5, VA %7, VtJhVJ2, YU 3, V:.i4, ν: Ι5; V-ltS, Vs 17, Vs.lB, Vt.19, Vf.2Cl or V< 2Lete. The various combinations of hea\ y «.ham \ ariablc regions rosy be -combined with any of the various eombmahonsof jightehain variable {catons as is apparent to one of skill in the: 5 art. M other instances, the antigen binding protein contains two identical light chain tic»l heavy chain variable regions. an esathpiov ibo antigen binding pi olein may be an antibody or imrounologicallyrimeiiooai ftagmeot that Ineliidba two light chain variable regions and two hc»\ y chain variable regions m cotnbinaii6M'Of'i^it^;-0;C 10 light chain \ .iriahlo region1· and pairs «i Usny chain %affable regions &amp;s listed hi Table 3. Some antigen binding proteins that are provided: comprise a. heavy chain: variable domain eptbprisi^ amino aeidriha! diibirafe^ chain 15 20 variable domain selected from Vufr Vh2, Vh3, VnA VViS, Vi A Vh7, VtA Vkb YUO, Vyi I, Void, and Vni.3 afoidy 12223,4,5,6, 7, ?\ 0.. 10,11,1¾ 13, II or IS ammo acid residues, wherein each ^clr ^rpbnce difference is independeutly eiihcr a deletion, insertion or substitution ofone amino acid, with feedeletions, feserboni and/dr substitutions resulting in no more than 15 amino acid changes relative to the foregoing variable domain sequences. 'S he heavy chain variable region in some antigen binding proteins comprises a sequence of amino acids that has at least 70%, 75%, 80%,JS%, P0tkM%,:97% or99%sequence identity toihe amino Ad sequences of the heavy chain vartablerogionoLVhI, VrA 5%¾ Yn4, ViS5, Ys6, νκ?Λ„Κ \ Vh10, Yfrib Vnl2. -md Vu 13.. Cooum antigen btttdmg pmtcutseompriye&amp;Hghtohaio vartable^domain eomprisinga sequence of amino acids that differs twnt tlw Sequettec of a 1¾¾ chain variable ipntam seketed frotn \\ 1, Vt2, V-. 3, Vj4, Vj.5, Yid, Vc.7, Yffl, VtA Ye 10, VUb btJ2, Y?. U, Ygl:4, Ypl5, Vlti\ or Vs. 17 at only L2, 3,4, 5,6, 7,3, % HL II, 12, 13, 14 or IS amino acid residues, wherein each such sequence difference is independently either a deletion, insertion or substitution ofone amino acid, with the deletions, insertions and/or substitutions resulring/m rut more than 15 amino acid changes relative to the foregoing variable domain setjnonces. The light chain variable region in some antigen binding proteins comprises a sequence of amino acids that has at least 70%, 75%, 80%, B5%, 90%, 95%, 97% or 99% sequence identity to the amino add sequences of the light chain variable region of VYI, V: 2, Vi 3, V.i.4, V, 5. Vs 6, V- 7,

Yi8, Vt;.% Yil 0, Vi. 1!, Yl 13., YU€ %J 3|:Y1.1 6y or Yyl 7 ·

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The sRuefore atfo ymperiiga of 03Rs: within 'δ naturally oecurrhig: antibody baa been, described, sn|?m. Briefly* in a teflifeaaiinsiiihddy* the CDRs sre:e?nbedde4:W3thm a framework in the heavy and light chain. variable region where they consiitiue she regions $ respondhle for antigen binding and recognition. A variable region eompt mes at I east; three-heavy or light chain CORs, aw, supra f Rabat at a!., 1991, Sequences qfjRmfmm qf h>m>uf;<dye m v. Publu Bcabh Scm me VI H . liethewla, MD;,wi also ( bothia and Uask* 19B7, ,/. »W«/. Bfoi. 196:901-917; Chothia «?/ af>, 1989, Nutate 342: 877-8831, within a framework region 'designated Stonework regions 1-4* FR15 FR2, FR3, and FR.4, by Rabat# 10 ul., 1991. supra: sac also ChotMa and Lesk, I9B7,mpmk The·€7¾pfovldsd berebb 2016244220 11 Oct 2016 however, may not only be used to define the andgen binding <lc#^^fttodiModal antibody structure, but may be embedded in a variety of other polypeptide structures* as described herein, in one aspect the CORs provided are (a) a CDRH selected from the group consisting of 15 < i U CORΠ i selected ™ ths group consisting of 8¾ ID N07V7R 79* 82, &amp;$> 88* 92,97, add 109: (is) a CDRB2 seleeted fmm the group conaiathig of BEf| 10 NO: 74* 77V 80, 83yS6, 89, 91,93, 95,98, ! 01, and 120; (in) a CDRH3 selected fern the group ConaistiogofREQ © N075, 78, 8 L 84, 87 90, 96, 99, 102, and 123; and riv) a CDRH of (i), (ii) and (iii) that contains one or more, e,g„ one, two, three, tour dr more amino acid Sdhatitudons {e;g*, 20 conservative amino acid substitutions), deletions or insertions of no more dtan rive, four, three, two. or one amino acids; :|B) a CORE selected Rom the group consisting of U> a CDRL1 wlc, rid iron' 'he pin -p eonMWsr; w SI 0 ID NO 4 \ ·ς 48, 51, 54, V, {7 rO, no vfo ' 9, in) a CPRL2 selected from the group consisting of SEQ ID NOsO* 36, 49, 52., 55,58, 6!, 63, *'7, and 7U, (iii) a iVDRI.3 selected from the group consisting of SEQ ID NO:44,47, SO., 53, 56·, 59, 25 64, 68, 71", stud 72, and (iv) a CDRL of (i>, (ii) and mi) that eomai.ns one or more„ c.g,, one, two, three,: fbnr or tnoreritntpd aetd: sabdbuifohs fe ^.yednservaflVd: amino acid anhathntips#}* deletions or insertions of no more than five, four, three, two, or one annuo acids amino acids.

In another aspheVaaonbgen binding protein includes R5L 3, 9* Rdor:6 fnriaitt: forms of the t I>Ra 1 -NteO < I ibu> 4Λ aru M ,,, η η λ i < t "e ,v. Hr ( s- op >,, crr ps» ( ,, >* ; 30 identity to a CDR sequence listed in Tables 4A and 4B. Some antigen binding proteins mdudh 1,2,3,4,5, »n ft of the CDR* Iwwd w Tal K'n 4 \ aM 4li o-ohdlfieting by «0 more Ι6ηύ::1* 2, 3,4 ar 5 ami.nd acids Lidm the CDRs listed in these tables;. 2016244220 11 Oct 2016

In vet jnu.ither aspect, the CDR.\ disclosed herein include consensus sequences derived from groups of related mopoc tonal antibodisa. As described herein,: a: : 5 referbdd «minis aeidseqhedees having conserved amino acids common among a number of sequences and variable amino adds that vary within, a given ammo add §:β^|Ιδ»β^|,··";11ί:Φ' €PE.; consensus sequences provided include CDRs corresponding to each of CDlQll, CQ&amp;H2, ί 'DRI13, < DR I I, CORL. 2 and ODR1 3.

In soil another aspect, an antigen binding piotein includes the iOijdwihg associations of !0 CDR.U, C.DRL2 and CDR1.3- SEQ ID MX 42,43, aid40 SEQ I'D NOs: 45,46, and 47; BEQipMX48,49, and 50; SEQ ID NOs; .51, 52.. and 53; SEQ ID NQs::;5% 55, and 56; SEQ IDNCk:57, 58, and 59; SEQ ID \Os: 60, 55, and 56; SEQ ID SO,: 45,61, and 47: SEQ TD MB 62. 65. and 64; SEQ ID MX 65. 55, and 56; SEQ ID NO,v 66, 67, add6H; SEQ ID NG.v. iH, 70 and / R and SEQ ID NOs; 69, 70, and 72. t.5 : Id ah additional aspect, protein includes the ;&amp;11βν4η|| aasodations of CDRB1, O)RH2and CDRH3: Sl·Q ID NOs; 73. 74. and 75; SEQ IDNOs; 76, 77,aud7S; SEQ IpNQs: 74, XQ, an<i XI, SEQ ID NOs- 82, S3, and 84; SEQ ID NGs. 85,86, and 87; SEQ ID MV; 88, 8R Und 40. SI Q JD At 6 76,91, and ?N SEQ ID NOs; 92,93, and 94; SEQ ID NOs; 76. 45 and ’S. SEQ ID MX "'3, 74, and 96; SEQ ID 20 NOv 100, 101, and 102.

In another aspect, An antigen binding protein includes the following associations of CD EL ί, CDRL2 and CDRL3 with CORED, CDRH2 and CDRM&amp;SEQ.ID NOs; 42, 43. and 44 with SEQ ID NOs' 73, 74, and 7¾ SEQ ID NOs; 45,46, and 47 SEQ ID NOs: 76,77, and 78; 81:53 ID MX 48,49, and 59 ividr SEQ ID NOs: 79, 80, and ;|I; SEQ ID NOs: 5:1, 52, 2.5 and 53 with SEQ ID NOs: 82, 83, and 84; SEQ ID NOs: 54155, and 56 with SEQ ID NOs; 85, 86, and 87; SEQ ID NOs: 57, 58, and 59 with SEQ ID NOs; 88, 89, and 90; SEQ ID NOs; 60, 55, and 56 ^ ixh SEQ ID NO»: 85, 86, and S'?; SEQ ID NOs; 45,61, and 47 with SEQ ID NOs; 76,91, and 78: SEQ {DNQs: 6¾ 63, and 64 with SEQ ID NGs: 92,93, and 94; SEQ ID NOs; 43,61, and 4? with SLQ ip NQg; 76,95, and 78; SEQ ID NOs; 65, 55, and 56 witfeSEQ ID 30 NOs: 85, 86, and 87; SEQ ID NOs: 42,43, and 44 with SEQ ID NOs; 73, 74* and 96; SEQ ID NOs: 66, 67, and 6| with'SEQ ID NOs; 97, 98, and 99; SEQ ID NOs; 69, 70, and 71 with SEQ ID NOs: 100, 101, and 102; and SEQ ID NOs: 69,70, and 72 with SEQ ID NOs: 100, 101, and 402. 76 'j‘>

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'p i;< 7' > sr. :X -y X ~ η λa 2 rpi I'd A\ D cs £4 :s? £fc:v Ό as 2016244220 11 Oct 2016 the of M X; y .selected idem die group consisting of lh X; and P* S;l selected from the gifctip 'e^^ig;:0X;L anti P, X* is selected from, the group consisting of C, W end S;. and X·· is selected from the group consisting of B and T. KS.Consettsus 5 CDR1 KSSQSLLHSX(GX>Xt VI V (SEQ ID NO;t lOh wherein X* is selected from the group consisting oi D and A, X? ;s selectedrfroni the group eonsisfrngof Eand 3G and Xjis selected from die group consisting of X and I. S2^J;ot]Sioses COR I Xj SSQSLLHSXR*\ ?XO’ LX5 tSfc'Q ID NO: 111 h wherein X; is selected from |Q: the group consisting Of E and K, \ w selected from the group consisting, of F, P and A, X-< is selected from the group consisting of Y, E and hC Xi is selected froth |he group consisting of N and T. and X> is selected .from die group consisting of D and 'V. t DIO \ \ SXRXro tfrht)ID NO i 12c One cm \ > e-Aed jo r 'he prone consisting of 1. and Ifr X; is selected from the group consisting of G and V, avid X; is selected 1.5 i from the group consisting of A and F: r$tm MQXiXjX.iX.PXiT (SEQ ID $6:3 13), wherein X: is selected from the group conSiMtUg of A and Ss Xfr is selected from die group consisting of f and 1\ X Gs solo., ted from the group consisting of Q and P, Xa k seipeled from the grotipconsisting of l and U and X» is sernaed from die group consisting of F gp&amp;jfr.?. 20 CDE2 EXjHQRES (SEQ ID NO: l 14), wherein X( is selected from the group

fro 1,2,3 Consensus

GDR1 SGSSSXieXiKX AOG (SEQ ID NCX115), wherein Xs Is selected from the 25 group consisting of N and S, X.? is selected from the group consisting of Y and T, and X >. is ghlected: from the group consisting of S, N! and V s :CDR2 XiXsMXsRFS (SEQ If) NO: 116), wherein X.; is selected from flip group consisting of D, T and R. X" is selected from the group consisting ot X and, $, &amp;n>f X» w selected from the group consisting of K and Q, 30 CDR3 Xi K?X DX.0X.-.J-XsX-VV (SfcQ IB the group consisting of G and A, X-> is selected from the group consisting of f and A, is selected from the group consisting of W and R, X4 is selected from the group consisting of $ and D, X5 is selected from the group consisting of E. and S, X* is selected fern the group : consisting oi S and N, and X·: is selected from the group consisting of and Cl.

KiAiiii 2016244220 11 Oct 2016 CDRl XiGXiXsSX4X5X^XHX^X!aXi; (SEQ ID NO: 11 Hi whereto X* is selected itiffitfse gpup X;> is .preset i or absent, and ifpwsenl is S« X? is selected tern die group eomisimg of S aodD, X„} is present or absent, and if present is N, X* is 5 selected front the group consistiogiof i and 1., Xs is selected mtm the group consisting of 0: andII, .¾its seiecied fetn fbe group consisting of N and R, X* is selected frnm ftte gnanp consisting of N and F, X<sis selected fetn tlfc group const sting:: oFV and T, Xu; is selected from the group consisting of V and A, and X* 1 tbe gropp consisting of S, N and X, CDR2 X|XaMX iRFS (SEQ ID NO: f 19 k wherein Mi Is selected; from the group SO consisting of iX Ο, T. and E.5 X> is selected from the group consisting of 'NgR and S^dddiXs is; selected from the group consisting of K, X and Q, CDR3 Xj X’X :DXiXsX(,XvXsX,sV' SEQ ID XO: 120), wherein X; is selected tehuho group consisting of t i, N and A. X; is selected iron; the group consisting of I', S and Λ, X is selected front the group eom^tinR of :W «ηά R»X4 is sciected. from the group conststingof $ -15 add Df X$ Is selected front the guntp eonsnstutg »fR and S, X* is selected from the group consisting of L and V, X? is selected front the group consisting of S, Y and X, X-, is selected dtOtif tfte gfoie-i co"sM'n<; o' ' 11 and if e IX. is selected from the group consistingof V and L. 20 25 30 CDR.I X, Y5 M.Xi(SB0XDMO:12is sciected front the group consisting of G and D, X.; is sciected from the groupeonsisdngofH and Ye CDR2 WIX, PNSGGTNYAQRFQG (SEQ ID NO;!22},whereus X* is selected Rom the group consisting ol N and S. CDR3 X Λ, X XX>X*X, XAXGXaXη·Χ,, X.>YYX1<OMDV (SEQ ID NO.liU wherein X; is selected from the croup consisting of O a no G, X is selected from the group const,sting of Q and G, X» is selected front die group consisting m M and 5 , X,. is selected fro ns the group consisting of 1 and 11, X- Is selected from the group consisting of I and V. Xs is sciected from the group consist ή: of M as id A.. X- ss p cv'm o' fvnt, < nd d’pres ut, id t Xf s\ mesons r-t absent, and if ptesem. :s R, Xs is sei.eeto;I fsom the group eosssisuag of Y and 1,, X-s is selc>..ted front: the group consisting of f and Υ,,Χο is selected fstsm the group consisting of F end S, X$*. is selected irons the gfrup consisting of P sutd IF astd Xp. is present or absent, and if presets?, i-Y. 70 i&amp;CoMtnsu* 2016244220 11 Oct 2016 mm RiKS.XrrD(KIT1'0YX:sAFVKO (SEQ IIYNO. 1.24 k whemin X; is selected s fkmQhdg0up consisting ofK and TsMdXe is selected ίρρ» the gimtp consisting of Tend X. iC3 Consensus 5 s CDR1 Xs ΥΧ^ΜΧλ (SEQ ID UQ ::125), wherein X is selected; from the group consisting oil end S, X;> ts selected from the group consisting of S and A., and X* is selected frdm the group costs! jfriug of M and S, CDR2 XdSX;frX ;X.vX>X,:YYADSVfr<'i (SEQ ID NO; 126), wherein X, is selected I feni the group eoeaimkig of $ imd: A, ;% ·&amp; selected from the group consisting of S and: C, Χλ 1(1 is fleeted ;fi»m the group < investing ot S ami Cfr \ 41\ sekvred from the <o o«m»ouMstmg of 8 and G, Xa ts selected from the groupconsisting ofY and R„ and X;·, is selected from the group eonsistmg of R and T. CORIf ;X|XaXsX4XsXsX?FYSXsX<>WYOYYYOMDV (SEQ ID NO; 12?). wherein X; is selected from the group consisting of Eastd ffr XJ is selected from the group consisting of 0 !.5 and Q* Χΐ Is selected ofV and 1,.¾ is selected from the group consisting ofX and E, Xs is selected: from the;group consisting of Q and V, X6 is selected from the group consisting ofrS and G. X-- is present of absent, and if presen t. Is $, X* is selected from the group consisting of I and S. and X« is selected from the group consisting of S and ¢1 iiiiLlQteSsE'' 20 CD1U SXXXvIH iSIrQ ID NO; 128), wherein Nj is selected from the group consisting off and Y, t DR2 V IS\ I Η »SX ΚΛ \ V ,I)SVKG (SEQ ID NO ! 2Ai, whecetn X, κ selected from the group consisting of f and V. \J is selected from the group consisting of 1 and Η, X,? is selected from the group consisting of S and V, and:¾ '&amp;·tte-.gpQidp .consisting«f 25 V and A. U>R3 X:RX;;X Y.A.iX,SY Y,;?A'X.Xsi,XnYYGXs,XLiV (SEQ ID NOjm wherofti X: is selected from the groue ^dsssnng of D and t, X- d ejected horn the group consisting of 1., and K, X» In selected from the group consisting of N and R. Xa is ed consisting ofY and v, X, X selected front the group consisting of Y .¾ 4dWed iron) 30 the group consisting of D and M« X? is selected from the group eousifiiugof X and Y* ^ is selected mo ru the gump consisting of G cud I. \ is selected uom the group consisting oft! apd Y, X|ii:i:spfclon!or isbseuE and if present, is Y, XS! i&amp;selected of K and K \n Is sof t icd t'«»n the group eomosliag of M and 1.., and X.i.5 is selected from the p'opp consisting of A. and D, 80 OCA Concensus 2016244220 11 Oct 2016

C'DfU XA'XAI X*«StD IP NO: 13 h, ά urtein X< »* -elected from tin,4 group CQii$|isli0.g:©f :IX and 5< X> is selected from lie group ephaisifttg of A< Y and id X? is selected hteteihe group Consisting of W5 A a»d;G, and X* is selected from iiO: consiPmg-of B 5 apdFIc.

Ci)R: XdX XxXA ΧΛιΧΛΑιΧΑ Ai X AnVKuiSI O in MO:!32>, wb^relts :¾ is selected fham. tfas; ":^αΐίΐρ · A and VjXg iaxeteeted fr«i the group consisting of k. S ami W. X * is selected from she group consisting oi S, G, F and Y, Xa presenior absent, and if present, ss selected from the gtoup conaisiingof K.and T,.Xs is present |C| i a absc N and if present, n R X w se*ected "Oir dm mmsp consisting of D and B, Y' is selected iron; the group consisting of G and the group consisting of T, E, E Ni and II, X-, is selected from. the group contesting oCT and: K, XKi is selected from the group teuteMing of D and f, Xu is selected from the group emtsistiog of Y and $, Χί2is selected fern the group consisting of T, A and V. Xu is selected from the group conteteing of A and D:, 1.5 and Xs.i is selected from, the group consisting ot'P add S , CDR3 %XAAAjXcXAAA ίιΐΧ;» X i AsXs4XisXsaXi"GX,Ai*V (SEQ ID NO' 13'5 wherein X. is selected from the gmen oiisi,sting of D, A and F, X, ss selected from the gtoup consisting of R, Q and G„ X» is sckcted from the group consisting of T5 Ri L G aud K, X; in selected Ron· dv gt««p consisting of G« B, X, 1-¾¾.¾¾.gt®«p: 2i consisting of Y, V cad Λ, X. $* «elected from dte group contesting of B, G, Y, A and ΐγΧ? is selected from the group consisting ofl;! P. Ds A ted MRX.» is present or absent, and if present, is selected horn the group consist:ng of-S; and YfXsis present or absent, and ifpressni, is selected from the group consisting of W, S and-l^ is sebe-ted:.fk»ui. the groupeoasisting of S, G and L, Xt; is selected from the group consisting of B, G, L and Y. is present or absepg 25 and tf present ts selected from nc *roup consisting of W and Y, Xu- Is selected consisting of Y and lb Xh is presetn or absent, and if present, is selected from the group conssstmg of 5 and IX X’- t« wdccLd from the group contestingof Y, X and lYX* is pteimf m- absent, and if present, is Y, X i is present or absent, and if present, is Y, X is selected from the group consisting of M and 1, and Xss is selected -ten the gtoup consisting of D and A. 30 HCBConsensus ( (>l<t \;X·X,X XmSFO ID NOd *4h v, heron» Xi is selected fmm the group consisting of N, G, CX B tnd A, X· is «elected tfom the group consisting of A, F and Y. Xi »s selected fi'mn. the group eonsisting ofW, Y, A and G, Xi is selected from the group copsMipg of M add L, and Xs is selected from the group consisting of S and il CDR? Χ^ΧΡΑΑΑΡΛΛΧΧΑ,ΛΥ,Χ,ΑοΧι «Χ^ΧιΛκΛιΌ(SFQ ID NO: 135), whereiu X; is selected from the group consisting of R, W, A, V, S and P, X.» is selected from ihc group eonwsmtg of K. N, S< W and R, X; is fleered from the group consisting of S, P< Ο» E and Y, X.·» is present or absent and if present. is sclented from the grove) consisting of K, T and 1 R, X; is present or absent, and if present, is selected from the grogp; consisting ofT and Λ-* A* i$ selected from me group consisting of D, X, B. S and V, X·? k selected from the group consisting:of 0 and S; X,, is selected from the groitp eonibtdhtg of G and S> Xs is selected Mm the gipgp copslstffigof T, G, R, L N, If agd Y, M}$ m selected- from the group consisting oflg :i K, R and P, Xu is selected from the group consisting of P, N. Y and E, Xi > is selected from the 2016244220 11 Oct 2016 10 group consisting of Y and S, XV; is selected from the gamp consisting of T, A and V, Xu is selected from the group consisting of A, Q and O, Xu> is selected from the group consisting of P, R and S< XH, is .selected from the group consisting, of V <jnd P, and X X -< kvieJ Pom the group consisting of K and Q, CDR3 XiXj-X%X A .;SX,X>XsXvX μ X Ai*X uX~ Xu.GXi -X. A (SOP 11) 15 XO:l.P‘,v therein Xi k selected from IX (u A and E. X; is selected fiiphct. the ..group consisting of R, U and; Qs X;? is shieeied Ant the grdgp consisting o f X ·1$,'Υγ· R, 1..., G and K, X.i is selected from, the· group consisting of G, S. B, X, f and R,X> is selected : from the group consisting of Y, I. G, V and A* X* Is selected from the group eoiMtsling of X Ύ, G, A arid Is X? is selected .from, the A, P and IX Xs is pteagtit of 20 absent, and if present, Is selected from the group consisting of S, L, and % X<, is present or absent, and if present, is selected from the group consisting of W, R, S and T, Xjq is selected from the group consisting of S, G and I,, Χ*> is selected horn the group consisting of S, V, I.., G and Y, Xis is pmsent dr absent, and if present, is selected; feont the tpbup consisting of F,;Y; and W, X) 5 group consisting of Y, F,: J and ft, X^ is present or absent and 25 ifpresent, is tlteP> O and H, Xo is selected from the

group const ating Of ¥. Rand F, Xu, is present or absent, and if present, is Yi, Kit is present or absent, and i f present, is Y, andXi* is selected Porn Ihe groiipYonsiMing#:M: and; M

In Μ.ιτηο c<i'.cs the ..ntigen bm-.img 110111/-01 comprises ai least one heav\ chain CTtP <, ., ('DR2, or ODR3 has mg one of die above consensus sequences, I η some eases, the antigen BA binding pmtcincotnpnses at: least one .light: chain CDItl, £0¾¾ or GDR3 havingpne of the : above consensus sequences. In other cases, the antigen MMing/pfOtetd hp:c| chgih GDRs according to the above eqnscnstis sududhees, and/or ;at fedsfiYo l ight chain ODIlY according m the above; consensus sequences. In: idtll; odtep cases, the: antigen binding: «0 protein 0¾¾¾ at least, three heavy 2016244220 11 Oct 2016 sequences, and/or at least three: light chain CDRs 51eeo.rdi.ng to the above consensus sequences.

According to one aspect, provided is an isolated antigen-binding protein; that fomdis 5 CORE11 comp rising (A) one or more he? ivy eh a ί n c om pierneniary doten1:m|ng:::|ip^iba| :{CDRH.s) select:, d »rorr is group «.mw * t , o| ί } i 1 tRH 1 evX 1 orthu group consisting of SEQ ID MO:73, 76, 70, 82. 85, 88. 43, 9ft ,md 100: tit) a 0DRH2 sehxted&amp;ni the group ancscvung of SEQ ID NO;74, 77, 80. RE K{>. 89, 91,93. 95, 98, 10.1, and 129; fin) a CORED selected fromrhcgroup consisting pf iLQ ID NO;~5, 78,81, 84,87,90. %> 99. 102, 10 ami 123; and (iv) a CDRD of (I), (u) and (in) that contains one or more, n.g,, one, two, three, : fmr-M-fimt: amino acid Mhstlmtiqns, deletions or maettiima of no more than dvegRnm three,/ four, two or one amino acids; (B) one or more light chain eomplementhrf determimui regions (CDRLs) selected from the group consisting oft (i) a CDRL I selected, from the group boni&amp;ig. of SEQiJjdi .^6:42,41,48» 51,54,57, 02,65,66,- and 69; (ufh CDRL2 selected 1.5 froth the group consisting of SEQ ID MO;43,46. 44, 52. 55,5X, ο 1.64,67. and '70; firi La CDRE3 selcct6d.;pGp. tib 'group consisting of SEQ ID HD:94,47f 50,55,56» 59,64» 6¾ 71, and 72; and (iv} a CDRL of (i t, (is) nod {hi} that contains doe or more, mg., ode, two, three, fenr or more dmlno acid suostituuoav deletionsor inseitions of ho more than live, lour, three, four,, two or one amino actus, or till one or more: heavy chain CI.>B.Hs of (A) and oneormore 29 light chain CDRLs of (8).

Inyettetheremlb^ibfcnt, the isolated antigen-binding protein muy comprisefAla CDRM selected fom the group consisting of (i) a CDRH1 ^elected from the group consisting of SEO 11):610:73, ?6,79» 82, 85. 88.92, 97» and 100; (n) a CDRH2 selected mom the group consisting of SEQ ID NO:74, 7?» 80. 83, 86, 89, 91,95, 95, 98, 101, and 129; and (ml a 2.5 CDRH4 selected front the group consi.hing of SEQ ID NONA. 78, 8 j, 84, 87. 40.96, 99, 10:¾ and PJDRiaCDRI selected from the group consisting of ;i> a CDRL I selected from the group consisting of SEQ ID NO;42,45, -18, 51. 5ft .57, 62, 65,66, and 69: (d) a CDRL2 selected from the group consisting of SEQ 1D NO:43,46,49» 52, 85» 58» 61,63, 6?» and 70; and ini) a ODRI.3 selected Rom the group consisting of SEQ ID NO;44, 47, 50, $3, .56; 59, 64, 30 68, "ft mid 73; or R ) one or more heavy chum CDRFh of (.At and one or more light chain CDRLs of (B). In one embodiment, the isolated antigen-binding protein may include (A) a CDRlil of SEQ ID NO:73» v6. 79, 82.85, 88» 92, 9ft and 100» a CDRH2 of SEQ ID NO:74p 77, 80» 85. 86, 89, 91,93, 95, 98, ΗΠ , and 129, and a CDR H3 of SEQ ID NODS, 78, 81,84, 87, 90, 96, 99. 102, and 123, and W) a CDRL 1 of SEQ ID NO:42,45,48, 51, 54,57» 62665, m and 6¾ a CDRL2 ofSLQ ID 140:43, 46,4¾ S2,: 56,61,63,67, and ?0, and a CDRI 3 of SEQ;iDMD-44, 47i 5 56,59.64, 68, ?I, and 72. 2016244220 11 Oct 2016

In another embodiment, she heavy chain variable region IVj?) h&amp;s at bast 70%, 75%, 80%, 83%, 7064, 95%, 97¾ or99% sequence identity wiife an bsvind acid seqtmuee selected 5 from the group consisting of SBQ ;ID 'NOcl5¾ 176, and/or fe ¥t, has at feast 70%,75%, 80%, 15%, 90%, 05%,97% or99% aopdteo:Idditliy with an amino acid .sequence selected from tbs group consisting ofSEQ ID NO: 13?» 153. In a further embodiment, the Vg d aolacted from the group €0MMing;6f$BQ-'©^0i 158-170, and/or the 'thd group censiStrqg; ofSEQ ID NO: /137-153. 10 In anotyr japePE also provided is an !aoIytod:anligen binding prdtoin that specifically binds to an epitope formed of amino acid .residues from both the CRLR and RAMP I oomponetds of the CQRP R, in yet another embodiment, the isolated ami gen bindings protein described hereinabove comprises a first amino acid sequence comprising at least one of the CORE! consensus 15 sequences disclosed herein, and a second amino acid sequence comprising at least one of the CDRL eotwensus spquonees disclosed beretd. amino acid sequence comprises at least two of dm aud/or the second amino acid seqyenee comprises at least mo of the C DHL consensus sequences, in certain emixidlrnents, the fust and the second amino acid sequence are covalently 2() bonded:: to each other?: be first amino at Id sequence of ih^' protein includes the C7DRH3 of SEQ ID NO.7.5, 78, 81,84, 87, 90, 96f99,1¾ and 1% CORK: of SEO ID NO:74, 77, 80, 83. 86, 89, 91, 93,9¾ 98, 101, and 129, and CDRHI of SEQ (D 190:71, 76, 70, 82, 85, 69,'0, 97, and 100. and or fite second mourn acid sequence of 25 pc Isolated antigen binding probin comprisesThe CDRL3 of SEQ ID NO:44,47, 50, 53.56, 59. 64, 68,71, and 72, CDR 1.-2 ofSEQ iPNO:43. 46,49,52, 55, 58, 61,63,67. and 70, and CDRL l of SEO ID NO;42, 45,48, 5L 54,5%: 62,65*% and 69.

In a further embodhnem, the antigen binding protein comprises at least two CDR.fl sequences t.rhoavy chain sequences HI, H2, H3,114, B5, H6, !J7, HR EI9, HID, Id I, H12, or 30 Η1.3* m shown m Table 3A. In: again; a farther embodiment, the antigen binding, protein comprises at bast to o C'DRI -wsp settee-- of In ht duett wquetu ,-s 1,!, 1 2.1.3.1.4, E5, E6, L7, Uf19, LH), LIE L12,L13, L14, L15, Lit?, or 117, as shown in Table SB. In again a further ::embodiment, the antigen binding protein comprises at tca-t two C7DRH sequences of hem, > chain sequences Hi, 132. H3,ER H5, H6.117. HR H9, HS0, HI!, HI2. or H13, as shown In 84

TaHc 54 , anti at ictusi uvo CDRf s of light chain sequences 1,1, (..2, L3„'14S'L5,1-ii L7:,T,8S LA 1.10, ( 11,1.1 1.13, L 14, Li X I. (6, or L (7:; as .shown in Tabic 5B. 2016244220 11 Oct 2016 hi «main iuutthcr cmhud intent. the antigen binding protein comprises the CDR.Hi , Π,ΗΗ 12. and C-DRH3 sequences of heavy chain sequences Hi, H2, (13, H4,115, H6, Ho |-|h, 5 119, H10, H I 1, HI 2, or II13, as shown in Table SA, In yet; another eptbodimerh, the prOgen landing protein comprises the CDRLI, CDPI 2, ««id CDRL3 sequences of hgltt chain sequences L1, i 2,1 3 1 4.. 1.5,1.6,1.7, LA Mil0, LΠ, L12,1.13, !. 14.115, Li6, or L! 7, as s'<v, n m Lade 5li in. yet another embodiment dig .antigen binding protein comprises all sm: CDRs of 1,1 1(1 <jnd Hi, or 1.3. and 112, or 1...I and LU, or (..4 and (14, or 1.. 5 and U5. or L6 and Π1, or 1 7 and B6, or L8 and MS , or 1,9 and 11 1 , or i l l) and B7, or L i 1 and. 118, or 1,12 and 119, or LtZ. add H16, or LI3 and (15, or 1(4 and HI!, or 1.15 and H12, or L16 add 013,of (.17 and 0 13,. as shoe. n in Tables 5Λ ami SB.

Table SA - Lstnophtry Heavy Chain Ami»» Acid IldgioM § gy U >*> > Jp £L *** is 1 8 w o &amp; m gy U >> o 'V <HNf f®. _ x s £ 8S 4»· ex 2S rjr o «ϊ £ s: to 0 "f _ ss §7 O 1 I -¾ o x X > S ,E O 4» ru so O 11 o o O tu *0 H ea u o O O' to OS o X tsc o o o ga a lefcl m O u 1 El 1 : HI 29 VhT 158 73 74 75 1H7 m- 30 Vh2 139 ?6 77 78 28.7 H3 31 Vh3 <o «Ϊ3 79 SQ 81 388 H4 32 Vh4 161 32 33 34 m HS 33 Vh5 162 35 36 37 4E4 HI 29 ¥h1 158 73 74 7f. 4H8 H6 34 Vh6 163 88 89 90 5F5 HS 33 V«5 162 35 36 37 904 HI 29 Vh1 168 73 74 75 9F5 H7 35 W 164 76 91 78 10E4 H8 36 Vh8 165 92 93 94 85 2016244220 11 Oct 2016 ·,✓ v

8 1 a :»A: x '~-S .^4. ΓΠ ,,4¾ Reference -Or r~ z> ϋ Full light Chain Croup -λ-Λ· m 5¾ t. S3 Ks Full light Chain BBQ ID NO C- < ui .¾ Opt Chatf Variable Region Creep 4¾ 1 1 i ^4·: c<-> “Oght Chain Variable Region SEG ID NO S O'! Is 8 JS C0RL1 SEQ ID NO 8?; s 'O m &amp; CDRL2 SEQID NO &amp; a 8 *>4 CDRL3 SECt ID NO

I

I

8 04 8 4¾. 8 ! § 8 1 1 1 .-,,¾ g Reference X X IS X .,,¾ K> X ν^Λ. T3Z. CX; X o i full Heavy Chain Group <w)y 8 8 8 $ C,<* --4 Full Heavy Chain .$£010 NO < X .•.✓Λ < • >i. „Λ 0> c X tr? C :x y/» < X -,.¾. < X: .,,¾ N> <; ;x /'A. S < o « 8 Heavy Chain Variable tag inn Group ~£!. 3 :^4 to "A .-^5. a a 1 Xt·: m ^-¾ 8 8 ^¾. 8 Heavy Chain Variable Reg inn 5EQ ID NO ..^¾ 8 1 8 a 8 -4 m ~~s m CDRB1 SEQIDNO >^4· o o •~X' 8 a 8 m m CDRH2 SFQ ID NO -¾ 8 s 8 8 8 --4 a CORNS SK ID NO 2016244220 11 Oct 2016 qosuoip luotimwj ttmpuiq OoSpur? A'poqous ur u» 'Apuquue ayia-Triyuimu r ‘ \poquuu ουοαϋΐρ x> 'Apoqt#»! p,viueiuni{ « \4:poqqti« upaaMf f ^oqpEO pKmqmoooi a Mpoqumi fUUOjaAiod e LCpoqtjtm feimpouom

? 1 ,4&amp;; 1 1 5 o on a 1 '0 § ft m 11H9 W.^. p 1 U1 5 8 O'* 1 1 jMero?iea 5 1 © J i ™ \ r* ~-i r ' m r- 05 r~ -vyvV ;—· --., ΪΑΪ ..... ».x ?V; !-· ?C •νΛ, r~ δ £ £ r~ v~4 — <n Fui! Light Cham Group © ί I Ο 1 8 a 8 8 a 8 8 δ δ p: Ful Light Cham SCO ID NO B. i % <: Ψ % >'T ---, a, 1 < 8 :< 40 < f“·. wi. OS g 05 <; ί~- Or g £ < r*·. wjt. -r- .*A ί-ό a- ί·ό < *A < o- a <£j < m < «2? ........Llpt'Cham Variable Region Group I i '2 ...ίο cq y^·. § | s ® s -^5. 12 i O' . A„v< 1 8 ss ..rx 1 .^¾. 0, c.:-5 8 δ fc» zl N> Light Cham Variable Region smiDJIG "0 ί 3 s. P" © _ 8 s 8 0* 0© 8 a 8 8 8 5v- 8 m ~~3, 0,: 5--.5; CDRLi SiC ID MO a. P r a o 8 S3 8 05 •~4· p 8 8 a 8 8 S3 CDRLISCaiDMO a ;-gj 8 8 ~~t ~4 2 0, _ t 8 8 £ CDRL3 SCO ID NO provided herein can be a Fab fragment, a Fab: fragment, an F(ab‘ti a 2016244220 11 Oct 2016 : diabody, or a single chain

In a farther embodbpdnti Ihp Isolated ahbgsn bindmgjproteiii provided herein is a human "'$ antibody and can bv of the IgGK lgG3~ igGo- or I"6-Mype,

In another· a nuodiment, the antigen binding |«T5tein copniM^ of a just a IlghtAftibeayy chain polypeptide as some embodiments, the antigen : binding: : piotem consuls wO oi a tight chum vumtile sir be o> eh ea vanahU· dmuuin meti as those hxtao in fables 5 A*5B. Such- antigen .'bidding proteins am be pegy luted. wi th one or mole1 FEG i |C| molecules.. lit yet another α,ψχχ tite japtaied entigen-bindmg pmteip:;^y:ided Itereltiebirbb coupled to a labeling group and can compete fotibih^ihgtsiF ,-’ίΟ^-ϊ^ιϊΙΐ. with an antigen bunting protein of one of the isolated antigen-binding proteins pirn ided bortin,: in one embodiment the isolated anugen birtiilug protein pro-, ided herein can reduce monocyte: I .S i ehtiffiotads:, inhibit monocyte migration i nto tumoM or Inhibit aceomhlatinn and. ftmetihn of tumor associated; macrophage Id a iuotor when adptmlsterod Id a patient,

As wiO be appredahjd by tiiosgih die aAife any antigen binding protein with more than into COR horn the depleted scquoueeSj uhy eomhinahopof CDfe independently selected fmm ibo depicted secjpencea is Useful, Thus, teltigcA bludlogp^fcidi tyith une, two, three, 20 lour, five or six. of independently selected CDRs can be generated. However, as will be appreciated by those in the art, sptibtlic: embodimptis generally ttiiliee dopibinatiorisioFClDis that are non-repetitive, e,g., antigen binding proteins are generally not made with two CDRI id regions, etc.

Some of the anti gen binding proteins provided are discussed nr more detail helotiy 25 Antigen Binding Proteins And Bindlnn Epitopes and Binding Domains

When an antigen boating protein is said to bind an epitope, such as one or both components of COUP example, what is meant is that the antigen binding protein specifically binds to a specified portion of CORF R, which may he on CRJJl, RAM-PI, m ‘'pan portions of both CRLRand RAMPK In cases where the 30 antigen binding protein binds only CRLR (and not RAMP I>, the antigen binding protein would not he expected to wtiv hwiy bind (X 1R.P R because ( Rl R is slutted, mice u/na, with AM I and AMI receptors. Similarly., in eases where the antigen binding protein binds only RAMP I (and tint Π11 R), dm antigen tinkling ptotem would not tic expected to torn' timd CGRP R because RAM PI is shared* inter aha, with AMY1 receptor. In cases where the antigen binding

Bl "wSSfe:and RAMP! , the antigen binding protein is expected to bind residues or sequences of residues, or regions in both CRLR and RAMP I. in none of the foregoing embodintents s\ ,m antigen binding ptokun e\period to totUuct o err residue vuthm CRLR or RAMP S. Similarly* not every amino acid substd^ CRl:<R? 2016244220 11 Oct 2016 5 iRAMEI or tho extracellular domains iheiedf is

Methods detailed, c.g., in Example 10, maybe used to assess what region^ of ipuitimeEc meepmrs* such as CORP R* may bo Involved In binding to seketed antigen binding protems. fkmnetlng Antidon Binding Pmtelns 10 in another aspect, antigen binding pmteihs afdpMyided^ ffi with one of the exemplified, or Aeierenee^ antibodies or Emotional: Rapnen^ epitope described above lor specific binding to CORF R. Sneh antigen binding proteins nosy also hind to the same epitope as one of the herein exemplified antigen binding proteins, or an overlapping epitopCi •Aad^::bjndiagpr0tdn«-aad:fri^^^dh^too.m|ktO'W^.WI?»^l to the same epitope 1.5 as the eveinplrlkd Or reference antigen -pro|3^3^,. The exemplified antigen binding proteins and with dsn heavy and light 0½¾¾.y&amp;mhte.ifcgiott.domains VM- Vtl? and Vnl~ VkIS* and CDRs included in Tables 2A, 28, 3,4A, 48, 5A and 58. Tims, as a specific example* the antigen binding proteins that ate proyided Include those that compete with an antibody having: 20 (a) all 6 of the CQRs listed for an antibody listed In Tables 3A and 38; <b) a V» and a Vj and lisRB fer an antibody listed in 'fables 3A And 58: or (e) t wo light chains and two heavy chains as specified tor an antibody listed in Tables 5.A and 5B. Other examples of suitable reference: antibodies include those that have a heavy chain variable region having a sequence corresponding to any of the sequences identified as EEQ IP 25 NO; 154-1 ?() and a ligh t chain variable region having a sequende eotves|mudl:hg to any of the sequences identified as SBQ ID MO; 137~ i .53.

Binding competition may be assessed, for example* using a Mnning assay s sneh as the BiaeOre assay derided in Exampb 7 > below. In tbsi example, IR antibodies desOfibed herein were tested against each of sis 'YefercncB' antibodies — five nentrabeing antibodies (Π D11, 586, 30 41%, 1204, and 9F5) and one non-neutrahking antibody (34E3). The assay results, shown in

Table 13, im (l£t UP?,2E?3B6.3CR4Ed,4H6,5F5,9D4,9F5J0E4J 1011,1 lB9J2ER12GfU 382 and 32B?) fund to cuteo bully the same region of OGRE IT whmh is di.wsnet from the mgion oft 'GRP E dut is bound by the non-neutralieing antibodies tested (32H8,33S5,33B4 and 3483). Based on these B9 data, the neutral iying make exemplary mihtysRce antigen fejatllsg poteibs 2016244220 11 Oct 2016 in a competition assay, particularly any of die neutralizing antibodies that were immobilized in the assay described in Example 7' --- I tOi !, 1B6,41¾ 12GB, and 9PS,

Monoclonal Antibodies 5 The antigen binding proteins that arc provided indude monoclonal antibodies that bind to CGRP R. Monoclonal antibodies may be. produced using any technique known in the art, eg;, by immortalizing spleen celts harvested bona the tranagenie animal after eetmpledoa pi'the immunization ssheduM The spleen ceils can be immortalized using any technique known in : the art, e.g., % myeloma coils to psMdoco bybridomas; Myeloma cells: for use 10 in hybridom a-ptodboltf g fei0b;ft^deduib»'p:#lbr»blf-'aroi:;i^jR^s^|^d^pNiwo]Rtg*. have high

Riston effioieney, '^;op!^^iialtdionc-w ihs|; pender^^tbcm insapablo^of gmwmgas ecttam selective media which support the growth of only the desired fused cells (hybridomas). Examples of suitable cell linos for use in mouse lusiohsi’ndnde Sfk20, P3-K63/AgB, P3-X6S-AgRb53, NSl/1 .Ag 4; 1, Sp21 Mtgl 4, FO, NSO/lh MPC-i1, MPGilMC4S-GTG Ifrand IS S I94/5.XXO Bnl; examples of Coll fines used in rathisioos iodude 12I0.RGXdv Y3~Ag 1.2S, IE0S3F add 4B210, Other eclllmbs usoftd lor eeilBtsidos are ll-Obb, OM'ld00»GRG2i LICE-LG^~FI:My2 and U€?29-b, An CaOmplary mbthodd&amp;f pf^tihg; mo«d0l0«»l''tebObodtea is described m Example 2. below. fu some msnuuvs a hybridoma cell line is produced by immunizing an animal teg, a 20 rnuisgeiheapimai haying human tnnntnioglbhhllu sequsnoes) ban esting spleen: cells tMtn tbo irmnunized. amhfalyftsing the myeloma ceil lino, thereby generating hybridoma cells; establisbmg bybrirtoma cdl lines Spm the hybridoma ceils,, and identifying a hybridoma cell line that produces an antibody that binds CGRP R s'e,g.; as described in Examples 1-3, below). Such hybridoma cell hues, and anti-25 CGRP R monoclonal antibodies produced by them, am aspects of the present application.

Monoclonal antibodies secreted by a hybridoma cell line can bo part lied using any technique known in the art. Hybridomas or mAbs may be further screened to identify mAbs with particular properties, such as the ability to bind cells expressing CX5EF^|riJify:;ftilbMbi. dC interfere the binding of the CGRP ligand or C'.'GRPse? peptide, or the abil ity to functionally 30 block the receptor, e,g., rising a cAMP assay, c.g„ as described below Chimeric and FI u rn a n feed. A mi bod i es

Chi merle and humanized antibodies based upon the foregoing sequences are also pros ided. Monoclonal antibodies for use as therapeutic agents may be modi bed in various ways prior to use. One example is a chimeric antibody, which is an antibody composed of -ο es 0 Ρ» θ' ί -) < τ < < ·0·. re 1 re 1 re- Λ< S/ 0' O ό q re :.'Λ' p' re £/ <T re 1 A Λ ?'·; /; ft CP S'· c re- ft C' ire '// re. (AAA/ 5W '•/p o re P Λ/ r Si 5' Ό. '^v «/ re. P p o’ re ft a ό % =M U/ JvJ ’x-/' -J re- ft rre. δ O re re P re re < re "-re rer >./> re H 1 /Γ^·' -ft 5: ϊ·.> ;*4 re. 'c ;re <·ί re Sa o‘ ft D a ΐ >xr· 1 '< P Tj re· re*' r re»: '# re o < ai re re ,χ,·'· d Γ/ <.^ O' re 3 Zs^ re re v/vy>':' /" ?3 '/. s ‘O X re 3 s 1 < >r, ' 1., f s; O &amp; r·:·· re re- re' 'v. Ui P re re: re δ' x S3! s~ S' -a: < :·..···< ? re px ft χ· ;% re re 1 re re Ϊ' re '•^/5 < Φ :0 re re re; is 1 s X re. : <./j re. re re·· < Xj o> X 0 0 0i i O g ../-: < is lire ^re fi s a Z re re ft < ?' S'- <> 9:' s €L X 1¾ re* S ·/. _,: £. y-v o δ·- ft ^x· <1=, f'·· B' '.Λ-ί^ u> ?ΐ s re Q < n Ό s® w 's. "ft res x <~S < re S' £ i.yj ή ft re X· &amp; re re· re ·*: X £ ft o ft X5 re re 5 13 •re re 5Γ &amp; % 3 ΛΑ/ Ρ £ ο' Vi Ο Ο, &amp; “Γ '•re >./ χ ί? Ρ ‘iJTi 2016244220 11 Oct 2016 r J£ $κ 0 Pis, 'η' ϊτ ί'·5 ;χ X ft r r %>, 1/. Κ}\ ft χ re> ο χ- ;# ££ Χ3 α. € C χΐ ίΡ ο

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Vtito and Vf.I? can be grafted to consensus human FRs. To createconsensus human FRs, FRs from several human heavy chain or light chain amino acid .sequences may be aligned to identify 4 consensus amino acid .sequence, in other embodiments, the Fife of a heavy chain or light chain disclosed herein are replaced with the ills from a different heavy ebam or light 5 pham. Id one aapedd rafe amino acids in the FRs of (ho heavy and lighfehams of anti-CORP R aritihqdy·:are not replaced, while the jestofthe i^anfto.acids arergpiaced· A '‘rare amine aeidis ;ia a apciSc aotino aeidfhaf id in a position ®which this padietdaiyamitto acid is not umdh tours.i n < ;ι I P VherneuxeK the gnrtod sarsahio uv’ons Iron '.he on*· ho 00- o'" Lght chain may be used with a constant region that is different from tits constant region· of that 10 avt'es : v hcas > m s . n \r as d'v„ o-< 0 teem loot e mbodn w* 0 the r S ,-d sarabse regions am part of a single chain Pv antibody. 2016244220 11 Oct 2016 : Ip: pertain emfeodimmrt&amp; ΐ$ρ$ρβί· $to|h(^ebtos oiler thari human can be used: : along w ith the hnwuu sau-tole res. sops? to produce hybrid antibodies.

Fully: Human Xmibodlcs 1.5 I ally iuunan ahtifeddies afeafeoprodded. Methods are available formaking fully hitman antibodies spec iFc tor a given antipn without exposing human beings to the anfiged : f'tolly human antibodies”). One .specific means provided for implementing the production of fulls hu cum antibodies is the tocunaurzattoto of the mouse humoral immune system, introduction of human imtnunplobillin Og) loci info mice in which the endogprous fg pees 21': have been inactivated is op tmsans of producing fdli^Runmu-thopfeionai antibodies (mAhs)

In mouse, an atnmal that can be ihmmmzed Uaing fhlly huntan anttbodip can. imnimthc the imtnuno gente and allergic responses that cap: sometimes p cansed by; adptmisfering mouse or mouse der! v ed mAhs to humans as therapeutic agents.

Fully human antibodies can be produced by immunising uansgenie animal·' (usually 25 mice's ?>·χ·.', am capable of pu»Jucut« a repertoire of human amibodies in the absence of endogenous immunoglobulin produtoon, Antigens tor this purpose typical!}· hu\e sis or more : contiguous amuto acids, and optionally arc conjugated to a carrier, such as a hapten, .tore rcg., Jakobovnx et«/., 1993, Pr.<«. ,Ym/ taiti Sck (tod 90 2 >51-255A iakpitovits φ-'αί^. 1993? Nature. 362:255-258; and Brnggernmnn et aL, 1993, tbar in In one example of 30 such a method* transgenic anitnals are pmdtfeed by meapadtdmg the endogenous mouse immunoglobulin loci encoding the moose heavy and tight immunoglobulin chains therein, and ihsbton g; mto the mouse genome 1urge fmgntduis of hu man; ^usme DNA cpntai ain g tod that • 'Farilittylaai^lfidd^tihtfals, which have less than thie toll po mpl eptont of human: tmmnnpglpbulin lqty,,ure then eroMtotod to obtum an 92 2016244220 11 Oct 2016

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Fuiiy huntse antibodies can also be derived font phage-display libraries (as disclosed in i:h>ogenboom a/«/., 1091,,/. .Wo/. Bint. 227:38 L and Marks e/ at., 1991,./. Mol Biot. 222:58!), Phage display techniques mimic immune selection through the display of antibody IQ: rep>. rtoires on the surface of filamentous bacteriophage, and subsequent selection of phage by: their hjndm „ to an antigen of choice. One such technique is described in PCT Publication No, Wti f9/l|Ml4|hereby incorporated by the isolatidpiofltlgb affinity and functional agonistic antibodies for MPL- and msk-receptoss using such an approach. IS Bispccilic Or Bifimcfo&amp;j£i Antmeu liiudinu Pmfcfofr

The antigen btndmg proteins that are pmviddd al so include bispeciiic: and birimetiuna! antibodies that include ode or mote €DRs or one or mon? variable regions as described above, A bispecific or bidmctiOdal antibody in some instances is angrtifielal Imbi: id ami body having two different hcavy/iight cltain pairs Bispeeiric audbedses may 20 be produced by a variety of methods including, but not limited to, fusion of hybridomas or baking of Fab’ 1990, Glitk £kp. Jmmuml. 79,1 i 5-321; Kostoiny et a/., 1992, J. Immmot. 148:)547-1553,

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Some of tbe anti gen binding proteins that are pro vided are variant forms of the antigen 25 bmdmg proteins disclosed above ie.g., those having the sequehees listed in Tables 2-5). For instance, some Of die mmgen binding; proteins have one or more conservative amino acid '^bstiouionl:m?^-crtt^ of the heavy or light chains, variable regions: or €DRs listed i«: Tables 2-5,

Naturally-occurring amino adds may be divided into classes based on common side 30 chain: properties: 1) hydrophobic: notiencinc, Met, Ala, Vai,Leu, lie; 2) neutral hydrophilic; Cys, $crt Tbr, A,sn, Gin: 31 acidic: Asp, <ilu: 4t basic: His, tys, ,\rg; 94 l-ft ij'k

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A skilled artisan will be able to MriaiHN of polypeptides as set forth 2016244220 11 Oct 2016 herein using well-known techniques, One «skilled in the art may identify suitable arena of the targeting regions not bdievM to 5 fee iinportant S?r activity* 11hc;sk&amp; to identify rcsidnos and:portions are- conserved among similar polypeptides. In furlhcr^lt^im^v^ft areas that snap fee tnspdAani fbr biological aptAdy or fe strttcfnre tnay be· subject to conservative and no acid substitutions without destroying the biological activity or without adversely aileetnig the polypeptide structure: 10; Additionally, one ski lied in the art can reyimy sifnotore-fnnotidB Studies idesdi tying residaes in similar polypeptides that are important for acti vity or structure, in view of such a ::comparison, one can predict the importance ofaffiino acid residues in a protein that correspond to amino acid residues important for activity or structure in similar proteins. Qudskiifcd in the art -may opt for chemically similar amino ueid Substitutionssfor sodhpfedhded ImpoAaut amino .13 acid residues.

One skilled in the: art can also analyse the b folmensipnll. structure and amino acid «sequence tn relation to that structure (n-similar polypeptides. In vtew of such itiforinMion, one ?fonkd tn the art may predict die alignment of amino acid residues of an and! -udjr with$&amp;i$pfc; to its ihrfeo: dimchsiottal: stihcfofov One skilicd. id the art may t^didal: 20 changes to aunndacid ttatdues predicted to be on the surface of the protem, since such ; residues may he invol ved in. important urieraeiions with other mhiuettfos . Moreover .one skilled In tb.^a.rt:p^;-g^tP:atp|eafva*|pu%pdKiairung'a'siiJ^p^it^i^E4d.^N»titq%j3:af catch desired adtino acid restdae: iTbosp variants can then be scrocnedlusing'assays for CiCIRP fo ndatraiillng Activity, yioldisgdttSpriialipn fogarding.#Mch amino 23 acids can be changed and which must not be changed. In other words, based on information gathered.?from such rtrutiue eaperimoots, ono skilled in tho up can readily deteftuinc the amino acid positions where further substitutions should be avoided either alone or in continuation with mho·· piulnfidUs,

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Derhathms of the antigen binding proteins that are described hereto arc also provided. The dcrivatiecd antigen binding pmtcte cap comprise gay molecule or substance diet imparts "'5 a desired property to the antibody or d'ggoteptbsucJt as: increased Mf-lile in s« partiudar use. Iftod^v turned anriggg blpdipgprotei-i cap. cqmprlspv&amp;t· example, a deieetablWfor labeling}: moiety (c.y., a radioactive, colorimetric, antigenic dr er&amp;mnntic molecule, a detectable head (such as a magnetic or clcctrodense (e.g., gold} bead), or a molecule that, binds to another molecule ty.ge, biotin or Mreptavidln.?), a thenipetoicor diagnostic moiety (regn 10 eyiotosic* or pharoiacouta-alis active monuy to or·»aaolecnle ter increases the suitability of the antigen feitidmg pmtdie for a pariteulabuse fp-gve^biplstratioo. to a subfcct, such as a human subject. or other in vivo or in vitro uses). Examples pf ipoletetethat cap buPMd to dotivattoe ar antigen Wndmg protein include album m o\e, human serum aihununi and polyethylene glycol (PECri, Albumin*! inked and PEQyhued derivatives: of antigen hiading proteins cun he 1.5 pmpafbd/umte known indite art. Certaid antigen binding pmteins Include a rpcgylnted: single chain polypeptide as described, hetoiri, ^©^^.bodird^:^ antigen: binding ptoteln is conjugated or otherwise linked ro tmnsthyrein (TTR) or a TTR, variant; The 'TTR or TTR variant can be chemically modified w uh, for example, a ehefoical selected foom 20 glyeril Itotoopplympm·, polypropylene dxide/etfeylePe oxide· eo-polysnets, plyoxyethylafod •pplyols andpolyvinyi akohui».

Other derivatives include covalent or:aggregative potpgates o.f€T)B.P R hipdiPg· proteins with other proteins or polypeptides, such as by expression ol rccombtttant foktop proteins comprising heterologous polypeptide* fused to the bMermifms or C~tetmthhs;pf a 25 CUR.P R binding protein, fer example, the conjugated peptide nno be a heterologous signal tor leader; polypeptide. < y., the yew utph,i-m> tor loader, or a w-pudo *neh as an epitope tag. C6RP antigen binding proteiu-ebntaining fusion proteins can vompriro peptides added to f unlit am purification or identification of the WORE R binding now m y , poR -Htsl A CURE k I 'nj'ug p uteui also cue be wka<. n> the l 1 V 1 papt ie as cos, "dwd m Hupp. foi, 30 lOSb, Bio/lockmhgy b;:12i|4; and. Dniled States;patent Mo; 5,0!! ,912, The E;kA® pepnde is highly antigenic and pnn ides an epitope rm enribly bound by a specific monoclonal antibody TroAb), enabling rapid assay and facile purineptfon of expressed recombinant protvin Reagenta useful for proper i;tg fusion, proteins in which the FLAG peptide is teed to a given polypeptide are eommetwially available iSienta.. St, Louis, 1VK)), 100 iJTs 2016244220 11 Oct 2016 tjy, polypeptides derived from the t-c region of an antibody. Truncated forms of such polypeptides eon taming the hinge region that promotes dimerization also arc included. Fusion proteins comprising Pc moieties {'and oligomers formed therefrom) offer the advantage ot tadie· puriilcaiion by affinity chromatography over Protein A or Protein G columns.

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Oln, and dmlno acid 22Chaa been The matein exhibitl reduced affinity tot Fc receptors, lb; other embodltoenN, the Yaoablecpb^ionopte hea|y .attd/or light chain* of a COR.? R brndbig protein atteh as disclosed herein may he substituted tor the variable poftion of an , antibody heavy and/or light chain..

Alietnahvely, the oligomer is a .thsion protein comprising nndtlple CCiRR R binding proteins, with or without peptide linhera lapacer peptides). .Among the suitable peptide linkers are: those,described in United States Patent . No. 4,751,1 hi) and No, 4,935.233,

Another method 5>r prepating oligomeric CIpRP R binding protein derivatives Invoices use oFd kneine eipper. FeucineTipper domaitJS are pt^tidea that ptotnote oligooietabatidn db the proteins in which they are .found. Leucine rippers were originally identified in several ? 198¾. 3bdw;.e240: t7$9h and have^ since beenibnnd 2f Id'h'Aarie^ofdpc^htpmtdMl; Among the kno« n leaeine; dp pern are naturally occurring :ppp.^fe:i^4!i^'8tive,s thereof thas d interne os tnmeriae, .Examples <d leucine zippet domains suitable for producing soluble oligomeric proteins an: described m PCT application;: \\O9i'030\ and the leuvine rippcj * so' «. hon m_ wub'Uur proiem D\bFDi ecwubed in Hoppe ct al, 1994» F£BS Letters 344· ioj, herebv muntoOKUeJ hv reference. The use of a 25 modified leucine zipper that allows for stable trimerrzation of a heterologous protein fused -: thereto <s kwer· bed m Fanslow *f rr>4, Senvn. Immunol 6:?6'V'S in οη>· approach, recombinant fusion proteins comprising a CGRP R binding protein migment or derivative fused to a leucine zipper peptide are expressed in suitable host ceils, and fhe soluble oligomeric < tiF P R I ϊndum puCcm fragments m atfses dial foru are recovered from ihe culture supernatant,: lit:dditain embodimepis, the antigen binding protein has a Kf> (epulllbrinm binding affinity) of less than 1 pivf. !0ρΜ> 1 Ob pM. 1 nVf 2 n\L 5 o'M 10 nM, 25 nM or 50 nM Another aspect provides an antigen-biudiug protein having a balLlilp of at ,-u-t one day in Htm or m xho b-.g., when administered to a human subject). In one unibodimcrit, me antigen binding protein ha*> a half-life of at le:# three day* Inmndther embodirtte!#, Che aotioodv or portion thereof has a haU-Sifa ot tour days o> longer. In another embodiment,-tlf&amp;b antibody Or portion thetvofbas a Ua.1f-Ute of eight days or longer. In another embodiment, the antibods or mt aen land ng rnruon Ίιοιοο - act --.. teed m modified such tout it he·; a longer Tubfdife as compared to the undcriv.niecd or unmodified antibody. 2016244220 11 Oct 2016 antigen binding, protein contains point mutations to increase serum - in WO 0()139560., published Fob. 24, 2000, ineotponrted by relbrenee,

Givcmviation. !0 ! 5 20 25

The antigen-binding protein may have a glycossdationpaddm Chat is different or alibied Tram that found ip. tbs native species. As is knotyn in the art, giyebvsyiatiott parterus pstn, ilbpend on hpibThe sgliiwesqb of the pmibin presened or dbaenee of paidieblar glycosy laden an·:no acid residues^ dlscnased beleyf), or the hostpet! or oriadibmCiP/gdtibhitlte protein is produced..(Particular expression systems are discussed below,;

Olyeosylation of polypeptides is typically either N-Hnbcd or CMIhhei,: Mdmked refbes to the attachment of the carbohydrate moleiytd the aids chain, of an asparagine residua,I The :fri-pophde seqoene&amp;faaparagme^-serinb and X is any anhno acid esedpf pjoling, ate fhe ^cognition aoditeddea Ibf enayxMtib udacltment of the carbohydrate moiety to the asparagine side 00«, Thus, the p^tnm^MMwMW^P· inb peptide sequence'- in ,·. polypeptide creates a potential glyeosylation site. O-lmked glyeosylatioo refers to the attachment of one ofthe sugars Noteetylgalaciosaminc, galactose, of xylose, to a hydroxyami.no acid, most eotbrndnly Mnng or threonine, although 5-bydtoaypjblitte or S-hydroayiysme may also; ho uaed. .Addition of glycosylation sites to the antigen binding protein is conveniently aeoottrpilshod hy altoring the amino sold sequence sucb.%MTt mdid-QTifeb···· abo¥e-desedbed tri^epd;dosoqueaoes (tbr N-iinked glycosylation sites). The alteration may •ilso;^:,j0^%:'the addition of or substitution by, one oTMot&amp;^.seor thfeamao i the starting seqaenee (for O-lmksd glycosylation sites). For ease, the antigen bmdmg: pr<M:n amino acid sequence may be altered through changes at 1¾.¾. mutatmg dm Ό\ Λ enaalmgthe t.uget pel·, pepnde at preseLxuetl bnsea aoch that eoddus are generated that: will translate itth):the desired amino-apids.

Another means of increasing tbo number of oaf body dtide moieties on. the autigpn :'binding proiein Is'by ehetnieafor eoapudic coitpluig; of glycosides to the protein.. These/' procedures ate advantageous in that they do not require product]on of the protein in ahop pdf thatlhasgiycosylatioa capabilities Cor N- and O linked glycosylation. Depending on the coupling mode used, the to is) arginme and hisddihe* fb) ffiia 2016244220 11 Oct 2016 earbbsyf :gionps, ib| if ee sulfhydrf·| group; $ud* as: those of cysteine,; (d) free bydzoxyi -groups such as those of serine. thredithie,-Or hydroxypmllhe, te) aromatic rcsukico ouch ax those of ; pemdaiamru, tyrosine, ot try ptopluu, or ff) the amide group of glutmmoe. I hese methods are -::ii4%s&amp;crilbe<i:ir^,.^|ji'-:^7/053:3-0-jpt]b‘|=isillEeii Sep, 11, 19B7S aiid itt Ajtlm and Wristom 1981, CSC·' pp' 259-306,

Removal of carbohydrate moieties present on the starting amigen to may he accomplished chemically or enzymatically. C'hemlcal deglveosyiation .requires exposure of the protein to the contpound lti.uuoromethancs!.iifontc acid, or an equivalent compound. This treatment onsuha <n the cleavage of most or ait sugars except the linking sugar (M-acetylglucosamine or N-acetylgalactosamine}, while leaving the polypeptide intact. Chctnical deglyoosylaiion is described by llnkimuddin &amp; v/.., 1987, Arch. Biochcm. Bi<!phy<. 259:52 and by Edge et ah, i 981, AaaL B;<h kc>n, 118:131, Enayniatic cleavage of carbohydrate moieties on polypeptides cam be achieved by the use of a variety of endo- and cxo-giyeosid&amp;ses ns 1.5 deserdjedby Thoiaknm ei at, 1987, i/ct/v. Enzytml. .1.:18:35(). Glycosylution at potential i glyeosylation sites may bpipmyehtedby the usd of the cosjtpound tunieamycin as desertbedhy Duskin et ah, 1*1*2, J. BiahtAMm. 25.7:3195, Ta^tofayoin. hlodtisthh'iformialtoa glycoside linkages.

Hence* aspc> vs include glyeosyUnion variants of the antigen hiodthg proteins whorein 29 the dumber and/of type of glyeosylMion siteisl has homt altered compared^to the amino acid sequehdek of the par^iit poIy|te|!tide. In ceftatn embodiments, antibody protein variants > compose a greater or a ks\«r number ofN-huked glyeoxylaiion she-* than the name untshodv. An Mdinked glyeosylation sue.is cham^ti^tby or Asn^X-Tfc wherein the amino acid residue designated as X may be any amino acid residue except proline, 25 The substitution of amino acid residues to create this sequence pro vides a potential new site for the addition of an N-linked carbohydrate chain. Ahcrnstively, substitutions that eliminate or 30 alter this sequence will prevent addition ofan N-linked carbohydrate chain present in the native polypeptide Tor «sample, the glycosylauon can be reduced by the deletion of an Amor by substituting the Aso' with a^dtf%»?tt.anatoo-'aei4i;i'M other cmhodtmepty^ pne or more new Id-linked: sites are omaiedt Anlihodios typically have a N-lioked glycosylation site in the Fc region.

Labels and Effector Groans

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labela (i.·.^·., magnetic panicles;; c; redox active moieties, d) optical byes. cnev marie grnup\ <ϊλcf horseradi.v.i peroxidase, β-yaiactosidasc, lucifcrase. alkaline phosphatase), et bunun luted groups*, and Γ) predetermined polypeptide epitopes recognized by a secondary repouer q.g., leucine dipper parr "cquences, binding sites for secondary antibodies, metal binding domain", cpiwpe tags, etc, k in some embodiments, the labeling group h coupled to the amigen binding pppaimo (q tmloiim Sbisoq io oAqoeotpsj oq .A'mt qotqm, %:|pqp| otdotosq, (a "potopisop sq eg ;stu &amp;sip qosq.n us .\ssyf? eqi no fhqpuotbp ’snss'ftp in hosies t> oun :pu spqrq 'punuait tq *οο«η,φΐηΐ|; ousts fetpipod sanpsu ay qqtfktsj snoupA jq suhb aeoads vm atotard Bopop W$*W* αφ oypsfdnco si dnoBf icqooip oqj *sqiamtpoqitio omos iq 'ottipupttux |mg msdm«i;»pjsS %mppunti mtsfmusqsqua O /- &amp; s y £2 P/ 1 n zr o P' '/) 3 o £. /- y

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2016244220 11 Oct 2016

2016244220 11 Oct 2016

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•^4 1 s m I o $ 1 1 m mA .vwi».· m cs 1; a-; 8 4v i γ-Λ. M —4 m § a s i IS i s s 1 -J·- $ 8 e« i -4 OO 5! 5 Variable Light SEQ id NO, o I sr >wX; I 1 1 *£> I 3 a « 1 s 8 1 a Variable Heavy SEQ ID NO, 1 s 1 i 8 I s 8 3 8 8 8 8 8 C'.% o 8 i ; Full Light SEQ ID NO. 1 %3 i? st -v.>. s i 1 1 1 1 8 (S3- S3 1 I 1 fV; 5» 8 1 Full Heavy SEQ. ID NO

Table 9 xhows the SEQ ID NO.\ of exemplary nucleic acid sequences encoding complete heavy sad light chains, as well as heavy and light chain variable regions, of exemplary isolated anitgcii~hhidhig proteins, specifically, hCGRP R binding proteins, disclosed herein.

Table 9 - EsesnpUrv tf£, L€? Vn sshI V* \hsddc Add Sequence SEQ !I> NOs 2016244220 11 Oct 2016 s 10 s 32H7CS I "St M 3 , <s O > « £3 f I Jt as <ts s· ϊ i Q <» w3 S5£ *2 o o o m Φ ' >S 3 183 210 T 258 Ί 32H8 185 m ? 3385 177 : 'eip;; - 331::4 2ii ? 34 E 3 : 190 212 ": ,ΛονΙοη dckk etvodmg cerium umnom binding proteins, or portions !lu'wfir,j, full length Antibody, bbkvy or light chain, variable domain,os CDRH L CDRH2, CORB3, CDRL1, or CDRtdf May be isolated from B~ce!ls of mice shat have been mrmnm<:4 with CGRP R or immdnogeme eo:t0;|?iMO«tii thereof; . «,g,, by (comprising:both CR LR and RAMF1 )t w ith the extracellular domain of CORF R {comprising extracellular domains of OILR. and RAMF1), with whole coils expressing CORF R, with membranes prepared from ceils expressmg CORF R, with fusion protein*, e,g„ Fe Rumors, comprising C'RCR, RAMP! tor extracellular domains thereof) fused to Fe, and other methods known in. te· at., for *a die Samples 03 herein, The nucleic aeid may he isolated by conventional ptoeedusws Such $$ tfcR^* Fhage display is another example of a Mmyrn terhn1t|ue whereby derivatives of antibodies and other antigen binding proteins may be prepared, In one; approach, of an antigen binding ptoteln of interest are expressed in any suitable recombinant expression 15 system, *md' the? -.pO!l.ypqpS^M are allowed/M' assemble ip form antigen binding protein tnoieetdea.

Tltenneiete acids provided in Tables 7-9 are exemplary only. Due to the degcneracs of the genetic code, each ofthe polypeptide sequestees listed in Tables .2-5 or otherwise depicted herein are also encoded by a large number of otbci nueune stud stcaenees hestdes tkwe provided. One: of ordinary skill in, the atf will apprepillo that the pmsetit application thus 11? p^yides adequate written :^^*36ierate oaoleotide: 2016244220 11 Oct 2016 etwoding eagh anfigen bfocfingprotein.

An aspect farther provide nucleic acids that ftyWd&amp;#:' fobO-fobr'- fofoliNl sdi C^ES nucleic acids comprising a nucleotide sequence listed m I able 2, Table8, Table 9 audfor SEQ $A ID :f|'i^;:224*25S);^^F $tetfon.inr 'hybry.iz4tiii3i ':e^diiiMt· Methods for iiefdji gfo: pdiAfjo'Wpsiibfoe ,51·. e, eg.s Current ifo.no cols in Molecular Biology, John Wiley ί&amp;'·&amp;^,&amp;.Υ. (1989), 6.3.1-63.6, As denned herats, a moderately stringent liybdilimdqn condition uses a prew&amp;shing solution eohtfoning 5x sodium dtioride/soduun citrate (SHC), 0.5% SDS, i .0 mM. EDI A (pH 8.0), hybridisation buifof of about .50% formamide, 6x SSC, !0 and a hybridisation temperature? of 553.' (or other similar hybridisation sole dons, such as one : amuming''ifoG:ttt 50$| .fotmimidc* with a hybridfoation temperature of 42S'C), and washing conditions of§0c€> In 0.5x SSC 0.1% SDS, A- airiftgMbhyfe^^ bx $SC •at^Ca.follow^'':.&amp;$' one in morn washes in 0,1 x SSC', 0.2% $P$ ^6 68¾. fdtrdtennpfopone of skill in foe art can manipnlafo the hybridisation and-'or s\'asbmg.eohdiifons 1.5 3 to increase tris decreed tbe:,A.in'i|eney i>f'B||^di^iiftsi. vgjch i&amp;ab i^d.ofo acids, comprising nucleotide sequences that: are at least 655% 20%,;..T 5%, 86%*. 355», 90%, 95% fB:% or 99% .identical to vrach other u pfodly remain hybridised to each other;

The Ivmc parameters affecting the chpieb of hybridization. ebhdiifons and guidance for doviMug <-«!tabic conditions are set forth by, for example, Sambrook, fotsch. and Maniatis 20 (200L Molecular Cloning: Λ Laboratory Manual, Cold Spring Harbor Laboratory dress. (Oh!

Spring Harbor, 'SLY.. \apnr. and Current Protocols in Molecular Biology. 1995, Ausubel or uL eds., John Wiley &amp; Sons, Inc., sections 2,10 and 63-6.4), and can he readily determined by those havi ng dr&amp;inars skill in the art- based on, e g * the length and or base com)?osiiion Of the nucleic acid. 25 Changes can be introduced by mutation into a nudefo acid* thereby lending to change-·; fh tbe amino acui smiuenee of a polypeptide ό/.g., an antibody, qf. antibody dem <msc) that It encodes, IMutitions can be introduced using any technique (known. in the art, In one:1 embodiment* one or mom particular amino acid residues are changed using* for example, a site-directed mutagenesis protocol, la another embodiment, one or more randomly selected 30 residues ss changed using, for example, a random mutagenesis: protocol.: However it is made, a mutant polypeptide can be expressed and screened

Xfonfoqns chn be introduced info a tmetcie acid Avitbont significantly alieting the:: biological activity of a polypeptide that it encodes. For example* one can make nucleotide substitutions leading to amino acid substitutions at non-essential amino acid residues. 118 totto W thiftibs )tettftdiu$^\teto % nuclein acid that selectively 2016244220 11 Oct 2016 changes the biological activity of a polypeptide that it encodes, For example, the mutation can a|u^ttKatiygiy: or qualitatiyely bMnge the btolbgtcai activity.: Examples of quanttiativo changes include increasing, reducing or eliminating the activity·,;: Examples of qualitative changes d mcliide changing the ttutlgeri sgeeilichy of an antibody. 'In one embodiment, a nucleic acid encoding any antigen, binding protem described herein can be imitated to alter the amino acid sequence nstogimoieetbar biology techniques that are welkeSthblihhcd in; the art; \umher a--pe-, i provide1;, ruselmo acid mo'ecnies that am suitable to? a\ frmtem or hybridisation probes tor the detection of nucleic acid sequences, A miclctc acid molecule cat) 10 comprise: only a portion of a nucleic acid sequence encoding a full-length polypeptide, tor mapple.,: a; fegtneht: that can be used: hi:;&amp; probe or primer or a; fragment enhqdiog an: active GC3RPR, binding portions of a polypeptide, fhgbes based ph &amp;e sequence of a nucleic acid can tee used to detect the ntMeioactd or similar nhcletc acids,: for example, transcripts encoding apolypeptide. The probe eiu dompriso 15 a tabol: group,: v.g., a radioisotope, a Euafesccht impound, co-faetno :Eitqh;probda pan bo used to identify a coll thaf expresses the polypeptides

Anolhor aspedt provides vectors compfMhgja nucleic acid encoding a polypeptide of a portion thereof (ej*. a fragment containing one or more CDRs or one prmore variable xegiou; dosmdns), fcamgtos of vectors include, hut are not limited to, plasmids, viral vectors,, «Pft-2h -^komaf matftfttali^t vectors and expression vectors, for example, recombmant expression vectors*. The recombinant expseasion tee ors c u< comprise a nucleic acid ip;a train suitable for expression of the nucleic acid in a host ceil The recombinant expression vectors include one or more regulatory sequences,, .selected on the basis of the host tells to le used for expression, which is operahiy linked to the nucleic acid sequence to be expressed, Regtdatory sequences 25 include those that direct constitutive expression of a nucleotide sequence tn many types of host cells (e,|p, §¥40 early gene enhancer, Rous sarcoma virus prompter apd cytomegalovirus promoter), those that direct expression of the nucleotide sequence only in certain host cells Pip , tiaskito^pcciflc regulatory sequences,,tea, Voss etal, 1%6, Tistpir Rldcicrp, Sc/. 11:287, Maniatis ei o/., 1987, Science 2.36:123?, incorporated by reference herein in their entireties), JO and those that direct inducible expression of a nucleotide sequence in mspbnsb to particular tietoneni or condition <y y , the metalioti-mnu! pnm'tftor m mammalian -..,As and the tiet-tosponsife ahdtor itreptemyuih responsive promoter in bom prokaryotic and eukaryotic £$.&amp; It teili be appreciated by'-tbo^· in design of the expression vector can depend on such factors as the choice of the host cell to he transformed, ! 19 the level; of expsmidW· etc, The expmssiop veemrs can be inift3ileee:d ml© 2016244220 11 Oct 2016 best; della to thereby produce pmtetM: 'Ot :ψοχέψ$ · or. ;pept|id% encoded % rmpMe ^Mids as described hscoln,

Atmfhef; aspect povidea host cells i«to which a recombinant; expression yeetof hae heed 5 introduced, 'φϋ-χ^Ρ· mf cell (for cxample¥.£: eo/f) or eokaryhtic cblT (for .h^ebfe:; <?f> cells ba^,, CH0 ceij.ss). Vector DMA can be introduced idfb Iprdkis^^^ celts vM, eodyentlonal trapffciS»adon or dahsibebou techniques^ "’for stable tranatectiou of mammalian cells, it is known that, denend|n|| epoa tbe ; ex;pesakva vectOj· and. transfection technique used, only' a small fraction of cells may integrate 10 the for hw DMA .into their genome. In order to identify and xekv* these integrant,·>,. a gene that encodes a sclee^bk marker for maixfanCed© Mo lb© host, cells along with the gene of interest Preferred selectable markers include those which confer resistance to drugs, such as G4IB, hygromycin and methotrexate. Cells stably transfected with the raltodueednucleic acid can he Idenlfed by drag flection Tepp, cells that 15 baxe incorporated the sel&amp;table m:arfeer gene will survive, while the other cells die), among; other methods,

Mon-lumum antibodies that arc provided can be, for example, derived from any antibody-prodaemg anin -a!, sadi as mouse, rai, rabbit, goat,, donkey, or non-haman primate 211 (such as monkey <V.g., cynomoigus or thorns monkey} or ape (r.y,, chimpanzee)), Non-hnman antibodies can be used, for instance, inmMb© cell culture and cell-cuUum based applicmlpnSv or any ofher appburdor: where an immune response to tire antibody does not occur or is insignificant, can be prevented, is not. a concern, or is desired. In certain embodiments, the antibodies may be produced by immunizing animals using methods known in the art, as 25 described ,tbo\ a and/or in Examples 1 ~3 below. The examples describe dm generation of anti CHRP K embodies using three different immunogen preparations - (i) ’whole ceils expressing full-length versions of two major components of CORE R ~ RAMP 1 and CRLR; f.ii) n.mobrane extracts bvm -,twh cell*; and till) soluble CflRP R obtained, by co-expressiog and : purify mg the N-termtnul extracellular domains of CRf.R and © AMPE The an n bodies may be 30: polyclonal, monocloualyor may he symtbesized in host ceils by expressing recombinant DMA, Folly hdmari antibodtea may be prepared as described above by immunizing transgenic animals pomainitlg human imtmmogibbplin loci or by selecting a phage display library that is expressing a repertoire of human antibodies. ί-a 9 9 V V ,,, - c 9 t* g

2 I a s' H JS5· t *£* > I, fe es μ % \ί :< *X; JJh. o U δ-a B. r ξ I I ~ h ^ ca a ξΓ ώ .o t -S' -r/. :dr &amp; 1 NW CX rx; -¾

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"S5 δ Z O >? »v a --4 -4 X gp --ί f" antigen-binding monomers, or they can form mule: no:/ :.u.g., dimers, (rimers. or iciraroers), 20 depending on the length of a ilsNihfc (inker between the too variable domains (Koni d al,, \WL Proi. £bg. j. 0:423: Korn dais 200:, BU>wol £.¾. ll^b-lOm, By combining different V- end Vj! "Comprising polypeptides, one can form maltinierie seFvs dial bind lo different epitopes {Kriangkmn vi ah, 2001. Biomol. Eng. jfK\31-40),- Techniques developed for (he iJTi.

The single chain antibodies that are provided may be formed by linking heavy and light chain variable domain .(1¾ region) fragments via- arramlno: acid bridge (short peptide linker):,. resulting in a single polypeptide chain Such single-chain Fvs (seFvs; may be prepared ivy fusing DMA encoding a peptide linker between DMAs encoding 0:-,.- two variable domain polypeptides ( Vi: and Vh ). The resulting polypeptides can fold. back on themselves to form 2016244220 11 Oct 2016 tjy, ‘rti 9 o o <zg. o a £2 m -< Έ. ce. o z> 9 't -1' % r.: C5 O' Ci

ioqio Op Cgtspcp -A/s'./y 'Op: 'upjpsp,· put? josqoyj jo enhnnpm uo:n-vu'n.tqAu gee menu os ptaping/ cut /vnotopoipou.: kpoquua pnsopououi noamuo-vuoo hutpnj.nn mm!>iu:pm 40 Ajouua a Aq pnanpmd aq nun (spy m) /mpoqu-n; jsmopouou: eq : fthtihody),. but also 04¾¾¾ vri.th antibody ffofype oosufeelasis 2016244220 11 Oct 2016 :dil^re5itfi'om tfeat ofthe patent antibody. feeonfomstn DNA techmqpektm&amp;y be employed. Γloned DA A encoding p artfonku' antibody polypppil des may e g,, DMA encoding the x> astern domain of an; apilbe sdy of th ;of dt, *U02. \te;hiki$ Mo /, Biol 1^:303-316.,, Aceoidiugly, the antibodies that are provided Include ; the variable domain com bmations do apriheds Pffodl, having a

IgA. 1A D. IA A: uCH, 1 g )4, L'J and IgDt as well as F< b m I mb') tagm m- f e.ool Moteoser, u an Im *4 K desired. d may t.ko be desired to introduces point mutaibn s'C'FS(.'fo 1(1 :>CPPCP) in the hinge region as described in Bloom e> a/:, S {»>}7,'Perrin ScicntK *y40~, iiteorpprd^ by reference herein) to alleviate a tendency to form intra-H chain disulfide bonds that,:efii lend ip; heterogeneity in the lgG4 antibodies.

Morrowj, techniques for deriving antibodies having different properties (/.«·.. varying .Affinities for the antigen to which they binds are also known. Gnemteh tedhniquei referred to :; 1.5 as chant shuffling, involves displaying immunoglobulin variable doMain^gehe tepsrtoltesph i the surface of filamentous bacteriophage, often referred to as phage display.: Chain shuMipg: has heeufilsed to prepare high affinity antibodies to the described by Marks vioh, 1 342, SialVdwol·>i*y j0:77‘>

Conservative modifications may be made to the"heavy- and light elmin vatiable nsgtons 20 described in Table 3, or the CDRs described in Tables 4A and 411¾¾ corresponding niodtllcaiioas to the encoding nucleic mmM to produce a OGRP R binding proiem basing certain desirable functional and biochemical eharacteristicsv rbodlfichfions 4re described, above) CORF antigen binding proteins may be further modified in various ways. For example) 25 if they are to be used for tberapetdie purposes, they may be to^gaied with polyethylene glycol ipegylatedi to prolong the scrum, half-life or to enhance protein delivery. Alternatively, tbb ¥ r^ionof the suigect antibodies or fragments themof may be fused with the Dtfogiirtof a different antibody nioleenlo; The ffo region used for this purpose: may be modified sb that it does not bind complement, thus reducing the likelihood of induemg cell lysis in the patient 30 when the fusion protein is used as atherapeutteagent In addition, the subject antibodies or fimctiona! fragments thereof max bo conjugated Vvith human serum albumin to enhance the serum halMIs of the andbody or ap tigenibmdSpg^dfogmem^ffi^ useful felob partner for the antigen, binding proteins or fragments thereof us transthyretin (TTR). TTR: has 12- : the papaeity TO form M tehnruqF thus m antibodyGirR, fusion protein f|p form &amp; omltivalcnt antibody;: which may increase its binding avidity, 2016244220 11 Oct 2016

Adnrmmvdv, \u !-> *tt. mod Ικ< tons i h < v 101» . Jodo neonoal dMmct&amp;daties ofiito described Herein tm$" be achieved by creating 5 i sdbstitntipaa i n the amino acid seqHeoee of the heavy and light chains that differ signific|bity; in their effect on maintaining (a) the structure of the molecular backbone in the area of the examp Ic, as a sheet or helical conformation, (h) the charge or hydrophohleity of the molecule at the target site, or ft} the hidkmess of the aide chain, A: Veonservatlve amino acid substitution'5 may involve a stslnaitotion of a native amino acid residue with a nonnative 10 msidob that· has lit tie or ho effect On: the polarity or charge of the that:: position, Seef Table 4, supra. Furthermore, any native residue in the polypeptide may also be substituted with described for alanine scanning oinfegpaests,

Aouno acid substitutions (whether conservati ve or non-conservati ve) of the subject antibodies can be implemented by those drilled in die aft byapplying.routine techniques. 15 Am mo at id substitutions can be used to identify important residues of the antibodies provided herein, or to memase of decrease the affinity of those antibodies tor human €GRP R or for modifying thv bulling affinity of other aptigen-binding proteins described herein.

Methods :Of Expressing An tied» Binding Proteins

Bkptoasfoit systems and eppsfomis in theforio of^plMiBid.s, expression v'ecfofo* 2f nmiseripttos or expression cassettes that comprise at least one polynucleotide as described above are also provided herein, as w ell host cells comprising such expression systems or constructs.

The antigen binding proteins provided Heroin may be pmpared by any of a number of convcniiotj&amp;l techniques. Fm example, CGRP R antigen binding proteins may be produced by 2$ recombinant expmssion systems, using any technique known in the art. See, e,g., Monoclonal;

Antibodies, Hybotiooiaa: A New Dimension in Biological Ana]yscs;,Tfennet ct ai. (edsif Piemtm Frew New \ oil r ffibOi and \iunodtes \labounots Manual I for loo and 1 am. fddsT, Gold spring Barber, N ,¥l £1988:).

Antigen binding proteins can be expressed in hyhridoma eel! lines freg., in particular 3¾ antibodies may He: expressed in hybndotnas) or in cel l lines other th an hybr idomafe Expression constructs encoding the antibodies can he itsed to transform a reanmuhan, insect ot microbial host cell, Ixanpa^^ dan He performed tssing any known method: for introducing polynueieotidefs Into a .host cell, inelndlng, .^;0xnmpj.p:padkagmgtfe'^fy^Hd!l^lfe ura yirux or bacteriophage and transducing a host cell with the construct by transfection procedures ns O'* 2016244220 11 Oct 2016 tj··, typically include one or mors·, of file tbllowing mtel.e0ii.de sequences;, a. promoter, one or mows enhance· sequences. an origin of rcpheation, a transcriptional termination aequencc, a complete intron sequence containing a donor ;md acceptor splice site, a sequence encoding a leader sequence tor polypeptide secretion, n nbosome binding \;ie, a polyadeuylation sequence. a I CJ3 o ft *S·' r*

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Optionally, the sector may contain a 't»gM*enccKimg sequence, /.. e., S'«,:6i.igO«iiidl.^d^-rnoiccuL located at the- A or 0' end of the CXiRP R binding protein coding sequence; the 5 oligorna too tide sequence encodes poly®* Aceh as hexaBis}, or another ‘'tag’’ such as FLAG*, ; BA iliepraglutihiu: fqiluenpa. vims), or mye, for whfch. eopiomreiafry available; apiihodiesie^tst,: T his tag is typically fused ίο the of the polypeptide, and can serve as a means for affinity purification or deteciion of the CGRP R binding protein from the hoM eell Affinity pnrMeadon ean be accompltshedv ibr e^aqtpio, by; column chromatography using 10 antibodies against the tag as an' affinity Matrix, Optionally, the tag can subsequently be removed from the purified' CGRP R binding protein by various meins such as usi ng certain: peptidases tor cleavage.

Flanking sequences may be homologous (An,, tfom the same species andAM atrain hs the host cell), heterologous (be.. from a species other than the host cell species or strain), hybrid ! .5 ;{?.,.·.. a combination, of flanking ^quensesfcrti MdMitfeM:cme::kititCd|diyMfced’e or native. As wuch, the source of a flanking sequence may be day prokaryotic dr eukaryotte orga.nism, ;any vertebrate or investebtnie provided that the Banking sequence Is functional in, and can be activated by, the bost cell machinery.

Flanking sequences useful in the vectors way be obtained by any of several methods 2() weiI fenoiyn in. the art Typically, flanking sequences useful herein will have been previously identified by mapping and/or by restriction endonuclease digestion and can thus bo isolated from the proper tissue source using the appropriate restriction endonucleases. In some eases, the full nucleotide sequence of a Ranking sequence may be knob n. Here, the Banking sequence may besyntbeidaed using the methods described .herein for nucleic acid syutbeslx 25 or cloning.

Wbetb# Ml or only a portion of the flanking sequence m using polymerase chain reaction (PCBj and or bv screening a genomic library with a suitable omho «ueh &amp;s an obgonu· lorn eh’ anO >; flanking seqvt nt c iHgmcm uo.'u the same <v ns η her specie^. Where the flanking sequence is not known, a fragment of'DNA coma mine a flanking 3:0 : sequence may be Isolated from a larger piece of ON A: that may contain, for example, a coding, sequenee or even, another gene or genes. Isolation qtay he accomplished by fesirtetion endonuclease digestion to produce the proper DMA fragment followed by isolation using agarose gbl c|^^at0girapi%^CfciakbW^.,:· ©kb or other methods iJTi. 2016244220 11 Oct 2016 ij··, 'Ui ΐί:αθϊ|ί.ρΐί03 iopUft S||30 pSim'qiSaKJ! axp Mf; pssodms; Si Pinguid a0|500|3g ',Ϊ0|3®Α Pip i.u )u;.wq.k1 ;>upV< pip j<j pnu; x 2; '.' \i vjpv o) UP'okp? AppUum :.u?; \pir;iauuMiiu: Pip A;UO α>Ρα·:-·;Λ\ Mnsvad uisnP^jP-i jppup pop'pi an: Sjunu.uo^un,u qpp ιρρ;ί:ηηΐΐ?·|·\; 'S'PupS psiusis pis· pun -ap vappPimumu pun Ι^ΡΠΚΡ Panrmp;;n ppqapup -app pappus sqpp amjnuuuau .up nappinui piqiuppps pppunw jo nPKkuvxq aaninpan.ooi jo saopniPUPa p' '1 p 72. 3 •ft m $* ft" ft ·£ *7.5 ^ Z n % ft >v. {%3 % £:. 3 &amp; -4 m ft :ix$. &amp; K £> ;r, op ft£f V v a7? ft &amp; &amp; Όs o cu •:c c 3" H V">δ £7 >r3 &amp; ZL· M &amp; 7? ft £r ?? s 3 r. y 'Si- i;.7 p £T, r! ίί y 7’ s £5 C ‘ft δ (7 .£5' £i. ' '£L Ο.: Λ 3 ft; ft o Hi ft :.7 ft, y 'ft ft; :7 <—v y> Hi Ti. ft o *7> 77' o '-y r·.· o £7 s. -¾ 3> q t Cft ft' s δ" δ <7 yy 3/ r/ &amp; 2' 77 3 >-s 1¾ :.7 o 2 E. a Γ; ? 3 ft?· &amp; >3' » ft a. 3. s 7*7 ft-; O O z?.. ft 7; Sv: g. ίί o S ?* 5« </ 3 % >3 c ST 6 1 ,,<· y Λ O 2 δ y 3' 8, f 3 ft.. iq. O" o ft ft; g 3 3 7’ί Cl cr ST .w 3 o ? '3 3 o; C} 33 <4, o £3 o. ~k y '··, >y·. Ό c o 3' W ft. £3 8 3 1 r:·. 5* 8 6 :,ft: Ά •r ?S V*· 3 ft 'ft *5 g: 8 xy 3' /- "g o” Pft 3' c 3· δ ft ft <*; j-y ft·; ft- §' ft; O r-v C;~ o c:: X 7· £? ip ift I -•3 /- δ £ .c. o rv S a ,2 3; 7j 3 £3 X ft' ft ft 3 /*·, ’“< 7X .7, *3 Zft ftft ft?: 3' r; 31 1 w;i. ,3' V- ¢7 £ g . £ p; n o' “1 3' '<" fy; 1 o E ift 77 O V fti δ <ft i δ O :r.< o ft :ττ' t ? a >3 O •“ft 3' p 8 y*v ci Έ. if a ~Hs δ £r O 3ft £ 3 sa o' o &amp; r; tL >-ϊ o ! i &amp; rr O 3" •“ft; ft o' δ >7 ft, ?r ft5· m. ii δ.δ 3' XS 7C. ζ> "! S' S. S'1 -¾ SL$s i ¢7 o cx' 3 :^.- Ϊ3 C ίΧ > z> *77 rr <¥ I: I δ- r~l SV; £ί. v*· Γ/ •7^· Cj; ig 3 >3 o. S c*1' :¾ 7? O1' £ za '•~1: cp- 3 t? C ·£·; <v '3L '3- ft- % zs Ψ. a <-»·, o Ε 0 ¢5 7.5

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Albeit the Mmeefttetion pf sdieetioh agent id the mebmiu it?cr«as0l/t:te5^?y leading m the gene and the DMA; that encodes another gene, such as an andgnn binding protein th,u binds io:CMfffFli; As a result, increased quantities of a polypeptide snch as an antigen synthesized from the jmpbOed DMA,

* A tyboiM she i:| usqally neeessdpy lor ipnaiaddh toltiadon. of mllNA and A churn», ferized by a ShiaedMgaxno «qubnee (prokaryotes) or u KLazak sequence (eukaryotes). The clement is typically located 3* tq the promoter and 5' to the coding sequence' ofthe poly peptide to be expressed, 10 In some cases, such as gi;y«Oh|!tdios is desired In. a eukaryohe host cell expression systeni, one; may manipulate: IldiVarious pro- or prexsoq ounces to improve gKooy\ h i on or \ told fm 'ample, one may a her the pznndase Joevmm site of a paitieuUr signal pepricb, hr add ptosequeuees. which also m«j> ei.fect glyeosyiatiom The final protein product may haye,: in: the i position (relative s« rhe nrst atptno apid of the mature protemkone 15 or more additionai ammo acids incident to exprcs^m:p.#hhikii^::iiot has c been totally removed For example^ the final protein» prod act· may M&amp;ye-hne of two ammo acid residues found xwto the ;atnte4erthiu.a.S, Alternatively, use of some enzyme cleavageattes mb)? result m a slightly truncated form of the desired polypeptide, ifthecngytne cuts at such are;) vcid-in the mature polypeptide. 20 : Expression and cloning will typically contain a promoter that is recognised by the host organism and opembiy Inked to Riblddmipeoteim: Frootoicrsi are uptran scribed sequences located: upstream (E&amp; , 5'} to the start i gune?^; v#d^.;abmit· 100 to lOOO bp) that uiutrol transcription of the structural geho. Promoters are conventional!} grouped xntr» one of two clus-us; inducible pmrnotem apd 25 -constitutive promoters; Inducible promoters Initiate increased ie\c!s of transcription from DMA under their control'in response to some change in culture conditions such as the presence or absence of a nutrient or a: change in temperthuiM Constitutive promoters, on the other hand, urefbrmly transcribe a gene Ip Mfeiohdlmy areoperahty linked, that is, u itb Ilrtlf? OfMcoutiM over gcuc expression. A large number of promoters, recognized by a \ aneiy of potential host M -cells, arc well known. A suitable pmnmtef avoidably linked io the DMA encoding heavy chain or light chain comprising a CGRP R bludmg protein by amoving the proptoter from the source DMA by restriction enzyme digestion asd inserting the desired promoterdequeued into: |he vector.

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:X χ· 53' ΪΧa and hcribono gene: co«ti»il^gx»ti-|fei,isibe kvpothalaaTws 2016244220 11 Oct 2016 (Mason etai., \m, Science 234:.1372--1378). ' AA'euhMqqrsequence indy be inserted lutd the vector to Inefmse trmcdptloti of .CXNA Ineoding iigitf ciSiam or hetivy chai a comprising. a. hbmtm CGRF Erliindmg protect l^ltigltdr $ eukaryotes. Enhancers are eis-scting elemea^ of ;OMA,: ymtally ahon! 1:0-300 bp ίο length, that act on the pronto ter to iocrea.se transcription. Enhancers are relatively orientation and position iodependebfc,: haying been found a| positions both 5^· '3A-t^ ·:Λ&amp;©··-msltc Several enhance· sequences available from mammalian genes ate known {e,g.. glohm, chsmsc. aibumin, aipha^feto^pmtein and insulin)- Tygiculrvy however,m nrtbaneerfmm^a^¥tTO:;i«'''nsibiv 10 The h\ 40 enhances, the *.> toroegakn mis carl} promoter enhance?, the polyoma enhancer, and adetwmms enhancers known in the art arc exemplary enhancing dements for the activation of enkaryosic promoters. A bbe an enhancer may he positioned m the \ actor cither:5;i Or 13’ to a coding sequence, it is typically located at a site 5' from the promoter. A .sequence encoding an appropriate natue or heterologous signal sequence (leader .sequence or signal peptide) can be 15 incorporated i nto an expression vector, m promote cxtraceilnlar secret i on of the antibody . The choice ofmgnal peptide or leader depends on the type of host colls in which the antibody is to be produced, and a heterologous signal sequence can replace the nati ve signal sequence.. Examples of signal peptides that are functional in mammalian host cells include the following: the sighs! soqueme for inmrieukm-v 01.— t described in US Patent No. 4,963*19$; tin:signal 20 sequence for interIsukin-2 receptor described'in Cosmsn et at., 1984, Ataflwv 332'768; tbq Imirieukin-1 receptor signal peptide described in HP Patent No. 036? 566; the type 1 .interisukm-l receptor sign a i peptide described in US. Patent No. 4.968.697; the type 0 interleukin·-! .receptor sign;d pepn'de described in EP Event No. 0 460 s-16. i'bc expression s ectors that are prosuded may he constmeted front a .starting \ ectm· 25 such as a commercially available vector. Such vectors may or may not contain all ui the desired Rankine sequences. Where one or rnmv of mo flanking sequences described herein are not already present in she vector, they may k mdoHuially obtained and ligated mto the vector, Mc'Jmon i.i-ft d for obtaimm: oa- . of th - thinking sequence*· am web know n m om' ski Med m the art. M, After the vet tor has been constructed and a nucleic add molecule encoding light chain, a heavy chain, or a light chain and a heavy chain con"·prising a CGRP R. am men binding sequence has been inserted into the proper site of the ’vector, the completed vector may be inserted into a suitable host, cell-for amplification and or polypep tide expression. The fraustbrmatiqn of an expression vector for an entigcn hlnoinu protein mto a selected hbsii cell 129 may be accomplished by well known methods including mmsfechou, infection, cidcrum phosphate c«-pmcipiiation. electroporation, oucromjectioa, lipoieetion, DEAB-deximu mediated trMaihetiot), or Other known technique#;, will In putt he ύ 2016244220 11 Oct 2016 : function of tM typo of ho# cell to be used, Those methods and oiboit amiablo methods are well 5 known to the skilled artisan, and ate set :forthy for examples in Samhmbk pi &amp;l, 2001, mptv. ; A host cell, when culnitcd under appropriate conditions. .synthesizes an antigen binding pmtem that catt'ktiip^uetttly· fecoiioetetl ifedhh the culture medium (if the; host coll secretes if inn· the mod'am) or due. tlv hot! t, \yo eol.l ptoe a. apt n (0 a e rot secreted) Ike vdcuton of an appropriate host ceil will depend upon various Utetors, sudi as desired expression levels, !0 :polypephde modification.·, that are desirable or necessary tor activity (such:as giyeosyiMioh;:hr phpsphhryfstidp); and ease of folding into a biologically active molecule. lykmmaliah oell lines available as hosts for expression are well feowti in the art and include, but are not hunted ίο, immortalized eel; hue* asaifable from the American Type Culture Collection (ATC O, including but not limned m Chinese hamster os 1.5 ffeLa cells, baby hasnsier kidney iBHK > eelU, monkey kidney cells (COS), human hepaieeeflakf eareiooma Cells f&amp;gg: Hep 02¾ and a number of other pell hoes, : in certain: embodiments* cell lines may be selected through dete^imug. which cell lines kawehigh express-on levels and conatit«lively produce antigen hlnding protemawdth GGEP 18. bidding properties. In another embodiment, λ eel; line from, the B cell lineage that does Pbi tn&amp;keits 20 owh. antibody But has a;capacity to snake and seemte a beteraiogpos anti&amp;dy cap he aidocted, OSe df Htuihaa CORF dntigen Bindina Broteins fer Blagnostlu mid rhcrancntlc Fumoscs 1: Antigen binding fifoieins are useful. lor dotceiingiCQKi51¾ id biological, samples and identltlcatioii of veils or tissues that produce CGRRR,. Fur Inst; meo, the CGRP R antigen binding proteins can be used in diagnostic assays, o.,y, "binding assays ro detect and o> quantify 25 CCIRk R expressed tp a. tissue or: cell: Antigen Bindmgtprotcins that speciheally bind, to: CGRl* F can also be used ip tteamiepfpF dissasea related to CGF.P R in apatieubui nqgdtdteteof In addition,,GQKF E antigen binding proteins can be used to inhibit GGR.F RItomiiomuPg :a. οοοψΟ'χ v, n>i us ligand ( GRP, there'y ojodnlating the biologic# at to by oi CGRP R in λ cob or tissue, examples of activities that can be modulated include, but are not limited to. M mhihitiug vasodialation and-'or decrease neurogenic inflammation. Antigen binding proteins: that hmd to CGRF tTlhus can modulate und or block interaction with othci binding coptpognds :^M^h.::hiii:hav0in ameliorating diseases related to CGRP R. 130 A dieondiitch associatedWith Imman CCIR!S !ί ;i:B|todes any dlseasp dr condition w hose onset in a patient, is caused by, at least in part, the interaction of CGRP R with its ligand, CGRP. The severity of tine disease or condition can also be increased or decreased, · I ,b\ the intctaction of CGRP R. with CGRP, Examples of diseases :ahd conditions that cun bo •treated with the antigen binding protests describes! herein .i^icldd^'^daeia.w suds as cluster headaches, migmine, including migraine hendudis% efepdc:$$fi*type U diabetes mdktns, inflammation, e.g., neurogenic inflammation. cardiovascular disorders, and homodyoaohe :derangement associated with endotoxomta and sepsis. 2016244220 11 Oct 2016 10 in particular, antigen binding proteins dt^efibod boixdo can bbst hdgmhld, cither us m acute- treatment commencing after a tnigpafcb athtek has eombssiced, and/or as h ;prophyMcbe;%Stbient: adnylhlsfdlih, 'bigy daily, mttddy, biweekly. monthly, bimonthly, •Hannuahy, etc,5 to prevent or reduce the fmqueoey and or severity of,symptoms, e,g., pam -;ympmms, associated with migraine attacks 15 ΓΓ:Ιι^;·:».π^ι^ή·:!·:^έΐ»ΐΐ63ί·τϊ£» described herein can be used for diagnostic purposes to detect, diagnose, or monitor diseases a mb or conditions Also provided are methods for die detection o! the presence of ("CHIP II in a sample using classical immunohisMogicai methods known to those oi skill in the art (e-jp, Ttjsaep:, 195?3> Practice 2d and Theory >>} ItapHi. /amm/ton.-mm*. Vol IS t Eds R,H, &amp;Mun and F,fi. vm Emppenherg, lElacvsur, Amsterdam*; Zola. Ρ>87. ^koiochnaί JniBioJiep M QfTmhmquep.ppy 147- 158 ιΠΚ lb ess, Inc.}; lalUneu «.·) aL mS.J. C k //. Biul, lWt J. Ceil BioL 105:30b ?··30*>ω. The detection u? CORF R. cart be pG'fotbied in v<Vo or m tiMh Diasmostic applications crowded herein include use of the aptigen binding proteins tp 25 detect expression of CGRP R and binning of the Uganda to CORF 11. Examples of methods useful in the detection of the presence of CGRP R include immunoassays, such s.., the enzyme Hiked mirnuromrbeni avov Si I IRA) and the M.Kmnrumoussay (RLA), fot dfuguost" mpht alums the antigen brndmu protein ty piodly a ill V labeled aUh a detectable labeling group. Suitable labeling groups include, but are not limited to, the M following: radioisotopes or radionuclides ΰ.ρ , 11. "t\ K'N, ''sS. W V, yiTe,115in, ^1. ,Mih fluorescent groups I 1TC, rhodamme. hmtne wv phosphors), enrvu\,tw gtoptw u e , horseradish peroxidase b-uaiactosids,'>e, luviferase. alkaline phosphatase), chemiluminescent, groups, bkHiny! groups, or predetermined polyps, glide epitopesreeognkcrl by a secondary reporter te.g,. leucine zipper pair sequence,·", binding sues for secondary antibodies, metal 13:

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Dosing ftequeney will depend upon the pkmmaeokmone parameters of the particular hitrndo CCiRF R dntigen hinding protein in the formulation used, Typically, 1.5 administers the eoo^ositiM^idiwitfef^g is reached that achieves toe desired eftoct. The =-be adtolhigeted as a single dose, or as two or more doses (whieh: may or may noieotitato the same amouht nf the desired eonfineous infusion via ad. itnptonftottoi 'ddytoe-nr cttp^^vAp^priaie dMa^idmyb# aseeftained through use of appropriate dose-tosponse data. In certain embodimenfeh the 20 antigen binding proteins can he administered to patpnls throughout an estendfd time period. Chronic administmtion of an antigen hinding protein minimises the ad verse immune or allergie response commonly assoeiated with antigen binding proteins that are not fully human, for extonple an antibody faisdd against a human antigen In. &amp; &amp;pnto«in#3^ a nnn-Mly hnman antohody or nontonman antibody protoiced in a nphtonman: ^secies, 25 0

The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally, through injection by intravenous, intrapentonesI, int racerebraj {totra-parenebyrnai), intraccrcbroventricvdar, intramuscular. intra-ocular, imraarterial, intraportal, or totrafosionai routes; by sustained release systems or by implantation devices.. In certain embodiments, toe cotnposdions may be admigisfotod By bolus injection or eontinunmly By infusion, or by implantation device.

The composition also .may tie administered locally rki implantation of a tobmbrahto sponge or another appropriate material onto which the desired molecule has been absorbed or ehcapshlated, to certtohrtepitodimohts, where ah impiMM dm. tee is used, the device :mky 137 he ΐίτφΐAnted gaiitiible tissue or organ, and delivery dfthe desired molecule may be vfo 2016244220 11 Oct 2016 dtf&amp;ioR, 'boI.iiS»Or· c^dnitods admiaisiraddRi

It also may be desirable ίο CGRR R antigen binding protein pharmaceutical compositions; ev vivo. In such instaoees., cells, tissues or organs that have been removed from· 5 :; : the patioa! atd: exposed to trumau CQfd* E and|bp binding: pfotoih phaOTapebtlcdl compositions after which the cells, hssues ami or organs arc subsequently impkmu.n kwh into the patient. in particular; hhmaK CClKF E atRtpn bmdmg proteins bait he delivered by implanting eetttt9^¢elte.thabM^i:.b¾;^^^%.ettpϊ?ee*ed< using methodssunk aa lliose desedbed 10 herein, to express and secrete the polypeptide. In certain embodiments, such cells may he animal or human cells, and may be autologous, beterologous, or xenogmimc. In eetiato embodiments, the cells may be nnmortahked, In other embodiments, in order to decrease the chance oikn mtmnnologtcdl tespouse, the edk nu> he encapsulated to avoid infiltration of surrounding tissues. In further embodiments, the encapsulation materials are typically 1.5 MoeompatlMe, sttonrptotoreabie that allow the: release of thdprotem prbducns) hut preveoOtio deitmertOb of the ceft#%:-'fcp.^ientfs: imntoue sysptt or by other detrimental faeiom''^pl|fe0^tirrdiU^i»g tissues.

The following exautples, tnduding the experiments conducted and the results adueved, pe ptokded tor ftluslmiive purposes only and are not tohe eopstrusdas Ilhutihg the scope of 20 dhp appended claims. -Mil: pm

A, Moleeular cloning of iramao CRLR and RAMRI

Human CRLR eDNA (GeuBank Accession No. 01741¾$EQ 1:0 AO: 1) andtlAMF I 25 oDldA: (CionBaok Aeeessiou Mo. AM ! 014; SEQ lO MOO) were doned into the majpmatiap: cell expression vectors pcDNA3 k/eo and pePMAl.Idlyg {ln\dtrc^e«,:iT^|3^|:Q^},. respectively, for transfections of HER 293EBNA ceils (Invitrogen) as described below. The hCRLR cPN A and hRAMPI cDNA were also cloned into the pDSR:h24 vector (Kirn, Η. Y. el ah J. hvv. Derm. Eymp. Proc. (2007) 12; 41-49) tor trausfcetions of AM-1 Π ΙΟ cells (U.S. 30 Patent Number 6,210,924 ).

Es Sta blydkansfeefod Cell Lines

Hi K 29B P<\ \ i,s (,λ clah' leu- \Ui o hmttogeo; wok waded at a dr 'ct^ o* I 5x10* cells per 100mm dish. After 24 {mars, the cells were cotransfected wtp 6gg

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ο SQ /£I o ''XI. 5- « p o 25. X Γ; :jc P<: νΟ X: I r/ rr· !?Cf ΤΛ/ ;ρ 3_ Ο' χ o ;p o P > 0Ϊ£? CO ii! z :cp c:ήXaf G Za N; 0 ? a n < . .3' Q, P •ai· r; <v <T/ •Tf i£2o TO·' H 0:. peDN A3.EzeodnfoynoCRf.R pins peDNA.V1 /hygromydn eynoRAVIP 1. But?) emiGrucis were linearlxed w iih Fspl, Alter 48 hours the cells were subcultured into growth medium containing 20D,ug ml zcocin F 400!tg/m! «no at dilutions of 1:30,. ί :4§? 1;:100, and 2016244220 11 Oct 2016 I ,300. The medianVWas changed tv, ice weekly. \ftcr two weeks, 96 transfected colonies 3 #ere isolated using efogbig rings. Theclones werepssfyed for their response to stimulation by CGR P ligand, .Spvpptl clones slfowed :slhi||at high levels of response and one was selected for use in anhsetnicidT^pdonrents. CL Isolation of btgb-ciprfeiislhg €€?RP receptor ceils A CGRF < ,.?7 peptide analog was synthesized (Midwest Bio-Tech Inc. Fishefo, IN) with to 1.5 the sequence below:

Ac-WVTFiilLAGEFBBBCFW ID NO:9)

The peptide was labeled with Afexa 647-Nl IS following foe TnamrfoctureFs : Ibatwttona' (MolecdteFtt^bes, Inc. Gat A-3000). The Alexa (i^N^led CC3i?aA7^bbW^I' specific staining of GGRF receptor tranufoeted cells and not the nfeOansfoeted pa rental ceils and was used as the FACS reagent.

The huGGRP reeeptor>tmnafeeted 393EBNA end AMd €BQ cell poofo (gei^taied aa above) were sorted repeatedly up to four times pools using with Alexa 64?-labeled CGR.IN,;?? ;pepude,: Iligit expressing cells were collected at fond sorting frozenihfb vials. The AM-·I CHO/huCGR P R cells w efo used for iimmufoenifon as described below, and the 3<)3EBNA/huf'GR.F 11 cells were used for titering mouse sera, after immUnixation and in binding screens of the hybridorns superaafopfo. fk Qotforaftoi* of fpfoble CGRF receptor

Soluble CGRP receptor polypeptides containing the Ndermlnal extracellular domains (ECDp of human CR1.R tSEQ ll> NO :6) and human RAMP.! (SEQ ID NO:H) w ere generated by traEsicpiy co-transfodlng 293 6E cells (Diuocher, ei Nucleic AciiixMm 30;E9 (2()02)) With Yecfofo poniainiug the conswpondiug cDNAs (SEQ ID NO:5 or SE$ ID NOTI aS· described below Commonly used tags (polyHw, Flag, HA and/or Fe) were employed fo Fu'iHtaw: see redoc. and or Mibxepienr purification. A soluble hetemdimerk CGRF R £€1> fused to Fe was prepared by PCR ciomng with the appropriate primem mtO; the transient cxpr<^kni:|^tor pTF5

The CR( R N-termimd ! if'Π-Fe consisted of the V terminal ax trace! I n lar domain o f CRLll TSEQ ID NOfo) fused to human IgGl Fo, The RAMF1 EGD-Fe COTtaind the extraoeliular: domain of R AMR I (SEQ ID NC):B) fused to human IgGl Fe. in both cases, there was a linker consisting of live consecutive glycines between the BCD domain and Fe. 140 :Τ|ΐ&amp;:®|»Μο heterodlmeric CGRP receptor was expressed. by eostmnsfeehng tlm^feicr, constrmns as follows 203-61· cell* at Kid' ceils ml m shako ftasdtojtjWere O.Smg!· DNA;l^CM..E:.}S^U5rECD~Fc/pTT5 and huRAMPl ECD-Fc/p'FFS) with 3mi ifi/mg: DMA (in.vitogen). Cells tvere grrmm In suspension 1». Fred^^le £93 2016244220 11 Oct 2016 5 expression medium supplemented with 0.1% Pluronic P68 and 50 ug/rol Gcnctidn for 7 days and harvested tor purification.

Puritoaiions from conditioned media CX€M A were performed by buffering the CM with the addition of 50.mM I ris, 400rnM sodium citrate, and adjusting the pH to 8.5 Use buffered CM wax then passed over a Protein A affinity column equilibmted in SOmM Ins, ! 0 400mM sodium citrate and pH adjusted to pH 8,5. Thu Protein. A column wax washed with

PBS anil the Fc fesiott protein eluted with 0.1 N HOAc. The eluted peak contained both CRLR and RAMPI components wheomsted Iwwestern biot uslsrg lndividun! anubodms specific to either CRLR or RAMPT FmtherLif-MS and N-terminai sequencing confirmed the presence ofbmh CROCK AMPl 0οίορο4ίχηηΓ and CRLRCBXiR-ha'pciEi^r in appmlttngfcly 15,: '«2:3} ratio. Thw '\olubie(. f IRPreceptor"Aatsshotmrecotb|^mln: A]exa647 labeled CGRPg >r binding to CORE receptor expressing recombmam cells in t he PMAT analysis, although it failed to bind CORF ligand a'' determined u&amp;ihgBidowhtsiettai' was usedas an mtmttuogeu acd^ribed In Example, despite, inter and jacfcs^ORF ligand binding. 20 E.

Membrane extracts were prepared tom CGRP fehepior expressing cells using a method described by Bossc* R, Μ dfe 3(4): 2H5492 (.1998)}. 30

Brefh , uppmglmately 5 grams of eell; paste were pellrded in 50 ml of PBS at 3,000 rpm for 10 mm at TO and m-suxpettdcd in 30 ml: of cold lysis Duffer (25 mM HFPES, pH 7,4,3 mM Mg€l> plus one Roche protease Inhibitor cocktail tablet/ 50ml.). The lysate was homogenized with Glax-Col (Teton-glass honrogenker) wut.lt ' 20 strokes at 5,000 rp.m ami spun in a IA:21 rotor at 20,000 rprn for 15 min at This process wax repeated once more and the final pellet was re-suspended in -M~S ml ·ΗΜ gelleO buffer (25 mM 11EPHS, pH 7,4,3 mM MgCb:, HI % (w/v) sucrose pins one Roche protease inhibitor boCktail tablet·' SOtftL), The membrane extracts were sheared Dy passing through in G and 25 G needles 2-5 tones iota! membrane ptpfein emieeutFation wasdefemtined withla MfemplateBDA Protein Assay (Rierec), 141 Μ 2016244220 11 Oct 2016 tj·, % '2. 9 S r? u a* ίΧ il X. r, Ci &amp; O Cu a % \ --

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For coin:*to' screens, the parental AM-! CHO cells or HEK 293 cells were seeded 2016244220 11 Oct 2016 screened % Wbk$£· bn these celle to parallel to diffireotiate mdi elliApne hsbridornas binding to cellular pmteips, but not to the CGRP peepers ® Identification of bift$$«g antibodies by llgpntl binding competition

5 assay through FMAT Λ hgand binding i.oiopeunon method *<5-- dm done,· to identify antibodies on the hybr i doroa so porn a tants) that bind CGRP receptor and bloel; CGRP ligand binding. 3R4-wells plates (Coming Coster, Cat:#37l2) were prepared with 5,000 AM-1 huCGRP R PoolJceil® and 20,000 nnirattsfeeted iMOS bells in each well. 20gl of aoii-CGRF E hybridoma 10 supernatant were added to each well, and the plates were incubated tor I hr at room

temperature;: 1 ΐϊμΐ of 2.8pg/m! Alexahdl-CGRPao?pegttdowere- then added to cadi well and the plates were incubated tor a dirtltet 3 hours at roomi tempempre, lire tmonnt of Aie^addf-CGRPn «*bound to the ceils was assayed on a FM.AT B200 Cellular Detection System (Applied Bio·.'•stems) Output data were both a numerical PL I mine of signal intensity t higher PL I 1.5 :: walues Indicate ^iaisiia:- iitiags- of the ceils.

The esperltncnG included negative eontMlhyhridorna adperaatanlp The «vcmgC: Pti value observed in these negative,control exprinpnts was adopted as the maximum possible aiguat :¾ the assay, lixpertmcntal supernatants were compared to this maximum signal and a percent inhibition was calculated for each well (% Inhibition;:'s(lA'PL! ofthe aoti-GGRP If 20 hybricorna snpema tan CM ax intern f 1., I signal)}.

An overview of the data is shown in Fig. 6, In this e.xpcrtm.ent, 1092 anti-CGRP R sujpP^t&amp;uts wem tested ^hfe-dhia. o.tderodei^lag the average percept: inhibition,: Mnety supernatants had >25% average inhibition, SI of these were >50% and 7 were >70% average inhibition. 25 An ahhrcYiated data set is shown m fable 10, below. Sample ID Noa,i-5 illustrate : examples of ami-CGRP R hybridoma supernatants which inhibited the binding Ale\aP41-CGRPvu? peptide to CGRP receptor and Sample ID Nos 536 ··· 540 illustrate eMmples of antA CC1R P R hybridoma supernatants which did not inhibit the binding of the Alexa647-CGRPs.. o peptide to the CGRP receptor. 145 2016244220 11 Oct 2016

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5 BIND1NC COMPETITION

Biueore «tnaiyses (Karl*son, R ct aL Methods: .4 Companion to Methods in. Etm'm>b;r}\ 6' 99-1 10 {19941 were carried out as lb* lows, Immobilisation of anti-CORF rcccpiot antibodies to the CMS sensor dun surface was performed according to manufacturer's instructions, using a continuous flow of tOinM HOPES. 0. i 5M NaC E 3.4mM BPTA, 0.005% 10 P'20, pH 7,4 (RBS-EP bullet). Carboxyl groups on the sensor chip surfaces were::soilvared by injecting 00 μΐ of a mixture containing. 0.2 M N-cthyi-N' idimefhylarntnopropyiicarbodiimide Π.4Χ) and 0.05 M N-hydiOxysuccirdmide (NMS). Specific surfaces were obtained by injecting Id) μ! oi'anti-OGRPreceptor antibody diluted in i0 tnM acetate. pH -1.0 at a COOCCnttmtion of 30 jig/mL, Excess reactive· groups on die surfaces wore deactivated by 1:5 injecting 00 fiL of 1 M etimnolamtne. Pinal immob.iii2.ed levels for die individual antit were us follows:

Antibody Resonance Units (RU) 11D; i -52)00 5B6 -7,200 20 4H6 -53)00 2016244220 11 Oct 2016

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10 .RECEPTOR IN WESTERS BLOT

Three rcptvHSitatne i 'GRP receptor block isig antibodies 'a cre tested using Western blots tin hudnp: to a soluble GGRP reecpior-tuuFo fusion protein. 153 100ng of purified €GRP R-mstFc (produced am! purified as described above for the CCUiF R-huFc except the mouse 1¾ was used and the linker between RAMPI or CRLR BCD : and mufc wnkMtMged to ^GOdie¥pGQC3QOV- (SFQ ID 140:213)) was diluted in PBS . with FAGE .sample buffer with (reduced) or without {«on-rednccd) ixtot^rnereaptoetlnmol 5 (f)ME) at 13,3% concentration. The sample containing |5ME was then boiled for 4 min. 2016244220 11 Oct 2016 samples were loaded ο.όίΟ“·^|^Ρ!|#:440^ Τί^-giydfe -gels.·· i (Tnviirogen) with alternating tanas of €GRP RPc protein and molecular weight markers Bnvitmgeji). Gels wes-e giseirohlottod onto 0.2)tm f be Slots were washed ^di-Tii^ulferecl.^jKe + 1 % Tween 20 (IBSTFnMthen blocked with TEST f 10 5% powemd dry milk for 30tnie. The blots were cut into strip; along the mokeular Weight marker lanes. One strip each with reduced and nonwedueed CHRP E-muFc warn incubated with purified huCGRP R antibodies 4E4,91¾ or 3M (1:500 dilution in TEST > 5% milk), goat an.t:i~hoR/\VlPl N-20 (1:500; Santa Com Biotechnology,.Inc), rabbit anti-mouse IgG-Fe-HRP (1 TO.OOUi (Fierce), or goat ami-human IgG-Fc-HRP (1:10..000) (Pierce). Blots were 15 incubated x oh the antibodies for one hour followed by TslOmin waslres with TBS1' f 1% milk. The blots treated wuh the hhGGRPR antibodies were then iBcuMted with goaf nrrtR; mouse lgG-Γ, -HRP (IΊ 0 000 in TEST A1% milk) and the blots treated with arto-huRAMPl C%-20 agtERAMFl goat poiyeloniu atihhddy, Santa ThimBioteeh, €A)were incubated with rabbit anti-goat I'gCi-Te-HRF (!: 10.000) tor 20rnin, Blots were washed 3x!3miu with TEST, 20 The huCGRP R and anti-huRAMF 1 antibody blots were treated with Pierce Superstgnal West Pico Detection reagent, and the anti-mouse arid anti-human were (rested; with Pierce standard Dstectidn 'Reagent (1 min,). Blots were then exposed with Rodakliidtnan MS X -ray film.

All of the three C'GRP receptor antibodies, 4E4, 9F5 and 3B6 v, ere able to detect the 25 soluble CGR P R-rouFc (containing RAMP l-ECD and CR LR BCD) under non-reduced condemn hut not under reduced condition indicating that the binding epitope of these CGRF R antibodies was conlhrmahonal and; sensitive to the disulfide linkages (5 pahs imRAMFl “ECO and 3 pairs in CRLR K'-ter BCD). In contrast, the eonunorcini anti-RAMPS antibody N-20 (Santa Crux Biotech) bound RAMP S under both reduced and no reduced conditions indicating 30 that the binding she for N-20 antibody was primarily linear and not sensitive to disulfide linkages. 154 EXAMPLE 9

RECEPTORS 2016244220 11 Oct 2016 CGEF receptors funned of cither native RAM P I with chimeric €R t.R;, or native CRLR 5 with chimeric RAMP !, were used to identify CGRP receptor sequences involved in antibody binding. Smec all of die human CGRP leeeptor blocking antibodies tested laded to *hov\ fouedondl activity to the ού:ΕβΕΡ teeeptor, the chi meric components dhit sequence in a human sequence background. The following chimeras were generated for binding analysis by FAC'S: 1 &amp;ΑΜΕθΜ«Εί.*ΜΑ3^

Amino acid residues Q2R to A34 in the human RAMPI were replaced with the corresponding sequences from rat RAM Pi. This stretch included tfve amino acid residues that arc different between human and rat RAMPI, i .5 Amino acid residues Q43 to E53 in the human RAMP I were replaced with the s corresponding sequences from rat RAMP!. This stretch included sis amino acid residues that, arc duVcu'iU IvoAv-en human and nit RAMPI,

RAMPl.g!iM

Amiud eetd residues R67 to E7b in the human RAMPl die 2d corresponding sequences from rat RAMP!. i his stretch included seven amino acid residues that arc different between human and rat RAMPI, CRLRchm*^ .Amino acid residues 1.21 to Q33 in the human CRLR were replaced with the corresponding sequences from mt < Ri.R. This stretch Included eight amino acid resltltieadtat 25 are diSeretn between |itman and: mi CRLR,

Fig. i! shows an alignment of RAMPI amino acid sequences born oynomolgus monkey (SEQ IE) NQ:215}. human (SLQ ID NO:4), rat (S(:,Q ID NO:2i ;1) and rhesus monkey (STQ ID NO'216), together w ith sequences of RAMP I chimera 7 i (bLQ I.D NO:217bchimera -)2 (ShQ ID NO 2 Ih) and i !r no λ ' > ιΜ,Π ID \G 2i°s ' vs 12 \ and 1215 - nn\ an 2¾) .ihgmnent of CRLR amino acid -sequences from human (SE0 ID 6)0:2}* eystomolghs monkey tSEQ ID NO;221), dmsus monkey t'SLQ ID NO :222). rat CSPQ ID amino »e:d sequence of CRLR chimem k\ (SEQ iD NQ:223). 293-6E cells were transiently transfected with CGRP R chimera DNA epnStrttdts iCRLR wt a- RAMPI Q28-A34. CRLR w! ·(· RAMPI Q43-L53; CRLR wt 4- RAMPI 1167- 155 B7% €RLK T 744,)33 ' wi - RAMP! wo pTTS vectorcontrol). Cei ls Wide 2016244220 11 Oct 2016 liar\f^Med:auor 72hr. washed wtth PBS + 0.5^:. RSA. und eoanted, Basil S&amp;tdlpdod ctigli.i&amp;er was teMikpended at a dilution of 5x10' colls per iOOu!. FBS/BSA,.. IDOjil of eel! sdspM&amp;loB wasdligabt per well in a dS-well meaddiottom plate (Fafeon). Theeeils were pelleted at 11 iSdOrpmfbr S min. The supvrnmartfw^ removed1and mplaeedwith^ co?5i&amp;tBingf,5pg punned huCGRP R antibodies S H7, 2E7, 386,9¥$:>4®% IMS, 3¾¾¾.* 11¾ 311Β> or 33B5. Control '.veils were treated with anti4)NP bolgG2 (Oug), Aie^aM7-CO!iF:peptide I0.5ug), or FBS/BSA alone. Ceils were incubated on ine for Ihr, astdthen Washed twice wiib : FBS/BSA. The ceik were resir“'pended: in. ΙΟΟμΙ/well FBS/BSA eoatammg aatBhng-FedFiTC 50 v0.5ngt gweepi tor -\ieW'~r~i GRP traced cells). Cells were mat bated on lee in the dark for /I&amp;fepbd foeti washed iw ice wids FBS/BSA, Celia were resuspended in 2(%U FBS/BSA and analysed using a FACS Cfolfonr,

Ten representative blocking antibodies (3Bd, RES, 4ίί4·::ί·2Ό8,::3C<lvίδΕ4,32ίί7, 4E4, 11DI 1 and 1H?) arid two non Hockhig·^ttxbpdy{3^B0:;aBd:33:BS) w arn tested . Repretentative 15 data CB'5 antibody) ate show ο m Figs, in A, DBand V3C. Fig. I3A Shows binding to the wild-type OGRF feeeptor; Fig, lllishow binding to CORF receptors ecptahnng the GEER L24-Q33 chimera^ and Fig. 13C show binding to CURT receptors containing the RAMFl Q28-A34 chimera. The FACS analysts shewed that ail 12 antibodies bind wild type Roman CORF receptor control os ekpeetelE AH 12 antihodlcavlbdwed s^iBcadtt^'t^dddcd'B^idgte'a^'-'CiC 20 the three3¾¾¾FI. ehtmeradCAMFl (Q2S-A3% {Q43-E53> and (1167-- E78). This could result item 1Π the n presto !<" :i off e > to met a recemorwas much low α,G) the RAMFl ctumera Impaired dte folding With human C'RLR apd'aiut^d and'or t3)dtew three seleewd regions on R$$$p I -the^SB-umthodieN to CGRF rsceproi. 2$ When the l \CS tmeng was ean d to;ttdpddBblysmall^pressing*' cell nop Guonw the nor~Moekom umt bodies 13B5 mi 1 32H8 mpeared to .oiwestarto- hind Lws well (ieA’er Geo iiySeansItpThe EAMP1 Q4.3*B.53 eblteera as-' ijr-tfoorhey, suggesting h nding to ike R A\!R i Q-B-FS3 reg cm may be more Important he- the gpafoloekmg antibodies. On the ether hand, 3385 and 32118 consistently bound better to the SO RAlBFl R0-"E78 ehimet« that!the blocking antlbodidiSs/snggeatrng the BAMF:l/R;67sE7S SCgbCitee otay be more important lor the blocking: antibodies,

Alt: GOER receptor intihodies tested hound ceasooably/well Is? the CRLR chimera (CI4-Q33). suegemtog this site ts not essential tor binding of blocking antibodies. 15:6 h» surriiiuiiyx the data show tbai three discontinuous regions an RAMP l -- $Q38-A34k (Q43 · E55) und (R67-E76) ~ coo id be involved hi CGR.P receptor antibody binding, with '(R67-FTB) more important ro the blocking antibodies. The N-terminal sequences (1,.24-033) of OU.R did not appear ro be critically involved in binding for the CORF receptor antibodies 3 m analyzed by this method This approach does not rule out additional binding sites that share nmnitcai or sstnilas >w ptemim hatv^emi hum m and on CTIRP iccepfor·' 'Much v< e > no! fame ten. 2016244220 11 Oct 2016 in the analysis^: P ::

The: CRLR pqrdph in the mature form -of the CR LR-% fusion molecule (with signal peptide :mm®od:fd:iselosdd hemin as SE% TP 10) contains 116 annuo adds (preceding the gKu * Lnhci) <1.11 has th an n [mnui^suoaL s iounationof dime msulime bonds. The three ddnliide bonds in CRLR are Cyst aiisequenceposition 36(all. CROC 1.5 : sepehce poaitionit listed' in this paragraph are with respect to the: mature sequence presented m &amp;E(|lO NO: 10} linked to 0ys3 at sequence position 52 (referred to as €RLR CRC33, €ys2 ah sequence position 43 finked to Oys5 at sequence position 83 (reienod to ns CRLR €2425¾:: Cy&amp;4 at sequence position no linked to Cysb at sequence posidon 105 (referred to m CRLR €4436). RAMP 1 portion in nmiure form of RAMPi-Fe fusion moleculwOT 20 aesds *SFO ΙΟ NO ! Π pr« memo 4». eAema Inthm. uluch also forms threeihtramoibcukr disulfide bonds. The three disulfide bonds in RAMPi are Cyal at sequence position l (all RAMFl sequehee positions listed Mthbs pa$j&amp;g&amp;ph,^^ibtfespcciAo the mature sequence nn.">enfed as SEQ ID NO: i I) linked to Cvs5 at sequence position 36 (reterred to as RAMPT C 14). Cys2 at sequence position 14 linked ίο Os s4 at sequence position 46 (referred to as 25 RAMPI C2-C4), CAM at sequenceposhion 3 i linked to Cys6 at sequence position 76 (refMftd Id as RAM Pi C3-C6) : Regions of the humda CdRF rhneptor protein bound1 by anti -CORP neutralizing1 monoclonal antibodies were identified by fragmenting n CORF R i mo nap tides wife specific proteases, and determining the sequence of rhe resulting h CORF R peptides a,#,., both, 3d: disulfide· and non-distdndn“Contatning:pbpttde togmenls for CRLR and RAMPI portions). A protease moieeuott assay was du.u perimnied in determine the pjoieolytie digestion <>fh( GRP K i n the presence of bxhd:ing .mon«clondl antibodies. The ihneral principle of this sssay is that binding: of a mAh to CGRP R. can. result in pnrtegf idp pimOtain. specific protease cleavage sites ami this inlottrtatleu can be used to del ermine the region or portion, of GQRFit where the m2

Briefly, the peptide digests wet e subjected to BPt.C peptide mappiPgittic individual peaks ware collected* tuM the peptides identified and mapped by on-line electrospray 2016244220 11 Oct 2016

ioffis&amp;tioa EC-MS CESI%£>AtSt analyses and/or by All HI analyses higthese studies were performed using a .«arrow bore roversc-phasc CHS o using a capiUary reverse phase GIB eo knnn (0.5rum Ld. a 25 cm Vydae C IS MS, .5 pm; The Separation Group) for LC-MS, FfPEC peptide mapping was performed with a linear gradient IQ from 0.05%!rlfluemacefie actd (tpobi! e phase A.) to 90% acetonitrile ίο 0,05% trifluoroncetis. acid. Columns were developed pverjsfi !) minutes at a flow rate of 0..25 ml/mirs for narrow horn 11PLC' for off-line or on-hue 1 ,€~M8 a. nalvSes, and 0,01S ssl/fnin for capillary HF1.X2 ior ou- (. -MS analyses.

Mature term mmiau yGRf R s fwlnch cleaves: after aspartic IS : aci d and home glutamic acid residues K at I.Q mgirnl in 0.1M sodium phospi pgof CClRP ndetpH 6.5) fdr2Q hrs at 37°C With 2 pg oCAspHi HRLG chromatography of the / VspK digests gederaidd a peptide profile: as ahowo in Fig,rid (each^sample 3Qgg injected), e aromatogtam labeled A for CORF R alone (concentration 1 mg/ml), while' a contr oi digestion with a similar amount of CORF R IQ ueatruliantg antibody. Gone 12 Gb, she ws that the antibody is essentially resistant to A.spM endoprotelnas© (chmmaiogram iabelec B; CGRP R;a«tibody ratio. 100:2; KM):?; lR0t20,weighf by weighh respectively).: Segnettee aiialyses were emtducted by oh~! M$/M$ and by Eifrnen sequencing on the peptide peaks recovered from l iPl.C. On-line FS1 CCSMS analyses of the peptide digest < were performed to determine the precise mass and 25 sequence of the peptides that were·: sep* arated hy HFLC. The identifies of sevetai peptides present in the peptiddpeaks bmp/theX (indicated as truTubcted peaks Ini:Fig, 14), Ibbhyllk helms, shows the location's of these peptide sequencer in the eorrtsponding component (CRL R or RA MP!) of the hCGRP R. A capital letter C followed by a number or X represents a peptide identified a.\ a CRLR. peptide; a capital letter 3Q followed by a number or X is a RAMI3 1. peptide and "Fc^reprewnN the large, undigested Re Augment released Apm the CRLR-Fet md RAMP'i - Pc fbsleti molecules, : O it U* 2016244220 11 Oct 2016

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to a region ol'CRf.R which includes the C'Rl.R t ’!~C5 and CR( R C4-C'6 disulfide region together with the loop region between Cys53 and CysbG

File AspN mapping of hCGRP R also identified a RAMP1 disulfide peptide (R2) and a 14 and Mg, ,-1% In die presence of any of the 10 above-mentioned neutral rang antibodies {12Gb * !0F4\4H4, 3 86 or 3Cb), peptide R-X was recovered at a significantly what was obtained bean tbe digeattoo with no antibody in die sample. Maas and aepitpsee analyses showed that R-ot contains a single polypeptide chant corresponding to the RAMP i set|uonee iierween Cysl and ArgRb. These experiments indicate that CGRP Rneutralizing antibody can pot sect a. Significant region of 15 RAMP I from AspN proteolytic digestion.

To assess whether the protective effect of CGRP R Aspl^ proteolysis is specific to CGRP R-ueutrafofing (blocking j antibodies (as eoinpared with anti-CGRP R tx>o-oeuira!lzing antibodies), an Asplg digestion of CGRP R was performed in the presence of an unrelated control monoclonal antibody which does not neutralize CGRP R activity. The resul ts are 20 shdwtt inf ig. 15 in chromatogram D. The pbn-neutndmmg anuhndy docs nos show any Significant Mocking effect on GGRP R AspN proteolysis; indeed,foe peptide map profile |«lu«nmtograoi 13} is nearly infilstinguishabie in the relevantaspects to the profile deriyed:fiom digestion of €GRR R alette (ehtontatogram A},

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I κ·" ο a ο ζ recepiOr density). No staining was observed in the parent C 'HO cell line, OK) cells sgpresshlg. ah unrelated recomBnatn protein CpO/|ORF R ceils a|or|S'eafcsoji>:tiot? wuh the 2016244220 11 Oct 2016 corresponding 32i|T antigen, CHO ηφ· MfebOnmauliin receptor :2 ptLRtRAMP31 MCF-7 cells endogonousiy oxprcsMng amylln receptors, HJ*: ^ c:eHs expressing recombinant human adrcnorneduiHn receptor 1 lC.RI*Ri'RAMPd), or she parent FiBK ceils, 1'ltedata from these experiments are sum-rs&amp;necd in 'Table 16, below, ’l^fele ItS: oi: indicated cells

Cell line Staining intensity (visual scene) CTjH P/CBQ ;: 4t SK-N-MC H CUD 0 TRPM8CHO 0 CIORM'HO pmadsorbed o AM2:CHQ " ::-0- MCF-7 .......Ψ- AM! 11FK 0 HUK 0

All patents and other piMkr^ incorporated herein ny m for 1¾¾.phrase of eAuthpIc, tne methodotogtes described in suck ptihtlicahons'-ih&amp;t' thlgfetfJso jtpcHjip. odPPOCtion. with tne suoject maUCi disclosed herein. These publications are pmvided solely for their disclosure prior to the riling date of the present application. Nothing m thiN regard shorn ri be construed as an admission tnat the Inventors are Snieiiel^iei.such disclosure .^-yi^ie-iaFpriOEPeio^eNoSi^,^ι,ί^Γ?«a!^· li uth>, r tea sots A11 shoetneno a« to ?h< - date o< n-pruaentdmw α» to rtw eonmnn of these docuntenis is based on the information available to the appiieants and docs not constitute any admission as to the correctnessof the dams or cont^.af%^:tenotdn^.·· 163

Claims (23)

1. WHAT m CLAIMED IS: !. An fv dated aiHigendtinding protein, wherein the Isolated antigen. binding protein selectively inhibits the human CGRP receptor, "2< The isolated, antigen binding protein: of claim I, wherein the isolated, antigen binding proton; selectively inhibits the human CGRP receptor with a scIceiA ity ratio of 100 or more..
2. 3, The isolated amigen binding protein of i(aim 3, therein the isolated antigen C .dr./ nuncio selectively inhibits the hitman CGRP reccpirn vuth a sGemo η\ ratio of 500 or more., -4,. The isolated .&amp;atigea Mnding protein of claim L wherein the isolated antigen binding protein specifically hinds to liftman CCIBf R with, a ·Κ»<!00 hM,
3. 5, The isolated, antigen binding: protein of claim 4, wherein the isolated, antigen binding proton; specifically binds to human ( GRP K with a Kd fit) nM as determined using a. FAC'S binding assay,
4. 6, The isolated antigen binding protein of ehrim h wherein the isolated antigen binding protein lias a Ki of less than Hi nM m a CGRP binding competition assay.
5. 7, The isolated antigen binding protein of claim 6. wherein the isolated antigen bsndntg protent has a Ki of less than I nM in a radiolabeled :"LCGRP binning; competition assay to membranes from cells expressing human CGRP P. S fUe -.solaied emlgen-binchng proiem of claim 1, wherein the i so feed antigen binding protein competes iot binding to human ("GRP R with a reference antibody, said retlronec antibody comprising til u heavy chain variable region comprising a sequence selected from the group consisting of SL'Q II.) NOs; lb!. KG, 164, 166 and I6R; and id) a light chain variable region comprising a sequence selected bom the group consisting of SEQ If) NOs. 140. 143, 146. 148 and 130. 9 The isolated am;gen bhtiiing protein of claim K. wherein the referenee antibody comprises pi ; a heavy chain defined by a sequence selected Iron; the group consisting of ShQ ID NOs;325 34,. :35, 37 and 39; and (lif a light chain bedned. by a segnesce seleetad from the group consisting of SEQ ID NOs; IS, IS, 21, 23 and 25. ip: The:ofelainf 9, whefdinthe reference andhodE cotngnses a henry chain sne! a liglit chain deEhed by one of the fblloNingpah'S or sequences; :;BEQXBNQ;: 32andNEQlDHO; IS; SEQ IO;HO; 34 and|EgiD HO; 18;; SEQ:,X:B NO; 35 and SEQ ID NO; 21; ; SEQ £) NO' A and SEQ ID HO; 23; end; SEQ ID NO: 39 and SEQ ID HO; 23.
6. 11. All Notated «illigcn-'b;ad;ng protein comprising (A) one or mure heavy chad? coo-pDnseoiary determining reyo'-n-. ;( DR; E-> «ονοίΈ from the group eormstmu of (Da COR!·;I having SRO ID M* 134; (ii) a CPRH2 having "vEQ fD ΝΟΊ35; (hi) a if>RH3 having SEQ ID HP Lh\ and (i\ ι * CDRH of uh (in or (in,* that .contains onoyiwo^hreehr iburamino acid Mihstumions, deletions or msdrtbns; :(13} one or rndre light; chain cemplsMetriaty detdrnhnihg: regidna iCDRLs) ^looted : front the group consisting pf {i) :s;€;DliLl selected: dioxp;the group eoMleiing ofSEQID M),s Hi7, ! 1 > and 118. (m a t DRl 2 K'iePod hum the group consisting of SEQ 10 Μ Is 108, 112 end 119;·{ί«) a. CDRL3 selected from the group consisting af SEQIB NOs; 10¾ 113 and 1¾ and optionally (ivj a CORDof that ifedstaihs ortef Mo, direeor tour amino acid substitutions, deietions or insertions; or (C) one or more heavy chain C.'ORBs of (A) ami one or more light chain CDRJLs of (B) 12. ; The isolated antigen binding protein of claim 11 * wherein the CDRHs are further selected from the group consisting of; til a CDRHI having SEQ ID HO: 131; (ii) &amp; CD.RH2 having SEQ ID NO;132; tin} a CDRH3 having SEQ ID NO: 133; and <iv) a CDRH of two or throe amino acid nuhstitutipes, deietidhs or msertlonsv 13 The isolated antigen huiding rnotoin of claim 12, wherein the CDRHs are EMhsr selectedfrom the group con-onmg of til a CDRH l selected from the gmup consisting of SEQ;ID'NO.;?6s IB, 101), 131, 1 Ή and 138, (si) a CDRH2 Hdesmd faun th« group consisting of SEQ; ID HQ: 8¾ 1(11, 1.2% 124. 12m md 124; fim a ( ΗΚΠ3 selected from the group: -S.B-Q 1102, 03, 127« and 130;and (iv) a CORE of (?},(«) and (iii} dint eotualM ops(:twti or three amino apM ;sHl)gitpioBS,:de!ftsoiM or insertions. 14. %e: Isolated antigen binding protein of «!ik: 1¾. " ihti CPE®.:^ farther selected consisting of. (i) a CDRITI «selected from the group consisting of S EQ I D NO: 73, 76, /0. 82, 85, 88. 92, 07, and 100; (it) a CORNS selected Item the group Eonsi&amp;goFSEO ID NO: ?4, 77, S0, 83. BO, 1¾ 9:1(93p:%:0,. Μ, ·Μ&amp;·ί% P) * CDRE3 selected from the group consisting of ,\F,Q ID NO: 73,:782 Bl, 84, 87, 00.00,90, iti2,aod 123; and (iv) a CDRE of (ih (ii) and (hi) thatE^tlains: ohQTwo or dune ammo add substitution*)*.: deletions or insertions
7. 15. The isolated antigen binding protein of claim 11, wherein the CPREs are further selected from the group consisting of: (i> a CORE S selected from the group consisting of SEQ IP NOs:J07, 111 and 115; ui) a CORES selected from the gnutpConsisting ofSFQ TP NOs: 1.0$: 112 and I Kc (m) a ( DSD 1 selected from the group consisting m SEQ U) NTK SO*1, 113 and S1 and (tv) a CORE of ti), (ii) and (iii) that cantairts: Otup ti*o, three, or font* amino add aubsmuhons, deletions or snsertions. lb; ; The isolated antigen binding, prolein of claim IS, wherein the CORES are further selected f«. the gtt?np insisting of SEQ IDNOs; 42, 45, 51,57, 62,60, 1(13, and Π0; (ii) a CPRE2 selected Boot the gtoup consisting of SEQ ID-140$: %52, 55,58, 63, 70, 104, SOB, and .1S4; (hi) a CORES selected from the group consisting of SEQ ID NOs: 44, 47, 53, 56, 59, 64, 105.. and 106; ami (iv) a CORE of (i), (ii) and (Iii:) that contains one, two or three amino add substitutions, deletions or insertions.
8. 17, The isolated antigen binding protein of claim 16, wherein the CDRLs are farther selected ikon thegtonp consisting of (IfaQDRLl selected front the group consisting of SEQ SO NOs: 42, 45, 48, 5f, 54, 57, 62, 65, 66, and 69; lii) a CDRL2 selected Com the group consisting of SEQ IP ISOs: 43, 46, 49, 52, 55, 58, 61, 63, 67, and 70; (iti) a CDRT 3 sdected from the group consisting of SEQ ID NOs; 44, 47, 50, 53, 56., 59, 64, 68, 71, and ?2; and (?v) a CDRE of (0, (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions. IB. 1'he isolated antigen binding protein of any of claims 11 ~ 17, wherein the Isolated anti gendBnding protein comprises at least one CORE and at least one CORE, 1.9, p>feJsft!ate4 antigen hmdmg ptotem of claim IK whemm itfePoland l>mdiag f mtK» com|jriMS at least two CDRB and at feast two C'DRl.
9. 20. The isoktod antigen binding protein of auy of claims if - 19. wherein the isolated sansgen-bsnding protons con sprigs a CDR ΗI. a CDRRl a CDRH3. a C.DR.LS, a CDRL2 and a CDRI.J,
10. 21. An isolated antigen-binding protein comprising a heavy chain variable regioo ( V'ij) sequence that has at !c.«d 90% sequence Identity with art amino acid^ tqqnenoe Meotdd from tbo group consisting ol'SF.Q ID NOs :)58-170,
11. 22. An isolated antigen-binding protein dbpipririsig a light, chain variable region {Vf] sequence that, tea at feast sequqoee identity wifi an amino acid sequeneq sbledfed: ihirn tl-ίό group consisting of SEQ ID M(>&amp;:, 13 7«! S3.
12. 23. An isolated antigen-bindi ng protons comprising a Vf sequence that Isas at least 90% seqstence identity with an amino acid sequence selected frosn the group consisting of SEQ ID NO»: :l5fe fS9ptetd 102-172, apd a % sequsstoo fhat has at least 90% sequence identity with ats ammo acid sequence .selected from the group consisting of SEQ ID NOs: 137, .138, '^14%d48-l51,aiii5341S7. ::24, lilfe isolated antigen binding -of clafe. 1 - 23y whqfein the iisbfepi: l.^'jpa.“hii)fiidistg protein is selected flout the group consisting Of a mbaeoloteT antibody, a Fab fragment an Fab* imgmm%: an 17¾y:|fagmdn:f; an Fv fragment, a diabody, and a single chain antibody
13. 25. The Isolated antigen. binding protein of claim 24, xvheroro thedsolaietl antigen-’binding protein, is a monoclonal amibody ncIccosI from die gr$up cosisisiusg of a fully Ifumau uni!body*« fesmanfeed and body and a chi men e antibody.
14. 26. Tbo isolated ami gen binding protein of claim 25, wherein the monoclonal lgG3~, or lgG4-type atHtbody,
15. 27. The isolated antigen binding protein of claim 26, wherein the monoclonal antibody is an IgG I or 3gG2 antibody. ,1:18. An isolated auefeie acid polynucleotide that encodes an anfigsm-biadiag; protein ; of any of claims b>27. 29. 'life: kolated tmfeleie:acid. ''·0;ί" 28>: kUfeidia. the poIpaM^iidt' c$m|Sgihea a .sequence that is. 80% or more identical svith a sequence selected I from th< i group ronsbaing of SEQ ID NOs:t?5, i?6, 178, 11% 180, 181, 182, 183, 184 W% lEBklm if l, 1¾ 193. 194. 195, 196, 19?, 20«. 20 L 202, 203. 204, 205, 206, 207. 208, 209 and .240. 30. :The isolated:: nucleic acid polymscledttdc of claim 20, Aherem the polynucleotide comprises a sequence that is X0% or .more identical with a sequence selected : shorn the ipoup conStpug of SbQ ID NOs:2:24-258.
16. 31. The isolated nucleic acid polynucleotide of claim 28, wherein the ^l^udifepiii# comprises a sequence capable of hybridizing under »utngervt hybridation conditions-with a sequence selected iroro lie group copsisting of SI: Q iD NO,-5:224-258,
17. 32. An expresioh vector ebnrpr istug;an. isolated polynucleotide of any ,ρί claims: 28-31. 33: : A/eell line transformed with expression vector iof claim IS,
18. 34, A method of Making: an antigen-binding protein of any of claims 1 -27, comprising propariog the antigen: binding protein from a host efeU that Sfecretes the antigen-binding protein,

    33. The method of claim 34, wherein said antigeo binding protein is generated using an immunogen comprising sol able CORF receptor,
19. 36. The method of felaim 33, wherein said soluble CGRP roeeptor is obtained by co- ; expressing and purifying an N-tferrofflabextraeclInlar domain (ECD) of.human CRLR and an ECO of human RAMP!.

    32. The method, of claim 36, wherein said ECD of human GRLIy comprises SEQ ID NO: 6 and $aid ECP of RAMP] comprises SEQ ID NO: X.
20. 38. A pmomatxniit d -. (.imposition comprising an antigen binding protein of any of claims i-27 and a phiemaccutH.aU> acceptable exciptunt:
21. 39, A metiiod for vreaiing a condition associated with CGRP R in a patient, eonrpbsing adoumsteoug to a patient an effective amount, of an isolated antigen-binding protom of any of claims 1-27.
22. 49. The method of oIMm- 39, -wtetift the oonditlim k headache, 4] < The ihe£h«d. of ύύί&amp; 99, wherein the coMitlp je
23. 42, The oiedtod of any of claims 39 m 41, wherein the method eoinprises frrofdiylaeho ireatmeot,