AU2018203471A1 - 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

BACKGROUND

The instant application contains a Sequence Listing which has been submitted via

EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 14, 2009, is named A1472PCT.txt, and is 312,447 bytes in size.

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

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

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

2018203471 16 May 2018 the CGRP family. (Katafuchi, T and Minamino, N, Structure and biological properties of three calcitonin receptor-stimulating peptides, novel members ofthe calcitonin generelated peptide family, Peptides, 25(11):2039-2045 (2004)). _ la

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The calcitonin superfamily peptides act through seven-transmembrane-domain Gprotein-coupled receptors (GPCRs). The calcitonin receptor (“CT”, “CTR” or “CT receptor”) and CGRP receptors are type II (family B) GPCRs, which family includes other GPCRs that recognize regulatory peptides such as secretin, glucagon and vasoactive intestinal polypeptide 5 (VIP). The best characterized splice variants of human calcitonin receptor differ depending on the presence (formerly CTRn, or CTR1, now known as CT_(b)) or absence (the major splice variant, formerly CTRn_ or CTR₂, now known as CT_(aj) of 16 amino acids in the first intracellular loop. (Gorn et al., Expression of two human skeletal calcitonin receptor isoforms cloned from a giant cell tumor of bone: the first intracellular domain modulates ligand binding 10 and signal transduction, J. Clin. Invest., 95:2680-2691 (1995); Hay et al., Amylin receptors: molecular composition and pharmacology, Biochem. Soc, Trans., 32:865-867 (2004); Poyner et al., 2002). The existence of at least two CGRP receptor subtypes had been proposed from differential antagonist affinities and agonist potencies in a variety of in vivo and in vitro bioassays. (Dennis ct al., CGRP8-37, A calcitonin gene-related peptide antagonist revealing 15 calcitonin gene-related peptide receptor heterogeneity in brain and periphery, J. Pharmacol. Exp. Thcr,, 254:123-128 (1990); Dennis et ah, Structure-activity profile of calcitonin generelated peptide in peripheral and brain tissues. Evidence for multiplicity, J. Pharmacol. Exp. Ther., 251:718-725 (1989); Dumont et aL, A potent and selective CGRP2 agonist, [Cys(Et)2,7]hCGRP: comparison in prototypical CGRPi and CGRP2 in vitro assays, Can. J.

Physiol. Pharmacol., 75:671-676 (1997)).

The CGRPi receptor subtype was found to be sensitive to the antagonist fragment CGRP(8-37). (Chiba et al., Calcitonin gene-related peptide receptor antagonist human CGRP(8-37), Am. J. Physiol., 256:E331-E335 (1989); Dennis et al. (1990); Mimeault etal., 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.

Pharmacol. Exp. Ther., 258:1084-1090 (1991)). By contrast, the CGRP₂ receptor was sensitive to linear human CGRP (hCGRP) analogs, in which the cysteine residues at positions 2 and 7 were derivatized (e.g., with acetoaminomethyl [Cys(ACM)²’⁷] or cthylamide [Cys(Et)²'⁷]) but CGRP₂ receptor was insensitive to fragment CGRP(8-37). (Dennis et al. (1989); Dennis et al. 30 (1990); Dumont et al. (1997)).

Ligand specificity of calcitonin receptor and calcitonin-like receptor (“CL”, “CLR” or “CRLR”) depend on the co-expression of members of a family of accessory proteins called the receptor activity modifying proteins (RAMPs). The RAMP family includes three polypeptides (RAMP1, RAMP2 and RAMP3) that act as receptor modulators that determine the ligand

2018203471 16 May 2018 specificity of receptors for the calcitonin family members. RAMPs are type J transmembrane proteins that share about 30% amino acid sequence identity and a common predicted topology, with short cytoplasmic C-termini, one trans-membrane domain and large extracellular Ntermini that are responsible for the specificity. (McLatchie et al., (1998) RAMPs regulate the 5 transport and ligand specificity of the calcitonin-rcceptor-like receptor, Nature, 393:333-339; Fraser et al., (1999) The amino terminus of receptor activity modifying proteins is a critical determinant of glycosylation state and ligand binding of calcitonin receptor-like receptor, Molecular Pharmacology, 55:1054-1059).

In 1998, the C'GRPi receptor was identified as a heterodimer composed of a novel single transmembrane domain accessory protein, receptor activity-modifying protein I (RAMPl), and CRLR. (McLatchie et al., supra). Cross-linking experiments suggested the CORP receptor consisted of a one-to-one stoichiometric arrangement of CRLR and RAMP1 (Hilairet et al, JBC 276,42182-42190 (2001)), more recent studies using several methodologies such as BRET and BiFC revealed that the functional CGRP receptor complex may be composed of asymmetric homo-oligomer of CRLR and monomer of RAMP 1 (Heroux et al. JBC 282, 31610-31620 (2007)).

A purified CRLR N-terminal domain has been shown to specifically bind ¹²⁵I-CGRP (Chauhan et al. Biochemistry 44, 782 (2005)), confirming the important and direct interaction between the CRLR with CGRP ligand. In particular, Leu 24 and Leu 34 of CRLR are believed to constitute the docking site of the C-terminus Phc37 of CGRP (Banerjee et al. BMC

Pharmacol. 6, 9 (2006)). Furthermore, Koller et al. (FEBS Lett. 531, 464-468 (2002)) obtained evidence that that the N-terminal 18 amino acid residues of CRLR contributes the selective interaction with CGRP or adrenomedullin, and I finer et al (Biochemistry 44, 5749- 5754 (2005)) suggested that the N-terminal amino acid residues 23- 60 of CRLR mediate association with RAMP I.

A structure-function analysis of RAMP I identified residues 91-103, which correlate to “helix 3” (Simms et al. Biophys. J. 91, 662 - 669 (2006)), as potentially significant in interaction with CRLR, and residues Trp74 and Phe92 as potentially interacting with the CGRP ligand in connection with its binding to the CGRP receptor complex. Ligand binding studies using a human/rat RAMP 1 chimera suggest that the binding site for certain small molecule inltibitors of CGRP R (e.g., BIBN4096BS), is located within a region which includes amino acids 66-102 of RAMP 1 (Mallee et al. JBC 277, 14294- 14298 (2002)).

CRLR has 55% overall amino acid sequence identity with CTR, although the transmembrane domains arc almost 80% identical. (McLatchie et al, (1998); Poyner et al.,

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International union of pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin and calcitonin receptors, Pharmacol. Rev., 54:233-246 (2002)).

CRLR has been shown to form a high affinity receptor for CGRP, when associated with 5 RAMP I, or. to preferentially bind adrenomedullin when associated with RAMP2 or RAMP3. (McLatchie et al. (1998); Sexton et al., Receptor activity modifying proteins. Cellular Signaling, 13:73-83 (2001); Conner et al., Interaction of calcitonin-gene-rclatcd peptide with its receptors, Biochemical Society Transactions 30(Part 4): 451-454 (2002)). The glycosylation state of CRLR is associated with its pharmacology. RAMPs 1, 2, and 3 transport CRLR to the 10 plasma membrane with similar efficiencies, however RAMP1 presents CRLR as a terminally glycosylated, mature glycoprotein and a CGRP receptor, whereas RAMPs 2 and 3 present CRLR as an immature, core glycosylated adrenomedullin receptor (“AM” or “AMR” or “AM receptor”. (Fraser et al. (1999)). Characterization of the CRLR/RAMP2 and CRLR/RAMP3 receptors in HEK293T cells by radioligand binding (^l2:,I-adrenomcduilin as radioligand), functional assay (cAMP measurement), or biochemical analysis (SDS-polyacrylamide gel electrophoresis) revealed them to be indistinguishable, even though RAMPs 2 and 3 share only 30% amino acid sequence identity. (Fraser et al. 1999)). Differences have been observed, however, in the pharmacology for CRLR expressed with RAMP 2 versus RAMP 3. Both CGRP and CGRP8-37, as well as adrenomedullin and the adrenomedutlin-derived peptide AM 20 22-52, are active at the RAMP 3 hetcrodimer, indicating that this complex may act as both a

CGRP and an AM receptor. (Howitt et al., British Journal of Pharmacology, 140:477-486 (2003); Muff et al., Hypertens. Res., 26:S3-S8 (2003)), Co-expression of human CRLR with rat RAMP1, and vice versa, suggested that the RAMP1 species determined the pharmacological characteristics of the CRLR/RAMP1 complex with respect to several small 25 molecule CGRP receptor antagonists tested. (Malice et ah, Receptor Activity-Modifying

Protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists, J. Biol. Chem., 277( 16): 14294-14298 (2002)), Unless associated with a RAMP, CRLR is not known to bind any endogenous ligand; it is currently the only GPCR thought to behave this way.

(Conner et al,, A key role for transmembrane prolines in calcitonin receptor-like agonist 30 binding and signaling; implications for family B G-protein-coupled receptors, Molec. Pharmacol,, 67(1):20-31 (2005)).

Calcitonin receptor (CT) has also been demonstrated to form heterodimeric complexes with RAMPs, which are known as amylin receptors (“AMY”, “AMY R or “AMY receptor”). Generally, CT/RAMP1 receptors (referred to as “AMY|” or “AMYI”) have high affinity for

2018203471 16 May 2018 salmon calcitonin, amylin and CGRP and lower affinity for mammalian calcitonins. For CT/RAMP2 receptors (“AMY₂ or “AMY2”) and CT/RAMP3 receptors (“AMY₃” or “AMY3”), a similar pattern is principally observed, although the affinity for CGRP is lower and may not be significant at physiologically relevant ligand concentrations. The precise 5 receptor phenotype is dependent on cell type and CTR splice variant (CT(_aJ or CT(_bj), particularly for RAMP2-generated amylin receptors. For example, a pure population of osteoclast-like cells reportedly expressed RAMP2, CTR, and CRLR, but not RAMP1 or RAMP3, (Hay et al, (2004)* Christopoulos et al,_} Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product, Molecular 10 Pharmacology, 56:235-242 (1999); Muff et al., An amylin receptor is revealed following cotransfection of a calcitonin receptor with receptor activity modifying proteins-1 or -3, Endocrinology, 140:2924-2927 (1999); Sexton et al. (2001); Leuthauser et al., Receptoractivity-modifying protein 1 forms heterodimers with two G-protein-coupIed receptors to define ligand recognition, Biochem. J., 351:347-351 (2000); Tilakaratne et al., Amylin receptor 15 phenotypes derived from human calcitonin rcceptor/RAMP co-expression exhibit pharmacological differences dependent on receptor isoform and host cell environment, J. Pharmacol. Exp. Ther., 294:61-72 (2000); Nakamura et ah, Osteoclast-like cells express receptor activity modifying protein 2: application of laser capture microdissection, J. Molec. Endocrinol., 34:257-261 (2005)).

Table 1, below, summarizes the relationship of the receptor components discussed above.

Table 1

Receptor Component	CRLR (CL)	CT (calcitonin receptor)
RAMP 1 ;	CGRP receptor	AMY! receptor
RAMP2	AM I receptor	AMY2 receptor
RAMP3	AM2 receptor	AMY3 receptor

Therapeutic uses of CGRP antagonists have been proposed. Noda et al. described the 25 use of CGRP or CGRP derivatives for inhibiting platelet aggregation and for the treatment or prevention of arteriosclerosis or thrombosis. (EP 0385712 BI), Liu et al, disclosed therapeutic agents that modulate the activity of CTR, including vehicle-conjugated peptides such as calcitonin and human aCGRP. (WO 01/83526 A2; US 2002/0090646 Al), Vasoactive CGRP peptide antagonists and their use in a method for inhibiting CGRP binding to CGRP receptors

2018203471 16 May 2018 were disclosed by Smith et al,; such CGRP peptide antagonists were shown to inhibit CGRP binding to coronary artery membranes and to relax capsaicin-treated pig coronary arteries. (U.S. Pat. No. 6,268,474 BI; and U,S, Pat. No. 6,756,205 B2), Rist et al. disclosed peptide analogs with CGRP receptor antagonist activity and their use in a drug for treatment and 5 prophylaxis of a variety of disorders. (DE 19732944 A1).

CGRP is a potent vasodilator that has been implicated in the pathology of a number of vasomotor symptoms, such as all forms of vascular headache, including migraines (with or without aura) and cluster headache. Durham, N, Engl, J. Med. 350:1073-1 075, 2004.

Migraine pathophysiology involves the activation of the trigeminal ganglia, where CGRP is 10 localized, and CGRP levels significantly increase during a migraine attack. This in turn, promotes cranial blood vessel dilation and neurogenic inflammation and sensitization, (Doods, H., Curt, Opin. Investig. Drugs, 2:1261-1268 (2001)). Further, the serum levels of CGRP in the external jugular vein are elevated in patients during migraine headache. Goadsby et al., Ann. Neurol. 28:183-7, 1990. Intravenous administration of human ci-CGRP induced 15 headache and migraine in patients suffering from migraine without aura, supporting the view that CGRP has a causative role in migraine (Lassen ct al, Cephalalgia 22:54-61,2002),

Migraine is a complex, common neurological condition that is characterized by severe, episodic attacks of headache and associated features, which may include nausea, vomiting, sensitivity to light, sound or movement. In some patients, the headache is preceded or 20 accompanied by an aura. The headache pain may be severe and may also be unilateral in certain patients. Migraine attacks are disruptive to daily life. In US and Western Europe, the overall prevalence of migraine sufferers is 11% of the general population (6% males; 15-18% females). Furthermore, the median frequency of attacks in an individual is 1.5/month. While there are a number of treatments available to alleviate or reduce symptoms, preventive therapy 25 is recommended for those patients having more than 3-4 attacks of migraine per month.

Goadsby, ct al. New Engl. J. Med. 346(4): 257-275, 2002. Some migraine patients have been treated with topiramate, an anticonvulsant that blocks voltage-dependent sodium channels and certain glutamate receptors (AMPA-kainate), potentiates GABA-A receptor activity, and blocks carbonic anhydrase. The relatively recent success of serotonin 5HT-I B/1D and/or 5HT30 la receptor agonists, such as sumatriptan, in some patients has led researchers to propose a serotonergic etiology of the disorder. Unfortunately, while some patients respond well to this treatment, others are relatively resistant to its effects.

Possible CGRP involvement in migraine has been the basis for the development and testing of a number of compounds that inhibit release of CGRP (e.g., sumatriptan), antagonize

2018203471 16 May 2018 at the CGRP receptor (e.g., dipeptide derivative BIBN4096BS (Boehrirtger Ingelheim); CGRP(8-37')), or interact with one or more of receptor-associated proteins, such as, RAMP1. Brain, S. et al., Trends in Pharmacological Sciences 23:51-53,2002. Alpha-2 adrenoceptor subtypes and adenosine Al receptors also control (inhibit) CGRP release and trigeminal 5 activation (Goadsby ct al.. Brain 125:1392- 401,2002). On the other hand, treatment with compounds that exclusively inhibit neurogenic inflammation (e.g., tachykinin NKI receptor antagonists) or trigeminal activation (e.g., 5HT10 receptor agonists) appears to be relatively ineffective as acute treatments for migraine, leading some to question whether inhibiting release of CGRP is the basis of effective anti-migraine treatments. Arulmani et ah, Eur. J.

Pharmacol. 500:315-330, 2004.

Although the precise pathophysiology of migraine is not yet well understood, the therapeutic use of CGRP antagonists and CGRP-targeting ap tamers has been proposed for the treatment of migraine and other disorders. (E.g., Olesen et ah, Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine, New Engl. J. Med,,

350:1104-1110 (2004); Perspective: CGRP-reccptor antagonists—a fresh approach to migraine,

New Engl. J. Med., 350:1075 (2004); Vater et ah, Short bioactive Spiegclmers to migraineassociated calcitonin gene-related peptide rapidly identified by a novel approach: tailoredSELEX, Nuc. Acids Res., 31(21 el30): 1-7 (2003); WO 96/03993). Further, a potent smallmolecule CGRP antagonist has been shown to relieve moderate-to-severe migraine attacks, including migraine pain and migraine-associated symptoms, in a recent Phase III clinical trial (Connor, et al. Efficacy and Safety of telcagepant (MK-0974), a Novel Oral CGRP Receptor Antagonist, for Acute Migraine Attacks. Poster, European Headache and Migraine Trust International Congress, London, England, September 2008).

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

SUMMARY

Isolated antibodies, antigen-binding fragments thereof and other isolated antigenbinding proteins that bind CGRP R, particularly primate CGRP R, e.g., human CGRP R, are described herein. Such isolated antigen-binding proteins may selectively inhibit primate CGRP R (as compared with primate AM 1, AM2, CT or amylin receptors), and may bind both

2018203471 16 May 2018 the CRLR and RAMP1 components of CGRP R. The CGRP R binding proteins were found to inhibit, interfere with, or modulate at least one of the biological responses related to CGRP R, and as such, are useful for ameliorating the effects of CGRP R-related diseases or disorders. Binding of certain antigen-binding proteins to CGRP R can, therefore, have one or more of the 5 following activities: inhibiting, interfering with, or modulating CGRP R, inhibiting vasodialation, decreasing neurogenic inflammation, and alleviating, ameliorating, treating, preventing, or reducing symptoms of chronic pain or migraine.

In one exemplary aspect, the isolated antigen-binding proteins selectively inhibit human CGRP receptor (as compared with the human AMI, AM2 or amylin receptors). In some 10 embodiments, the isolated antigen binding protein selectively inhibits the hitman CGRP receptor with a selectivity ratio of 50 or more, 75 or more, 100 or more, 150 or more, 200 or more, 250 or more, 300 or more, 400 or more, 500 or more, 750 or more or 1,000 or more. The degree of selective inhibition may be determined using any suitable method, e.g., using a cAMP assay as described in the Examples herein. In some embodiments, the isolated antigen binding protein 15 specifically binds to both human CRLR and human RAMP1, and docs not specifically bind to human AM 1, human AM2 or a human amylin receptor (e.g., AMY1 or AMY2). For example, the isolated antigen binding protein may specifically bind human CGRP R with a Kd<1 μΜ, <100 nM, <10 nM, or <5 nM. In some embodiments, the isolated antigen binding protein specifically binds to human CGRP R with a Ko<100 nM, <10 nM, or <5 nM as determined 20 using a FACS binding assay and analyzed, for example, using methods described in

Rathanaswami, et al., Biochemical and Biophysical Research Communications 334 (2005) 1004-1013. In some embodiments, the isolated antigen binding protein has a Ki of <100 nM, <10 nM, <1 nM, <0.5 nM or <0.1 nM in a CGRP binding competition assay. In some embodiments, the isolated antigen binding protein has a Ki of <100 nM, <50 nM, <20 nM, <10 25 nM, <1 nM, <0.5 nM or <0.1 nM in a radiolabeled ^l25I-CGRP binding competition assay to membranes from cells expressing human CGRP R, for example, the assay described in Example 5 herein.

In another exemplary aspect, the isolated antigen-binding proteins compete for binding to human CGRP R, e.g., the extracellular portion of CGRP R, with a reference antibody comprising a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NO: 15 8-170 and a light chain variable region comprising a sequence selected from the group consisting of SEQ ID NO: 137-153. In some embodiments, binding competition is assessed using a binning assays, e.g., using a Biacore analysis, for example, as described in Example 7 herein. In some embodiments, the isolated antigen binding protein

2018203471 16 May 2018 competes for binding to human CGRP R with a reference antibody, the reference antibody comprising (i) a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs:161, 163, 164, 166 and 168; and (ii) a light chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs: 140, 143, 146, 148 5 and 150. In certain embodiments, the reference antibody comprises (i) a heavy chain defined by a sequence selected from the group consisting of SEQ ID NOs:32, 34, 35, 37 and 39; and (ii) a light chain defined by a sequence selected from the group consisting of SEQ ID NOs: 15,

18, 21,23 and 25. In more specific embodiments, the reference antibody comprises a heavy chain and a light chain defined by one of the following pairs of sequences; (i) SEQ ID NO: 32 10 and SEQ ID NO: 15; (ii) SEQ ID NO: 34 and SEQ ID NO: 18; (iii) SEQ ID NO: 35 and SEQ ID NO; 21; (iv) SEQ ID NO: 37 and SEQ ID NO: 23; and (v) SEQ ID NO: 39 and SEQ ID NO: 25, In one such embodiment, the reference antibody comprises a heavy chain comprising SEQ ID NO: 32 and a light chain comprising SEQ ID NO: 15. In another such embodiment, the reference antibody comprises a heavy chain comprising SEQ ID NO: 34 and a light chain 15 comprising SEQ ID NO: 18. In another such embodiment, the reference antibody comprises a heavy chain comprising SEQ ID NO: 35 and a light chain comprising SEQ ID NO: 21. In another such embodiment, the reference antibody comprises a heavy chain comprising SEQ ID NO: 37 and a light chain comprising SEQ ID NO: 23. In another such embodiment, the reference antibody comprises a heavy chain comprising SEQ ID NO: 39 and a light chain 20 comprising SEQ ID NO: 25.

In certain embodiments, the isolated antigen-binding proteins that compete for binding to human CORP R also selectively inhibit the human CORP receptor, e.g., with a selectivity ratio of 100 or more, 250 or more, 500 or more, 750 or more, 1,000 or more, 2,500 or more, 5,000 or more or 10,000 or more, and such selectivity may be determined, e.g., using a cAMP assay as described in the Examples herein. In related embodiments, the isolated antigen-binding proteins that compete for binding to human CGRP R specifically binds to human CORP R with a KriSl μΜ, <100 nM, <10 nM, or <5 nM, e.g., as determined using a FACS binding assay and analyzed, for example, using methods described in Rathanaswami, et a!.. Biochemical and Biophysical Research Communications 334 (2005) 1004-1013. In related embodiments, the isolated antigen-binding proteins that compete for binding to human CGRP R have a Ki of <1 00 nM, <10 nM, <1 nM, <0.5 nM or <0.1 nM in a CGRP binding competition assay, e.g., in a radiolabeled ^l2il-CGRP binding competition assay to membranes from cells expressing human CGRP R, for example, the assay described in Example 5 herein.

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In any of the above-mentioned embodiments, the isolated antigen-binding protein that competes for binding to human CGRP R may be, for example, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human (e.g., fully human) antibody, a humanized antibody, a chimeric antibody, a multi-specific antibody, or an antigen binding fragment thereof.

Further, the antibody fragment of the isolated antigen-binding protein that competes for binding to human CGRP R can be a Fab fragment, and Fab' fragment, an F(ab'fr fragment, an Fv fragment, a diabody or a single chain antibody molecule; and may be, for example, a human monoclonal antibody, e.g., an IgG 1-, IgG2-, IgG3-, or IgG4-type antibody. In certain embodiments, the isolated antigen binding proteins that compete for binding to human CGRP R 10 may be neutralizing 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 chain complementary determining regions (CDRHs) selected from the group consisting of; (i) a CDRH1 having SEQ ID NO:134; (ii) aCDRH2 having SEQ ID NO: 135; (iii)aCDRH3 15 having SEQ ID NO; 136; and optionally (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions that collectively total no more than four amino acids; (B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs: 107, 111 and 118; (ii) a CDRL2 20 selected from the group consisting of SEQ ID NOs; 108, 112 and 119; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 109, 113 and 120; and optionally (iv) a CDRL of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more, amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions that collectively total no more than four amino acids; or (C) one or more heavy chain CDRHs of 25 (A) and one or more light chain CDRLs of (B).

In some embodiments, the CDRHs are further selected from the group consisting of: (i) a CDRH I having SEQ ID NO: 131; (ii) a CDRH2 having SEQ ID NO; 132; (iii) a CDRH3 having SEQ ID NO: 133; and optionally (iv) a CDRH of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid 30 substitutions), deletions or insertions that collectively total no more than three amino acids. In related embodiments, the CDRHs are further selected from the group consisting of; (i) a CDRH1 selected from the group consisting of SEQ ID NO :76, 88, 100, 121, 125 and 128; (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 89, 101, 122, 124, 126, and 129;

(iii) a CDRH3 selected from the group consisting of SEQ ID NO: 78, 90, 102, 123, 127, and

2018203471 16 May 2018

130; and optionally (iv) a CDRH of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions that collectively total no more than two amino acids. In other related embodiments, the CDRHs are further selected from the group consisting of: (i) a CDRH I 5 selected from the group consisting of SEQ ID NO: 73, 76, 79, 82, 85, 88, 92, 97, and 100; (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 74, 77, 80, 83, 86, 89, 91, 93, 95, 98, 101, and 129; (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 75, 78, 81, 84, 87, 90, 96, 99, 102, and 123; and optionally (iv) a CDRH of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative 10 amino acid substitutions), deletions or insertions that collectively total no more than two amino acids.

In some embodiments, the C'DRLs are further selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs;107, 111 and 115; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 108, 112 and 116; (iii) a CDRL3 selected 15 from the group consisting of SEQ ID NOs: 109, 113 and 117; and optionally (iv)a CDRL of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In some embodiments, the amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions collectively total no more than three amino acids per CDRL. In some 20 embodiments, the amino acid substitutions, deletions or insertions collectively total no more than two amino acids per CDRL, In related embodiments, the C'DRLs are further selected from the group consisting of; (i) a CDRL1 selected from the group consisting of SEQ ID NOs: 42, 45, 51, 57, 62, 69, 103, and 110; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 43, 52, 55, 58, 63, 70, 104, 108, and 114; (iii) a CDRL3 selected from the group 25 consisting of SEQ ID NOs: 44, 47, 53, 56, 59, 64, 105, and 106; and optionally (iv) a CDRL of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions that collectively total no more than two amino acids. In additional related embodiments, the CDRLs are further selected from the group consisting of: (i) a CDRL I selected from the group 30 consisting of SEQ ID NOs: 42, 45, 48, 51,54, 57, 62, 65, 66, and 69; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 43,46, 49, 52, 55, 58, 61,63, 67, and 70; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 44,47, 50, 53, 56,59, 64, 68, 71, and 72; and optionally (iv) a CDRL of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions),

2018203471 16 May 2018 deletions or insertions. In one embodiment, the total number of amino acid substitutions, deletions or insertions is no more than two amino acids per CDR. Jn another embodiment, the amino acid substitutions are conservative substitutions.

In another embodiment, the isolated antigen-binding protein comprises at least one or 5 two CDRH of any of the above-mentioned (A) and at least one or two CDRL of any of the above-mentioned (B). In yet another embodiment, the isolated antigen-binding protein comprises (i ) at least three CDRH of any of the above-mentioned (A), where the three CDRHs include CDRH 1, a CDRH2 and a CDRH3, and (ti) at least three CDRL of any of the abovementioned (B), where the three CDRLs include CDRL1, a CDRL2 and a CDRL3. In 10 additional embodiments, the isolated antigen binding proteins described above comprise a first amino acid sequence comprising at least one CDRH and a second amino acid sequence comprising at least one CDRL. In one embodiment, the first and the second amino acid sequences arc covalently bonded to each other.

In another aspect, the isolated antigen-binding protein includes a CDRH 1, a CDRH2 15 and a CDRH3. In one embodiment, CDRH! comprises SEQ ID NO:73, CDRH2 comprises SEQ ID NO:74 and CDRH3 comprises SEQ ID NO:75. In another embodiment, CDRH1 comprises SEQ ID NO:76, CDRH2 comprises SEQ ID NO:77 and CDRH3 comprises SEQ ID NO:78. In another embodiment, CDRHI comprises SEQ ID NO:79, CDRH2 comprises SEQ ID NO:80 and CDRH3 comprises SEQ ID NO:81. In another embodiment, CDRHI comprises 20 SEQ ID NO;82, CDRH2 comprises SEQ ID NO:83 and CDRH3 comprises SEQ ID NO:84. In another embodiment, CDRH! comprises SEQ ID NO:85, CDRH2 comprises SEQ ID NO:86 and CDRH3 comprises SEQ ID NO:87. In another embodiment, CDRH 1 comprises SEQ ID NO:88, CDRH2 comprises SEQ ID NO:89 and CDRH3 comprises SEQ ID NO:90. In another embodiment, CDRHI comprises SEQ ID NO:76, CDRH2 comprises SEQ ID NO:91 and 25 CDRH3 comprises SEQ ID NO;78. In another embodiment, CDRHI comprises SEQ ID

NO:92, CDRH2 comprises SEQ ID NO:93 and CDRH3 comprises SEQ ID NO:94. In another embodiment, CDRHI comprises SEQ ID NO:76, CDRH2 comprises SEQ ID NO:95 and CDRH3 comprises SEQ ID NO:78. In another embodiment, CDRH 1 comprises SEQ ID NO:73, CDRH2 comprises SEQ ID NO:74 and CDRH3 comprises SEQ ID NO:96. In another 30 embodiment, CDRH 1 comprises SEQ ID NO:97, CDRH2 comprises SEQ ID NO:98 and CDRH3 comprises SEQ ID NO;99. In another embodiment, CDRH 1 comprises SEQ ID NO: 100, CDRH2 comprises SEQ ID NO: 101 and CDRH3 comprises SEQ ID NO: 102.

In another aspect, the isolated antigen-binding protein includes a CDRL1 sequence, a CDRL2 sequence and a CDRL3 sequence. In one embodiment, CDRL1 comprises SEQ ID

2018203471 16 May 2018

NO:42, CDRL2 comprises SEQ ID NO:43 and CDRL3 comprises SEQ ID NO:44. In another embodiment, CDRLI comprises SEQ ID NO:45, CDRL2 comprises SEQ ID NO:46 and CDRL3 comprises SEQ ID NO:47. In another embodiment, CDRLI comprises SEQ ID NO:48, CDRL2 comprises SEQ ID NO:49 and CDRL3 comprises SEQ ID »0:50. In another 5 embodiment, CDRL1 comprises SEQ ID NO:51, CDRL2 comprises SEQ ID NO:52 and CDRL3 comprises SEQ ID NO:53. In another embodiment, CDRLI comprises SEQ ID NO:54, CDRL2 comprises SEQ ID NO:55 and CDRL3 comprises SEQ ID NO:56. In another embodiment, CDRLI comprises SEQ ID NO;57, CDRL2 comprises SEQ ID NO:58 and CDRL3 comprises SEQ ID NO:59. In another embodiment, CDRLI comprises SEQ ID 10 NO:60, CDRL2 comprises SEQ ID NO:55 and CDRL3 comprises SEQ ID NO:56. In another embodiment, CDRLI comprises SEQ ID NO:45, CDRL2 comprises SEQ ID NO:61 and CDRL3 comprises SEQ ID NO:47. In another embodiment, CDRLI comprises SEQ ID NO:62, CDRL2 comprises SEQ ID NO:63 and CDRL3 comprises SEQ ID NO:64. In another embodiment, CDRLI comprises SEQ ID NO:65, CDRL2 comprises SEQ ID NO:55 and 15 CDRL3 comprises SEQ ID NO:56. In another embodiment, CDRL I comprises SEQ ID

NO:66, CDRL2 comprises SEQ ID NO:67 and CDRL3 comprises SEQ ID NO:68. In another embodiment, CDRLI comprises SEQ ID NO:69, CDRL2 comprises SEQ ID NO:70 and CDRL3 comprises SEQ ID NO:71. In another embodiment, CDRLI comprises SEQ ID NO:69, CDRL2 comprises SEQ ID NO:70 and CDRL3 comprises SEQ ID NO:72.

In another aspect, the isolated antigen-bhiding protein includes a CDRLI sequence, a

CDRL2 sequence, a CDRL3 sequence, a CDRLI I sequence, a CDRH2 sequence and a CDRH3 sequence. In one embodiment, CDRLI comprises SEQ ID NO;42, CDRL2 comprises SEQ ID NO:43, CDRL3 comprises SEQ ID NO:44, C'DRHl comprises SEQ ID NO:73, CDRH2 comprises SEQ ID NO:74 and CDRH3 comprises SEQ ID NO:75. In another embodiment,

CDRLI comprises SEQ ID NO:45, CDRL2 comprises SEQ ID NO:46, CDRL3 comprises SEQ ID NO:47, CDRHI comprises SEQ ID NO:76, CDRH2 comprises SEQ ID NO:77 and CDRH3 comprises SEQ ID NO;78. In another embodiment, CDRLI comprises SEQ ID NO:48, CDRL2 comprises SEQ ID NO:49, CDRL3 comprises SEQ ID NO:50, CDRHI comprises SEQ ID NO:79, CDRH2 comprises SEQ ID NO:80 and CDRH3 comprises SEQ ID 30 NO;81. In another embodiment, CDRLI comprises SEQ ID NO:51, CDRL2 comprises SEQ

IDNO:52, CDRL3 comprises SEQ ID NO:53, CDRHI comprises SEQ ID NO:82, CDRH2 comprises SEQ 1DNO:83 and CDRH3 comprises SEQ ID NO:84. In another embodiment, CDRLI comprises SEQ ID NO:54, C-DRL2 comprises SEQ ID NO:55, CDRL3 comprises SEQ ID NO:56, CDRH1 comprises SEQ ID NO:85, CDRH2 comprises SEQ ID NO:86 and

2018203471 16 May 2018

CDRH 3 comprises SEQ ID NO:87. In another embodiment, CDRLI comprises SEQ ID NO:57, CDRL2 comprises SEQ ID NO:58, CDRL3 comprises SEQ ID NO:59, CDRHI comprises SEQ ID NO:88, CDRH2 comprises SEQ ID NO:89 and CDRH3 comprises SEQ ID NO:90. In another embodiment, CDRL I comprises SEQ ID NO:60, CDRL2 comprises SEQ 5 1DNO:55, CDRL3 comprises SEQ ID NO:56, CDRHI comprises SEQ IDNO:85, CDRH2 comprises SEQ ID NO:86 and CDRH3 comprises SEQ ID NO:87, In another embodiment, CDRLI comprises SEQ ID NO:45, CDRL2 comprises SEQ ID NO:61, CDRL3 comprises SEQ ID NO:47, CDRH 1 comprises SEQ ID NO:76, CDRH2 comprises SEQ ID NO:91 and CDRH3 comprises SEQ ID NO:78. In another embodiment, CDRLI comprises SEQ ID 10 NO:62, CDRL2 comprises SEQ ID NO:63, CDRL3 comprises SEQ ID NO:64, CDRH 1 comprises SEQ ID NO:92, CDRH2 comprises SEQ ID NO:93 and CDRH3 comprises SEQ ID NO:94. In another embodiment, CDRLI comprises SEQ IDNO:45, CDRL2 comprises SEQ ID NO:61₅ CDRL3 comprises SEQ ID NO:47, CDRHI comprises SEQ ID NO:76, CDRH2 comprises SEQ ID NO:95 and CDRH3 comprises SEQ ID NO:78. In another embodiment,

CDRLI comprises SEQ ID NO:65, CDRL2 comprises SEQ ID NO:55, CDRL3 comprises SEQ ID NO:56, CDRHI comprises SEQ ID NO:85, CDRH2 comprises SEQ ID NO:86 and CDRH3 comprises SEQ ID NO:87. In another embodiment, CDRL1 comprises SEQ ID NO:42, CDRL2 comprises SEQ ID NO:43, CDRL3 comprises SEQ ID NO:44, CDRH I comprises SEQ ID NO:73, CDRH2 comprises SEQ ID NO:74 and CDRH3 comprises SEQ ID 20 NO;96. In another embodiment, CDRLI comprises SEQ ID NO:66, CDRL2 comprises SEQ

ID NO:67, CDRL3 comprises SEQ ID NO:68, CDRHI comprises SEQ ID NO:97, CDRH2 comprises SEQ ID NO:98 and CDRH3 comprises SEQ ID NO:99. In another embodiment, CDRLI comprises SEQ ID NO:69, CDRL2 comprises SEQ ID NO:70, CDRL3 comprises SEQ ID NO:71, CDRH 1 comprises SEQ ID NO: 100, CDRH2 comprises SEQ ID NO: 101 and 25 CDRH3 comprises SEQ ID NO: 102. In another embodiment, CDRL 1 comprises SEQ ID NO:69, CDRL2 comprises SEQ ID NO:70, CDRL3 comprises SEQ ID NO:72, CDRHI comprises SEQ ID NO: 100, CDRH2 comprises SEQ ID NO; 101 and CDRH3 comprises SEQ 1DNO:102.

In any of the above-mentioned sequence-defined embodiments, the isolated antigen30 binding protein may be, for example, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human (e.g,, fully human) antibody, a humanized antibody, a chimeric antibody, a multi-specific antibody, or an antigen binding fragment thereof. Further, the antibody fragment of the isolated antigen-binding proteins may be a Fab fragment, and Fab' fragment, an Ffab’L fragment, an Fv fragment, a diabody, or a single chain antibody molecule. For example.

2018203471 16 May 2018 the isolated antigen binding protein may be a human monoclonal antibody, and may be, e.g., an IgGl-, lgG2-, IgG3-, or IgG4-type antibody. Further, the isolated antigen binding proteins may be neutralizing antigen binding proteins.

In any of the above-mentioned sequence-defined embodiments, the isolated antigen5 binding protein may specifically bind to both human CRLR and human RAM Pl and not specifically bind to AMI, AM2 or a human amylin receptor (e.g., AMY 1), for example, the isolated antigen binding protein may specifically bind to human CGRP R with a Κ_ο<1 μΜ, <100 nM, <10 nM, or <5 nM, e.g., as determined using a FACS binding assay and analyzed, for example, using methods described in Rathanaswami, etal., Biochemical and Biophysical 10 Research Communications 334 (2005) 1004-1013. In any of the above-mentioned sequencedefined embodiments, the isolated antigen-binding protein may selectively inhibit human CGRP R, relative to the human the AMI, AM2 or AMY1 receptors, e.g., with a selectivity ratio of 100 or more, 250 or more, 500 or more, 750 or more, 1,000 or more, 2,500 or more, 5,000 or more or 10,000 or more, where the degree of selective inhibition may be determined using any suitable 15 method, e.g., using a c AMP assay as described in the Examples herein. In any of the abovementioned scqucncc-dcfined embodiments, the isolated antigen-binding protein may have a Ki of <100 nM, <10 nM, <1 nM, <0.5 nM or <0.1 nM in a CGRP binding competition assay, e.g., in a radiolabeled ^l25I-CGRP binding competition assay to membranes from cells expressing human CGRP R, e.g., the assay described in Example 5 herein.

Another set of embodiment includes isolated antigen-binding proteins that include one or a combination of CDRs having the consensus sequences described below, and optionally, bind human CGRP R. The consensus sequences are derived from phylogenetically related CDR sequences. In one aspect, the CDRs from the various groups may be mixed and matched in any particular isolated antigen-binding protein that binds human CGRP R. In another aspect, the antigen binding protein comprises heavy and light chain CDRs that are derived from the same phylogenetical ly-re I ated group of antibody clones. Exemplary CDR consensus sequences are as follows:

Kl Consensus

C'DRl RASQGIRXiDLG (SEQ ID NO: 103), wherein Xj is selected from the group consisting of N and K.

CDR2 XiASSLQS (SEQ ID NO: 104), wherein Xi is selected from the group consisting of A and G.

CDR3 LQYNX|XjPWT (SEQ ID NO:I05), wherein Xj is selected from the group consisting of 1 and S, and X₂ is selected from the group consisting of Y and F.

2018203471 16 May 2018

K4 Consensus

CDR3 QQYGNSLXjR (SEQ ID NO: 106), wherein Xi is selected from the group consisting of S and C.

K1.4 Consensus

CDR1 RASQXiXzXQGGXsLXfi (SEQ ID NO:107), wherein X, is selected from the group consisting of S and G, X₂ is selected from the group consisting of V and 1, X₃ is selected from the group consisting of S and R, X; is selected from the group consisting of S, N and K, X₅ is selected from the group consisting of Y and D, and Xs is selected from the group consisting of T and G.

CDR2 X[ASSX₂X₃X| (SEQ ID NO: 108), wherein X] is selected from the group consisting of G and A, X₂ is selected from the group consisting of R and L, X< is selected from the group consisting of A and Q, and X₄ is selected from the group consisting of T and S.

CDR3 XiQYXzX^^XsXeX? (SEQ ID NO: 109), wherein Xj is selected from the group consisting of Q and L, X₂ is selected from the group consisting of G and N, X₃ is selected from the group consisting of N and T, X4 is selected from the group consisting of S, Y and F, X₅ is selected from the group consisting of L and P, X_f, is selected from the group consisting of C, W and S, and X7 is selected from the group consisting of R and T.

K3 Consensus

CDR1 KSSQSLU ISXAiX.-X A'LY (SEQ ID NO:110), wherein X_t is selected from the group consisting of D and A, X₂ is selected from the group consisting of R and K, and X₃ is selected from the group consisting of N and T.

K2.3 Consensus

CDR1 X₁SSQSLLHSX₂GX₃X₄YLX₅ (SEQ ID NO: l 11), wherein X! is selected from the group consisting of R and K, X₂ is selected from the group consisting of F, D and A, X₃ is selected from the group consisting of Y, R and K, X₄ is selected from the group consisting of N and T, and X5 is selected from the group consisting of D and Y.

CDR2 XiX₂SNRX₃S (SEQ ID NO: 112), wherein X| is selected from the group consisting of L and E, X₂ is selected from the group consisting of G and V, and X₃ is selected from the group consisting of A and F,

CDR3 MQX|X₂X₃X4PX₅T (SEQ ID NO; 113), wherein X| is selected from the group consisting of A and S, X₂ is selected from the group consisting of L and F, X₃ is selected from the group consisting of Q and P, X₄ is selected from the group consisting of T and L, and X5 is selected from, the group consisting of F and L,

Lm3 Consensus

2018203471 16 May 2018

CDR2 RXjNQRPS (SEQ ID NO: 114), wherein Xi is selected from the group consisting of N and S.

Lm 1,2,3 Consensus

CDR1 SGSSSNIGX,NX₂VX₃ (SEQ ID NO: 115), wherein Xj is selected from the group consisting of N and S, X₂ is selected from the group consisting of Y and T, and X; is selected from the group consisting of S, N and Y.

CDR2 X1X2NX3RPS (SEQ ID NO: 116), wherein Xi is selected from the group consisting of D, T and R, X₂ is selected from the group consisting of N and S, and X₃ is selected from the group consisting of K and Q.

CDR3 XiX₂X₃DX₄X₅LX₆X7W (SEQ ID NO: 117), wherein X, is selected from the group consisting of G and A, X₂ is selected from the group consisting of T and A, X₃ is selected from the group consisting of W and'R, X₄ is selected from the group consisting of S and D, X₅ is selected from the group consisting of R and S, Xs is selected from the group consisting of S and N, and X? is selected from the group consisting of A and G,

LmAll Consensus

CDR1 X₁GX2X₃SX₄X₅X₆X7X8X9XioXii (SEQ ID NO: 118), wherein Xi is selected from the group consisting of S and Q, X ; is present or absent, and if present, is S, X.* is selected from the group consisting of S and D, X4 is present or absent, and if present, is N, X₅ is selected from the group consisting of I and L, Xe is selected from the group consisting of G and R, X7 is selected from the group consisting of N and S, X₈ is selected from the group consisting of N and F, Xy is selected from the group consisting ofY and T, Xiy is selected from the group consisting of V and A, and Xu is selected from the group consisting of S, N and Y.

CDR2 XiX₂NX₃RPS (SEQ ID NO:119), wherein Xj is selected from the group consisting of D, G, T, and R, X₂ is selected from the group consisting of N, K and S, and X₃ is selected from the group consisting of K, N and Q.

CDR3 ΧιΧ₂Χ₃ΟΧ₄Χ₅ΧόΧ₇ΧίίΧ9ν (SEQ ID NO: 120), wherein X, is selected from the group consisting of G, N and A, X₂ is selected from the group consisting of T, S and A, Xi is selected from the group consisting of W and R, X₄ is selected from the group consisting of S and D, X₅ is selected from the group consisting of R and S, Xr, is selected from the group consisting of L and V, X₇ is selected from the group consisting of S, Y and N, X₈ is selected from the group consisting of A, H and G, and X₉ is selected from the group consisting of V and L.

HCI Consensus

2018203471 16 May 2018

CDR1 X[YYMX₂ (SEQ ID NO: 121), wherein Xi is selected from the group consisting of G and D, X₂ is selected from the group consisting of H and Y.

CDR2 WIXiPNSGGTNYAQKFQG (SEQ ID NO: 122), wherein X, is selected from the group consisting of N and S.

CDR3 X,X₂X3SXjX₅X6X7XsGX_i,XioXiiXi2YYXi3GMDV (SEQ ID NO: 123), wherein Xi is selected from the group consisting of D and G, X₂ is selected from the group consisting of Q and G, X₃ is selected from the group consisting of M and Y, X₄ is selected from the group consisting of I and G, X5 is selected from the group consisting of 1 and Y, Xe is selected from 10 the group consisting of M and A, X7 is present or absent, and if present, is L, X_g is present or absent, and if present, is R, Xy is selected from the group consisting of V and L, Xm is selected from the group consisting of F and Y, Xi 1 is selected from the group consisting of P and S, Xi₂ is selected from the group consisting of P and H, and Xj₃ is present or absent, and if present, is Y.

HC2 Consensus

CDR2 RIKSX|TDGGTTDYX₂APVKG (SEQ ID NO: 124), wherein X, is selected from the group consisting of K and T, and X₂ is selected from the group consisting of T and A.

HC3 Consensus

CDR.1 XiYX₂MX₃ (SEQ ID NO: 125), wherein X| is selected from the group 20 consisting of T and S, X₂ is selected from the group consisting of S and A, and X₃ is selected from the group consisting of N and S.

CDR2 XiISXzSX^X^XsXcYYADSVKG (SEQ ID NO: 126), wherein X, is selected from the group consisting of S and A, X₂ is selected from the group consisting of S and G, X₃ is selected from the group consisting of S and G, X₄ is selected from the group consisting of S and G, Xs is selected from the group consisting of Y and R, and Xe is selected from the group consisting of R and T.

CDR3 XiX₂X₃X4X5X6X7PYSX_RX₉WYDYYYGMDV (SEQ ID NO; 127), wherein X, is selected from the group consisting of E and D, X₂ is selected from the group consisting of G and Q, X₃ is selected from the group consisting of V and R, X₄ is selected from the group consisting of S and E, X5 is selected from the group consisting of G and V, Xf, is selected from the group consisting of S and G, X? is present or absent, and if present, is S, X_s is selected from the group consisting of I and S, and Xy is selected from the group consisting of S and G.

2018203471 16 May 2018

HC4 Consensus

CDR.1 SXiGMH (SEQ ID NO: 128), wherein Xi is selected from the group consisting of F and Y.

CDR2 V1SX|DGSX₂KYXQGDSVKG (SEQ ID NO:I29), wherein X, is selected from 5 the group consisting of F and Y, X? is selected from the group consisting of 1 and Η, X? is selected from the group consisting of S and Y, and X₄ is selected from the group consisting of V and A.

CDR3 XLRXzXjXiXsXfiSXvXsYYXgXiuXuYYGXtzXuV (SEQ ID NO; 130), wherein Xi is selected from the group consisting of D and E, X₂ is selected from the group consisting of 10 L and EC, X? is selected from the group consisting of N and R, X₄ is selected from the group consisting of Y and V, X5 is selected from the group consisting of Y and T, Xg is selected from the group consisting of D and M, X₇ is selected from the group consisting of S and T, X« is selected from the group consisting of G and L, X9 is selected from the group consisting of H and Y, X10 vs present or absent, and if present, is Y, Xi t is selected from the group consisting 15 of K and F, X₁₂ is selected from the group consisting of M and L, and X13 is selected from the group consisting of A and D.

HCA Consensus

CDR1 X1X2X1MX4 (SEQ ID NO: 131), wherein Xj is selected from the group consisting of N and S, X; is selected from the group consisting of A, Y and F, X3 is selected from the group consisting of W, A and G, and X₄ is selected from the group consisting of S and H.

CDR2 X,IX₂X₃X4X5XeGX7X8X9XtoXiiXi2Xt3XMVKG (SEQ IDNO:132), wherein Xi is selected from the group consisting of R, A and V, X₂ is selected from the group consisting of K, S and W, X₄ is selected from the group consisting of S, G, F and Y, X₄ is present or absent, and if present, is selected from the group consisting of K and Τ, X5 is present or absent, and if present, is Τ, Xs is selected from the group consisting of D and S, X? is selected from the group consisting of G and S, X» is selected from the group consisting of T, R, I, N and H, Xg is selected from the group consisting of T and K, Xw is selected from the group consisting of D and Y, Xi i is selected from the group consisting of Y and S, Xiz is selected from the group consisting of T, A and V, X13 is selected from the group consisting of A and D, and X|₄ is selected from the group consisting of P and S.

CDR3 XiXX_?X₄X₅X₆X7XXXioXiiXi2XlXi4Xi5Xi6Xi7GXi₈XwV(SEQ ID NO: 133), wherein X| is selected from the group consisting of D, A and Ε, X? is selected from the group consisting of R, Q and G, X3 is selected from the group consisting of T, R, L, G and

2018203471 16 May 2018

Κ, X₄ is selected from the group consisting of G, E, N, I and R, Xs is selected from the group consisting of Y, V and A, Xe is selected from the group consisting of S, G, Y, A and T, X; is selected from the group consisting of I, P, D, A and M, X_s is present or absent, and if present, is selected from the group consisting of S and Y, Xg is present or absent, and if present, is 5 selected from the group consisting of W, S and T, Xjo is selected from the group consisting of S, G and L, X| ι is selected from the group consisting of S, G, L and Y, Xj₂ is present or absent, and if present, is selected from the group consisting of W and Y, Xu is selected from the group consisting of Y and H, X_}4 is present or absent, and if present, is selected from the group consisting of Y and D, Xu is selected from the group consisting of Y, K and F, Xu, is present 10 or absent, and if present, is Y, Xp is present or absent, and if present, is Y, Xis is selected from the group consisting of M and L, and X19 is selected from the group consisting of D and A, HCB Consensus

CDR1 X1X2X3X4X5 (SEQ ID NO: 134), wherein Xi is selected from the group consisting of N, G, D, S and A, X₂ is selected from the group consisting of A, F and Y, Xi is 15 selected from the group consisting of W, Y, A and G, X₄ is selected from the group consisting of M and L, and Xs is selected from the group consisting of S and H.

CDR2 X, 1X2X3X4X5X6X7X3X9X10X11X12X13X14X15X16X170 (SEQ ID NO: 135), wherein X[ is selected from the group consisting of R, W, A, V, S and F, X₂ is selected from the group consisting of K, N, S, W and R, X₃ is selected from the group consisting of S, P, G, F 20 and Y, X4 is present or absent, and if present, is selected from the group consisting of K, T and R, X₅ is present or absent, and if present, is selected from the group consisting of T and A, X_f, is selected from the group consisting of D, N, H, S and Y, X₇ is selected from the group consisting of G and S, X_s is selected from the group consisting of G and S, X₉ is selected from the group consisting of T, G, R, I, N, H and Y, X_I0 is selected from the group consisting of T, 25 K, R and P, X) 1 is selected from the group consisting of D, N, Y and E, Xj₂ is selected from the group consisting of Y and S, Xu is selected from the group consisting of T, A and V, Χμ is selected from the group consisting of A, Q and D, Xu is selected from the group consisting of P, K and S, X|₆ is selected from the group consisting of V and F, and Xp is selected from the group consisting of K and Q.

CDR3 XiXAiXiXsSXeXvXsXoXiuXnXuXLxXiiXisXicGXrXisV (SEQ ID NO: 136), wherein X] is selected from the group consisting of D, G, A and E, X₂ is selected from the group consisting of R, G and Q, X₃ is selected from the group consisting of T, Μ, Y, R, L, G and K, X₄ is selected from the group consisting of G, S, E, N, I and R, X₅ is selected from the group consisting of Y, I, G, V and A, Xf, is selected from the group consisting of S, 1, Y, G, A

2018203471 16 May 2018 and T, X₇ is selected from the group consisting of I, M, A, P and D, Xs is present or absent, and if present, is selected from the group consisting of S, L and Y, Xy is present or absent, and if present, is selected from the group consisting of W, R, S and T, X_]0 is selected from the group consisting of S, G and L, Xj i is selected from the group consisting of S, V, L, G and Y,

Xi2 is present or absent, and if present, is selected from the group consisting of F, Y and W,

Xis is selected from the group consisting ofY, P, S and Η, Χμ is present or absent, and if present, is selected from the group consisting of Y, P, D and Η, X15 is selected from the group consisting of Y, K and F, Χκ, is present or absent, and if present, is Y, X_J7 is present or absent, and if present, is Y and Xjg is selected from the group consisting of M and L.

In any of the above-mentioned consensus sequence defined embodiments, the isolated antigen-binding protein may be, for example, an AVIMER polypeptide, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human (e,g„ fully human) antibody, a humanized antibody, a chimeric antibody, a multi-specific antibody, or an antigen binding fragment thereof. Further, the antibody fragment of the isolated antigen-binding proteins may be a Fab fragment, and Fab' fragment, an F(ab')? fragment, an Fv fragment, a diabody, or a single chain antibody molecule. For example, the isolated antigen binding protein may be a human monoclonal antibody, and may be, e.g., an IgG 1-, IgG2-, lgG3-, or IgG4-type antibody. Further, the isolated antigen binding proteins may be neutralizing antigen binding proteins.

In any of the above-mentioned consensus sequence defined embodiments, the isolated antigen-binding protein may specifically bind to both human CRLR and human RAMP1 and not specifically bind to AMI, AM2 or a human amylin receptor (e.g., AMY 1), for example, the isolated antigen binding protein may specifically bind to human CGRP R with a Kd<1 μΜ, <100 nM, <10 nM, or <5 11M, e.g., as determined using a FACS binding assay and analyzed, for example, using methods described in Rathanaswami, etafi Biochemical and Biophysical

Research Communications 334 (2005) 1004-1013. In any of the above-mentioned consensus sequence defined embodiments, the isolated antigen-binding protein may selectively inhibit human CGRP R, relative to the human the AM I, AM2 or AMY I receptors, e.g., with a selectivity ratio of 100 or more, 250 or more, 500 or more, 750 or more, 1,000 or more, 2,500 or more, 5,000 or more or 10,000 or more, where the degree of selective inhibition may be determined using any suitable method, e.g., using a cAMP assay as described in the Examples herein. In any of the above-mentioned consensus sequence defined embodiments, the isolated antigen-binding protein may have a Kj of <100 nM, <10 nM, <1 nM, <0.5 nM or <0.1 nM in a CGRP binding competition assay, e.g., in a radiolabeled ^l25I-CGRP binding competition assay to membranes from cells expressing human CGRP R, e.g., the assay described in Example 5 herein.

2018203471 16 May 2018

Some of the isolated antigen-binding proteins described comprise a heavy chain variable region (Vh) sequence that has at least 80%, 85%, and 90% or 95% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 158-170. Some of the isolated antigen-binding proteins described comprise a light chain variable region 5 (V[J sequence that has at least 80%, 85%, and 90% or 95% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-153. Some of the isolated antigen-binding proteins described comprise a Vh sequence that has at least 80%,

85%, 90% or 95% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 158-170, and a V_L that has at least 80%, 85%, 90% or 95% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-153, In some embodiments, the isolated antigen-binding proteins comprise (A) a heavy chain variable region (V_H) comprising a sequence (i) selected from the group consisting of SEQ ID NOs: 158-170, or (ii) as defined by (i) and containing one or more (e.g., five, ten, fifteen or twenty) amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; (B) a Vt comprising a sequence (iii) selected from the group consisting of SEQ ID NOs: 137-153, or (iv) as defined by (iii) containing one or more (e.g., five, ten, fifteen or twenty) amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; or (C) a Vh of ( A) and a V_L of (B). In some embodiments, the isolated antigen-binding proteins comprise a heavy chain variable region (Vu) comprising a sequence 20 selected from the group consisting of SEQ ID NOs: 158-170 and a V[_ comprising a sequence selected from the group consisting of SEQ ID NOs: 137-153.

In one embodiment, the isolated antigen-binding protein comprises a heavy chain variable region (Vh) comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 158, (ii) a sequence that is at least 90% or 95% identical to the sequence 25 defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vh comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 159, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) 30 containing up to ten amino acid substitutions (e,g„ conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vu comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 160, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (c,g.,

2018203471 16 May 2018 conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vn comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 161, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to 5 ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vh comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 162, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative 10 amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigenbinding protein comprises a Vu comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO; 163, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (I) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another 15 embodiment, the isolated antigen-binding protein comprises a Vh comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 164, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises 20 a Vn comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 165, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i)„ and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a V_H comprising an amino acid sequence selected 25 from the group consisting of (i) SEQ ID NO: 166, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vn comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 167, 30 (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigenbinding protein comprises a Vh comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 168, (ii) a sequence that is at least 90% or 95% identical to the

2018203471 16 May 2018 sequence defined by (i), and (iii) a sequence as defined by (i). containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vh comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 169, (ii) a sequence that is at 5 least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a V_H comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 170, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In one embodiment, the isolated antigen-binding protein comprises a light chain variable region (V_rJ comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 137, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 138, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated anti gen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 139, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:140, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 141, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen24

2018203471 16 May 2018 binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:142, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another 5 embodiment, the isolated antigen-binding protein comprises a V). comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 143, (ii) a sequence that is at ieast 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises 10 a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 144, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vi. comprising an amino acid sequence selected 15 from the group consisting of(i) SEQ ID NO: 145, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 146, 20 (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (hi) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigenbinding protein comprises a V_L comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 147, (ii) a sequence that is at least 90% or 95% identical to the 25 sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 148, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) 30 containing up to ten amino acid substitutions (e,g„ conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 149, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g.,

2018203471 16 May 2018 conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a V_L comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 150, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to 5 ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigen-binding protein comprises a Vr, comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:151, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative 10 amino acid substitutions), deletions or insertions. In another embodiment, the isolated antigenbinding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO :152, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions. In another 15 embodiment, the isolated antigen-binding protein comprises a Vl comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 153, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In any of the above-mentioned Vl and Vn sequence defined embodiments, the isolated antigen-binding protein may be, for example, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human (e.g., fully human) antibody, a humanized antibody, a chimeric antibody, a multi-specific antibody, or an antigen binding fragment thereof. Further, the antibody fragment of the isolated antigen-binding proteins may be a Fab fragment, and Fab' fragment, an

Ffab'h fragment, an Fv fragment, a diabody, or a single chain antibody molecule. For example, the isolated antigen binding protein may be a human monoclonal antibody, and may be, e.g., an IgG I-, lgG2-„ lgG3-, or lgG4-type antibody. Further, the isolated antigen binding proteins may be neutralizing antigen binding proteins.

In any of the above-mentioned Vl and Vn sequence defined embodiments, the isolated antigen-binding protein may specifically bind to both human CRLR and human RAMP! and not specifically bind to AMI, AM2 or a human amylin receptor (e.g., AMY 1), for example, the isolated antigen binding protein may specifically bind to human CGRP R with a Kn£f μΜ, <100 nM, <10 nM, or <5 nM, e.g., as determined using a FACS binding assay and analyzed, for example, using methods described in Rathanaswami, etal.. Biochemical and Biophysical

2018203471 16 May 2018

Research Communications 334 (2005) 1004-1013. In any of the above-mentioned Vl and Vn sequence defined embodiments, the isolated antigen-binding protein may selectively inhibit human CGRP R, relative to the human the AM 1, AM2 or AMY I receptors, e.g., with a selectivity ratio of 100 or more, 250 or more, 500 or more, 750 or more, 1,000 or more, 2,500 or more, 5,000 5 or more or 10,000 or more, where the degree of selective inhibition may be determined using any suitable method, e.g., using a cAMP assay as described in the Examples herein. In any of the above-mentioned Vr. and V_H sequence-defined embodiments, the isolated antigen-binding protein may have a Ki of <100 nM, <10 nM, <1 πΜ, <0.5 nM or <0.1 nM in a CGRP binding competition assay, e.g., in a radiolabeled ’ ’ i-CGRP binding competition assay to membranes 10 from cells expressing human CGRP R, e.g., the assay described in Example 5 herein.

In one aspect, the isolated antigen-binding proteins comprise a heavy chain sequence that has at least 80%, 85%, 90% or 95% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:29-41. Some of the isolated antigenbinding proteins described comprise a light chain sequence that has at least 80%, 85%, 90% or 15 95% sequence identity with an amino acid sequence selected from the group consisting of SEQ

ID NOs: 12-28. Some of the isolated antigen-binding proteins comprise a heavy chain sequence that has at least 80%, 85%, 90% or 95% sequence identity with an ammo acid sequence selected from the group consisting of SEQ ID NOs: 29-41, and a light chain sequence that has at least 80%, 85%, 90% or 95% sequence identity with an amino acid sequence 20 selected from the group consisting of SEQ ID NOs: 12-28. In some embodiments, the isolated antigen-binding proteins comprise (A) a heavy chain comprising a sequence (i) selected from the group consisting of SEQ ID NOs: 29-41, or (ii) as defined by (i) and containing one or more (e.g., five, ten, fifteen or twenty) amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; (B) a light chain comprising a sequence (iii) selected 25 from the group consisting of SEQ ID NOs: 12-28, or (iv) as defined by (iii) containing one or more (e.g., five, ten, fifteen or twenty) amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; or (C) a heavy chain of (A) and a light chain of (B). In some embodiments, the isolated antigen-binding proteins comprise a heavy chain comprising a sequence selected from the group consisting of SEQ ID NOs: 29-41 and a light chain 30 comprising a sequence selected from the group consisting of SEQ ID NOs: 12-28.

In one embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:29, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (c.g., conservative

2018203471 16 May 2018 amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 12, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:30, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (in) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 13, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:31, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (in) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 14, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID

NO:32, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:15, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID

2018203471 16 May 2018

NO:33, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid 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, (ii) a 5 sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g,, conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID 10 NO:29, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:17, (fi) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a 15 sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:34, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and 20 (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO: 18, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (!) containing up to ten amino acid substitutions (e.g., conservative 25 amino acid substitutions), deletions or insertions.

Jn another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:33, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i ) SEQ ID NO: 19, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

2018203471 16 May 2018

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:29, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (I) SEQ ID NO:20, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:35, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:21, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:36, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:22, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated anti gen-bin ding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID 30 NO:37, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:23, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a

2018203471 16 May 2018 sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID 5 NO;38, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO;23, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a 10 sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:33, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and 15 (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO;24, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative 20 amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO;39, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:25, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g,, conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:40, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising

2018203471 16 May 2018 an amino acid sequence selected from the group consisting of (i) SEQ ID NO:26, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative ammo acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:41, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising 10 an amino acid sequence selected from the group consisting of (i) SEQ ID NO:27, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions.

In another embodiment, the isolated antigen-binding protein comprises (A) a heavy chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:41, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions; and (B) a light chain comprising an amino acid sequence selected from the group consisting of (i) SEQ ID NO:28, (ii) a sequence that is at least 90% or 95% identical to the sequence defined by (i), and (iii) a sequence as defined by (i) containing up to ten amino acid substitutions (e.g,, conservative amino acid substitutions), deletions or insertions.

In any of the above-mentioned light and heavy chain sequence defined embodiments, the isolated antigen-binding protein may comprise the specified heavy and/or light chain 25 sequence, but with a different signal peptide or with no signal peptide. In any of the abovementioned light and heavy chain sequence defined embodiments, the isolated antigen-binding protein may be, for example, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human (e.g., fully human) antibody, a humanized antibody, a chimeric antibody, a multi-specific antibody, or an antigen binding fragment thereof. Further, the antibody fragment of 30 the isolated antigen-binding proteins may be a Fab fragment, and Fab' fragment, an Ftab’fr fragment, an Fv fragment, a diabody, or a single chain antibody molecule. For example, the isolated antigen binding protein may be a human monoclonal antibody, and may be, e.g., an lgGI, IgG2-, IgG3-, or IgG4-type antibody. Further, the isolated antigen binding proteins may be neutralizing antigen binding proteins.

2018203471 16 May 2018

In any of the above-mentioned light and heavy chain sequence defined embodiments, the isolated antigen-binding protein may specifically bind to both human CRLR and human RAMP1 and not specifically bind to AM I, AM2 or a human amylin receptor (e.g., AMY J), for example, the isolated antigen binding protein may specifically bind to human CGRP R with a 5 Kd<1 μΜ, <100 nM, <10 nM, or <5 nM, e.g., as determined using a FACS binding assay and analyzed, for example, using methods described in Rathanaswami, et al., Biochemical and Biophysical Research Communications 334 (2005) 1004-1013. In any of the above-mentioned light and heavy chain sequence defined embodiments, the isolated antigen-binding protein may selectively inhibit human CGRP R, relative to the human the AMI, AM2 or AMY I receptors,

e.g., with a selectivity ratio of 100 or more, 250 or more, 500 or more, 750 or more, 1,000 or more, 2,500 or more, 5,000 or more or 10,000 or more, where the degree of selective inhibition may be determined using any suitable method, e.g., using a cAMP assay as described in the Examples herein. In any of the above-mentioned light and heavy chain sequence-defined embodiments, the isolated antigen-binding protein may have a Κί of <100 nM, <10 nM, <1 nM, 15 <0,5 nM or <0.1 nM in a CGRP binding competition assay, e.g., in a radiolabeled ¹²⁵I-CGRP binding competition assay to membranes from cells expressing human CGRP R, e.g., the assay described in Example 5 herein.

In a further aspect, also provided are isolated nucleic acid polynucleotides that encode any of the CGRP R antigen-binding proteins summarized above. In one embodiment, the isolated polynucleotide comprises a sequence selected from the group consisting of SEQ ID NOs:175, 176, 178, 179, 180, 181, 182, 183, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 200,201,202, 203, 204, 205, 206, 207, 208,209 and 210. In another embodiment, the isolated polynucleotide comprises a sequence selected from the group consisting of SEQ ID NOs:224-258. In another embodiment, the isolated polynucleotide comprises a sequence capable of hybridizing under stringent hybridization conditions with a sequence selected from the group consisting of SEQ ID NOs:224-258. In another embodiment, the isolated polynucleotide comprises a sequence that is about 80%, 85%, 90% or 95% or more identical to a sequence selected from the group consisting of SEQ ID NOs:224-258. In some instances, the isolated nucleic acid molecules are operably-linked to a control sequence. In related embodiments, the isolated polynucleotides are incorporated into an expression vector,

Also included are cell lines transformed with expression vectors comprising isolated polynucleotides as described above. In a related aspect, also provided are expression vectors and host cells transformed or transfected with the expression vectors that comprise the

2018203471 16 May 2018 aforementioned isolated nucleic acid molecules that encode CGRP R antigen-binding proteins described above

In another aspect, also provided is a method of preparing the antigen-binding proteins that includes the step of preparing the antigen binding protein from a host cell that secretes the 5 antigen-binding protein. In some embodiments, the antigen binding protein is generated using an immunogen comprising soluble CGRP receptor. In some embodiments, such soluble CGRP receptor is obtained by co-expressing and purifying an N-terminal extracellular domain (ECD) of human CRLR and an ECD of human RAMP I, e.g., an ECD of human CRLR comprising SEQ ID NO: 6 and an ECD of RAMP 1 comprising SEQ ID NO: 8, for example, as described in Examples 10 I and 2 herein.

In yet another aspect, a pharmaceutical composition is provided comprising at least one of the antigen-binding proteins summarized above and a pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition may comprise an additional active agent that is selected from the group consisting of a radioisotope, radionuclide, a toxin, or a 15 therapeutic and a chemotherapeutic group.

In one aspect, the isolated antigen binding protein is effective to inhibit vasodialation and/or decrease neurogenic inflammation when administered to a patient. In one embodiment, the isolated antigen binding protein is effective to reduce the frequency and/or severity of headaches, for example, migraine headaches. For example, the antigen binding protein may be 20 used as an acute treatment of migraine, and/or as a prophylactic treatment to prevent or reduce the frequency and/or severity of symptoms, particularly pain symptoms, associated with a migraine attack.

Other aspects further provide methods for treating or preventing a condition associated with CGRP R in a patient, comprising administering to a patient an effective amount of at least one isolated antigen-binding protein summarized above. In one embodiment, the condition is a headache, for example, a migraine headache or a cluster headache or another type of pain, e.g., a chronic pain; in another embodiment it is diabetes mcllitus (type II); in another embodiment it is inflammation, particularly neurogenic inflammation; in another embodiment it is a cardiovascular disorder; in another embodiment it is a hemodynamic derangement associated with endotoxemia and sepsis; in another embodiment it is vasodialation.

In another aspect, also provided is a method of inhibiting binding of CGRP to human

CGRP R, e.g., the extracellular portion of CGRP R, in a patient comprising administering an effective amount of at least one antigen-binding protein provided herein and/or summarized above.

2018203471 16 May 2018

These and other aspects will he described in greater detail herein. Each of the aspects provided can encompass various embodiments provided herein. It is therefore anticipated that each of the embodiments involving one element or combinations of elements can be included in each aspect described, and all such combinations of the above aspects and embodiments are 5 expressly considered. Other features, objects, and advantages of the invention are apparent in the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows an alignment of RAMP-1 sequences from human, cynomolgus monkey and rat.

Fig. 2 shows an alignment of CRLR sequences from human, cynomolgus monkey and rat.

Figs 3 A and 3B show phylogenetically-based sequence alignments of light chain CDRs from the indicated anti-CGRP receptor antibody clones having kappa light chains, and certain corresponding consensus sequences.

Fig. 4 shows phylogenetically-based sequence alignments of light chain CDRs from the indicated anti-CGRP receptor antibody clones having lambda light chains, and certain corresponding consensus sequences.

Figs. 5A, 5B, 5C, 5D and 5E show phylogenetically-based sequence alignments of heavy chain CDRs from the indicated anti-CGRP receptor antibody clones, and certain corresponding consensus sequences.

Fig. 5F shows consensus sequences of exemplary anti-CGRP receptor antibody heavy chain CDRs disclosed herein.

Fig. 6 is a plot of data from two experiments showing percent inhibition of labeled ligand binding to CGRP R by 1092 anti-CGRP R hybridoma supernatants (diamonds) and 68 negative control supernatants (squares).

Figs. 7A-D show exemplary cAMP assay IC50 data from cells expressing hCGRP receptor (Fig. 7A), hAM 1 (Fig. 7B), hAM2 (Fig. 7C) and human amylin receptors (Fig. 7D) for three indicated anti-CGRP R mAbs.

Fig. 8 shows an example of ^l2SI-CGRP binding data such as may be used to determine the Ki of mAbs to human CGRP receptor.

Figs. 9A-D show Biacore competition data for selected antibodies disclosed herein.

Fig. 10 shows a FACS Kd determination of mAh I2G8.

Fig. 11 shows an alignment of cynomolgus, human, human chimeras, rat, and rhesus RAMP1 sequences.

2018203471 16 May 2018

Figs. 12A-B show an alignment of human, cynomolgus, rhesus, rat, human chimera and consensus CRLR sequences.

Figs. 13A-13C show representative FACS data of different chimeric CGRP receptors binding to anti-CGRP R antibodies.

Fig. 14 shows peptide maps derived from AspN digestions of CGRP R alone (chromatogram A) and from digestion of a control sample containing CGRP R monoclonal antibody 12G8 (chromatogram B).

Fig. 15 shows AspN digestions of CGRP R in the presence of different concentrations of CGRP R neutralizing antibody.

Fig. 16 shows AspN digestions of CGRP R in the presence of different concentration of

CGRP R neutralizing antibody, 4E4,

Fig. 17 shows immunohistochemistry staining intensity of celts expressing various receptor components with antibody 32H7.

DETAILED DESCRIPTION

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well known and commonly used in the art. The methods and techniques of the present application are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al,, Molecular Cloning: A Laboratory Manual, 3rd ed.. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001), Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and

Lane Antibodies; A Laboratory Manual Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990), which are incorporated herein by reference. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The terminology used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry,

2018203471 16 May 2018 and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc,, described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as 10 modified in all instances by the term “about.” The term “about” when used in connection with percentages means +J %.

Definitions

The term “polynucleotide” or “nucleic acid” includes both single-stranded and doublestranded nucleotide polymers. The nucleotides comprising the polynucleotide can be 15 ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Said modifications include base modifications such as bromouridine and inosine derivatives, ribose modifications such as 2’,3’-dideoxyribose, and intcmucleotide linkage modifications such as phosphorothioatc, phosphorodithioatc, phosphoroselenoatc, phosphorodisclenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate.

The term “oligonucleotide” means a polynucleotide comprising 200 or fewer nucleotides. In some embodiments, oligonucleotides are 10 to 60 bases in length. In other embodiments, oligonucleotides are 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 nucleotides in length. Oligonucleotides may be single stranded or double stranded, e.g., for use in the construction of a mutant gene. Oligonucleotides may be sense or antisense oligonucleotides.

An oligonucleotide can include a label, including a radiolabel, a fluorescent label, a hapten or an antigenic label, for detection assays. Oligonucleotides may be used, for example, as PCR primers, cloning primers or hybridization probes.

An “isolated nucleic acid molecule” means a DNA or RNA of genomic, mRNA, cDNA, or synthetic origin or some combination thereof which is not associated with all or a 30 portion of a polynucleotide in which the isolated polynucleotide is found in nature, or is linked to a polynucleotide to which it is not linked in nature. For purposes of this disclosure, it should be understood that “a nucleic acid molecule comprising” a particular nucleotide sequence does not encompass intact chromosomes. Isolated nucleic acid molecules “comprising” specified nucleic acid sequences may include, in addition to the specified sequences, coding sequences

2018203471 16 May 2018 for up to ten or even up to twenty other proteins or portions thereof, or may include operably linked regulatory sequences that control expression of the coding region of the recited nucleic acid sequences, and/or may include vector sequences.

Unless specified otherwise, the left-hand end of any single-stranded polynucleotide 5 sequence discussed herein is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5' to 3' addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 5' to the 5' end of the RNA transcript are referred to as “upstream sequences;” sequence regions on the DNA strand 10 having the same sequence as the RNA transcript that are 3' to the 3' end of the RNA transcript are referred to as “downstream sequences.”

The term “control sequence” refers to a polynucleotide sequence that can affect the expression and processing of coding sequences to which it is ligated. The nature of such control sequences may depend upon the host organism. In particular embodiments, control 15 sequences for prokaryotes may include a promoter, a ribosomal binding site, and a transcription termination sequence. For example, control sequences for eukaryotes may include promoters comprising one or a plurality of recognition sites for transcription factors, transcription enhancer sequences, and transcription termination sequence. “Control sequences” can include leader sequences and/or fusion partner sequences.

The term “vector” means any molecule or entity (e.g., 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 vector that is suitable for transformation of a host cell and contains nucleic acid sequences that direct and/or control (in conjunction with the host cell) expression of one or more heterologous coding regions operatively linked thereto. An expression construct may include, but is not limited to, sequences that affect or control transcription, translation, and, if introns are present, affect RNA splicing of a coding region operably linked thereto.

As used herein, “operably linked” means that the components to which the term is applied are in a relationship that allows them to cany out their inherent functions under 30 suitable conditions. For example, a control sequence in a vector that is operably linked to a protein coding sequence is ligated thereto so that expression of the protein coding sequence is achieved under conditions compatible with the transcriptional activity of the control sequences

The term “host cell” means a cell that has been transformed, or is capable of being transformed, with a nucleic acid sequence and thereby expresses a gene of interest. The term

2018203471 16 May 2018 includes the progeny of the parent cell, whether or not the progeny is identical in morphology or in genetic make-up to the original parent cell, so long as the gene of interest is present.

The term “transduction” means the transfer of genes from one bacterium to another, usually by bacteriophage. “Transduction” also refers to the acquisition and transfer of 5 eukaryotic cellular sequences by replication defective retroviruses.

The term “transfection” means the uptake of foreign or exogenous DNA by a ceil, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art and are disclosed herein. See, e.g., Graham etal., 1973, Virology 52:456; Sam brook et al., 2001, Molecular 10 Cloning: A Laboratory Manual, supra', Davis et al., 1986, Basic Methods in Molecular

Biology, Elsevier; Chu et al., 1981, Gene 13:197. Such techniques can be used to introduce one or more exogenous DNA moieties into suitable host celts.

The term “transformation” refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain new DNA or RNA. For 15 example, a cell is transformed where it is genetically modified from its native state by introducing new genetic material via transfection, transduction, or other techniques. Following transfection or transduction, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, or may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A 20 cell is considered to have been “stably transformed” when the transforming DNA is replicated with the division of the cell.

The terms polypeptide” or “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms also apply to amino acid polymers in which one or more amino acid residues is an analog or mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. The terms can also encompass amino acid polymers that have been modified, e.g., by the addition of carbohydrate residues to form glycoproteins, or phosphorylated. Polypeptides and proteins can be produced by a naturally-occurring and non-recombinant cell; or it is produced by a geneticallyengineered or recombinant cell, and comprise molecules having the amino acid sequence of the native protein, or molecules having deletions from, additions to, and/or substitutions of one or more amino acids of the native sequence. The terms “polypeptide” and “protein” specifically encompass antigen binding proteins, e.g., CGRP R antigen-binding proteins, CGRP R binding proteins, antibodies, or sequences that have deletions from, additions to, and/or substitutions of one or more amino acids of an antigen-binding protein. The term “polypeptide fragment”

2018203471 16 May 2018 refers to a polypeptide that has an amino-terminal deletion, a carboxyl-terminal deletion, and/or an internal deletion as compared with the full-length protein. Such fragments may also contain modified amino acids as compared with the full-length protein. In certain embodiments, fragments are about five to 500“amino acids long. For example, fragments may 5 be at least 5, 6, 8, 10, 14,20,50,70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids long. Useful polypeptide fragments include immunologically functional fragments of antibodies, including binding domains. In the case of a CGRP R-binding antibody, useful fragments include but are not limited to a CDR region, a variable domain of a heavy or light chain, a portion of an antibody chain or just its variable domain including two C'DRs, and the 10 like. The“CGRP receptor”, or “CGRP R”, is understood to comprise RAMP1 and CRLR.

The term “isolated protein” (e.g., isolated antigen binding protein), “isolated polypeptide” or “isolated antibody” means that a subject protein, polypeptide or antibody (1) is free of at least some other proteins with which it would normally be found, (2) is essentially free of other proteins from the same source, e.g., from the same species, (3) is expressed by a 15 cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (6) does not occur in nature. Typically, an “isolated protein”, “isolated polypeptide” or “isolated antibody” constitutes at least about 5%, at least 20 about 10%, at least about 25%, or at least about 50% of a given sample. Genomic DMA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof may encode such an isolated protein. Preferably, the isolated protein polypeptide or antibody is substantially free from other proteins or other polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic, research 25 or other use.

A “variant” of a polypeptide (e.g., an antigen binding protein, or an antibody) comprises an amino acid sequence wherein one or more amino acid residues are inserted into, deleted front and/or substituted into the amino acid sequence relative to another polypeptide sequence. Variants include fusion proteins.

A “derivative” of a polypeptide is a polypeptide (e.g., an antigen binding protein, or an antibody) that has been chemically modified in some manner distinct from insertion, deletion, or substitution variants, e.g., via conjugation to another chemical moiety.

2018203471 16 May 2018

The term “naturally occurring” as used throughout the specification in connection with biological materials such as polypeptides, nucleic acids, host cells, and the like, refers to materials which are found in nature.

An “antigen binding protein” as used herein means a protein that specifically binds a 5 specified target antigen, such as CGRP R, particularly primate, e.g., human CGRP R. A CGRP R antigen binding protein specifically binds the human CGRP receptor.

An antigen binding protein is said to “specifically bind” its target when the dissociation constant (Ko) is <10^ M. The antibody specifically binds the target antigen with “high u

affinity” when the K·) is <lx 10' M. In one embodiment, the antibodies will bind to CGRP R, 10 or human CGRP R with a K_D<5x 1 O'⁷; in another embodiment the antibodies will bind with a

Kd <1x 10'⁷; in another embodiment the antibodies will bind with a Kd <5x I0’^r; in another embodiment the antibodies will bind with a <lx I O'⁸; in another embodiment the antibodies will bind with a fQ> <5x 1 O’⁹; in another embodiment the antibodies will bind with a Kr <1 x 10‘⁹; in another embodiment the antibodies will bind with a Kn <5x 10'¹”; in another 15 embodiment the antibodies will bind with a K_D <lx IO'¹⁰.

An antibody, antigen binding fragment thereof or antigen binding protein “selectively inhibits” a specific receptor relative to other receptors 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 another “reference” receptor. The “selectivity ratio” is the IC50 of the reference receptor divided by 1C50 ofthe specific receptor. An antibody, antigen binding fragment thereof or antigen binding protein selectively inhibits the human CGRP receptor if the IC50 of the antibody, antigen binding fragment thereof or antigen binding protein in a cAMP assay, e.g., the cAMP inhibition assay as described in Example 4 herein, is at least 50-fold lower than the IC50 of that same antibody, 25 antigen binding fragment thereof or antigen binding protein in an inhibition assay of the human AMI, AM2 or an amylin receptor (e.g., AMY1). By way of non-limiting example, if the IC50 of a specific anti-CGRP R antibody in a cAMP assay of hCGRP R is, e.g., between 0.1 nM and 20 nM, and the IC50 of the same antibody in a cAMP assay of the bAMl, hAM2 or human AMY1 receptor is 1000 nM or more, that antibody selectively inhibits the hCGRP receptor.

An antigen binding protein that selectively inhibits a specific receptor is also understood to be a neutralizing antigen binding protein with respect to that receptor.

“Antigen binding region” means a protein, or a portion of a protein, that specifically binds a specified antigen. For example, that portion of an antigen binding protein that contains the amino acid residues that interact with an antigen and confer on the antigen binding protein

2018203471 16 May 2018 its specificity and affinity for the antigen is referred to as “antigen binding region.” An antigen binding region typically includes one or more “complementary binding regions” (“CDRs”). Certain antigen binding regions also include one or more “framework” regions. A “CDR” is an amino acid sequence that contributes to antigen binding specificity and affinity.

’’Framework” regions can aid in maintaining the proper conformation of the CDRs to promote binding between the antigen binding region and an antigen.

In certain aspects, recombinant antigen binding proteins that bind CORP R protein, or human CORP R, are provided. In this context, a “recombinant protein” is a protein made using recombinant techniques, i.e., through the expression of a recombinant nucleic acid as described 10 herein. Methods and techniques for the production of recombinant proteins are well known in the art.

The term “antibody” refers to an intact immunoglobulin of any isotype, or an antigen binding fragment thereof that can compete with the intact antibody for specific binding to the target antigen, and includes, for instance, chimeric, humanized, fully human, and bispecific 15 antibodies. An “antibody” as such is a species of an antigen binding protein. An intact antibody generally will comprise at least two full-length heavy chains and two full-length light chains, but in some instances may include fewer chains such as antibodies naturally occurring in camelids which may comprise only heavy chains. Antibodies may be derived solely from a single source, or may be “chimeric,” that is, different portions of the antibody may be derived 20 from two different antibodies as described further below. The antigen binding proteins, antibodies, or binding fragments may be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term “antibody” includes, in addition to antibodies comprising two full-length heavy chains and two full-length light chains, derivatives, variants, fragments, and mutations 25 thereof, examples of which arc described below.

The term “light chain” includes a full-length light chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length light chain includes a variable region domain, Vl, and a constant region domain, C_L. The variable region domain of the light chain is at the amino-terminus of the polypeptide. Light chains include 30 kappa chains and lambda chains.

The term “heavy chain” includes a full-length heavy chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length heavy chain includes a variable region domain, V_H, and three constant region domains, ChI, C_h2, and Ch3. The Vh domain is at the amino-terminus of the polypeptide, and the Ch domains arc at

2018203471 16 May 2018 the carboxy l-termin us, with the Ch3 being closest to the carboxy-terminus of the polypeptide. Heavy chains may be of any isotype, including IgG (including IgGl, IgG2, lgG3 and IgG4 subtypes), IgA (including IgAl and IgA2 subtypes), IgM and IgE.

The term “signal sequence”, “leader sequence” or “signal peptide” refers to a short (35 60 amino acids long) peptide chain that directs the transport of a protein. Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals.

Some signal peptides are cleaved from the protein by signal peptidase after the proteins are transported, such that the biologically active form of the protein (e.g., an antigen binding protein as described herein) is the cleaved, shorter form. Accordingly, terms such as “antibody 10 comprising a heavy chain...”, “antibody comprising a light chain...”, etc., where the antibody is characterized as having a heavy and/or light chain with a particular identified sequence, are understood to include antibodies having the specific identified sequences, antibodies having the specific identified sequences except that the signal sequences are replaced by different signal sequences, as well as antibodies having the identified sequences, minus any signal 15 sequences.

The term “antigen binding fragment” (or simply “fragment”) of an antibody or immunoglobulin chain (heavy or light chain), as used herein, comprises a portion (regardless of how that portion is obtained or synthesized) of an antibody that lacks at least some of the amino acids present in a full-length chain but which is capable of specifically binding to an antigen. Such fragments arc biologically active in that they bind specifically to the target antigen and can compete with other antigen binding proteins, including intact antibodies, for specific binding to a given epitope. In one aspect, such a fragment will retain at least one CDR present in the full-length light or heavy chain, and in some embodiments will comprise a single heavy chain and/or light chain or portion thereof. These biologically active fragments may be produced by recombinant DNA techniques, or may be produced by enzymatic or chemical cleavage of antigen binding proteins, including intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, Fab, Fab', Ffab'E, Fv, domain antibodies and single-chain antibodies, and may be derived from any mammalian source, including but not limited to human, mouse, rat, camelid or rabbit. It is contemplated further that a functional portion of the antigen binding proteins disclosed herein, for example, one or more CDRs, could be covalently bound to a second protein or to a small molecule to create a therapeutic agent directed to a particular target in the body, possessing bifunctional therapeutic properties, or having a prolonged serum half-life.

2018203471 16 May 2018

An “Fab fragment” is comprised of one light chain and the Cut and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

An “Fc” region contains two heavy chain fragments comprising the C_H l and C_H2 5 domains of an antibody. The two heavy chain fragments arc held together by two or more disulfide bonds and by hydrophobic interactions of the Cr3 domains.

An “Fab¹ fragment” contains one light chain and a portion of one heavy chain that contains the Vu domain and the C^l domain and also the region between the CjJ and Cn2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of 10 two Fab' fragments to form an Ffab'h molecule.

An “Ffab’E fragment” contains two light chains and two heavy chains containing a portion of the constant region between the C_H1 and Ch2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A Ffab’E fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains. 15 The “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

“Single-chain antibodies” are 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 forms an antigen-binding region. Single chain antibodies are discussed in detail in

International Patent Application Publication No. WO 88/01649 and United States Patent No. 4,946,778 and No, 5,260,203, the disclosures of which are incorporated by reference.

A “domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. I n some instances, two or more V_H regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two Vh regions of a bivalent domain antibody may target the same or different antigens.

A “bivalent antigen binding protein” or “bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. Bivalent antigen binding proteins and bivalent antibodies may be bispecific, see, infra.

A “multispecific antigen binding protein” or “multispecific antibody” is one that targets more than one antigen or epitope.

A Unspecific,” “dual-specific” or “bifunctional” antigen binding protein or antibody is a hybrid antigen binding protein or antibody, respectively, having two different antigen binding sites. Bispecific antigen binding proteins and antibodies are a species of multispccific antigen

2018203471 16 May 2018 binding protein or multispecific antibody and may be produced by a variety of methods including, but not limited to, fusion of hybridomas or linking of Fab' fragments. See, e.g„ Songsivilai and Lachmann, 1990, Clin. Exp. Immunol, 79:315-321; Kostelny et al., 1992,7. Immunol. 148:1547-1553. The two binding sites of a bispecific antigen binding protein or 5 antibody will bind to two different epitopes, which may reside on the same or different protein targets.

The term “neutralizing antigen binding protein” or “neutralizing antibody” refers to an antigen binding protein or antibody, respectively, that binds to a ligand, prevents binding of the ligand to its binding partner and interrupts the biological response that otherwise would result 10 from the ligand binding to its binding partner. In assessing the binding and specificity of an antigen binding protein, e.g., an antibody or immunologicalty functional antigen binding fragment thereof, an antibody or fragment will substantially inhibit binding of a ligand to its binding partner when an excess of antibody reduces the quantity of binding partner bound to the ligand by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%,

99% or more (as measured in an in vitro competitive binding assay). In the case of a CGRP R binding protein, such a neutralizing molecule will diminish the ability of CGRP R to bind CGRP.

The term compete”, when used in the context of antigen binding proteins that may bind the same region on a target antigen, means competition between antigen binding proteins is determined by an assay in which the antigen binding protein (e.g., antibody or immunologically functional antigen binding fragment thereof) under test prevents or inhibits specific binding of a reference antigen binding protein (e.g., a ligand, or a reference antibody) to a common antigen (e.g., CGRP R or an antigen binding fragment thereof). Any of a number of competitive binding assays can be used, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (ElA), sandwich competition assay (see, e.g., Stahli etal., 1983, Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland etal,, 1986,7. Immunol. 137:3614-3619) solid phase direct labeled assay, solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using 1-125 label (see, e.g., Morel etal., 1988, Molec, Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see, e.g., Cheung, etal., 1990, Virology 176:546-552); and direct labeled RIA (Moldenhauer etal., 1990, Scand. J, Immunol. 32:77-82). Such an assay may involve the use of purified antigen bound to a solid surface or cells bearing either of these, an un labelled test antigen binding protein and a labeled reference antigen binding

2018203471 16 May 2018 protein. Competitive inhibition may measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen binding protein. Antigen binding proteins identified by competition assay (competing antigen binding proteins) include antigen binding proteins binding to the same epitope as the reference antigen binding proteins and 5 antigen binding proteins binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antigen binding protein for stearic hindrance to occur. Usually, when a competing antigen binding protein is present in excess, it will inhibit specific binding of a reference antigen binding protein to a common antigen by at least 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%. In some instance, binding is inhibited by at least 80%, 85%, 90%, 95%, or 10 97% or more. Competitive inhibition may also be measured by immobilizing a reference antigen binding protein to a substrate, e.g., a “sensor chip”, capturing antigen on the substrate via binding to the reference antibody, and assaying whether a different antigen binding protein (a competing antigen binding protein) can additionally bind to the antigen. An example of the latter competitive binding assay employs a Biacore analysis, and 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 protein (including, e.g., an antibody or immunological functional antigen binding fragment thereof), and additionally capable of being used in an animal to produce antibodies capable of binding to that antigen. An antigen may possess one or more epitopes that arc capable of interacting with different antigen binding proteins, e.g., antibodies.

The term “epitope” is the portion of a molecule that is bound by an antigen binding protein (for example, an antibody). The term includes any determinant capable of specifically binding to an antigen binding protein, such as an antibody or to a T-cell receptor. An epitope can be contiguous or non-contiguous (e.g., (i) in a single-chain polypeptide, amino acid residues that are not contiguous to one another in the polypeptide sequence but that within in context of the molecule are bound by the antigen binding protein, or (ii) in a multimeric receptor, e.g., CGRP R, comprising two or more individual components, e.g., RAMP1 and CRLR, amino acid residues present on two or more of the individual components, but that within the context of the multimeric receptor are bound by the antigen binding protein). In certain embodiments, epitopes may be mimetic in that they comprise a three dimensional structure that is similar to an epitope used to generate the antigen binding protein, yet comprise none or only some of the amino acid residues found in that epitope used to generate the antigen binding protein. Most often, epitopes reside on proteins, but in some instances may reside on

2018203471 16 May 2018 other kinds of molecules, such as nucleic acids. Epitope determinants may incl ude chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three dimensional structural characteristics, and/or specific charge characteristics. Generally, antibodies specific for a particular target antigen 5 will preferentially recognize an epitope on the target antigen in a complex mixture of proteins and/or macromolcculcs.

The term “identity” refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. “Percent identity” means the percent of identical residues between 10 the amino acids or nucleotides in the compared molecules and is calculated based on the size of the smallest of the molecules being compared. For these calculations, gaps in alignments (if any) must be addressed by a particular mathematical model or computer program (i.e., an “algorithm”), Methods that can be used to calculate the identity of the aligned nucleic acids or polypeptides include those described in Computational Molecular Biology, (Lesk, A. M., ed.), 15 1988, New York: Oxford University Press; Biocomputing Informatics and Genome Projects, (Smith, D. W., cd.), 1993, New York: Academic Press; Computer Analysis of Sequence Data, Part 1, (Griffin, A. M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press; von Heinje, G., 1987, Sequence Analysis in Molecular Biology, New York: Academic Press; Sequence Analysis Primer, (Gribskov, M. and Devereux, J., eds.), 1991, New York: M. Stockton Press;

and Carillo et al., 1988, SIAM J. Applied Math. 48:1073.

In calculating percent identity, the sequences being compared are aligned in a way that gives the largest match between the sequences. The computer program used to determine percent identity is the GCG program package, which includes GAP (Devereux et al., 1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, WI).

The computer algorithm GAP is used to align the two polypeptides or polynucleotides for which the percent sequence identity is to be determined. The sequences are aligned for optimal matching of their respective amino acid or nucleotide (the “matched span”, as determined by the algorithm). A gap opening penalty (which is calculated as 3x the average diagonal, wherein the “average diagonal” is the average of the diagonal of the comparison matrix being 30 used; the “diagonal” is the score or number assigned to each perfect amino acid match by the particular comparison matrix) and a gap extension penalty (which is usually 1/10 times the gap opening penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62 are used in conjunction with the algorithm. In certain embodiments, a standard comparison matrix (.vce, Dayhoff et ah, 1978, Atlas of Protein Sequence and Structure 5:345-352 for the PAM 250

2018203471 16 May 2018 comparison matrix; HenikofF et al., 1992, Proc. Natl. Acad. Sci. U.S. A, 89; 10915-10919 for the BLOSUM 62 comparison matrix) is also used by the algorithm.

Recommended parameters for determining percent identity for polypeptides or nucleotide sequences using the GAP program are the following:

Algorithm: Needleman et al., 1970, J. Mol. Biol. 48:443-453;

Comparison matrix: BLOSUM 62 from HenikofF et al., 1992, supra',

Gap Penalty; 12 (but with no penalty for end gaps)

Gap Length Penalty: 4

Threshold of Similarity: 0

Certain alignment schemes for aligning two amino acid sequences may result in matching of only a short region of the two sequences, and this small aligned region may have very high sequence identity even though there is no significant relationship between the two full-length sequences. Accordingly, the selected alignment method (GAP program) can be adjusted if so desired to result in an alignment that spans at least 50 contiguous amino acids of the target polypeptide.

As used herein, “substantially pure means that the described species of molecule is the predominant species present, that is, on a molar basis it is more abundant than any other individual species in the same mixture. In certain embodiments, a substantially pure molecule is a composition wherein the object species comprises at least 50% (on a molar basis) of all macromolecular species present. In other embodiments, a substantially pure composition will comprise at least 80%, 85%, 90%, 95%, or 99% of all macromolecular species present in the composition. In other embodiments, the object species is purified to essential homogeneity wherein contaminating species cannot be detected in the composition by conventional detection methods and thus the composition consists of a single detectable macromolecular species.

The term “treating” refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.

The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, certain methods presented herein successfully treat migraine headaches either prophylactic ally or as an acute treatment, decreasing the frequency

2018203471 16 May 2018 of migraine headaches, decreasing the severity of migraine headaches, and/or ameliorating a symptom associated with migraine headaches.

An “effective amount” Ls generally an amount sufficient to reduce the severity and/or frequency of symptoms, eliminate the symptoms and/or underlying cause, prevent the 5 occurrence of symptoms and/or their underlying cause, and/or improve or remediate the damage that results from or is associated with migraine headache. In some embodiments, the effective amount is a therapeutically effective amount or a prophylactically effective amount.

A “therapeutically effective amount” is an amount sufficient to remedy a disease state (e.g. migraine headache) or symptoms, particularly a state or symptoms associated with the disease 10 state, or otherwise prevent, hinder, retard or reverse the progression ofthe disease state or any other undesirable symptom associated with the disease in any way whatsoever, A “prophylactically effective amount” is an amount of a pharmaceutical composition that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of migraine headache, or reducing the likelihood of the 15 onset (or reoccurrence) of migraine headache or migraine headache symptoms. The full therapeutic or prophylactic effect docs not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically or prophylactically effective amount may be administered in one or more administrations.

“Amino acid” includes its normal meaning in the art. The twenty naturally-occurring 20 amino acids and their abbreviations follow conventional usage. See, Immunology-A Synthesis, 2nd Edition, (E. S. Golub and D. R. Green, eds.), Sinauer Associates: Sunderland, Mass.

(1991), incorporated herein by reference for any purpose. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as α-,α-disubstituted amino acids, N-alkyl amino acids, and other unconventional amino acids may also be suitable 25 components for polypeptides and are included in the phrase “amino acid.” Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, ε-Ν,Ν,Νtrimethy I lysine, ε-Ν-acetyllysine, O-phosphoscrine, N-acetylserine, N-formylmethionine, 3methylhistidine, 5-hydroxylysinc, σ-Ν-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand 30 direction is the amino terminal direction and the right-hand direction is the carboxyl-terminal direction, in accordance with standard usage and convention.

General Overview

Antigen-binding proteins that bind CGRP R protein, including human CGRP R (hCGRP R) protein arc provided herein. The antigen binding proteins provided arc

2018203471 16 May 2018 polypeptides into which one or more complementary determining regions (CDRs), as described herein, are embedded and/or joined. In some antigen binding proteins, the CDRs are embedded into a “framework” region, which orients the CDR(s) such that the proper antigen binding properties of the CDR(s) is achieved. In general, antigen binding proteins that are 5 provided can interfere with, block, reduce or modulate the interaction between CGRP and CGRP R.

Certain antigen binding proteins described herein are antibodies or are derived from antibodies. In certain embodiments, the polypeptide structure of the antigen binding proteins is based on antibodies, including, but not limited to, monoclonal antibodies, bispecific antibodies, 10 minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), and fragments thereof. The various structures are further described herein below.

The antigen binding proteins provided herein have been demonstrated to bind to CGRP 15 R, in particular human CGRP R. As described further in the examples below, certain antigen binding proteins were tested and found to bind to epitopes different from those bound by a number of other antibodies directed against one or the other of the components of CGRP R.

The antigen binding proteins that are provided compete with CGRP and thereby prevent CGRP from binding to its receptor. As a consequence, the antigen binding proteins provided herein 20 are capable of inhibiting CGRP R activity. In particular, antigen binding proteins binding to these epitopes can have one or more of the following activities: inhibiting, inter alia, induction of CGRP R signal transduction pathways, inhibiting vasodialation, causing vasoconstriction, decreasing inflammation, e.g., neurogenic inflammation, and other physiological effects induced by CGRP R upon CGRP binding.

The antigen binding proteins that are disclosed herein have a variety of utilities. Some of the antigen binding proteins, for instance, arc useful in specific binding assays, affinity purification of CGRP R, in particular liCGRP R or its ligands and in screening assays to identify other antagonists of CGRP R activity. Some of the antigen-binding proteins are useful for inhibiting binding of CGRP to CGRP R.

The antigen-binding proteins can be used in a variety of treatment applications, as explained herein. For example, certain CGRP R antigen-binding proteins are useful for treating conditions associated with CGRP R mediated signaling, such as reducing, alleviating, or treating the frequency and/or severity of migraine headache, reducing, alleviating, or treating cluster headache, reducing, alleviating, or treating chronic pain, alleviating or treating

2018203471 16 May 2018 diabetes mellitus (type II), reducing, alleviating, or treating cardiovascular disorders, and reducing, alleviating, or treating hemodynamic derangements associated with endotoxemia and sepsis in a patient. Other uses for the antigen binding proteins include, for example, diagnosis of CGRP R-associated diseases or conditions and screening assays to determine the presence 5 or absence of CGRP R. Some of the antigen binding proteins described herein arc useful in treating consequences, symptoms, and/or the pathology associated with CGRP R activity. These include, but are not limited to, various types of migraine headaches.

CGRP Receptor

The antigen binding proteins disclosed herein bind to CGRP R, in particular human 10 CGRP R. CGRP R is a multimer that includes both CRLR and RAMPL The nucleotide sequence of human CRLR is provided herein as SEQ ID NO: I, The amino acid sequence of human CRLR is provided herein as SEQ ID NO:2. The nucleotide sequence of human RAMP I is provided herein as SEQ ID NO:3. The amino acid sequence of human RAMP I is provided herein as SEQ ID NO:4. The antigen binding proteins described herein bind the 15 extracellular portion of CGRP R, which comprises the extracellular portions of CRLR and RAMPL An exemplary extracellular domain (“ECD”) of human CRLR is encoded by the nucleotide sequence presented as SEQ ID NO:5, and has the amino acid sequence presented as SEQ ID NO:6. This sequence includes a signal peptide; an exemplaiy mature (minus the signal peptide) CRLR ECD has the amino acid sequence presented as SEQ ID NO: 10. An 20 exemplary ECD of human RAMP! is encoded by the nucleotide sequence presented as SEQ ID NO:7, and has the amino acid sequence presented as SEQ ID NO:8, This sequence includes a signal peptide; an exemplary mature (minus the signal peptide) RAMP1 ECD has the amino acid sequence presented as SEQ ID NO:11. As described below, CGRP R proteins may also include fragments. As used herein, the terms are used interchangeably to mean a receptor, in 25 particular, unless otherwise specified, a human receptor that binds specifically to CGRP.

The term CGRP R also includes post-translational modifications of the CGRP R amino acid sequence, for example, possible N-linked glycosylation sites. Thus, the antigen binding proteins may bind to or be generated from proteins glycosylated at one or more of the positions.

CGRP Receptor Binding Proteins

A variety of selective binding agents useful for regulating the activity of CGRP R are provided. These agents include, for instance, antigen binding proteins that contain an antigen binding domain (e.g., single chain antibodies, domain antibodies, immunoadhesions, and polypeptides with an antigen binding region) and specifically bind to CGRP R, in particular

2018203471 16 May 2018 human CGRP R. Some of the agents, for example, are useful in inhibiting the binding of CGRP to CGRP R, and can thus be used to inhibit, interfere with or modulate one or more activities associated with CGRP R signaling.

In general, the antigen binding proteins that are provided typically comprise one or more CDRs as described herein (e.g., 1, 2, 3, 4, 5 or 6). In some instances, the antigen binding protein comprises (a) a polypeptide structure and (b) one or more CDRs that are inserted into and/or joined to the polypeptide structure. The polypeptide structure can take a variety of different forms. For example, it can be, or comprise, the framework of a naturally occurring antibody, or fragment or variant thereof, or may be completely synthetic in nature. Examples 10 of various polypeptide structures are further described below.

In certain embodiments, the polypeptide structure of the antigen binding proteins is an antibody or is derived from an antibody, including, but not limited to, monoclonal antibodies, bispccific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), chimeric antibodies, humanized antibodies, antibody 15 fusions (sometimes referred to as “antibody conjugates”), and portions or fragments of each, respectively, In some instances, the antigen binding protein is an immunological fragment of an antibody (e.g., a Fab, a Fab’, a F(ab’)₂, or a scFv). The various structures are further described and defined herein.

Certain of the antigen binding proteins as provided herein specifically bind to human 20 CGRP R. In a specific embodiment, the antigen binding protein specifically binds to human CGRP R protein comprising human CRLR having the amino acid sequence of SEQ ID NO:2 and human RAMP1 having the amino acid sequence of SEQ ID NO:4,

In embodiments where the antigen binding protein is used for therapeutic applications, an antigen binding protein can inhibit, interfere with or modulate one or more biological activities of CGRP R. In this case, an antigen binding protein binds specifically and/or substantially inhibits binding of human CGRP R to CGRP when an excess of antibody reduces the quantity of human CGRP R bound to CGRP, or vice versa, by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% or more (for example by measuring binding in an in vitro competitive binding assay).

Naturally Occurring Antibody Structure

Some of the antigen binding proteins that are provided have the structure typically associated with naturally occurring antibodies. The structural units of these antibodies typically comprise one or more tetramers, each composed of two identical couplets of polypeptide chains, though some species of mammals also produce antibodies having only a

2018203471 16 May 2018 single heavy chain. In a typical antibody, each pair or couplet includes one full-length “light” chain (in certain embodiments, about 25 kDa) and one full-length heavy” chain (in certain embodiments, about 50-70 kDa). Each individual immunoglobulin chain is composed of several “immunoglobulin domains”, each consisting of roughly 90 to 1 10 amino acids and 5 expressing a characteristic folding pattern. These domains are the basic units of which antibody polypeptides are composed. The amino-terminal portion of each chain typically includes a variable domain that is responsible for antigen recognition. The carboxy-terminal portion is more conserved evolutionarily than the other end of the chain and is referred to as the “constant region” or “C region”. Human light chains generally are classified as kappa and 10 lambda light chains, and each of these contains one variable domain and one constant domain. Heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon chains, and these define the antibody's isotype as lgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subtypes, including, but not limited to, IgGl, lgG2, lgG3, and lgG4. IgM subtypes include IgM, and IgM2. IgA subtypes include IgAl and lgA2. In humans, the IgA and IgD isotypes 15 contain four heavy chains and four light chains; the IgG and IgE isotypes contain two heavy chains and two light chains; and the IgM isotype contains five heavy chains and five light chains. The heavy chain C region typically comprises one or more domains that may be responsible for effector function. The number of heavy chain constant region domains will depend on the isotype. IgG heavy chains, for example, each contain three C region domains 20 known as Ch 1, Ch2 and Cn3. The antibodies that are provided can have any of these isotypes and subtypes, in certain embodiments, the CGRP R antibody is of the IgG I, IgG2, or lgG4 subtype.

In full-length light and heavy chains, the variable and constant regions are joined by a “J” region of about twelve or more amino acids, with the heavy chain also including a “D” region of about ten more amino acids. See, e.g., Fundamental Immunology, 2nd cd., Ch. 7 (Paul, W., ed.) 1989, New York: Raven Press (hereby incorporated by reference in its entirety for all puiposes). The variable regions of each light/heavy chain pair typically form the antigen binding site.

One example of an IgG2 heavy constant domain of an exemplary CGRP R monoclonal antibody has the amino acid sequence;

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP

AVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAP

PVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFNWYVDGVEVHNAKTK

PREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQV

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YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (the last 326 residues of the sequence shown as SEQ. ID NO :29),

One example of a kappa Light Constant domain of an exemplary CGRP R monoclonal 5 antibody has the amino acid sequence:

RTVAAPSVF1FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (the last 107 residues of the sequence shown as SEQ ID NO: 14),

Variable regions of immunoglobulin chains generally exhibit the same overall 10 structure, comprising relatively conserved framework regions (FR) joined by three hypervariable regions, more often called “complementarity determining regions” or CDRs,

The CDRs from the two chains of each heavy chain/light chain pair mentioned above typically are aligned by the framework regions to form a structure that binds specifically with a specific epitope on the target protein (e.g., CGRP R). From N-terminal to C-tcrminal, natural ly15 occurring light and heavy chain variable regions both typically conform with the following order of these elements: FR1, CDRI, FR2, CDR2, FR3, CDR3 and FR4. A numbering system has been devised for assigning numbers to amino acids that occupy positions in each of these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, MD), or Chothia & Lesk, 1987, J. Moi, Biol. 196:901 20 917; Chothia et a!., 1989, Nature 342:878-883.

The various heavy chain and light chain variable regions provided herein are depicted in Table 3, Each of these variable regions may be attached to the above heavy and light chain constant regions to form a complete antibody heavy and light chain, respectively. Further, each of the so generated heavy and light chain sequences may be combined to form a complete 25 antibody structure. It should be understood that the heavy chain and light chain variable regions provided herein can also be attached to other constant domains having different sequences than the exemplary sequences listed above.

Specific examples of some of the full length light and heavy chains of the antibodies that are provided and their corresponding amino acid sequences are summarized in Tables 2A 30 and 2B. Table 2A shows exemplary light chain sequences, and Table 2B shows exemplary heavy chain sequences.

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Table 2A - Exemplary Antibody Light Chain Amino Acid Sequences

SEQ ID NO:	Design ation	Contained in Clone	Sequence
12	L1	01E11 LC	MDMRVPAQLLGLLLLWLRGARCQSVLTQPPSVSEAPGQKVTISC SGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGS KSGTSATLG1TGLQTGDEADYYCGTWDSRLSAWFGGGTKLTVL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ VTHEGSTVEKTVAPTECS
13	L2	01H7 LC	MDMRVPAQLLGLLLLWLRGARCQSVLTQPPSASGTPGQRVTISC SGSSSNIGSNYVYWYQQLPGAAPKLL1FRSNQRPSGVPDRFSGS KSGTSASLAISGLRSEDEADYYCAAWDDSLSGWVFGGGTKLTVL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ VTHEGSTVEKTVAPTECS
14	L3	02E7 LC	MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSLSASVGDRVTIT CRASQGIRNDLGWFQQKPGKAPKRLIYAASSLQSGVPSRFSGS GSGTEFTLTISSLQPEDLATYYCLQYNIYPWTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALG SGNSQESVTEGDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
15	L4	03B6 LC	MDMRVPAQLLGLLLLWLRGARCSSELTQDPTVSVALGGTVKITC QGDSLRSFYASWYQGKPGQAPVLVFYGKNNRPSGIPDRFSGSS SGNTASLTITGAQAEDEADYYCNSRDSSVYHLVLGGGTKLTVLG QPKANPTVTLFPPSSEELGANKATLVCLISDFYPGAVTVAWKADG SPVKAGVETTKPSKQSNNKYAASSYLSLTPEGWKSHRSYSCQV THEGSTVEKTVAPTECS
16	L5	03C8 LC	MDMRVPAQLLGLLLLWLRGARCDIILAQTPLSLSVTPGQPASISC KSSGSLLHSAGKTYLYWYLQKPGQPPQLLIYEVSNRFSGVPDRF SGSGSGTDFTLKISRVEAEDVGIYYCMQSFPLPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC
17	L6	04E4 LC	MDMRVPAQLLGLLLLWLRGARCQ5VLTQPPSVSAAPGGKVTISC

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			SGSSSNIGNNYVSWYGQLPGTAPKLLIYDNNKRPSGIPDRFSGS KSGTSTTLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVL GQPKANPTVTLFPPSSEELGANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEGWKSHRSYSCG VTHEGSTVEKTVAPTECS
18	L7	04H6 LC	MDMRVPAQLLGLLLLWLRGARCDIVMTQSPLSLPVTPGEPASISC RSSQSLLHSFGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRF SGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPFTFGPGTKVDI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC
19	L8	05F5 LC	MDMRVPAQLLGLLLLWLRGARCDHLTQTPLSLSVTPGQPASISC KSSQSLLHSDGKTYLYWYLQKPGQPPQLLIYEVSNRFSGEPDRF SGSGSGTDFTLKISRVEAEDVGTYYCMGSFPLPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC
20	L9	09D4 LC	MDMRVPAQLLGLLLLWLRGARCQSVLTQPPSVSAAPGQKVTISC SGSSSNIGNNYVSWYQQFPGTAPKLLIYDNNKRPSGIPDRFSGS KSGTSATLGITGLQTGDEADYYCGTWDSRLSAVVFGGGTKLTVL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEGWKSHRSYSCQ VTHEGSTVEKTVAPTECS
21	L10	09F5 LC	MDMRVPAQLLGLLLLWLRGARCQSVLTQSPSASGTPGQRVTISC SGSSSNIGSNYVYWYQQLPGAAPKLLILRNNQRPSGVPDRFSGS KSGTSASLTISGLRSEDEADYYCAAWDDSLSGWVFGGGTKLTVL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEGWKSHRSYSCG VTHEGSTVEKTVAPTECS
22	L11	10E4LC	MDMRVPAQLLGLLLLWLRGARCQSVLTGPPSASGTPGGRVTISC SGSSSNIGSNTVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGS KSGTSASLAISGLQSEDEADFYCAARDESLNGVVFGGGTKLTVL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ

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			VTHEGSTVEKTVAPTECS
23	L12	11D11 HL 11H9 LC	MDMRVPAGLLGLLLLWLRGARCQSVLTQPPSASGTPGGRVTISC SGSSSNIGSNYVYWYGGLPGAAPKLLIFRNNQRPSGVPDRFSGS KSGTSASLAISGLRSEDEADYYCAAWDDSLSGWVFGGGTKLTVL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ VTHEGSTVEKTVAPTECS
24	L13	12E8 LC	MDMRVPAQLLGLLLLWLRGARCDITLTQTPLSLSVSPGQPASISC KSSQSLLHSDGRNYLYWYLQKPGQPPQLLIYEVSNRFSGLPDRF SGSGSGTDFTLKISRVEAEDVGIYYCMGSFPLPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC
25	L14	12G8HL	MDMRVPAQLLGLLLLWLRGARCQSVLTQPPSVSAAPGQKVTISC SGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSGS KSGTSATLGITGLQTGDEADYYCGTWDSRLSAWFGGGTKLTVL GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD GSPVKAGVETTKPSKQSNNKYAASSYLSLTPEGWKSHRSYSCG VTHEGSTVEKTVAPTECS
26	L15	13H2 LC	MDMRVPAQLLGLLLLWLRGARCDIGMTQSPSSLSASVGDRVTIT CRASQGIRKDLGWYQQKPGKAPKRLIYGASSLQSGVPSRFSGS GSGTEFTLTISSLQPEDFATYYCLGYNSFPWTFGQGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH GGLSSPVTKSFNRGEC
27	L16	32H7 LC	METPAQLLFLLLLWLPDTTGEIVLTGSPGTLSLSPGERATLSCRA SQSVSSGYLTWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSG TDFTLTISRLEPEDFAVYYCQQYGNSLCRFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHGGL SSPVTKSFNRGEC
28	L17	32H7 CS LC	METPAGLLFLLLLWLPDTTGEIVLTGSPGTLSLSPGERATLSCRA SQSVSSGYLTWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSG TDFTLTISRLEPEDFAVYYCQQYGNSLSRFGQGTKLEIKRTVAAP

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SVF1FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALGSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC

Table 2B - Exemplary Antibody Heavy Chain Amino Acid Sequences

SEQ ID NO:	Design ation	Contained in Clone	Sequence
29	H1	01E11 HC 04E4 HC 09D4 HC	MDMRVPAGLLGLLLLWLRGARCQVGLVESGGGWQPGRSLRLS CAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVK GRFT1SRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGY YHYKYYGMAVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCP APPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEY KCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNGVS LTCLVKGFYPSDIAVEWESNGGPENNYKTTPPMLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
30	H2	01H7HC 1	MDMRVPAQLLGLLLLWLRGARCEVQLVESGGGLVKPGGSLRLS CAASGFTFSNAWMSWVRQAPGKGLEWVGRIKSTTDGGTTDYAA PVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTDRTGYSISW SSYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLGSSGLYSL SSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVGF NWYVDGVEVHNAKTKPREEGFNSTFRWSVLTWHQDWLNGKE YKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
31	H3	02E7 HC 1	MDMRVPAQLLGLLLLWLRGARCEVQLLESGGGLVQPGESLRLS CAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGRTYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDQREVGPYSS GWYDYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

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			SSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQF NWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKE YKCKVSNKGLPAPIEKTISKTKGQPREPGVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTGKSLSLSPGK
32	H4	03B6 HC	MDMRVPAGLLGLLLLWLRGARCQVQLVQSGAEVKKPGASVKVS CKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQK FQGRVTMTRDTSISTAYMELSRLRSDDTAVYFCARDQMSIIMLRG VFPPYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCP APPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEY KCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYS KLTVDKSRWGQGNVFSCSVMHEALHNHYTGKSLSLSPGK
33	H5	03C8 HC 05F5 HC 12E8 HC	MDMRVPAQLLGLLLLWLRGARCQVQLVESGGGVVQPGRSLRLS CAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSHESYADSV KGRFTISRDISKNTLYLQMNSLRAEDTAVYFCARERKRVTMSTLY YYFYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAP PVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNW YVDGVEVHNAKTKPREEGFNSTFRVVSVLTVVHQDWLNGKEYK CKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKKPPMLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
34	H6	04H6 HC	MDMRVPAQLLGLLLLWLRGARCEVQLVESGGGLVKPGRSLRLS CTASGFTFGDYAMSWFRQAPGKGLEWIGFIRSRAYGGTPEYAAS VKGRFTISRDDSKTIAYLQMNSLKTEDTAVYFCARGRGIAARWDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFFAVLQSSGLYSLSSWTVPSSNFG TQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFL

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			FPPKPKDTLMISRTPEVTCWVDVSHEDPEVGFNWYVDGVEVHN AKTKPREEQFNSTFRWSVLTWHQDWLNGKEYKCKVSNKGLPA PJEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGGPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWG QGNVFSCSVMHEALHNHYTQKSLSLSPGK
35	H7	09F5 HC	MDMRVPAGLLGLLLLWLRGARCEVGLVESGGGLVKPGGSLRLS CAASGFTFSNAWMSWVRGAPGKGLEWVGRIKSKTDGGTTDYTA PVKGRFTISRDDSKNTLYLQMNSLKAEDTAVYYCTTDRTGYSISW SSYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVGF NWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKE YKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
36	H8	10E4 HC	MDMRVPAQLLGLLLLWLRGARCQVQLVQSGAEVKKPGASVKVS CKASGYTFTDYYMYWVRQAPGQGLEWMGWISPNSGGTNYAQK FQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCVRGGYSGYAGL YSHYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS WTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA PPVAGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEY KCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTGKSLSLSPGK
37	H9	11D11 HC	MDMRVPAQLLGLLLLWLRGARCEVQLVESGGGLVKPGGSLRLS CAASGFTFGNAWMSWVRQAPGKGLEWVGRIKSKTDGGTTDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYFCTTDRTGYStS WSSYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPP CPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQ

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			FNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTWHGDWLNGK EYKCKVSNKGLPAPIEKTISKTKGGPREPQVYTLRPSREEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKnPPMLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
38	H10	11H9HC	MDMRVPAQLLGLLLLWLRGARCEVQLVESGGGLVKPGGSLRLS CAASGFTFGNAWMSWVRQAPGKGLEWVGRIKSKTDGGnDYA APVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTDRTGYSIS WSSYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPP CPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQ FNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTVVHQDWLNGK EYKCKVSNKGLPAPIEKTISKTKGQPREPGVYTLPPSREEMTKNG VSLTCLVKGFYPSDIAVEWESNGQPENNYKnPPMLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
39	H11	12G8 HC	MDMRVPAQLLGLLLLWLRGARCQVGLVESGGGWQPGRSLRLS CAASGFTFSSFGMHWVRQAPGKGLEWVAVISFDGSIKYSVDSVK GRFTISRDNSKNTLFLQMNSLRAEDTAVYYCARDRLNYYDSSGY YHYKYYGLAVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS WTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPA PPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEY KCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNGVS LTCLVKGFYPSDIAVEWESNGQPENNYKKPPMLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
40	H12	13H2HC	MDMRVPAGLLGLLLLWLRGARCEVGLVESGGGLVKPGGSLRLS CAASGYTFSTYSMNWVRQAPGKGLEWVSSISSSSSYRYYADSV KGRFTISRDNAKNSLYLQMSSLRAEDTAVYYCAREGVSGSSPYSI SWYDYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVFCPPC PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVGF NWYVDGVFVHNAKTKPREEQFNSTFRVVSVLTWHQDWLNGKE

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			YKCKVSNKGLPAPIEKTISKTKGQPREPGVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
41	H13	32H7 HC	MDMRVPAQLLGLLLLWLRGARCQVQLVESGGGWQPGRSLRLS CAASGFTFSSYGMHVWRQAPGKGLEWVAVIWYDGSNKYYADS VKGRFIISRDKSKNTLYLQMNSLRAEDTAVYYCARAGGIAAAGLY YYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPP VAGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVGFNWY VDGVEVHNAKTKPREEQFNSTFRVVSVLTWHQDWLNGKEYKC KVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKKPPMLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

The first 22 amino acids of each of the light chain sequences in Table 2A, except 32H7 and 32H7 CS, is a signal sequence. In the case of 32H7 and 32H7 CS, the signal sequence is 20 amino acids. Similarly, the first 22 amino acids of each of the heavy chain sequences in

Table 2B is a signal sequence. The signal peptides may be changed to signal peptides having different sequences, e.g., for more optimal expression in certain host cells. It will be therefore be understood that the invention also includes antibodies having the light and/or heavy chain sequences as specified in Tables 2A and 2B, but with different signal sequences.

Again, each of the exemplary heavy chains (Hl, H2, H3 etc.) listed in Table 2B can be combined with any of the exemplary light chains shown in Table 2A to form an antibody. Examples of such combinations include Hl combined with any of LI through L17; H2 combined with any of LI through L17; H3 combined with any of Li through LI 7, and so on. In some instances, the antibodies include at least- one heavy chain and one light chain from those listed in Tables 2A and 2B. In some instances, the antibodies comprise two different heavy chains and two different light chains listed in Tables 2A and 2B, In other instances, the antibodies contain two identical light chains and two identical heavy chains. As an example, an antibody or immunologically functional fragment may include two Hl heavy chains and two L1 light chains, or two H2 heavy chains and two L2 light chains, or two H3 heavy chains and two L3 light chains and other similar combinations of pairs of light chains and pairs of heavy chains as listed in Tables 2A and 2B.

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Other antigen binding proteins that are provided are variants of antibodies formed by combination of the heavy and light chains shown in Tables 2A and 2B and comprise light and/or heavy chains that each have at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% identity to the amino acid sequences of these chains. In some instances, such antibodies 5 include at least one heavy chain and one light chain, whereas in other instances the variant forms contain two identical light chains and two identical heavy chains.

Variable Domains of Antibodies

Also provided are antigen binding proteins that contain an antibody heavy chain variable region selected from the group consisting of Vul, Vh2, Vji3, Vh4, Vh5, Vh6, Vn7,

Vn8, Vh9, VnlO, Vul 1, Vnl2, and Vnl3, and/or an antibody light chain variable region selected from the group consisting of VlI, Vl2, Vl3, Vl4, Vl5, Vl6, Vi_7, Vl8, Vl9, Vl10,

V_L11, V,.12, V_l13, V_l14, V_l15, V_L16, and V_l17, as shown in Table 3 below, and immunologically functional fragments, derivatives, mutcins and variants of these light chain and heavy chain variable regions.

Sequence alignments of the various heavy and light chain variable regions, respectively, are provided in Figs. 1A and IB.

Antigen binding proteins of this type can generally be designated by the formula Vnx/ Vi.y, where x corresponds to the number of heavy chain variable regions and y corresponds to the number of the light chain variable regions.

Table 3: Exemplary Vn and V_L Chain Amino Add Sequences

Contained in Clone	Designation	SEQ ID NO.	Amino Acid Sequence
1E11	VL1	137	QSVLTQPPSVSEAPGQKVTISCSGSSSNIGNNYVSWYQQLP GTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDE ADYYCGTWDSRLSAWFGGGTKLTVL
1H7	Vl2	138	QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLP GAAPKLLIFRSNQRPSGVPDRFSGSKSGTSASLAISGLRSED EADYYCAAWDDSLSGWVFGGGTKLTVL
2E7	Vl3	139	DIQMTQSPSSLSASVGDRVTITCRASGGIRNDLGWFQQKPG KAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDLA TYYCLQYNIYPWTFGQGTKVEIK

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Contained in Clone	Designation	SEQ ID NO.	Amino Acid Sequence
3B6	Vl4	140	SSELTQDPTVSVALGQTVKITCQGDSLRSFYASWYQQKPGQ APVLVFYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEA DYYCNSRDSSVYHLVLGGGTKLTVL
3C8	Vl5	141	DIILAQTPLSLSVTPGQPASISCKSSQSLLHSAGKTYLYWYLG KPGQPPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEA EDVGIYYCMQSFPLPLTFGGGTKVEIK
4E4	Vl6	142	QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLP GTAPKLLIYDNNKRPSGIPDRFSGSKSGTSTTLGITGLQTGDE ADYYCGTWDSRLSAWFGGGTKLTVL
4H6	Vl7	143	DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSFGYNYLDWYL 1 QKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVE ' AEDVGVYYCMQALQTPFTFGPGTKVDIK
5F5	Vl8	144	DIILTQTPLSLSVTPGQPASISCKSSQSLLHSDGKTYLYWYLQ KPGQPPQLLIYEVSNRFSGEPDRFSGSGSGTDFTLKISRVEA EDVGTYYCMQSFPLPLTFGGGTKVEIK
9D4	Vl9	145	QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQFP GTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLGTGDE ' ADYYCGTWDSRLSAWFGGGTKLTVL
9F5	Vl10	146	QSVLTQSPSASGTPGQRVTISCSGSSSNIGSNYVYWYGQLP GAAPKLLILRNNQRPSGVPDRFSGSKSGTSASLTISGLRSED EADYYCAAWDDSLSGWVFGGGTKLTVL
10E4	Vl11	147	QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLP GTAPKLLIYTNNQRPSGVPDRFSGSKSGTSASLAISGLQSED EADFYCAARDESLNGWFGGGTKLTVL
11D11 11H9	Vl12	148	QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLP GAAPKLLIFRNNGRPSGVPDRFSGSKSGTSASLAISGLRSED EADYYCAAWDDSLSGWVFGGGTKLTVL

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Contained in Clone	Designation	SEQ ID NO.	Amino Acid Sequence
12E8	VL13	149	DITLTQTPLSLSVSPGQPASISCKSSQSLLHSDGRNYLYWYL QKPGQPPQLLIYEVSNRFSGLPDRFSGSGSGTDFTLKISRVE AEDVG1YYCMQSFPLPLTFGGGTKVEIK
12G8	Vl14	150	QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLP GTAPKLUYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDE ADYYCGTWDSRLSAWFGGGTKLTVL
13H2	Vl15	151	DIQMTQSPSSLSASVGDRVTITCRASGGIRKDLGWYQQKPG KAPKRLIYGASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFA TYYCLQYNSFPWTFGGGTKVEIK
32H7	Vl16	152	EIVLTQSPGTLSLSPGERATLSCRASQSVSSGYLTWYQQKP GQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDF AVYYCQQYGNSLCRFGQGTKLEIK
32H7 CS	Vl17	153	EIVLTQSPGTLSLSPGERATLSCRASQSVSSGYLTWYQQKP GQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDF AVYYCQQYGNSLSRFGQGTKLEIK
32H8	Vl18	154	DIVMTQSPDSLAVSLGERATINCKSSQSILDSSNNDNYLAWY QQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSL QAEDVAVYYCQQYYNTPFTFGPGTKVDIK
33B5	Vl19	155	DIQMTQSPSSLSASVGDRVTITCRASGGIRNDLGWYQQKPG KAPKRLIYVASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFA TYYCLQYNTYPLTFGGGTKVEIK
33E4	Vl20	156	EIVMTQSPATLSVSPGERATLSCRASQSVRSNLAWYQQKPG QAPRLLIHDASPRTAGIPARFSGSGSGTEFTLTINSLQSEDFA ' VYYCQQYNYWTPITFGQGTRLEIK
34E3	Vl21	157	QSVLTQPPSMSAAPGQKVTISCSGSSSNIGNNYVSWYQQLP GTAPKLLIYDNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDE ANYCCGTWDIGLSVWVFGGGTKLTVL

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Contained in Clone	Designation	SEQ ID NO.	Amino Acid Sequence
4E4 9D4 1E11	Vh1	158	QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQA ‘PGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQ MNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGMAVWGQ GTTVTVSS
1H7	Vh2	159	EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQA PGKGLEWVGRIKSTTDGGTTDYAAPVKGRFTISRDDSKNTLY 'LQMNSLKTEDTAVYYCTTDRTGYSISWSSYYYYYGMDVWG QGTTVTVSS
2E7	Vh3	160	EVQLLESGGGLVQPGESLRLSCAASGFTFSSYAMSWVRQA PGKGLEWVSAISGSGGRTYYADSVKGRFTISRDNSKNTLYL 1 QMNSLRAEDTAVYYCAKDQREVGPYSSGWYDYYYGMDVW GQGTTVTVSS
3B6	Vh4	161	QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQA PGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAY MELSRLRSDDTAVYFCARDGMSIIMLRGVFPPYYYGMDVWG QGTTVTVSS
3C8 12E8 5F5	Vh5	162	QVQLVESGGGWQPGRSLRLSCAASGFTFSSYGMHWVRQA 1 PGKGLEWVAVISYDGSHESYADSVKGRFTISRDISKNTLYLQ MNSLRAEDTAVYFCARERKRVTMSTLYYYFYYGMDVWGQG TTVTVSS
4H6	Vh6	163	EVQLVESGGGLVKPGRSLRLSCTASGFTFGDYAMSWFRQA ‘ PGKGLEWIGFIRSRAYGGTPEYAASVKGRFTISRDDSKTIAYL QMNSLKTEDTAVYFCARGRGIAARWDYWGQGTLVTVSS
9F5	Vh7	164	EVQLVESGGGLVKPGGSLRLSCAASGFTFSNAWMSWVRQA PGKGLEWVGRIKSKTDGGTTDYTAPVKGRFTISRDDSKNTLY iLQMNSLKAEDTAVYYCTTDRTGYSISWSSYYYYYGMDWVG QGTTVTVSS

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Contained in Clone	Designation	SEQ ID NO.	Amino Acid Sequence
10E4	Vh8	165	QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMYWVRQA PGQGLEWMGWISPNSGGTNYAQKFGGRVTMTRDTSISTAY MELSRLRSDDTAVYYCVRGGYSGYAGLYSHYYGMDVWGQ GTTVTVSS
11D11	Vh9	166	EVQLVESGGGLVKPGGSLRLSCAASGFTFGNAWMSWVRQA PGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDDSKNTLY LQMNSLKTEDTAVYFCTTDRTGYSISWSSYYYYYGMDVWG QGTTVTVSS
11H9	Vh10	167	EVQLVESGGGLVKPGGSLRLSCAASGFTFGNAWMSWVRQA PGKGLEWVGRIKSKTDGGTTDYAAPVKGRFTISRDDSKNTLY LQMNSLKTEDTAVYYCTTDRTGYSISWSSYYYYYGMDVWG , QGTTVTVSS
12G8	Vh11	168	QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQA- PGKGLEWVAVISFDGSIKYSVDSVKGRFTISRDNSKNTLFLQ MNSLRAEDTAVYYCARDRLNYYDSSGYYHYKYYGLAVWGQ GTTVTVSS
13H2	Vh12	169	EVQLVESGGGLVKPGGSLRLSCAASGYTFSTYSMNWVRQA PGKGLEWVSSISSSSSYRYYADSVKGRFTISRDNAKNSLYLQ MSSLRAEDTAVYYCAREGVSGSSPYSISWYDYYYGMDVWG QGTTVTVSS
32H7	Vh13	170	QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQA PGKGLEWVAVIWYDGSNKYYADSVKGRFIISRDKSKNTLYLQ MNSLRAEDTAVYYCARAGGIAAAGLYYYYGMDVWGQGTTV TVSS
32H8	Vh14	171	QVQLVQSGAEVKKPGASVKVSCKASGYTFTAYYLHWVRQA PGQGLEWMGWINPHSGGTNYAQKFQGRVTMTRDTSISTAY MELSRLRSDDTAVFYCARGRQWLGFDYWGQGTLVTVSS

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Contained in Clone	Designation	SEQ ID NO.	Amino Acid Sequence
33E4	Vh15	172	QVQLQQWGAGLLKPSETLSLSCAVYGGSFGGYYWSWIRQP PGKGLEWIGEINHSGGTKYNPSLKSRVTISVDTSKNQFSLKL SSVTAADTAVYFCARGDWGFFDYWGQGTLVTVSS
33B5	Vh16	173	QVQLVQSGAEVKKSGASVKVSCKASGYTFTGYYMHWVRQA PGQGLEWMGWINPNSGGTNYVGKFQGRVTMTRDTSISTAY MELSRLRSDDTAVYYCARNEYSSAWPLGYWGQGTLVTVSS
34E3	Vh17	174	QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVAWIRQPP GKALEWLALIYWTDDKRYSPSLKSRLTITKDTSKNQWLRMT NMDPLDTATYFCAHRPGGWFDPWGQGTLVTVSS

Each of the heavy chain variable regions listed in Table 3 may be combined with any of the light chain variable regions shown in Table 3 to form an antigen binding protein.

Examples of such combinations include Vnl combined with any of VlI, V_l2, Vl3, V_l4, Vl5,

V, 6, Vi.7, V_l8, V₍9, V_t10, VJ], VrlZ, V_l13, V,J4, V,. 15, V_r.I6, or V,J7; V_h2 combined with any of V_r.1, V_L2, V_l3, Vi 4, V,.5, V_L6, V_u7, V_f 8, V_r.9, V_LIO, V_L11, V_L12, V,.I3, V_t14, Vl>5, V| 16, or V_L17; Vh3 combined with any of V_L1, V_L2, Vl3, V_L4, Vl5, Vl6, V_l7, Vl8, V_l9, V_l10, V_L11, V_l12, V_l13, V_l14, V_l15, V_l16, or VJ7; and so on.

In some instances, the antigen binding protein includes at least one heavy chain variable region and/or one light chain variable region from those listed in Table 3. In some instances, the antigen binding protein includes at least two different heavy chain variable regions and/or light chain variable regions from those listed in Table 3. An example of such an antigen binding protein comprises (a) one Vnl, and (b) one of Vn2, Vn3, Vn4, Vn5, Vn6, Vu7, Vn8, Vh9, VhIO, VhII, Vh12, or Vnl3. Another example comprises (a) one Vn2, and (b) one of Vnl, V_n3, Vh4, V_h5, V_n6, Vu7, V_h8, V_n9, V_n10, Vnl 1, Vnl2, or V_HI3. Again another example comprises (a) one Vh3, and (b) one of Vnl, Vn2, Vn4, Vn5, Vn6, V„7, Vn8, Vn9,

V_H10, V_H11, V_H12, or V_h13, etc. Again another example of such an antigen binding protein comprises (a) one Vi 1, and (b) one of Vi.2, V_t.3, V_L4, V_L5, V_t6, V_L7, V_r8, V₍.9, V_L10, V_L11, Vi. 12, Vi.I3, V[,14, Vi, 15, VlI 6, or V_L17, Vi,18, VlI 9, Vj.20, or V_t21. Again another example of such an antigen binding protein comprises (a) one Vi.2, and (b) one of VlI, Vr.3, Vl4, Vi.5,

V_l6, V_l7, V_l8, V_l9, V_l10. V_lB, V_l12, V_l13, V_l14, V_l15, V_lI6, V_l17, V_l18, V_l19, V_l20, or Vl21 . Again another example of such an antigen binding protein comprises (a) one Vl3,

2018203471 16 May 2018 and (b) one of V_L1, V_L2, V_L4, V_L5, V_L6, V_L7, V_L8, V_L9, V_r_10, Vt.ll, VJ2, V_L13, V_L14, V_l15, V_lI6, V_l17, V_l18,V_l19, V_l20,or V_L21, etc.

The various combinations of heavy chain variable regions may be combined with any of the various combinations of light chain variable regions as is apparent to one of skill in the 5 art.

In other instances, the antigen binding protein contains two identical light chain variable regions and/or two identical heavy chain variable regions. As an example, the antigen binding protein may be an antibody or immunologically functional fragment that includes two light chain variable regions and two heavy chain variable regions in combinations of pairs of 10 light chain variable regions and pairs of heavy chain variable regions as listed in Table 3.

Some antigen binding proteins that are provided comprise a heavy chain variable domain comprising a sequence of amino acids that differs from the sequence of a heavy chain variable domain selected from V_Hl, V_H2, V_H3, Vh4, V^S, V_H6, V_H7, Vh8, V_h9, V_h10, V_h1 1, V_h12, and Vh33 at only 1,2, 3, 4, 5,6, 7, 8, 9, 10, II, 12, 13, 14 or 15 amino acid residues, wherein each such sequence difference is independently either a deletion, insertion or substitution of one amino acid, with the deletions, insertions and/or substitutions resulting in no more than 15 amino acid changes relative to the foregoing variable domain sequences. The heavy chain variable region in some antigen binding proteins comprises a sequence of amino acids that has at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity to the 20 amino acid sequences of the heavy chain variable region of Vnl, Vn2, Vn3, Vn4, Vn5, Vyb, Vu7, V_n8, Vj[9, VhIO, V„11, V_H12, and V_n13.

Certain antigen binding proteins comprise a light chain variable domain comprising a sequence of amino acids that differs from the sequence of a light chain variable domain selected from V,.l, V_t2, V_b3, V_L4, V_t5, V,6, V_L7, V_t8, Vj.9, V_L10, V,.l 1, V,.12, V,.13, V,.14, 25 Vi_15, Vj. 16, or V[.17 at only 1,2, 3,4, 5, 6, 7, 8, 9, 10, II, 12, 13, 14 or 15 amino acid residues, wherein each such sequence difference is independently cither a deletion, insertion or substitution of one amino acid, with the deletions, insertions and/or substitutions resulting in no more than 15 amino acid changes relative to the foregoing variable domain sequences. The light chain variable region in some antigen binding proteins comprises a sequence of amino 30 acids that has at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity to the amino acid sequences ofthe light chain variable region of V_L1, Vl2, V_l3, Vi4, V_L5, Vl6, V_l7, V_l8, Vl9, V_l10, V_L11, V_L12, V_L13, V_L14, V_LI5, V_L16,or V_L17.

In additional instances, antigen binding proteins comprise the following pairings of light chain and heavy chain variable domains: VL1 with VHl, VL2 with VH2, VL3 with VH3,

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VL4 with VH4, VL5 with VH5, VL6 with VHI, VL7 with VH6, VL8 with VH5, VL9 with VHI, VL10 with VH7, VL11 with , H8, VL12 with VH9, VL12 with VHIO, VL13 with VH5, VL14 with VHI 1, VL15 with VHI2, VL16 with VH13, and VL17 with VH13. In some instances, the antigen binding proteins in the above pairings may comprise amino acid 5 sequences that have 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity with the specified variable domains.

Still other antigen binding proteins, e.g., antibodies or immunologically functional fragments, include variant forms of a variant heavy chain and a variant light chain as just described.

CDRs

The antigen binding proteins disclosed herein are polypeptides into which one or more CDRs are grafted, inserted and/or joined. An antigen binding protein can have 1,2, 3, 4, 5 or 6 CDRs. An antigen binding protein thus can have, for example, one heavy chain CDR1 (“CDRH1”), and/or one heavy chain CDR2 (“CDRH2), and/or one heavy chain CDR3 15 (“CDRH3”), and/or one light chain CDR1 (“CDRLI”), and/or one light chain CDR2 (“CDRL2”), and/or one light chain CDR3 (“CDRL3”). Some antigen binding proteins include both a CDRH3 and a CDRL3. Specific heavy and light chain CDRs are identified in Tables 4A and 4B, respectively.

Complementarity determin ing regions (CDRsJ and framework regions (FR) of a given 20 antibody may be identified using the system described by Rabat et al. in Sequences of Proteins of Immunological Interest, 5th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991. Certain antibodies that are disclosed herein comprise one or more amino acid sequences that are identical or have substantial sequence identity to the amino acid sequences of one or more of the CDRs presented in Table 4A (CDRHs) and Table 4B (CDRLs).

Table 4A: Exemplary Heavy Chain CDR Amino Acid Sequences

Alt Num	SEQ ID NO:	Contained in Reference	Designation	Sequence
42	73	1E11HCDR1 4E4HCDR1 9D4HCDR1 12G8HCDR1	CDRH 1-1	SFGMH

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Alt Num	SEQ ID NO;	Contained in Reference	Designation	Sequence
43	76	1H7HCDR1 9F5HCDR1 11D11HCDR1 11H9HCDR1	CDRH 1-2	NAWMS
44	79	2E7HCDR1	CDRH 1-3	SYAMS |
45	82	3B6HCDR1	CDRH 1-4	GYYMH ||
46	85	3C8HCDR1 5F5HCDR1 12E8HCDR1	CDRH 1-5	SYGMH
47	88	4H6HCDR1	CDRH 1-6	DYAMS
48	92	10E4HCDR1	CDRH 1-7	DYYMY
49	97	13H2HCDR1	CDRH 1-8	TYSMN
50	100	32H7HCDR1	CDRH 1-9	SYGMH
51	74	1E11HCDR2 4E4HCDR2 9D4HCDR2 12G8HCDR2	CDRH 2-1	VISFDGSIKYSVDSVKG
52	77	1H7HCDR2	CDRH 2-2	RIKSTTlDGGnDYAAPVKG
53	80	2E7HCDR2	CDRH 2-3	AISGSGGRTYYADSVKG |
54	83	3B6HCDR2	CDRH 2-4	WINPNSGGTNYAQKFQG
55	86	3C8HCDR2 5F5HCDR2 12E8HCDR2	CDRH 2-5	VISYDGSHESYADSVKG
56	89	4H6HCDR2	CDRH 2-6	FIRSRAYGGTPEYAASVKG |
57	91	9F5HCDR2	CDRH 2-7	RIKSKTDGGTTDYTAPVKG
58	93	10E4HCDR2	CDRH 2-8	WISPNSGGTNYAQKFQG

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Alt Num	SEQ ID NO;	Contained in Reference	Designation	Sequence
59	95	11D11HCDR2 11H9HCDR2	CDRH 2-9	RIKSKTDGGHDYAAPVKG
60	98	13H2HCDR2	CDRH 2-10	SISSSSSYRYYADSVKG
61	101	32H7HCDR2	CDRH 2-11	VtWYDGSNKYYADSVKG
62	75	1E11HCDR3 4E4HCDR3 9D4HCDR3	CDRH 3-1	DRLNYYDSSGYYHYKYYGMAV
63	78	1H7HCDR3 9F5HCDR3 11D11HCDR3 11H9HCDR3	CDRH 3-2	DRTGYSISWSSYYYYYGMDV
64	81	2E7HCDR3	CDRH 3-3	DQREVGPYSSGWYDYYYGMDV ,
65	84	3B6HCDR3	CDRH 3-4	DQMSIIMLRGVFPPYYYGMDV
66	87	3C8HCDR3 5F5HCDR3 12E8HCDR3	CDRH 3-5	ERKRVTMSTLYYYFYYGMDV
67	90	4H6HCDR3	CDRH 3-6	GRGIAARWDY
68	94	10E4HCDR3	CDRH 3-7	GGYSGYAGLYSHYYGMDV
69	96	12G8HCDR3	CDRH 3-8	DRLNYYDSSGYYHYKYYGLAV |
70	99	13H2HCDR3	CDRH 3-9	EGVSGSSPYSISWYDYYYGMDV
71	102	32H7HCDR3	CDRH 3-10	AGGIAAAGLYYYYGMDV

Table 4B: Exemplary Light Chain CDR Amino Acid Sequences

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Alt Num	SEQ ID NO:	Contained in Reference	Designation	I Sequence
72	42	1E11LCD1 4E4LCD1 9D4LCD1 12G8LCD1	CDRL1-1	SGSSSNIGNNYVS
73	45	1H7LCD1 9F5LCD1 11D11LC1 11H9LCD1	CDRL 1-2	SGSSSNIGSNYVY
74	48	2E7LCD1	CDRL 1-3	RASQGIRNDLG
75	51	3B6LCD1	CDRL 1-4	QGDSLRSFYAS
76	54	3C8LCD1	CDRL 1-5	KSSQSLLHSAGKTYLY
77	57	4H6LCD1	CDRL 1-6	RSSQSLLHSFGYNYLD
78	60	5F5LCD1	CDRL 1-7	KSSQSLLHSDGKTYLY
79	62	10E4LCD1	CDRL 1-8	SGSSSNIGSNTVN
80	65	12E8LCD1	CDRL 1-9	KSSQSLLHSDGRNYLY »
81	66	13H2LCD1	CDRL 1-10	RASQGIRKDLG ||
82	69	_32H7 LCD1 32H7m LCD1	CDRL 1-11	RASQSVSSGYLT
83	43	1E11LCD2 4E4LCD2 9D4LCD2 12G8LCD2	CDRL 2-1	DNNKRPS
84	46	1H7LCD2	CDRL 2-2	RSNGRPS
85	49	2E7LCD2	CDRL 2-3	AASSLQS
86	52	3B6LCD2	CDRL 2-4	GKNNRPS

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Alt Num	SEQ ID NO;	Contained in Reference	Designation	Sequence
87	55	3C8LCD2 5F5LCD2 12E8LCD2	CDRL 2-5	EVSNRFS
88	58	4H6LCD2	CDRL 2-6	LGSNRAS
89	61	9F5LCD2 11D11LC2 11H9LCD2	CDRL 2-7	RNNQRPS
90	63	10E4LCD2	CDRL 2-8	TNNQRPS
91	67	13H2LCD2	CDRL 2-9	GASSLQS
92	70	32H7 LCD2 32H7m LCD2	CDRL 2-10	GASSRAT
93	44	1E11LCD3 4E4LCD3 9D4LCD3 12G8LCD3	CDRL 3-1	GTWDSRLSAW
94	47	1H7LCD3 9F5LCD3 11D11LC3 11H9LCD3	CDRL 3-2	AAWDDSLSGWV
95	50	2E7LCD3	CDRL 3-3	LQYNIYPWT
96	53	3B6LCD3	CDRL 3-4	NSRDSSVYHLV
97	56	3C8LCD3 5F5LCD3 12E8LCD3	CDRL 3-5	MQSFPLPLT
98	59	4H6LCD3	CDRL 3-6	MQALQTPFT
99	64	10E4LCD3	CDRL 3-7	AARDESLNGW
100	68	13H2LCD3	CDRL 3-8	LQYNSFPWT

Alt Num	SEQ ID NO:	Contained in Reference	Designation	Sequence
101	71	32H7 LCD3	CDRL 3-9	QQYGNSLCR
102	72	32H7m LCD3	CDRL 3-10	QQYGNSLSR

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The structure and properties of CDRs within a naturally occurring antibody has been described, supra. Briefly, in a traditional antibody, the CDRs are embedded within a framework in the heavy and light chain variable region where they constitute the regions 5 responsible for antigen binding and recognition. A variable region comprises at least three heavy or light chain CDRs, see, supra (Kabat et a!., 1991, Sequences of Proteins of Immunological Interest, Public Health Service N.I.H., Bethesda, MD; see also Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342: 877-883), within a framework region (designated framework regions 1-4, FR1, FR2, FR3, and FR4, by Kabat et 10 al., 1991, supra·, see also Chothia and Lesk, 1987, supra). The CDRs provided herein, however, may not only be used to define the antigen binding domain of a traditional antibody structure, but may be embedded in a variety of other polypeptide structures, as described herein.

In one aspect, the CDRs provided are (a) a CDRH selected from the group consisting of 15 (i) a CDRH 1 selected from the group consisting of SEQ ID NO:73, 76, 79, 82, 85, 88, 92, 97, and 100; (ii) a CDRH2 selected from the group consisting of SEQ ID NO:74, 77, 80, 83, 86,

89, 91,93, 95, 98, 101, and 129; (iii) a CDRH3 selected from the group consisting of SEQ ID NO:75, 78, 81, 84, 87, 90, 96, 99, 102, and 123; and (iv) a CDRH of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions of no more than five, four, three, two, or one amino acids; (B) a CDRL selected from the group consisting of (i) a CDRL] selected from the group consisting of SEQ ID NO:42, 45,48, 51,54, 57, 62, 65, 66, and 69; (ii) a CDRL2 selected from the group consisting of SEQ ID NO:43,46, 49, 52, 55, 58,61, 63, 67, and 70; (iii) aCDRL3 selected from the group consisting of SEQ ID NO:44,47,50, 53, 56, 59,

64, 68, 71, and 72; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions or insertions of no more than five, four, three, two, or one amino acids amino acids.

In another aspect, an antigen binding protein includes 1,2,3, 4, 5, or 6 variant forms of the CDRs listed in Tables 4A and 4B. each having at least 80%, 85%, 90% or 95% sequence identity to a CDR sequence listed in Tables 4A and 4B, Some antigen binding proteins include 75

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1, 2, 3,4, 5, or 6 of the CDRs listed in Tables 4A and 4B, each differing by no more than 1, 2, 3,4 or 5 amino acids from the CDRs listed in these tables.

In yet another aspect, the CDRs disclosed herein include consensus sequences derived from groups of related monoclonal antibodies. As described herein, a “consensus sequence” refers to amino acid sequences having conserved amino acids common among a number of sequences and variable amino acids that vary within a given amino acid sequences. The CDR consensus sequences provided include CDRs corresponding to each of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3.

In still another aspect, an antigen binding protein includes the following associations of

CDRL1, CDRL2 and CDRL3: SEQ ID NOs: 42,43, and 44; SEQ ID NOs: 45, 46, and 47;

SEQ ID NOs; 48, 49, and 50; SEQ ID NOs: 51, 52, and 53; SEQ ID NOs: 54, 55, and 56; SEQ ID NOs: 57, 58, and 59; SEQ ID NOs: 60, 55, and 56; SEQ ID NOs: 45, 61, and 47; SEQ ID NOs: 62, 63, and 64; SEQ ID NOs: 65, 55, and 56; SEQ ID NOs: 66, 67, and 68; SEQ ID NOs; 69, 70, and 71; and SEQ ID NOs: 69, 70, and 72.

In an additional aspect, an antigen binding protein includes the following associations of CDRH 1, CDRH2 and CDRH3: SEQ ID NOs: 73, 74, and 75; SEQ ID NOs: 76, 77, and 78; SEQ ID NOs: 79, 80, and 81; SEQ ID NOs: 82, 83, and 84; SEQ ID NOs: 85, 86, and 87; SEQ ID NOs: 88, 89, and 90; SEQ ID NOs: 76, 91, and 78; SEQ ID NOs: 92, 93, and 94; SEQ ID NOs: 76, 95, and 78; SEQ ID NOs: 73, 74, and 96; SEQ ID NOs: 97, 98, and 99; and SEQ ID

NOs: 100, 101, and 102.

In another aspect, an antigen binding protein includes the following associations of CDRL1, CDRL2 and CDRL3 with CDRH1, CDRH2 and CDRH3: SEQ ID NOs: 42,43, and 44 with SEQ ID NOs: 73, 74, and 75; SEQ ID NOs: 45,46, and 47 with SEQ ID NOs: 76, 77, and 78; SEQ ID NOs: 48, 49, and 50 with SEQ ID NOs: 79, 80, and 81; SEQ ID NOs: 51, 52, and 53 with SEQ ID NOs: 82, 83, and 84; SEQ ID NOs: 54, 55, 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 with SEQ ID NOs: 85, 86, and 87; SEQ ID NOs: 45, 61, and 47 with SEQ ID NOs: 76, 91, and 78; SEQ ID NOs: 62, 63, and 64 with SEQ ID NOs: 92, 93, and 94; SEQ ID NOs: 45, 61, and 47 with SEQ ID NOs: 76, 95, and 78; SEQ ID NOs: 65, 55, and 56 with SEQ ID

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 68 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 102.

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Consensus sequences were determined using standard phylogenic analyses of the CDRs corresponding to the Vn and Vl of anti-CGRP R antibodies. The consensus sequences were determined by keeping the CDRs contiguous within the same sequence corresponding to a Vn or V_L.

As illustrated in Figs. 3A, 3B, 4, 5A, 5B, 5C, 5D and 5E, lineage analysis of a variety of the antigen binding proteins provided herein resulted in groups of related sequences, designated as light chain CDR groups K.1, K2„ K3, and K4 (Figs. 3A and 3B), light chain CDR groups LI, L2, L3, and L4 (Fig. 4), and heavy chain CDR groups HCl (Fig. 5A), HC2 (Fig. 5B), HC3 (Fig. 5C), HC4 (Fig. 5C), HC5 (Fig. 5D) and HC6 (Fig. 5E). Some of the above 10 groups were used to generate additional consensus sequences, as illustrated in Figs. 3A, 3B, 4, and 5F, to yield light chain CDR groups K.1,4 (Fig. 3A), K.2,3 (Fig. 3B), LI,2,3 (Fig, 4), and LA11 (Fig. 4), and heavy chain CDR groups HCA and HCB (Fig. 5F).

The consensus sequences of the various CDR region groups are provided below;

K1 Consensus

CDRI RASQGIRXiDLG (SEQ ID NO:103), wherein Xi is selected from the group consisting of N and K.

CDR2 XiASSLQS (SEQ ID NO: 104), wherein Xj is selected from the group consisting of A and G.

CDR3 LQYNX|X₂PWT (SEQ ID NO:105), wherein Xi is selected from the group consisting of I and S, and X₂ is selected from the group consisting of Y and F.

K4 Consensus

CDR3 QQYGNSLXiR (SEQ ID NO: 106), wherein X| is selected from the group consisting of S and C.

K1,4 Consensus

CDRI RASQX|X₂XjX₄GX₅LX₆ (SEQ ID NO:107), wherein X, is selected from the group consisting of S and G, X₂ is selected from the group consisting of V and 1, X₃ is selected from the group consisting of S and R, X₄ is selected from the group consisting of S, N and K, X₅ is selected from the group consisting of Y and D, and X₆ is selected from the group consisting of T and G.

CDR2 XiASSX₂X₃X4 (SEQ ID NO: 108), wherein Xi is selected from the group consisting of G and A, X₂ is selected from the group consisting of R and L, X< is selected from the group consisting of A and Q, and X₄ is selected from the group consisting of T and S.

CDR3 X;QYX₃X,X,X,X6X. (SEQ ID NO: 109), wherein Xj is selected from the group consisting of Q and L, X₂ is selected from the group consisting of G and N, X₃ is selected from

2018203471 16 May 2018 the group consisting of N and Τ, X4 is selected from the group consisting of S, Y and F, X₅ is selected from the group consisting of L and P, X_;, is selected from the group consisting of C, W and S, and X₇ is selected from the group consisting of R and T.

K3 Consensus

CDR I KSSQSLLHSX|GX₂X?YLY (SEQ ID NO: 110), wherein X_t is selected from the group consisting of D and A, X₂ is selected from the group consisting of R and K, and X3 is selected from the group consisting of N and T.

K2,3 Consensus

CDR1 XiSSQSl.l.HSX>GX;X,-.YI.X_? (SEQ ID NO: 111 ), wherein X, is selected from the group consisting of R and K, X₂ is selected from the group consisting of F, D and A, Xj is selected from the group consisting of Y, R and K, X4 is selected from the group consisting of N and T, and X₅ is selected from the group consisting of D and Y.

CDR2 X1X2SNRX3S (SEQ ID NO;112), wherein X| is selected from the group consisting of L and E, X₂ is selected from the group consisting of G and V, and X3 is selected 15 from the group consisting of A and F.

CDR3 MQX1X2X3X4PX5T (SEQ ID NO;113), wherein X, is selected from the group consisting of A and S, X₂ is selected from the group consisting of L and F, X₃ is selected from the group consisting of Q and P, X4 is selected from the group consisting of T and L, and X₅ is selected from the group consisting of F and L.

Lm3 Consensus

CDR2 RXiNQRPS (SEQ ID NO;114), wherein X| is selected from the group consisting of N and S.

Lml,2,3 Consensus

CDR1 SGSSSNIGX1NX2VX3 (SEQ ID NO:115), wherein X₍ is selected from the 25 group consisting of N and S, X₂ is selected from the group consisting of Y and T, and X3 is selected from the group consisting of S, N and Y.

CDR2 X1X2NX3RPS (SEQ ID NO; 116), wherein Xi is selected from the group consisting of D, T and R, X₂ is selected from the group consisting of N and S, and X3 is selected from the group consisting of K and Q.

CDR3 XiXiX.fiOQXsLXeXvVV (SEQ ID NO; 117), wherein Xj is selected from the group consisting of G and A, X₂ is selected from the group consisting of T and A, X₃ is selected from the group consisting of W and R, X4 is selected from the group consisting of S and D, X₅ is selected from the group consisting of R and S, Xe is selected from the group consisting of S and N, and X? is selected from the group consisting of A and G.

2018203471 16 May 2018

LAll Consensus

CDR1 X1GX2X3SX4X5X6X7X8X9X10X11 (SEQ ID NO: 118), wherein Xj is selected from the group consisting of S and Q, X₂ is present or absent, and if present, is S, X? is selected from the group consisting of S and D, X4 is present or absent, and if present, is N, X₅ is selected from the group consisting of 1 and L, Xe is selected from the group consisting of G and R, X? is selected from the group consisting of N and S, Xs is selected from the group consisting of N and F, X_y is selected from the group consisting of Y and T, Xw is selected from the group consisting of V and A, and Xu is selected from the group consisting of S, N and Y.

CDR2 X1X2NX3RPS (SEQ ID NO: 119), wherein Xi is selected from the group 10 consisting of D, G, T, and R, X₂ is selected from the group consisting of N, K and S, and X? is selected from the group consisting of K, N and Q.

CDR3 X1X2X3DX4X5X6X7X11X9V (SEQ ID NO:120), wherein X, is selected from the group consisting of G, N and A, X₂ is selected from the group consisting of T, S and A, X; is selected from the group consisting of W and R, X4 is selected from the group consisting of S 15 and D, X₅ is selected from the group consisting of R and S, Xs is selected from the group consisting of L and V, X₇ is selected from the group consisting of S, Y and N, X₈ is selected from the group consisting of A, H and G, and Xy is selected from the group consisting of V and L.

HC1 Consensus

CDR1 X[YYMX₂ (SEQ ID NO: 121), wherein X is selected from the group consisting of G and D, X₂ is selected from the group consisting of H and Y,

CDR2 WIXiPNSGGTNYAQKFQG (SEQ ID NO: 122), wherein X_t is selected from the group consisting of N and S.

CDR3 X_lX₂X3SX₄X₅X₆X7XsGX9X|[_JXi iXizYYXiaGMDV (SEQ ID NO: 123), wherein 25 Xi is selected from the group consisting of D and G, X₂ is selected from the group consisting of Q and G, X3 is selected from the group consisting of M and Y, X4 is selected from the group consisting of 1 and G, X5 is selected from the group consisting of I and Y, Xs is selected from the group consisting of M and A, X₇ is present or absent, and if present, is L, X₈ is present or absent, and if present, is R, X9 is selected from the group consisting of V and L, Xm is selected from the group consisting of F and Y, Xu is selected from the group consisting of P and S, X12 is selected from the group consisting of P and H, and Xu is present or absent, and if present, is Y.

2018203471 16 May 2018

HC2 Consensus

CDR2 RIKSXiTDGGTTDYX₂APVKG (SEQ ID NO: 124), wherein X, is selected from the group consisting of K and T, and X₂ is selected from the group consisting of T and A.

HC3 Consensus

CDR1 X1YX2MX1 (SEQ ID NO: 125), wherein X| is selected from the group consisting of T and S, X₂ is selected from the group consisting of S and A, and X₃ is selected from the group consisting of N and S.

CDR2 X_liSX₂SX₃X₄X₅X₆YYADSVKG (SEQ ID NO: 126), wherein X, is selected from the group consisting of S and A, X₂ is selected from the group consisting of S and G, X₃ 10 is selected from the group consisting of S and G, X4 is selected from the group consisting of S and G, X5 is selected from the group consisting of Y and R, and X<, is selected from the group consisting of R and T.

CDR3 XiX^QQXiXfiXvPYSXsXgWYDYYYGMDV (SEQ ID NO: 127), wherein X, is selected from the group consisting of E and D, X₂ is selected from the group consisting of G 15 and Q, X? is selected from the group consisting of V and R, Xi is selected from the group consisting of S and E, X₃ is selected from the group consisting of G and V, X<, is selected from the group consisting of S and G, X is present or absent, and if present, is S, X₈ is selected from the group consisting of I and S, and X.j is selected from the group consisting of S and G.

HC4 Consensus

CDR1 SXjGMH (SEQ ID NO: 128), wherein X] is selected from the group consisting ofFandY.

CDR2 VISX|DGSX₂KYX₃XDSVKG (SEQ ID NO:129), wherein X, is selected from the group consisting of F and Y, X₂ is selected from the group consisting of 1 and H, X₃ is selected from the group consisting of S and Y, and X4 is selected from the group consisting of

V and A.

CDR3 XiRXPGX^XsXeSXTXsYYXsXioXnYYGXuXisV (SEQ ID NO: 130), wherein Xi is selected from the group consisting of D and E, X₂ is selected from the group consisting of L and K, X₃ is selected from the group consisting of N and R, X₄ is selected from the group consisting of Y and V, X₅ is selected from the group consisting of Y and T, Xe is selected from the group consisting of D and M, X7 is selected from the group consisting of S and T, Xs is selected from the group consisting of G and L, Xy is selected from the group consisting of H and Y, Xio is present or absent, and if present, is Y, Xu is selected from the group consisting of K and F, X₁₂ is selected from the group consisting of M and L, and X|₃ is selected from the group consisting of A and D.

2018203471 16 May 2018

HCA Consensus

CDR1 X1X2X3MX4 (SEQ ID NO: 131), wherein Xi is selected from the group consisting of N and S, X₂ is selected from the group consisting of A, Y and F, X₃ is selected from the group consisting of W, A and Q, and X₄ is selected from the group consisting of S 5 and H.

CDR2 XUXA^XsXeGXvXRXgXnjXiiXuXuXuVKG (SEQ IDNO:132), 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, X; is selected from the group consisting of S, G, F and Y, X₄ is present or absent, and if present, is selected from the group consisting of K and T, X> is present 10 or absent, and if present, is T, Χ_δ is selected from the group consisting of D and S, X? is selected from the group consisting of G and S, X« is selected from the group consisting of T, R, 1, N and H, Xy is selected from the group consisting of T and K., X|₍₎ is selected from the group consisting of D and Y, X| i is selected from the group consisting of Y and S, Xp is selected from the group consisting of T, A and V, Xu is selected from the group consisting of A and D, and Xh is selected from the group consisting of P and S.

CDR3 X_!X₂X_?X₄X₅X₆X₇XsX₉XioXiiXi2Xi3Xi4Xi5Xt6Xi7GX_lsX₁9V (SEQ ID NO: 133), wherein X| is selected from the group consisting of D, A and E, X₂ is selected from the group consisting of R, Q and G, X3 is selected from the group consisting of T, R, L, G and K, X₄ is selected from the group consisting of G, E, N, I and R, Xs is selected from the group 20 consisting of Y, V and A, Xc is selected from the group consisting of S, G, Y, A and T, X₇ is selected from the group consisting of 1, P, D, A and M, Xx is present or absent, and if present, is selected from the group consisting of S and Y, Xy is presenter absent, and if present, is selected from the group consisting of W, S and T, Xm is selected from the group consisting of S, G and L, X| i is selected from the group consisting of S, G, L and Y, X₁₂ is present or absent, 25 and if present, is selected from the group consisting of W and Y, Xu is selected from the group consisting of Y and H, Xj₄ is present or absent, and if present, is selected from the group consisting of Y and D, X15 is selected from the group consisting of Y, K and F, Xie is present or absent, and if present, is Y, Xp is present or absent, and if present, is Y, X|₈ is selected from the group consisting of M and L, and Xi₉ is selected from the group consisting of D and A.

HCB Consensus

CDR1 Χ,ΧζΧ.ΛΛ» (SEQ ID NO:134), wherein Xi is selected from the group consisting of N, G, D, S and A, X₂ is selected from the group consisting of A, F and Y, X₄ is selected from the group consisting of W, Y, A and G, X.: is selected from the group consisting of M and L, and X5 is selected from the group consisting of S and H.

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CDR2 XiIXzXiX+XjX^XsXsXioXnXnXnXHXisXieXnG (SEQ ID NO: 135), wherein X[ is selected from the group consisting of R, W, A, V, S and F, X₂ is selected from the group consisting of K, N, S, W and R, X- is selected from the group consisting of S, P, G, F and Y, X₄ is present or absent, and if present, is selected from the group consisting of K, T and 5 R, Xs is present or absent, and if present, is selected from the group consisting of T and A, Xf, is selected from the group consisting of D, N, H, S and Y, X7 is selected from the group consisting of G and S, Xs is selected from the group consisting of G and S, Xy is selected from the group consisting of T, G, R, I, N, H and Y, Xh> is selected from the group consisting of T, K., R and P, Xi 1 is selected from the group consisting of D, N, Y and E, Xu is selected from the 10 group consisting of Y and S, X13 is selected from the group consisting of T, A and V, Xj₄ is selected from the group consisting of A, Q and D, X15 is selected from the group consisting of P, K and S, X_i6 is selected from the group consisting of V and F, and X17 is selected from the group consisting of K and Q.

CDR3 X|X₂X₃X₄X₅SX6X7X8X9XioXiiXuXuXmXisXisGXpXisV (SEQ ID 15 NO: 136), wherein Xi is selected from the group consisting of D, G, A and E, X₂ is selected from the group consisting of R, G and Q, X₃ is selected from the group consisting of T, Μ, Y, R, L, G and K, X₄ is selected from the group consisting of G, S, E, N, 1 and R, X> is selected from the group consisting of Y, I, G, V and A, is selected from the group consisting of S, i, Y, G, A and T, X? is selected from the group consisting of I, M, A, P and D, Xr is present or absent, and if present, is selected from the group consisting of S, L and Y, Xy is present or absent, and if present, is selected from the group consisting of W, R, S and T, X|₀ is selected from the group consisting of S, G and L, Xu is selected from the group consisting of S, V, L,

G and Y, X|₂ is present or absent, and if present, is selected from the group consisting of F, Y and W, Xu is selected from the group consisting of Y, P, S and H, X₍₄ is present or absent, and if present, is selected from the group consisting of Y, P, D and H, X_!5 is selected from the group consisting of Y, K and F, is present or absent, and if present, is Y, X17 is present or absent, and if present, is Y, and Xis is selected from the group consisting of M and L.

In some cases the antigen binding protein comprises at least one heavy chain CDR I, CDR2, or CDR3 having one of the above consensus sequences. In some cases, the antigen binding protein comprises at least one light chain CDR 1, CDR2, or CDR3 having one of the above consensus sequences. In other cases, the antigen binding protein comprises at least two heavy chain CDRs according to the above consensus sequences, and/or at least two light chain CDRs according to the above consensus sequences. In still other cases, the antigen binding

2018203471 16 May 2018 protein comprises at least three heavy chain CDRs according to the above consensus sequences, and/or at least three light chain CDRs according to the above consensus sequences. Exemplary Antigen Binding Proteins

According to one aspect, provided is an isolated antigen-binding protein that binds

CGRP R comprising (A) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of: (i) a CDRH I selected from the group consisting of SEQ ID NO:73, 76, 79, 82, 85, 88, 92, 97, and 100; (it) a CDRH2 selected from the group consisting of SEQ ID NO:74, 77, 80, 83, 86, 89, 91,93, 95, 98, 101, and 129; (iii) a CDRH3 selected from the group consisting of SEQ IDNO:75, 78, 81, 84, 87, 90, 96, 99, 102, 10 and 123; and (iv) a CDRH of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions, deletions or insertions of no more than five, four, three, four, two or one amino acids; (B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRLI selected from the group consisting of SEQ ID NO:42, 45, 48, 51,54, 57, 62, 65, 66, and 69; (ii) a CDRL2 selected 15 from the group consisting of SEQ ID NO‘,43,46, 49, 52, 55, 58, 61,63, 67, and 70; (iii) a CDRL3 selected from the group consisting of SEQ ID NO:44,47, 50, 53, 56, 59, 64, 68, 71, and 72; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions, deletions or insertions of no more than five, four, three, four, two or one amino acids; or (C) one or more heavy chain CDRHs of (A) and one or more 20 light chain CDRLs of (B).

In yet another embodiment, the isolated antigen-binding protein may comprise (A) a CDRH selected from the group consisting of (i) a CDRH 1 selected from the group consisting of SEQ ID NO :73, 76, 79, 82, 85, 88, 92, 97, and 100; (ii) a CDRH2 selected from the group consisting of SEQ IDNO:74, 77, 80, 83, 86, 89, 91,93, 95, 98, 101, and 129; and (iii) a

CDRH3 selected from the group consisting of SEQ ID NO:75, 78, 81, 84, 87, 90, 96, 99, 102, and 123; (B) a CDRL selected from the group consisting of (i) a CDRL I selected from the group consisting of SEQ ID NO:42,45,48, 51, 54, 57, 62, 65, 66, and 69; (ii) a CDRL2 selected from the group consisting of SEQ ID NO:43, 46,49, 52, 55, 58, 61,63, 67, and 70; and (iii) a CDRL3 selected from the group consisting of SEQ ID NO :44, 47, 50, 53, 56, 59, 64,

68, 71, and 72; or (C) one or more heavy chain CDRHs of (A) and one or more light chain

CDRLs of (B). In one embodiment, the isolated antigen-binding protein may include (A) a CDRH1 of SEQ ID NO:73, 76, 79, 82, 85, 88, 92, 97, and 100, a CDRH2 of SEQ IDNO;74, 77, 80, 83, 86, 89, 91, 93, 95, 98, 101, and 129, and a CDRH3 of SEQ ID NO;75, 78, 81,84, 87, 90, 96, 99, 102, and 123, and (B) a CDRLI of SEQ ID NO:42,45, 48, 51,54, 57, 62, 65,

2018203471 16 May 2018

66, and 69, a CDRL2 of SEQ ID NO:43,46,49, 52, 55, 58, 61, 63, 67, and 70, and a CDRL3 of SEQ ID NO:44, 47, 50, 53, 56, 59, 64, 68, 71, and 72.

In another embodiment, the heavy chain variable region (Vh) has at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity with an amino acid sequence selected 5 from the group consisting of SEQ ID NO: 158-170, and/or the V[. has at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 137-153. In a further embodiment, the Vh is selected from the group consisting of SEQ ID NO: 158-170, and/or the V_L is selected from the group consisting of SEQ ID NO: 137-153.

In another aspect, also provided is an isolated antigen binding protein that specifically binds to an epitope formed of amino acid residues from both the CRLR and RAMP1 components of the CORP R.

In yet another embodiment, the isolated antigen binding protein described hereinabove comprises a first amino acid sequence comprising at least one of the CDRH consensus 15 sequences disclosed herein, and a second amino acid sequence comprising at least one of the CDRL consensus sequences disclosed herein. In one aspect, the first amino acid sequence comprises at least two of the CDRH consensus sequences, and/or the second amino acid sequence comprises at least two of the CDRL consensus sequences.

In certain embodiments, the first and the second amino acid sequence are covalently 20 bonded to each other.

In a further embodiment, the first amino acid sequence of the isolated antigen-binding protein includes the CDRH3 of SEQ ID NO:75, 78, 81, 84, 87, 90, 96, 99, 102, and 123, CDRH2 of SEQ ID NO:74, 77, 80, 83,86, 89,91,93, 95,98, 101, and 129, and CDRHI of SEQ ID NO:73, 76, 79, 82, 85, 88, 92, 97, and 100, and/or the second amino acid sequence of the isolated antigen binding protein comprises the CDRL3 of SEQ ID NO:44, 47, 50, 53, 56, 59, 64, 68, 71, and 72, CDRL2 of SEQ ID NO:43, 46, 49, 52, 55, 58, 61, 63, 67, and 70, and CDRL 1 of SEQ ID NO:42,45,48, 51, 54, 57, 62, 65, 66, and 69.

In a further embodiment, the antigen binding protein comprises at least two CDRH sequences of heavy chain sequences Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, Hl 2, or

H13, as shown in Table 5A. In again a further embodiment, the antigen binding protein comprises at least two CDRL sequences of light chain sequences LI, L2, L3, L4, L5, L6, L7, L8, L9, L10, LI 1, L12, L13, L14, L15, L16, or L17, as shown tnTable 5B. In again a further embodiment, the antigen binding protein comprises at Least two CDRH sequences of heavy chain sequences Hl, H2, H3, H4, H5, H6, H7, H8, H9, H10, Hl 1, Hl2, or Hl3, as shown in

2018203471 16 May 2018

Table 5A , and at least two CDRLs of light chain sequences LI, L2, L3, L4, L5, L6, L7, L8, L9, L10, LI 1, L12, L13, L14, L15, L16, or L17, as shown in Table 5B.

In again another embodiment, the antigen binding protein comprises the CDRH1, CDRH2, and CDRH3 sequences of heavy chain sequences HI, H2, H3, H4, H5, H6, H7, H8, 5 H9, H10, HI 1, Hl2, or H13, as shown in Table 5A. In yet another embodiment, the antigen binding protein comprises the CDRL1, CDRL2, and CDRL3 sequences of light chain sequences LI, L2, L3, L4, L5, L6, L7, L8, L9, LI0, LI I, LI2, LI3, LI4, LI5, LI6, or LI7, as shown in Table 5B.

In yet another embodiment, the antigen binding protein comprises all six CDRs of L1 10 and Hl, or L2 and H2, or L3 and H3, or L4 and H4, or L5 and H5, or L6 and Hl, or L7 and H6, or L8 and H5, or L9 and Hl, or L10 and H7, or LI 1 and H8, or LI2 and H9, or LI2 and H10, orL13 and H5, or L14 and Hll,orL15 andH12, orL16and H13, or L17 and H13, as shown in Tables 5A and 5B.

Table 5A- Exemplary Heavy Chain Amino Acid Sequence Regions

Reference	Full Heavy Chain Group	Full Heavy Chain SEQ ID NO	Heavy Chain Variable Region Group	Heavy Chain Variable Region SEQ ID NO	CDRH1 SEQ ID NO	CDRH2 SEQ ID NO	CDRH3 SEQ ID NO
1E11	H1	29	Vh1	158	73	74	75
1H7	H2	30	Vh2	159.	76	77	78
2E7	H3	31	Vh3	160	79	80	81
3B6	H4	32	Vh4	161	82	83	84
3C8	H5	33	Vh5	162	85	86	87
4E4	H1	29	VH1	158	73	74	75
4H6	H6	34	Vh6	163	88	89	90
5F5	H5	33	Vh5	162	85	86	87
9D4	H1	29	Vh1	158	73	74	75
9F5	H7	35	Vh7	164	76	91	78
10E4	H8	36	Vh8	165	92	93	94

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Reference	Full Heavy Chain Group	Full Heavy Chain SEQ ID NO	Heavy Chain Variable Region Group	Heavy Chain Variable Region SEQ ID NO	CDRH1 SEQ ID NO	CDRH2 SEQ ID NO	CDRH3 SEQ ID NO
11D11	H9	37	VH9	166	76	95	78
11H9	H10	38	Vh10	167	76	95	78
12E8	H5	33	Vh5	162’	85	86	87
12G8	H11	39	VH11	168	73	74	96
13H2	H12	40	Vh12	169	97	98	99
32H7	H13	41	Vh13	170	100	101	102
32H7 CS	H13	41	Vh13	170	100	101	102
32H8			Vh14	171
33B5			Vh15	172
33E4			Vh16	173
34E3			Vh17	174

Table 5B - Exemplary Light Chain Amino Acid Sequence Regions

Reference	Full Light Chain Group	Full Light Chain SEQ ID NO	Light Chain Variable Region Group	Light Cham Variable Region SEQ ID NO	CDRL1 SEQ ID NO	CDRL2 SEQ ID NO	CDRL3 SEQ ID NO
1E11	L1	12	VL1	137	42	43	44
1H7	L2	13	Vl2	138	45	46	47
2E7	L3	14	V|_3	139	48	49	50
3B6	L4	15	Vl4	140	51	52	53
3C8	L5	16	Vl5	141	54	55	56

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Reference	Full Light Chain Group	Full Light Chain SEQ ID NO	Light Chain Variable Region Group	Light Chain Variable Region SEQ ID NO	CDRL1 SEQ ID NO	CDRL2 SEQ ID NO	o Q σ LU CO co _l or □ o
4E4	L6	17	Vl6	142	42	43	44
4H6	L7	18	Vl7	143	57	58	59
5F5	L8	19	Vl8	144	60	55	56
9D4	L9	20	Vl9	145	42	43	44
9F5	L10	21	VL10	146	45	61	47
10E4	L11	22	Vl11	147	62	63	64
11D11	_ L12	23	Vl12	148	45	61	47
11H9	L12	23	Vl12	148	45	61	47
12E8	L13	24	Vl13	149	65	55	56
12G8	L14	25	Vl14	150	42	43	44
13H2	L15	26	Vl15	151	66	67	68
32H7	L16	27	Vl16	152	69	70	71
32H7 CS	L17	28	Vl17	153	69	70	72
32H8			Vl18	154
33B5			Vl19	155
33E4			Vl20	156
34E3			Vl21	157

In one aspect, the isolated antigen-binding proteins provided herein can be a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody antigen binding fragment thereof.

2018203471 16 May 2018

In another embodiment, the antibody fragment of the isolated antigen-binding proteins provided herein can be a Fab fragment, a Fab' fragment, an Ffab’h fragment, an Fv fragment, a diabody, or a single chain antibody molecule.

In a further embodiment, the isolated antigen binding protein provided herein is a human 5 antibody and can be of the IgG 1-, IgG2- lgG3- or IgG4-type.

In another embodiment, the antigen binding protein consists of a just a light or a heavy chain polypeptide as set forth in Tables 5A-5B. In some embodiments, the antigen binding protein consists just of a light chain variable or heavy chain variable domain such as those listed in Tables 5A-5B. Such antigen binding proteins can be pegylated with one or more PEG 10 molecules.

In yet another aspect, the isolated antigen-binding protein provided herein can be coupled to a labeling group and can compete for binding to the extracellular portion of human CGRP R with an antigen binding protein of one of the isolated antigen-binding proteins provided herein.

In one embodiment, the isolated antigen binding protein provided herein can reduce monocyte 15 chemotaxis, inhibit monocyte migration into tumors or inhibit accumulation and function of tumor associated macrophage in a tumor when administered to a patient.

As will be appreciated by those in the art, for any antigen binding protein with more than one CDR from the depicted sequences, any combination of CDRs independently selected from the depicted sequences is useful. Thus, antigen binding proteins with one, two, three, four, five or six of independently selected CDRs can be generated. However, as will be appreciated by those in the art, specific embodiments generally utilize combinations of CDRs that are non-repetitive, e.g., antigen binding proteins are generally not made with two CDRH2 regions, etc.

Some of the antigen binding proteins provided are discussed in more detai l below,

Antigen Binding Proteins And Binding Epitopes and Binding Domains

When an antigen binding protein is said to bind an epitope, such as one or both components of CGRP R, or the extracellular domain of CGRP R, for example, what is meant is that the antigen binding protein specifically binds to a specified portion of CGRP R, which may be on CRLR, RAMP 1, or span portions of both CRLR and RAMP 1. In cases where the antigen binding protein binds only CRLR (and not RAMP 1), the antigen binding protein would not be expected to selectively bind CGRP R because CRLR is shared, inter alia, with AM 1 and AMI receptors. Similarly, in cases where the antigen binding protein binds only RAM Pl (and not CRLR), the antigen binding protein would not be expected to selectively bind CGRP R because RAMP! is shared, inter alia, with AMY1 receptor. In cases where the antigen binding

2018203471 16 May 2018 protein interacts with both CRLR and RAMP1, the antigen binding protein is expected to bind residues or sequences of residues, or regions in both CRLR and RAMP 1, In none of the foregoing embodiments is an antigen binding protein expected to contact eveiy residue within CRLR or RAMP1. Similarly, not every amino acid substitution or deletion within CRLR,

RAMP! or the extracellular domains thereof is expected to significantly affect binding affinity. Methods detailed, e.g., in Example 10, maybe used to assess what regions of multimeric receptors, such as CGRP R, may be involved in binding to selected antigen binding proteins.

Competing Antigen Binding Proteins

In another aspect, antigen binding proteins are provided that compete with one of the exemplified, or “reference” antibodies or functional fragments binding to the epitope described above for specific binding to CGRP R. Such antigen binding proteins may also bind to the same epitope as one of the herein exemplified antigen binding proteins, or an overlapping epitope. Antigen binding proteins and fragments that compete with or bind to the same epitope as the exemplified or reference antigen binding proteins arc expected to show similar functional properties. The exemplified antigen binding proteins and fragments include those with the heavy and light chains, variable region domains VlI- VU7 and Vul- Vnl3, and CDRs included in Tables 2A, 2B, 3, 4A, 4B, 5A and 5B. Thus, as a specific example, the antigen binding proteins that are provided include those that compete with an antibody having:

(a) all 6 of the CDRs listed for an antibody listed in Tables 5A and 5B; (b) a Vn and a Vl selected from VlI - VlI7 and Vul- Vul3 and listed for an antibody listed in Tables 5A and 5B; or (c) two light chains and two heavy chains as specified for an antibody listed in Tables 5A 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 SEQ ID

NO: 158-170 and a light chain variable region having a sequence corresponding to any of the sequences identified as SEQ ID NO: 137-153.

Binding competition may he assessed, for example, using a binning assays, such as the Biacore assay described in Example 7, below. In that example, 19 antibodies described herein were tested against each of six “reference” antibodies — five neutralizing antibodies (11 DI 1, 3B6,

4H6, I2G8, and 9F5) and one non-neutralizing antibody (34E3), The assay results, shown in

Table 13, indicate that all of the tested neutralizing antibodies (1 El l,lH7,2E7,3B6,3C8,4E4,4H6,5F5,9D4,9F5,10E4,l ID J 1,11H9,I2E8,12G8,13H2 and 32H7) bind to essentially the same region of CGRP R, which is distinct from the region of CGRP R that is bound by the non-neutralizing antibodies tested (32H8,33B5,33E4 and 34E3). Based on these

2018203471 16 May 2018 data, any of the neutralizing antibodies would make exemplary reference antigen binding proteins in a competition assay, particularly any of the neutralizing antibodies that were immobilized in the assay described in Example 7 — 11D11,3B6,4H6, 12G8, and 9F5,

Monoclonal Antibodies

The antigen binding proteins that are provided include monoclonal antibodies that bind to CGRP R. Monoclonal antibodies may be produced using any technique known in the art, e.g., by immortalizing spleen cells harvested from the transgenic animal after completion of the immunization schedule. The spleen cells can be immortalized using any technique known in the art, e.g., by fusing them with myeloma cells to produce hybridomas. Myeloma cells for use 10 in hybridoma-producing fusion procedures preferably are non-antibody-producing, have high fusion efficiency, and enzyme deficiencies that render them incapable of growing in certain selective media which support the growth of only the desired fused cells (hybridomas). Examples of suitable ceil lines for use in mouse fusions include Sp-20, P3-X63/Ag8, P3-X63Ag8.653,NSI/l.Ag4 1, Sp210-Agl4, FO, NSO/U, MPC-II, MPCl 1-X45-GTG 1.7 and 15 SI94/5XXO Bui; examples of cell lines used in rat fusions include R210.RCY3, Y3-Ag 1.2.3, 1R983F and 4B210. Other cell lines useful for cell fusions are U-266, GM1500-GRG2, LICRLON-HMy2 and UC729-6. An exemplary method of preparing monoclonal antibodies is described in Example 2, below.

In some instances, a hybridoma cell line is produced by immunizing an animal (e.g., a transgenic animal having human immunoglobulin sequences) with a CGRP R immunogen: harvesting spleen cells from the immunized animal; fusing the harvested spleen cells to a myeloma cell line, thereby generating hybridoma cells; establishing hybridoma cell lines from the hybridoma cells, and identifying a hybridoma cell line that produces an antibody that binds CGRP R (e.g., as described in Examples J-3, below). Such hybridoma cell lines, and anti25 CGRP R monoclonal antibodies produced by them, are aspects of the present application. Monoclonal antibodies secreted by a hybridoma cell line can be purified 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 CGRP, ability to block or interfere the binding of the CGRP ligand or CGRPg-v peptide, or the ability to functionally block the receptor, e.g., using a cAMP assay, e.g., as described below.

Chimeric and Humanized Antibodies

Chimeric and humanized antibodies based upon the foregoing sequences are also provided. Monoclonal antibodies for use as therapeutic agents may be modified in various ways prior to use. One example is a chimeric antibody, which is an antibody composed of

2018203471 16 May 2018 protein segments from different antibodies that are covalently joined to produce functional immunoglobulin light or heavy chains or immunologically functional portions thereof. Generally, a portion of the heavy chain and/or light chain is identical with or homologous to a corresponding sequence in antibodies derived from a particular species or belonging to a 5 particular antibody class or subclass, while the remainder of the chain(s) is/arc identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For methods relating to chimeric antibodies, see, for example. United States Patent No. 4,816,567; and Morrison et al., 1985, Proc. Natl. Acad. Set. USA 81:6851-6855, which are hereby incorporated by reference. CDR grafting is 10 described, for example, in United States Patent No. 6,180,370, No. 5,693,762, No. 5,693,761, No. 5,585,089, and No. 5,530,101.

Generally, the goal of making a chimeric antibody is to create a chimera in which the number of amino acids from the intended patient species is maximized. One example is the CDR-grafted” antibody, in which the antibody comprises one or more complementarity 15 determining regions (CDRs) from a particular species or belonging to a particular antibody class or subclass, while the remainder of the antibody chain(s) is/are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For use in humans, the variable region or selected CDRs from a rodent antibody often are grafted into a human antibody, replacing the 20 naturally-occurring variable regions or CDRs of the human antibody.

One useful type of chimeric antibody is a humanized” antibody. Generally, a humanized antibody is produced from a monoclonal antibody raised initially in a non-human animal. Certain amino acid residues in this monoclonal antibody, typically from non-antigen recognizing portions of the antibody, are modified to be homologous to corresponding residues 25 in a human antibody of corresponding isotype. Humanization can be performed, for example, using various methods by substituting at least a portion of a rodent variable region for the corresponding regions of a human antibody (see, e.g., United States Patent No. 5,585,089, and No. 5,693,762; Jones etal., 1986, Nature 321:522-525; Riechmann etal., 1988,

Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-1536).

In one aspect, the CDRs of the light and heavy chain variable regions of the antibodies provided herein (see, Table 4) are grafted to framework regions (FRs) from antibodies from the same, or a different, phylogenetic species. For example, the CDRs of the heavy and light chain variable regions V_H1, V_H2, V„3, V_H4, V_H5, V_H6, V_H7, V_H8, V_H9, V_H10, V_H11, V_H12, and V_H13, and/or V,.I, Vi.2, V,,3, V_r4, V_t.5, V_t6, V,.7, V_L8, V_t9, V_L10, VJ 1, V,.12, V_tl3, V,J4,

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VlI 5, V_l16, and VlI 7 can be grafted to consensus human FRs. To create consensus human FRs, FRs from several human heavy chain or light chain amino acid sequences may be aligned to identify a consensus amino acid sequenee. In other embodiments, the FRs of a heavy chain or light chain disclosed herein are replaced with the FRs from a different heavy chain or light 5 chain. In one aspect, rare amino acids in the FRs of the heavy and light chains of anti-CGRP R antibody are not replaced, while the rest of the FR amino acids are replaced. A rare amino acid is a specific amino acid that is in a position in which this particular amino acid is not usually found in an FR, Alternatively, the grafted variable regions from the one heavy or light chain may be used with a constant region that is different from the constant region of that 10 particular heavy or light chain as disclosed herein. In other embodiments, the grafted variable regions are part of a single chain Fv antibody.

In certain embodiments, constant regions from species other than human can be used along with the human variable region(s) to produce hybrid antibodies.

Fully Human Antibodies

Fully human antibodies are also provided. Methods arc available for making fully human antibodies specific for a given antigen without exposing human beings to the antigen (“fully human antibodies”). One specific means provided for implementing the production of fully human antibodies is the humanization of the mouse humoral immune system. Introduction of human immunoglobulin (Ig) loci into mice in which the endogenous Ig genes have been inactivated is one means of producing fully human monoclonal antibodies (mAbs) in mouse, an animal that can be immunized with any desirable antigen. Using fully human antibodies can minimize the immunogenic and allergic responses that can sometimes he caused by administering mouse or mouse-derived mAbs to humans as therapeutic agents.

Fully human antibodies can be produced by immunizing transgenic animals (usually mice) that arc capable of producing a repertoire of human antibodies in the absence of endogenous immunoglobulin production. Antigens for this purpose typically have six or more contiguous amino acids, and optionally are conjugated to a carrier, such as a hapten. See, e.g., Jakobovits eta!., 1993, Proc. Natl. Acad. Sci. USA 90:2551 -2555; Jakobovits et ai., 1993, Nature 362:255-258; and Bruggermann et al., 1993, Year in Immunol. 7:33. In one example of such a method, transgenic animals are produced by incapacitating the endogenous mouse immunoglobulin loci encoding the mouse heavy and light immunoglobulin chains therein, and inserting into the mouse genome large fragments of human genome DNA containing loci that encode human heavy and light chain proteins. Partially modified animals, which have less than the full complement of human immunoglobulin loci, arc then cross-bred to obtain an

2018203471 16 May 2018 animal having all of the desired immune system modifications. When administered an immunogen, these transgenic animals produce antibodies that are immunospecific for the immunogen but have human rather than murine amino acid sequences, including the variable regions. For further details of such methods, see, for example, WO96/33735 and 5 W094/02602. Additional methods relating to transgenic mice for making human antibodies are described in United States Patent No. 5,545,807; No. 6,713,610; No. 6,673,986;

No. 6,162,963; No. 5,545,807; No. 6,300,129; No. 6,255,458; No. 5,877,397; No. 5,874,299 and No. 5,545,806; in PCT publications WO91/10741, W090/04036, and in EP 546073B1 and EP 546073A1.

The transgenic mice described above, referred to herein as HuMab mice, contain a human immunoglobulin gene minilocus that encodes unrearranged human heavy ([mu] and [gamma]) and [kappa] light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous [mu] and [kappa] chain loci (Lonberg et al,, 1994, Nature 368:856-859 ). Accordingly, the mice exhibit reduced expression of mouse IgM or [kappa] and in response to immunization, and the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG [kappa] monoclonal antibodies (Lonberg etal,, supra.; Lonberg and Huszar, 1995, Intern, Rev. Immunol. 13: 65-93; Harding and Lonberg, 1995, Ann. N.Y Acad. Sci. 764:536-546). The preparation of HuMab mice is described in detail in Taylor etal., 1992, Nucleic Acids

Research 20:6287-6295; Chen el al., 1993, International Immunology 5:647-656; Tuaillon et al., 1994,7, Immunol. 152:2912-2920: Lonberg et al., 1994, Nature 368:856-859; Lonberg, 1994, Handbook of Exp. Pharmacology 113:49-101; Taylor et al., 1994, International Immunology 6:579-591; Lonberg and Huszar, 1995, Intern. Rev. Immunol. 13:65-93; Harding and Lonberg, 1995, Ann. N.Y Acad. Sci. 764:536-546; Fishwild et al., 1996, Nature

Biotechnology 14:845-851; the foregoing references are hereby incorporated by reference in their entirety for all purposes. See, further United States Patent No. 5,545,806; No. 5,569,825; No. 5,625,126; No. 5,633,425; No. 5,789,650; No. 5,877,397; No. 5,661,016; No. 5,814,318; No. 5,874,299; and No. 5,770,429; as well as United States Patent No. 5,545,807; International Publication Nos. WO 93/1227; WO 92/22646; and WO 92/03918, the disclosures of all of which are hereby incorporated by reference in their entirety for all purposes. Technologies utilized for producing human antibodies in these transgenic mice are disclosed also in WO 98/24893, and Mendez et al., 1997, Nature Genetics 15:146-156. which are hereby incorporated by reference. For example, the HCo7 and HCol 2 transgenic mice strains can be

2018203471 16 May 2018 used to generate anti-CGRP R antibodies, Further details regarding the production of human antibodies using transgenic mice are provided in the examples below.

Using hybridoma technology, antigen-specific human mAbs with the desired specificity can be produced and selected from the transgenic mice such as those described above. Such 5 antibodies may be cloned and expressed using a suitable vector and host cell, or die antibodies can be harvested from cultured hybridoma cells.

Fully human antibodies can also be derived from phage-display libraries (as disclosed in Hoogenboom et al._s 1991, J. Mol. Biol. 227:381; and Marks et al., 1991, J. Mol, Biol. 222:581). Phage display techniques mimic immune selection through the display of antibody 10 repertoires on the surface of filamentous bacteriophage, and subsequent selection of phage by their binding to an antigen of choice. One such technique is described in PCT Publication No, WO 99/10494 (hereby incorporated by reference), which describes the isolation of high affinity and functional agonistic antibodies for MPL- and msk-receptors using such an approach.

Bispecific Or Bifunctional Antigen Binding Proteins

The antigen binding proteins that are provided also include bispecific and bifunctional antibodies that include one or more CDRs or one or more variable regions as described above. A bispecific or bifunctional antibody in some instances is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies may be produced by a variety of methods including, but not limited to, fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai and Lachmann, 1990, Clin. Exp. Immunol.

79:315-321; Kostelny et al., 1992,./. Immunol. 148:1547-1553.

Various Other Forms

Some of the antigen binding proteins that are provided are variant forms of the antigen binding proteins disclosed above (e.g., those having the sequences listed in Tables 2-5). For instance, some of the antigen binding proteins have one or more conservative amino acid substitutions in one or more of the heavy or light chains, variable regions or CDRs listed in Tables 2-5.

Naturally-occurring amino acids may be divided into classes based on common side chain properties:

1) hydrophobic: norleucine. Met, Ala, Val, Leu, He;

2) neutral hydrophilic; Cys, Ser, Thr, Asn, Gin;

3) acidic; Asp, Glu;

4) basic: His, Lys, Arg;

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5) residues that influence chain orientation: Gly, Pro; and

6) aromatic: Trp, Tyr, Phe.

Conservative amino acid substitutions may involve exchange of a member of one of these classes with another member of the same class. Conservative amino acid substitutions 5 may encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics and other reversed or inverted forms of amino acid moieties.

Non-conservative substitutions may involve the exchange of a member of one of the above classes for a member from another class. Such substituted residues may be introduced 10 into regions of the antibody that are homologous with human antibodies, or into the nonhomologous regions of the molecule.

In making such changes, according to certain embodiments, the hydropathic index of amino acids may be considered. The hydropathic profile of a protein is calculated by assigning each amino acid a numerical value (“hydropathy index”) and then repetitively averaging these 15 values along the peptide chain. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics. They are: isoleucinc (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (20 3.5); lysine (-3.9); and arginine (-4.5).

The importance of the hydropathic profile in conferring interactive biological function on a protein is understood in the art (see, e.g., Kyte et al., 1982, J. Mol. Biol. 157:105-131). It is known that certain amino acids may be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes 25 based upon the hydropathic index, in certain embodiments, the substitution of amino acids whose hydropathic indices are within ±2 is included. In some aspects, those which are within ±1 are included, and in other aspects, those within ±0.5 are included.

It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydro phi licity, particularly where the biologically functional protein 30 or peptide thereby created is intended for use in immunological embodiments, as in the present case. In certain embodiments, the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigen-binding or immunogenicity, that is, with a biological property of the protein.

The following hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0+1); glutamate (+3.0+1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0,5+1); alanine (-0.5); histidine (-0.5); cysteine (-1,0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (5 1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4). In making changes based upon similar hydrophilicity values, in certain embodiments, the substitution of amino acids whose hydrophilicity values arc within ±2 is included, in other embodiments, those which are within ±1 are included, and in still other embodiments, those within ±0.5 are included. In some instances, one may also identify epitopes from primary amino acid sequences on the basis of 10 hydrophilicity. These regions are also referred to as “epitopic core regions.”

Exemplary conservative amino acid substitutions are set forth in Table 6,

Table 6: Conservative Amino Acid Substitutions

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Original Residue	Exemplary Substitutions
Ala	Ser
Arg	Lys
Asn	Gin, His
Asp	Glu
Cys	Ser
Gin	Asn
Glu	Asp
Gly	Pro
His	Asn, Gin
lie	Leu, Val
Leu	lie, Val
Lys	Arg, Gin, Glu
Met	Leu, He
Phe	Met, Leu, Tyr
Ser	Thr
Thr	Ser

Original Residue	Exemplary' Substitutions
Trp	Tyr
Tyr	Trp, Phe
Val	lie, Leu

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A skilled artisan will be able to determine suitable variants of polypeptides as set forth herein using well-known techniques. One skilled in the art may identify suitable areas of the molecule that may be changed without destroying activity by targeting regions not believed to 5 be important for activity. The skilled artisan also will be able to identify residues and portions of the molecules that are conserved among similar polypeptides. In further embodiments, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.

Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues important for activity or structure in similar proteins. One skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues.

One skilled in the art can also analyze the 3-dimensional structure and amino acid sequence in relation to that structure in similar polypeptides. In view of such information, one skilled in the art may predict the alignment of amino acid residues of an antibody with respect to its three dimensional structure. One skilled in the art may choose not to make radical changes to amino acid residues predicted to be on the surface ofthe protein, since such residues may be involved in important interactions with other molecules. Moreover, one skilled in the art may generate test variants containing a single amino acid substitution at each desired amino acid residue. These variants can then be screened using assays for CGRP R neutralizing activity, (see examples below) thus yielding information regarding which amino acids can be changed and which must not be changed. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acid positions where further substitutions should he avoided either alone or in combination with other mutations.

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A number of scientific publications have been devoted to the prediction of secondary structure, See, Moult, 1996, Curr. Op. in Biotech. 7:422-427; Chou et al., 1974,

Biochem. 13:222-245: Chou et al., 1974, Biochemistry 113:211-222; Chou et al., 1978,.4i/v, Enzymal. Relat. Areas Mol. Biol. 47:45-148; Chou et al., 1979, Ann. Rev. Biochem. 47:2515 276; and Chou et al., 1979, Biophys. J. 26:367-384. Moreover, computer programs are currently available to assist with predicting secondary structure. One method of predicting secondary structure is based upon homology modeling. For example, two polypeptides or proteins that have a sequence identity of greater than 30%, or similarity greater than 40% can have similar structural topologies. The recent growth of the protein structural database (PDB) 10 has provided enhanced predictability of secondary structure, including the potential number of folds within a polypeptide's or protein's structure. See, Holm etal., 1999, Nucl. Acid. Res. 27:244-247. It has been suggested (Brenner et al., 1997, Curr. Op. Struct. Biol. 7:369-376) that there are a limited number of folds in a given polypeptide or protein and that once a critical number of structures have been resolved, structural prediction will become dramatically 15 more accurate.

Additional methods of predicting secondary structure include “threading” (Jones, 1997, Curr. Opin. Struct. Biol. 7:377-387; Sippl et al., 1996, Structure 4:15-19), “profile analysis” (Bowie et al., 1991, Science 253:164-170: Gribskov et al., 1990, Meth. Enzym. 183:146-159: Gribskov etal., 1987, Proc. Nat. Acad. Sci. 84:4355-4358), and “evolutionary linkage” (See,

Holm, 1999, supra; and Brenner, 1997, supra).

In some embodiments, amino acid substitutions are made that: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter ligand or antigen binding affinities, and/or (4) confer or modify other physicochemical or functional properties on such polypeptides. For example, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) may be made in the naturally-occurring sequence. Substitutions can be made in that portion of the antibody that lies outside the domain(s) forming intermolccular contacts).

In such embodiments, conservative amino acid substitutions can be used that do not substantially change the structural characteristics of the parent sequence (e.g., one or more replacement amino acids that do not disrupt the secondary structure that characterizes the parent or native antigen binding protein). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed.), 1984, W. H. New York: Freeman and Company; Introduction to Protein

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Structure (Branden and Tooze, eds.), 1991, New York: Garland Publishing; and Thornton et al., 1991, Nature 354:105, which are each incorporated herein by reference.

Additional preferred antibody variants include cysteine variants wherein one or more cysteine residues in the parent or native amino acid sequence are deleted from or substituted 5 with another amino acid (e.g., serine). Cysteine variants are useful, inter alia when antibodies must be refolded into a biologically active conformation. Cysteine variants may have fewer cysteine residues than the native antibody, and typically have an even number to minimize interactions resulting from unpaired cysteines.

The heavy and light chains, variable regions domains and CDRs that are disclosed can 10 be used to prepare polypeptides that contain an antigen binding region that can specifically bind to CGRP R. For example, one or more of the CDRs listed in Tables 4 and 5 can be incorporated into a molecule (e.g., a polypeptide) covalently or noncovalently to make an immunoadhesion. An immunoadhesion may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may 15 incorporate the CDR(s) noncovalently. The CDR(s) enable the immunoadhesion to bind specifically to a particular antigen of interest (e.g., CGRP R or epitope thereof).

Mimetics (e.g., “peptide mimetics” or “peptidomimeties”) based upon the variable region domains and CDRs that are described herein are also provided. These analogs can be peptides, non-peptides or combinations of peptide and non-peptide regions. Fauchere, 1986,

Adv. Drug Res. 15:29; Vebcr and Freidinger, 1985, TINS p. 392; and Evans et al., 1987, J. Med. Chem. 30:1229, which are incorporated herein by reference for any purpose. Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce a similar therapeutic or prophylactic effect. Such compounds are often developed with the aid of computerized molecular modeling. Generally, peptidomimeties are proteins that are 25 structurally similar to an antibody displaying a desired biological activity, such as here the ability to specifically bind CGRP R, but have one or more peptide linkages optionally replaced by a linkage selected from: -CH₂NH-, -CH₂S-, -CH2-CH2-, -CH-CH-(cis and trans), -COCH2-, -CH(OH)CH2-, and -CH₂SO-, by methods well known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., 30 D-lysine in place of L-lysine) may be used in certain embodiments to generate more stable proteins. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo and Gierasch, 1992, Ann. Rev. Biochem. 61.:387), incorporated herein by reference), for

2018203471 16 May 2018 example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cychze the peptide.

Derivatives of the antigen binding proteins that are described herein are also provided. The derivatized antigen binding proteins can comprise any molecule or substance that imparts 5 a desired property to the antibody or fragment, such as increased half-life in a particular use. The derivatized antigen binding protein can comprise, for example, a detectable (or labeling) moiety (e.g., a radioactive, colorimetric, antigenic or enzymatic molecule, a detectable bead (such as a magnetic or clectrodcnsc (e.g., gold) bead), or a molecule that binds to another molecule (e.g., biotin or streptavidin)), a therapeutic or diagnostic moiety (e.g., a radioactive, cytotoxic, or pharmaceutically active moiety), or a molecule that increases the suitability of the antigen binding protein for a particular use (e,g., administration to a subject, such as a human subject, or other in vivo or in vitro uses). Examples of molecules that can be used to derivatize an antigen binding protein include albumin (e.g., human serum albumin) and polyethylene glycol (PEG). Albumin-linked and PEGylatcd derivatives of antigen binding proteins can be 15 prepared using techniques well known in the art. Certain antigen binding proteins include a pegylated single chain polypeptide as described herein. In one embodiment, the antigen binding protein is conjugated or otherwise linked to transthyretin (TTR) or a TTR variant. The TTR or TTR variant can be chemically modified with, for example, a chemical selected from the group consisting of dextran, poly(n-vinyl pyrrolidone), polyethylene glycols, propropylene 20 glycol homopolymers, polypropylene oxidc/cthylenc oxide co-polymers, polyoxyethylatcd polyols and polyvinyl alcohols.

Other derivatives include covalent or aggregative conjugates of CGRP R binding proteins with other proteins or polypeptides, such as by expression of recombinant fusion proteins comprising heterologous polypeptides fused to the N-terminus or C-terminus of a

CGRP R binding protein. For example, the conjugated peptide may be a heterologous signal (or leader) polypeptide, e.g., the yeast alpha-factor leader, or a peptide such as an epitope tag. CGRP antigen binding protein-containing fusion proteins can comprise peptides added to facilitate purification or identification of the CGRP R binding protein (e.g., poly-His). A CGRP R binding protein also can be linked to the FLAG peptide as described in Hopp et a!.,

1988, Bio/Technology 6:1204; and United States Patent No. 5,011,912. The FLAG peptide is highly antigenic and provides an epitope reversibly bound by a specific monoclonal antibody (mAb), enabling rapid assay and facile purification of expressed recombinant protein.

Reagents useful for preparing fusion proteins in which the FLAG peptide is fused to a given polypeptide arc commercially available (Sigma, St. Louis, MO),

100

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Oligomers that contain one or more CGRP R binding proteins may be employed as CGRP R antagonists. Oligomers may be in the form of covalently-linked or non-covalentlyIinked dimers, trimers, or higher oligomers. Oligomers comprising two or more CGRP R binding proteins are contemplated for use, with one example being a homodimer. Other 5 oligomers include hetcrodimers, homotrimers, heterotrimers, homotctramers, heterotetramers, etc.

One embodiment is directed to oligomers comprising multiple CGRP R-binding polypeptides joined via covalent or non-covalent interactions between peptide moieties fused to the CGRP R binding proteins. Such peptides may be peptide linkers (spacers), or peptides 10 that have the property of promoting oligomerization. Leucine zippers and certain polypeptides derived from antibodies are among the peptides that can promote oligomerization of CGRP R binding proteins attached thereto, as described in more detail below.

In particular embodiments, the oligomers comprise from two to four CGRP R binding proteins. The CGRP R binding protein moieties of the oligomer may be in any of the forms 15 described above, e.g., variants or fragments. Preferably, the oligomers comprise CGRP R binding proteins that have CGRP R binding activity.

In one embodiment, an oligomer is prepared using polypeptides derived from immunoglobulins. Preparation of fusion proteins comprising certain heterologous polypeptides fused to various portions of antibody-derived polypeptides (including the Fc domain) has been 20 described, e.g., by Ashkenazi et al., 1991, Proc. Natl. Acad. Sci. USA 88:10535; Bym et ai, 1990, Nature 344:677; and Hollenbaugh et al., 1992 Construction of Immunoglobulin Fusion Proteins, in Current Protocols in Immunology, Suppl. 4, pages 10.19.1-10.19.11.

One embodiment is directed to a dimer comprising two fusion proteins created by fusing a CGRP R binding protein to the Fc region of an antibody. The dimer can be made by, 25 for example, inserting a gene fusion encoding the fusion protein into an appropriate expression vector, expressing the gene fusion in host cells transformed with the recombinant expression vector, and allowing the expressed fusion protein to assemble much like antibody molecules, whereupon interchain disulfide bonds form between the Fc moieties to yield the dimer.

The term “Fc polypeptide” as used herein includes native and mutein forms of 30 polypeptides derived from the Fc region of an antibody. Truncated forms of such polypeptides containing the hinge region that promotes dimerization also are included. Fusion proteins comprising Fc moieties (and oligomers formed therefrom) offer the advantage of facile purification by affinity chromatography over Protein A or Protein G columns.

101

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One suitable Fc polypeptide, described in PCT application WO 93/10151 and United States Patent. No. 5,426,048 and No. 5,262,522, is a single chain polypeptide extending from the N-terminal hinge region to the native C-terminus of the Fc region of a human IgG 1 antibody. Another useful Fc polypeptide is the Fc mutein described in United States Patent 5 No. 5,457,035, and in Baum eta!., 1994, EMBOJ. 13.:3992-4001. The amino acid sequence of this mutein is identical to that ofthe native Fc sequence presented in WO 93/10151, except that amino acid 19 has been changed from Leu to Ala, amino acid 20 has been changed from Leu to Glu, and amino acid 22 has been changed from Gly to Ala. The mutein exhibits reduced affinity for Fc receptors.

In other embodiments, the variable portion of the heavy and/or light chains of a CGRP

R binding protein such as disclosed herein may be substituted for the variable portion of an antibody heavy and/or light chain.

Alternatively, the oligomer is a fusion protein comprising multiple CGRP R binding proteins, with or without peptide linkers (spacer peptides). Among the suitable peptide linkers 15 are those described in United States Patent, No. 4,751,180 and No. 4,935,233.

Another method for preparing oligomeric CGRP R binding protein derivatives involves use of a leucine zipper. Leucine zipper domains are peptides that promote oligomerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA-binding proteins (Landschulz eta!., 1988, Science 240:1759), and have since been found 20 in a variety of different proteins. Among the known leucine zippers arc naturally occurring peptides and derivatives thereof that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble oligomeric proteins are described in PCT application WO 94/10308, and the leucine zipper derived from lung surfactant protein D (SPD) described in Hoppe et al., 1994, FEBS Letters 344:191, hereby incorporated by reference. The use of a 25 modified leucine zipper that allows for stable trimerization of a heterologous protein fused thereto is described in Fanslow et al., 1994, Semin. Immunol. 6:267-278. In one approach, recombinant fusion proteins comprising a CGRP R binding protein fragment or derivative fused to a leucine zipper peptide are expressed in suitable host cells, and the soluble oligomeric CGRP R binding protein fragments or derivatives that form are recovered from the culture 30 supernatant.

In certain embodiments, the antigen binding protein has a K-o (equilibrium binding affinity) of less than 1 pM, 10 pM, 100 pM, 1 nM, 2 nM, 5 nM, 10 nM, 25 nM or 50 nM.

Another aspect provides an antigen-binding protein having a half-life of at least one day in vitro or in vivo (e.g., when administered to a human subject). In one embodiment, the

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2018203471 16 May 2018 antigen binding protein has a half-life of at least three days. In another embodiment, the antibody or portion thereof has a half-life of four days or longer. In another embodiment, the antibody or portion thereof has a half-life of eight days or longer. In another embodiment, the antibody or antigen-binding portion thereof is derivatized or modified such that it has a longer 5 half-life as compared to the underivatized or unmodified antibody. In another embodiment, the antigen binding protein contains point mutations to increase serum half life, such as described in WO 00/09560, published Feb. 24, 2000, incorporated by reference.

Glycosylation

The antigen-binding protein may have a glycosylation pattern that is different or altered 10 from that found in the native species. As is known in the art, glycosylation patterns can depend on both the sequence of the protein (e.g., the presence or absence of particular glycosylation amino acid residues, discussed below), or the host cell or organism in which the protein is produced. Particular expression systems are discussed below.

Glycosylation of polypeptides is typically either N-linked or O-l inked. N-linked refers 15 to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tri-peptide sequences asparagine-X-scrine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked 20 glycosylation refers to the attachment of one of the sugars N-acctylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5hydroxyproline or 5-hydroxylysine may also be used.

Addition of glycosylation sites to the antigen binding protein is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the 25 above-described tri-peptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). For ease, the antigen binding protein amino acid sequence may he altered through changes at the DNA level, particularly by mutating the DNA encoding the target polypeptide at preselected bases such that codons are 30 generated that will translate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties on the antigen binding protein is by chemical or enzymatic coupling of glycosides to the protein. These procedures are advantageous in that they do not require production of the protein in a host cell that has glycosylation capabilities for N- and O-linked glycosylation. Depending on the

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2018203471 16 May 2018 coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. These methods are 5 described in WO 87/05330 published Sep. 11, 1987, and in Aptin and Wriston, 1981, CRC Crit. Rev, Biochem., pp. 259-306.

Removal of carbohydrate moieties present on the starting antigen binding protein may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the protein to the compound trifluoromethanesulfonic acid, or an equivalent compound. This 10 treatment results in the cleavage of most or all sugars except the linking sugar (Nacetylglucosamine or N-acetylgalactosamine), while leaving the polypeptide intact. Chemical deglycosylation is described by Hakimuddin etal., 1987, Arch. Biochem, Biophys. 259:52 and by Edge et al., 1981, Anal. Biochem. 118:131. Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as 15 described by Thotakura et al., 1987, Meth. Enzymol. 138:350. Glycosylation at potential glycosylation sites may be prevented by the use of the compound tunicamycin as described by Duskin etal., 1982, J. Biol. Chem, 257:3105. Tunicamycin blocks the formation ofprotein-Nglycoside linkages.

Hence, aspects include glycosylation variants ofthe antigen binding proteins wherein 20 the number and/or type of glycosylation site(s) has been altered compared to the amino acid sequences of the parent polypeptide. In certain embodiments, antibody protein variants comprise a greater or a lesser number of N-linked glycosylation sites than the native antibody. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X may be any amino acid residue except proline.

The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions that eliminate or alter this sequence will prevent addition of an N-linked carbohydrate chain present in the native polypeptide. For example, the glycosylation can be reduced by the deletion of an Asn or by substituting the Asn with a different amino acid. In other embodiments, one or more new

N-linked sites are created. Antibodies typically have a N-linked glycosylation site in the Fc region.

Labels and Effector Groups

In some embodiments, the antigen-binding comprises one or more labels. The term “labeling group” or “label” means any detectable label. Examples of suitable labeling groups

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2018203471 16 May 2018 include, but are not limited to, the following: radioisotopes or radionuclides (e.g., U, ^HC, ^l5N, ⁱ⁵S, ⁹⁰Y, ⁹⁹Tc,¹ in, ^l25I, ^13ll), fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic groups (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent groups, biotinyl groups, or predetermined 5 polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags). In some embodiments, the labeling group is coupled to the antigen binding protein via spacer arms of various lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art and may be used as is seen fit.

The term “effector group” means any group coupled to an antigen binding protein that acts as a cytotoxic agent. Examples for suitable effector groups are radioisotopes or radionuclides (e.g., ³H, *⁴C, ^l5N, ³⁵S, ^9tlY, ⁹⁹Tc,¹¹’in, ¹²⁵I, ^i3lI). Other suitable groups include toxins, therapeutic groups, or chemotherapeutic groups. Examples of suitable groups include calicheamicin, auristatins, geldanamycin and maytansine. In some embodiments, the effector group is coupled to the antigen binding protein via spacer arms of various lengths to reduce potential steric hindrance.

In general, labels fall into a variety of classes, depending on the assay in which they are to be detected: a) isotopic labels, which may be radioactive or heavy isotopes; b) magnetic labels (e.g., magnetic particles); c) redox active moieties; d) optical dyes; enzymatic groups (e.g. horseradish peroxidase, β-galactosidasc, luciferase, alkaline phosphatase); c) biotinylated groups; and f) predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags, etc.). In some embodiments, the labeling group is coupled to the antigen binding protein via spacer arms of various lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art.

Specific labels include optical dyes, including, but not limited to, chromophores, phosphors and fluorophores, with the latter being specific in many instances. Fluorophores can be either “small molecule” fluores, or proteinaceous fluorcs.

By ’‘fluorescent label” is meant any molecule that may be detected via its inherent fluorescent properties. Suitable fluorescent labels include, but are not limited to, fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosin, coumarin, methyl-coumarins, pyrene, Malacite green, stilbene, Lucifer Yellow, Cascade BlueJ, Texas Red, IAEDANS, EDANS, BODIPY FL, LC Red 640, Cy 5, Cy 5.5, LC Red 705, Oregon green, the Alexa-Fluor dyes (Alexa Fluor 350, Alexa Fluor 430, Alexa Fluor 488, Alcxa Fluor 546, Alcxa Fluor 568, Alexa

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Fluor 594, Alexa Fluor 633, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680), Cascade Blue, Cascade Yellow and R-phycoerythrin (PE) (Molecular Probes, Eugene, OR), F1TC, Rhodamine, and Texas Red (Pierce, Rockford, IL), Cy5, Cy5,5, Cy7 (Amersham Life Science, Pittsburgh, PA). Suitable optical dyes, including fluorophores, are described in Molecular 5 Probes Handbook by Richard P. Haugland, hereby expressly incorporated by reference.

Suitable proteinaceous fluorescent labels also include, but arc not limited to, green fluorescent protein, including a Renilla, Ptilosarcus, or Acquorca species of GFP (Chalfie et al., 1994, Science 263:802-805). EGFP (Clontech Labs., Inc., Gcnbank Accession Number U55762), blue fluorescent protein (BFP, Quantum Biotechnologies, Inc., Quebec, Canada;

Stauber, 1998, Biotechniques 24:462-41]; Heim et al., 1996, Curr. Biol. 6:178-182), enhanced yellow fluorescent protein (EYFP, Clontech Labs., Inc.), luciferase (lehiki et al., 1993, J Immunol. 150:5408-5417), β galactosidase (Nolan etai., 1988, Proc. Natl. Acad. Set.

U.S.A. 85:2603-2607) and Renilla (WO92/15673, WO95/07463, WO98/14605, WO98/26277, WO99/49019, United States Patents No. 5292658, No. 5418155, No. 5683888, No. 5741668,

No. 5777079, No. 5804387, No. 5874304, No. 5876995, No. 5925558).

Nucleic Acid Sequences Encoding CGRP Antigen Binding Proteins

Nucleic acids that encode for the antigen binding proteins described herein, or portions thereof, are also provided, including nucleic acids encoding one or both chains of an antibody, or a fragment, derivative, mutein, or variant thereof, polynucleotides encoding heavy chain 20 variable regions or only CDRs, polynucleotides sufficient for use as hybridization probes, PCR primers or sequencing primers for identifying, analyzing, mutating or amplifying a polynucleotide encoding a polypeptide, anti-sense nucleic acids for inhibiting expression of a polynucleotide, and complementary sequences of the foregoing. The nucleic acids can be any length. They can be, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 25 200, 250, 300, 350, 400, 450, 500, 750, 1,000, 1,500 or more nucleotides in length, and/or can comprise one or more additional sequences, for example, regulatory sequences, and/or be part of a larger nucleic acid, for example, a vector. The nucleic acids can be single-stranded or double-stranded and can comprise RNA and/or DNA nucleotides, and artificial variants thereof (e.g., peptide nucleic acids).

Table 7 shows exemplary nucleic acid sequences encoding an IgG2 heavy chain constant region, a kappa light chain constant region and a lambda hCL-1 light chain constant region. Any variable region provided herein may be attached to these constant regions to form complete heavy and light chain sequences. However, it should be understood that these constant regions sequences are provided as specific examples only -- one of skill in the art may

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2018203471 16 May 2018 employ other constant regions, including IgG 1 heavy chain constant region, lgG3 or lgG4 heavy chain constant regions, any of the seven lambda light chain constant regions, including hCL-1, hCL-2, hCL-3 and hCL-7; constant regions that have been modified for improved stability, expression, manufacturability or other desired characteristics, and the like. In some embodiments, the variable region sequences are joined to other constant region sequences that arc known in the art. Exemplary nucleic acid sequences encoding heavy and light chain variable regions are provided in Table 8.

Table 7: Exemplary Heavy And Light Chain Constant Region Nucleic Acid Sequences

Type	Nucleic Acid Sequence/SEQ ID NO.
lgG2 heavy chain	gctagcaccaagggcccatcggtcttccccctggcgccctgctecaggagcacctccgagagcacagcggcc ctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcgg cgtgcacaccttcccagctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagc aacttcggcacccagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagacagt tgagcgcaaatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggaccgtcagtcttcctcttcccc ccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccac gaagaccccgaggtccagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccacg ggaggagcagttcaacagcacgttccgtgtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggc aaggagtacaagtgcaaggtctccaacaaaggcctcccagcccccatcgagaaaaccatctccaaaaccaa agggcagccccgagaaccacaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggte agcctgacctgcctggtcaaaggcttctaccccagcgacategccgtggagtgggagagcaatgggcagcog gagaacaactacaagaccacacctcccatgctggactccgacggctccttcttcctctacagcaagctcaccgt ggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactac acgcagaagagcctctccctgtctccgggtaaatga [SEQ ID NO:259]
lgG2 kappa light chain	cgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaalctggaactgcctctgttgtgt gcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaa ctcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctg agcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgt cacaaagagcttcaacaggggagagtgttag [SEQ ID NO:260]
lgG2 lambda hCL- 1 light chain	ggtcagcocaaggccaaccccactgtcactctgttcccgccctcctctgaggagctccaagccaacaaggcca cactagtgtgtctgatcagtgacttctacccgggagctgtgacagtggcctggaaggcagatggcagccccgtc aaggcgggagtggagaccaccaaaccctccaaacagagcaacaacaagtacgcggccagcagctacctg agcctgacgcccgagcagtggaagtcccacagaagctacagctgccaggtcacgcatgaagggagcaccgt ggagaagacagtggcccctacagaatgttcatag [SEQ ID NO:261]

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Table 8 shows exemplary nucleic acid sequences encoding heavy chain and light chain variable regions, in which the various CDRL1, CDRL2 and CDRL3, or CDRHI, CDRH2 and CDRH3, sequences are embedded.

Table 8: Exemplary Light and Heavy Chain Variable Region Nucleic Acid Sequences

Reference	SEQ ID NO.	Nucleic Acid Sequence
2E7Vl	175	gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcactt gccgggcaagtcagggcattagaaatgatttaggctggtttcagcagaaaccagggaaagccc ctaagcgcctgatctatgctgcatccagtttgcaaagtggggtcecatcaaggttcagcggcagtg gatctgggacagaattcactctcacaatcagcagcctgcagcctgaagatttagcaacttattactg tctacagtataatatttacccgtggacgttcggccaagggaccaaggtggaaatcaaa
13H2 VL	176	gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccalcactt gccgggcaagtcagggcattagaaaggatttaggctggtatcagcagaaaccagggaaagcc cctaagcgcctgatctatggagcatccagtttgcaaagtggggtcccatcaaggttcagcggcagt ggatctgggacagaattcactctcacaatcagcagcctgcagcctgaagattttgcaacttattact gtctacagtataatagtttcccgtggacgttcggccaagggaccaaggtggaaatcaaa
33B5Vl	177	aggtgcagctggtgcagtctggggctgaggtgaagaagtctggggcctcagtgaaggtctcctgc aaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaagg gcttgagtggatgggatggatcaaccctaacagtggtggcacaaactatgtacagaaglttcagg gcagggtcaccatgaccagggacacgtccatcagcacagcctacatggagctgagcaggctg agatctgacgacacggccgtgtattactgtgcgagaaatgagtatagcagtgcctggcccttggg gtattggggccagggaaccctggtcaccgtctctagt
4H6 Vl	178	gatattgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctg caggtctagtcagagcctcctgcatagttttgggtacaactatttggattggtacctgcagaagccag ggcagtctccacagctcctgatctatttgggttctaatcgggcctccggggtccctgacaggttcagt ggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggatgttgggg tttattactgcatgcaagctctacaaactccattcactttcggccctgggaccaaagtggatatcaaa

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Reference	SEQ ID NO.	Nucleic Acid Sequence
3C8 Vl	179	gatattatactggcccagactccactttctctgtccgtcacccctggacagccggcctccatctcctg caagtctagtcagagcctcctgcacagtgctggaaagacctatttgtattggtacctgcagaagcc aggccagcctccacagctcctgatctatgaagtttccaaccggttctctggagtgccagataggttc agtggcagcgggtcagggacagatttcacactgaaaatcagccgggtggaggctgaggatgttg ggatttattactgcatgcaaagttttccgcttccgctcactttcggcggagggaccaaggtggagate aaa
5F5Vl	180	gatattattctgacccagactccactttctctgtcogtcacccctggacagccggcctccatctcctgc aagtctagtcagagcetcctgcacagtgatggaaagacctatttgtattggtacctgcagaagccc ggccagcctccacagctcctgatctatgaagtttccaaccggttctctggagagccagataggttca gtggcagcgggtcagggacagatttcacactgaaaatcagccgggtggaggctgaggaigttgg gacttattattgcatgcaaagttttccgcttecgctcacttfcggcggagggaccaaggtggagatca aa
12E8 Vl	181	gatattacactgacccagactccactttctctgtccgtctcccctggacagccggcctccatctectg caagtctagtcagagcctcctgcacagtgatggaaggaactatctgtattggtaoctgcagaagcc aggccagcctccacagctcctgatctatgaagtgtccaaccggttctctggactgccagataggttc agtggcagegggtcagggacagatttcacactgaaaatcagccgggtggaggctgaggatgttg ggatttattactgcatgcaaagttttccgcttccgctcactttcggcggagggaccaaggtggagatc aaa
32H7 VL	182	gaaattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagccaccctctccl gcagggccagtcagagtgttagcagcggctacttaacctggtaccagcagaaacctggccagg ctcccaggctcctcatctatggtgcatccagcagggccactggcatcccagacaggttcagtggc agtgggtctgggacagacttcactctcaccatcagcagactggagcctgaagattttgcagtgtatt actgteagcagtatggtaactcactgtgcaggtttggccaggggaccaagctggagatcaaa
32H7 CS Vl	183	gaaattgtgttgacgcagtctccaggcaccdgtctttgtctccaggggaaagagccaccctctcct gcagggccagtcagagtgttagcagcggctacttaacctggtaccagcagaaacctggccagg ctcccagactcctcatctatggtgcatccagcagggccactggcatcccagacaggttcagtggc agtgggtctgggacggacttcactetcaccatcagcagactggagcctgaagattttgcagtgtatt actgtcagcagtatggtaactcactgagcaggtttggccaggggaccaagctggagatcaaa

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Reference	SEQ ID NO.	Nucleic Acid Sequence
33E4 VL	184	gaaatagtgatgacgcagtctccagccaccctgtctgtgtctccaggggaaagagccaccctctc ctgtagggccagtoagagtgttcgcagcaatttagcctggtaccagcagaaacctggccaggcto ccaggctcctcattcatgatgcatcccccaggaccgctggtateccagccaggttcagtggcagtg gatctgggacagaattcactctcaccatcaacagcctgcagtctgaagattttgcagtttattaclgtc agcagtataattactggactccgatcaccttcggccaagggacacgactggagattaaa
32H8 Vl	185	gacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaa ctgeaagtccagccagagtattttagaeagctccaacaatgataactacttagcttggtaccagca gaaaccaggacagcctcctaaactgctcatttactgggcatctacccgggaatccggggtccctg accgattcagtggcagcgggtctgggacagatttcactctcaccatcagcagcctgcaggctgaa gatgtggcagtttattactgtcagcaatattataatactccattcactttcggccctgggaccaaagtg gatatcaaa
1E11 Vl	186	cagtctgtgttgacgcagccgccctcagtgtctgaggccccaggacagaaggtcaccatctcctg ctctggaagcagctccaacattgggaataattatgtatcctggtaccagcagctcccaggaacag cccccaaactcctcatttatgacaataataagcgaccctcagggattcctgaccgattctctggctc caagtctggcacgtcagccaccctgggcatcaccggactccagactggggacgaggccgattat tactgcggaacatgggatagccgcctgagtgctgtggttttcggcggagggaccaagctgacegt ccta
4E4 VL	187	cagtctgtgttgacgcagccgccctcagtgtctgcggccecaggacagaaggtcaccatctcctg ctctggaagcagctccaacattgggaataattatgtatcctggtaccagcagctcocaggaacag cccccaaactcctcatttatgacaataataagcgaccctcagggattcctgacogattctctggctc caagtctggcacgtcaaccaccctgggcatcaccggactccagactggggacgaggccgattat tactgcggaacatgggatagccgcctgagtgctgtggttttcggcggagggaccaagctgaccgt ccta
9D4 VL	188	cagtctgtgttgacgcagccgccctcagtgtctgcggccccaggacagaaggtcaccatctcctg ctctggaagcagctccaacattgggaataattatgtatcctggtaccagcagttcccaggaacagc ccccaaactcctcatttatgacaataataagogaccctcagggattcctgaccgattctctggctcc aagtctggcacgtcagceaccctgggcatcaccggactccagactggggacgaggccgattatt actgcggaacatgggatagccgcctgagtgctgtggttttcggcggagggaccaagctgaccgtc eta

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Reference	SEQ ID NO.	Nucleic Acid Sequence
12G8Vl	189	cagtctgtgttgacgcagccgccctcagtgtctgcggccccaggacagaaggtcaccatetaclg ctctggaagcagctccaacattgggaataattatgtatcctggtaccagcagctcccaggaacag cccccaaactcctcatttatgacaataataagcgaccctcagggattcctgaccgattctctggctc caagtctggcacgtcagccaccctgggcatcaccggactocagactggggacgaggccgattat tactgcggaacatgggatagccgcctgagtgctgtggttttcggcggagggaccaagctgaccgt ccta
34E3 VL	190	cagtctgtgttgacgcagccgccetcaatgtctgcggccccaggacagaaggtcaccatctcctg ctctggaagcagctccaacattgggaataattatgtatcctggtaccagcagcfcccaggaacag cccccaaactcctcatttatgacaataataagcgaccctcagggattcctgaccgattctctggctc caagtctggcacgtcagccaccctgggcatcaccggactecagactggggacgaggccaatta ctgetgcggaacatgggatatcggcctgagtgtttgggtgttcggcggagggaccaaactgaccg tecta
10E4 Vl	191	cagtctgtgctgactcagccaccctcagcgtctgggacccccgggcagagggtcaccatctcttgt tctggaagcagttccaatatcggaagtaatactgtgaactggtaccagcagctcccaggaacggc ccccaaactcctcatctatactaataatcagcggcectcaggggtccctgaccgattctctggctcc aagtctggcacctcagcctccctggccatcagtggactccagtctgaggatgaggctgatttttact gtgcagcgcgggatgagagcctgaatggtgtggtattcggcggagggaccaagctgaccgtcct a
11D11 VL 11H9 VL	192	cagtctgtgctgactcagccaccctcagcgtctgggacccccgggcagagagtcaccatctcttgt tctggaagcagctccaacatcggcagtaattatgtatactggtaccagcagctcccaggagcggc ccccaaactcctcatctttaggaataatcagcggccctcaggggtccctgaccgcttctctggctcc aagtctggcacctcagcctccctggccatcagtgggctccggtccgaggatgaggctgattattact gtgcagcatgggatgacagcctgagtggttgggtgttcggcggagggaccaagctgaccgtcct a
1H7 VL	193	cagtctgtgctgactcagccaccctcagcgtctgggacccccgggcagagagtcaccatctcttgt tctggaagcagctccaacatcggcagtaattatgtatactggtaccagcagctcccaggagcggc ccccaaactcctcatctttaggagtaatcagcggccctcaggggtccclgaccgaltctctggctcc aagtctggcacctcagcctccctggccatcagtgggctccggtccgaggatgaggctgattattact gtgcagcatgggatgacagcctgagtggttgggtgttcggcggagggaccaagctgaccgtcct a

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Reference	SEQ ID NO,	Nucleic Acid Sequence
9F5Vl	194	cagtctgtgctgactcagtcaccctcagcgtctgggacccccgggcagagagtcaccatctcttgtt ctggaagcagctccaacatcggcagtaattatgtatactggtaccagcagctcccaggagcggc ccccaaactcctcatccttaggaataatoagcggccctcaggggtccctgaccgattctctggctcc aagtctggcacctcagcctccctgaccatcagtgggctccggtccgaggatgaggctgactatlatt gtgcagcatgggatgacagcctgagtggttgggtgttcggcggagggaocaagctgaccgtcct a
3B6Vl	195	tcttctgagctgactcaggaccctaetgtgtctgtggccttgggacagacagtcaaaatcacatgcc aaggagacagcctcagaagtttttatgcaagctggtaccagcagaagccaggacaggcccctgt acttgtcttctatggtaaaaacaaccggccctcagggatcccagaccgattctctggctccagctca ggaaacacagcttccttgaccatcactggggctcaggoggaagatgaggctgaclattattgtaat tcccgggacagcagtgtttaccatctggtactcggcggagggaccaagctgaccgtccta
3B6 Vh	196	caggtgcagttggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcctg caaggcttctggatacaccttcaccggctactatatgcactgggtgcgacaggcccctggacaag ggcttgagtggatgggatggatcaaccctaacagtggtggcacaaactatgcacagaagttteag ggcagggtcaccatgaccagggacacgtccatcagcacagcctacatggagctgagcaggct gagatctgacgacacggecgtgtatttctgtgcgagagatcaaatgagtattattatgcttcgggga gtttttcccccttactattacggtatggacgtctggggccaagggaccacggtcaccgtctctagt
10E4 Vh	197	caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcct gcaaggcttctggatacaccttcaccgactactatatgtactgggtgcgacaggoccctggacaa gggcttgagtggatgggatggatcagccctaatagtggtggcacaaactatgcccagaagtttca gggcagggtcaccatgaccagggacacgtctatcagcacagcctacatggagctgagtaggct gagatotgacgacacggccgtgtattactgtgtgagaggaggatatagtggclacgctgggctcta ctcccactactacggtatggacgtctggggccaagggaccacggtcaccgtctctagt
32H8 VH	198	caggtgcagctggtgcagtctggggctgaggtgaagaagcctggggcctcagtgaaggtctcct gcaaggcttctggatacaccttcaccgcctactatttacactgggtgcgacaggcccctggacaag ggcttgagtggatgggatggatcaaccctcacagtggtggcacaaactatgcacagaagtttcag ggcagggtcaccatgaccagggacacgtccatcagcacagcctacatggagctgagcaggct gagatctgacgacacggccgtgttctactgtgcgagaggaaggcagtggctgggctttgactact ggggccagggaaccctggtcaccgtctctagt

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Reference	SEQ ID NO.	Nucleic Acid Sequence
33B5 VH	199	gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagttaccattacttg ccgggcaagtcagggcattagaaatgatttaggctggtatcagcagaaaccagggaaagcccc taagcgcctgatctatgttgcatccagtttgcaaagtggggtcccatcaaggttcagcggcagtgga tctgggacagaattcactctcacaatcagcagcctgcagoctgaagattttgcaacttattactgtct acagtataacacttacccgctcactttcggcggagggaccaaggtggagatcaag
11D11 Vh	200	gaggtacagctggtggagtctgggggaggcttggtaaagcctggggggtccctcagactctcctg tgcagcctctggattcactttcggtaacgcctggatgagctgggtccgccaggctccagggaagg ggctggagtgggttggccgtattaaaagcaaaactgatggtgggacaacagactaogctgcacc cgtgaaaggcagattcaccatctcaagagatgattcaaaaaacacgctgtatctgcaaatgaac agcctgaaaaccgaggacacagccgtgtatttctgtaccacagatcggaccgggtatagcatca gctggtctagttactactactactacggtatggacgtctggggccaagggaccacggtcaccgtct ctagt
9F5 Vh	201	gaggtgcagctggtggagtctgggggaggcttggtaaagcctggggggtcccttagactctcctgt gcagcctctggattcactttcagtaacgcetggatgagctgggtccgccaggctccagggaaggg gctggagtgggttggccgtattaaaagcaaaactgatggtgggacaacagactacactgcaccc gtgaaaggcagattcaccatctcaagagatgatteaaaaaacacgctgtatctgcaaatgaatag cctgaaagccgaggacacagccgtgtattactgtaccacagatcggaccgggtatagcatcagc tggtctagttactactactactacggtatggacgtctggggccaagggaccaoggtcaccglctcta gt
11H9 Vh	202	gaggtecagctggtggagtctgggggaggcttggtaaagcctggggggtcccttagactctcctgt gcagcctctggatlcactttcggtaacgcctggatgagctgggtccgccaggclccagggaaggg gctggagtgggttggccgtattaaaagcaaaactgatggtgggacaacagactacgctgcaccc gtgaaaggcagattcaccatctcaagagatgattcaaaaaacacgctgtatctgcaaatgaaca gcctgaaaaccgaggacacagccgtgtattactgtaccacagatcggaccggglatagcatcag ctggtctagttactactactactacggtatggacgtctggggccaagggaccacggtcaccgtctct agl

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Reference	SEQ ID NO.	Nucleic Acid Sequence
1H7 VH	203	gaggtgcagctggtggagtctgggggaggcttggtaaagcctggggggtccctlagactctcctgl gcagcctctggattcactttcagtaacgcctggatgagctgggtccgccaggctceagggaaggg gctggagtgggttggccgtattaaaagcacaactgatggtgggacaacagactacgctgcaccc gtgaaaggcagattcaccatctcaagagatgattcaaaaaacacgctgtatctgcaaatgaaca gcctgaaaaccgaggacacagccgtgtattactgtaccacagatcggaccggatatagcatcag ctggtctagttactactactactacggtatggacgtctggggccaagggaccacggtcaccgtctct agt
13H2 Vh	204	gaggtgcagctggtggagtctgggggaggcctggtcaagcctggggggtccctgagactdcctg tgcagcctctggatacaccttcagtacctatagcatgaactgggtccgccaggctccagggaagg ggctggagtgggtctcatccattagtagtagtagtagttacagatattacgcagactcagtgaaggg ccgattcaccatctccagagacaacgccaagaactcactgtatctgcaaatgagtagcctgaga gccgaggacacggctgtgtattactgtgcgagagaaggggtgtctggcagttcgccgtatagcat cagctggtacgactactattacggtatggacgtctggggccaagggaccacggtcaccgtctcta gt
2E7Vh	205	gaggtgcagctattggagtctgggggaggcttggtacagcctggggagtccctgagactetcctgt gcagcctctgggttcacctttagcagctatgccatgagctgggtccgccaggctccagggaaggg gctggagtgggtctcagctattagtggtagtggtggtcgcacatactacgcagactccgtgaaggg ccggttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaatagcctgagag ccgaggacacggccgtatattactgtgcgaaagatcaaagggaggtagggccgtatagcagtg gctggtacgactactactacggtatggacgtctggggccaagggaccacggtaaccgtctctagt
3C8 VH 12E8 Vh 5F5 Vh	206	caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctg tgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggg gctggagtgggtggcagttatttcatatgatggaagtcatgaatcctatgcagactcegtgaagggc cgattcaccatctccagagacatttccaagaacacgctgtatctgcaaatgaacagcctgagagc tgaggacacggctgtgtattlctgtgcgagagagaggaaacgggtlacgatgtctaccttatatlact acttctactacggtatggacgtctggggccaagggaccacggtcaccgtctctagt

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Reference	SEQ ID NO.	Nucleic Acid Sequence
4E4Vh 9D4 Vh 1E11 VH	207	caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaggtccctgagactctcctg tgcagcctctggattcaccttcagtagctttggcatgcactgggtccgccaggctccaggcaaggg gctggagtgggtggcagttatatcatttgatggaagtattaagtattctgtagactccgtgaagggcc gattcaccatctccagagacaattcaaagaacacgctgtttctgcaaatgaacagcctgcgagcc gaggacacggctgtgtattactgtgcgagagatcggctcaattactatgatagtagtggttattatca ctacaaatactacggtatggccgtctggggccaagggaccacggtcaccgtctctagt
12G8 Vh	208	caggtgcagctggtggaatctgggggaggcgtggtccagcctgggaggtcoctgagactctcctg tgcagcctctggattcaccttcagtagctttggcatgcattgggtccgccaggctccaggcaaggg gctggagtgggtggcagttatatcatttgatggaagtattaagtactctgtagaciccgtgaagggcc gattcaccatctccagagacaattcaaagaacacgctgtttctgcaaalgaacagcctgcgagcc gaggacacggctgtgtattactgtgcgagagatcggctcaattactatgatagtagtggttattatca ctacaaatactacggtctggccgtctggggccaagggaccacggtcaccgtctctagt
4H6 Vh	209	gaggtgcagctggtggagtctgggggaggcttggtaaagccagggcggtccctgagactctcct gtacagcttctggattcacctttggtgattatgctatgagctggttccgccaggctccagggaagggg ctggagtggataggtttcattagaagcagagcttatggtgggacaccagaatacgccgcgtctgtg aaaggcagattcaccatctcaagagatgattccaaaaccatcgcctatetgcaaatgaacagcct gaaaaccgaggacacagccgtgtatttctgtgctagaggacggggtattgcagctcgttgggact actggggccagggaaccctggtcaccgtctctagt
32H7Vh	210	caggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtacctgagactclcclg tgcagcgtctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaagg ggctggagtgggtggcagttatatggtatgatggaagtaataaatactatgcagactccgtgaagg gccgattcatcatctccagagataaatccaagaacacgctgtatctgcaaatgaacagcctgaga gccgaggacacggctgtgtattactgtgcgagagcggggggtatagcagcagctggcctctacta ctactacggtatggacgtctggggccaagggaccacggtcaccgtctctagt
33E4 VH	211	caggtgcagttacagcagtggggcgcaggactgttgaagccttcggagaccctgtccctcagctg cgctgtctatggtgggtccttcggtggttactactggagctggatccgccagcccccagggaaggg gctggagtggattggggaaatcaatcatagtggaggcaccaagtacaaccegtcccteaagagt cgagtcaccatatcagtagacacgtccaagaaccagttctccctgaagctgagctctgtgaccgc cgcggacacggctgtgtatttctgtgcgagaggcgatglagtaggtttctttgactattggggccagg gaaccctggtcaccgtctctagt

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Table 9 shows the SEQ ID NOs of exemplary nucleic acid sequences encoding complete heavy and light chains, as well as heavy and light chain variable regions, of exemplary isolated antigen-binding proteins, specifically, hCGRP R binding proteins, disclosed herein.

Table 9 - Exemplary HC, LC, Vn and Vi. Nucleic Acid Sequence SEQ ID NOs

k·— Φ q:	Variable Light SEQ ID NO.	Variable Heavy SEQ ID NO.	Full Light SEQ ID NO.	Full Heavy SEQ ID NO
2E7	175	205	226	244
13H2	176	204	239	257
4H6	178	209	230	248
3C8	179	206	228	246
5F5	180	206	231	249
12E8	181	206	237	255
1E11	186	207	224	242
4E4	187	207	229	247
9D4	188	207	232	250
12G8	189	208	238	256
10E4	191	197	234	252
11D11	192	200	235	253
11H9	192	202	236	254
1H7	193	203	225	243
9F5	194	201	233	251
3B6	195	196	227	245
32H7	182	210	240	258

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O) Di	Variable Light SEQ ID NO.	Variable Heavy SEQ ID NO.	Full Light SEQ ID NO.	Full Heavy SEQ ID NO
32H7 CS	183	210	241	258
32H8	185	198
33B5	177	199
33E4	184	211
34E3	190	212

Nucleic acids encoding certain antigen binding proteins, or portions thereof (e.g., full length antibody, heavy or light chain, variable domain, or CDRH 1, CDRH2, CDRH3, CDRL1, CDRL2, or CDRL3) may be isolated from B-cells of mice that have been immunized with

CGRP R or immunogenic components thereof, e.g., by immunizing with full-length CGRP R (comprising both CRLR and RAMP 1), with the extracellular domain of CGRP R (comprising extracellular domains of CRLR and RAMP1), with whole cells expressing CGRP R, with membranes prepared from cells expressing CGRP R, with fusion proteins, e.g., Fc fusions, comprising CRLR, RAMP1 (or extracellular domains thereof) fused to Fc, and other methods known in the art, for example, as described in the Examples 1-3 herein. The nucleic acid may be isolated by conventional procedures such as polymerase chain reaction (PCR). Phage display is another example of a known technique whereby derivatives of antibodies and other antigen binding proteins may be prepared. In one approach, polypeptides that are components of an antigen binding protein of interest are expressed in any suitable recombinant expression system, and the expressed polypeptides are allowed to assemble to form antigen binding protein molecules.

The nucleic acids provided in Tables 7-9 are exemplary only. Due to the degeneracy of the genetic code, each of the polypeptide sequences listed in Tables 2-5 or otherwise depicted herein are also encoded by a large number of other nucleic acid sequences besides those provided. One of ordinary skill in the art will appreciate that the present application thus

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2018203471 16 May 2018 provides adequate written description and enablement for each degenerate nucleotide sequence encoding each antigen binding protein.

An aspect further provides nucleic acids that hybridize to other nucleic acids (e.g., nucleic acids comprising a nucleotide sequence listed in Table 7, Table 8, Table 9 and/or SEQ 5 ID NOs:224-258) under particular hybridization conditions. Methods for hybridizing nucleic acids are well-known in the art. See. e.g.. Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. As defined herein, a moderately stringent hybridization condition uses a prewashing solution containing 5x sodium chloride/sodium citrate (SSC), 0.5% SDS, 1.0 mM EDTA (pH 8.0), hybridization buffer of about 50% formamide, 6x SSC, 10 and a hybridization temperature of 55°C (or other similar hybridization solutions, such as one containing about 50% formamide, with a hybridization temperature of 42°C), and washing conditions of 60°C, in Q.5x SSC, 0.1% SDS. A stringent hybridization condition hybridizes in 6x SSC at 45°C, followed by one or more washes in O.lx SSC, 0.2% SDS at 68°C. Furthermore, one of skill in the art can manipulate the hybridization and/or washing conditions 15 to increase or decrease the stringency of hybridization such that nucleic acids comprising nucleotide sequences that are at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to each other typically remain hybridized to each other.

The basic parameters affecting the choice of hybridization conditions and guidance for devising suitable conditions are set forth by, for example, Sambrook, Fritsch, and Maniatis 20 (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold

Spring Harbor, N.Y., supra\ and Current Protocols in Molecular Biology, 1995, Ausubel etat., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6,4), and can be readily determined by those having ordinary skill in the art based on, e.g., the length and/or base composition of the nucleic acid.

Changes can be introduced by mutation into a nucleic acid, thereby leading to changes in the amino acid sequence of a polypeptide (e.g., an antibody or antibody derivative) that it encodes. Mutations can be introduced using any technique known in the art. In one embodiment, one or more particular amino acid residues arc changed using, for example, a site-directed mutagenesis protocol. In another embodiment, one or more randomly selected residues is changed using, for example, a random mutagenesis protocol. However it is made, a mutant polypeptide can be expressed and screened for a desired property.

Mutations can be introduced into a nucleic acid without significantly altering 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.

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Alternatively, one or more mutations can be introduced into a nucleic acid that selectively changes the biological activity of a polypeptide that it encodes. For example, the mutation can quantitatively or qualitatively change the biological activity. Examples of quantitative changes include increasing, reducing or eliminating the activity. Examples of qualitative changes 5 include changing the antigen specificity of an antibody. In one embodiment, a nucleic acid encoding any antigen binding protein described herein can be mutated to alter the amino acid sequence using molecular biology techniques that are well-established in the art.

Another aspect provides nucleic acid molecules that are suitable for use as primers or hybridization probes for the detection of nucleic acid sequences. A nucleic acid molecule can 10 comprise only a portion of a nucleic acid sequence encoding a full-length polypeptide, for example, a fragment that can be used as a probe or primer or a fragment encoding an active portion (e.g., a CGRP R binding portion) of a polypeptide.

Probes based on the sequence of a nucleic acid can be used to detect the nucleic acid or similar nucleic acids, for example, transcripts encoding a polypeptide. The probe can comprise 15 a label group, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used to identify a cell that expresses the polypeptide.

Another aspect provides vectors comprising a nucleic acid encoding a polypeptide or a portion thereof (e.g., a fragment containing one or more CDRs or one or more variable region domains). Examples of vectors include, but are not limited to, plasmids, viral vectors, non20 cpisomal mammalian vectors and expression vectors, for example, recombinant expression vectors. The recombinant expression vectors can comprise a nucleic acid in a form suitable for expression of the nucleic acid in a host cell. The recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operably linked to the nucleic acid sequence to be expressed. Regulatory sequences 25 include those that direct constitutive expression of a nucleotide sequence in many types of host cells (e.g., SV40 early gene enhancer, Rous sarcoma virus promoter and cytomegalovirus promoter), those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences, see, Voss et al., 1986, Trends Biochem. Sci. 11:287. Maniatis et al., 1987, Science 236:1237. incorporated by reference herein in their entireties), 30 and those that direct inducible expression of a nucleotide sequence in response to particular treatment or condition (e.g., the metal lothionin promoter in mammalian cells and the tetresponsive and/or streptomycin responsive promoter in both prokaryotic and eukaryotic systems (see, id.). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed.

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2018203471 16 May 2018 the level of expression of protein desired, etc. The expression vectors can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.

Another aspect provides host cells into which a recombinant expression vector has been 5 introduced. A host cell can be any prokaryotic cell (for example, E. coli) or eukaryotic cell (for example, yeast, insect, or mammalian cells (e.g., CHO cells)). Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate 10 the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that 15 have incorporated the selectable marker gene will survive, while the other cells die), among other methods.

Preparing Of Antigen Binding Proteins

Non-human antibodies that are provided can be, for example, derived from any antibody-producing animal, such as mouse, rat, rabbit, goat, donkey, or non-human primate (such as monkey (e.g., cynomolgus or rhesus monkey) or ape (e.g., chimpanzee)). Non-human antibodies can be used, for instance, in in vitro cell culture and cell-culture based applications, or any other application where an immune response to the 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 described above and/or in Examples 1-3 below. The examples describe the generation of anti CGRP R antibodies using three different immunogen preparations - (i) whole cells expressing full-length versions of two major components of CGRP R - RAMP1 and CRLR; (ii) membrane extracts from such cells; and (iii) soluble CGRP R obtained by co-expressing and purifying the N-terminal extracellular domains of CRLR and RAMP1. The antibodies may be polyclonal, monoclonal, or may be synthesized in host cells by expressing recombinant DNA. Fully human antibodies may be prepared as described above by immunizing transgenic animals containing human immunoglobulin loci or by selecting a phage display library that is expressing a repertoire of human antibodies.

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The monoclonal antibodies (mAbs) can be produced by a variety of techniques, including conventional monoclonal antibody methodology, e.g., the standard somatic cell hybridization technique of Kohler and Milstein, 1975, Nature 256:495. Alternatively, other techniques for producing monoclonal antibodies can be employed, for example, the viral or 5 oncogenic transformation of B-lymphocytcs. One suitable animal system for preparing hybridomas is the murine system, which is a very well established procedure. Immunization protocols and techniques for isolation of immunized splenocytcs for fusion arc known in the art and illustrative approaches are described in the Examples, below. For such procedures, B cells from immunized mice are typically fused with a suitable immortalized fusion partner, such as a 10 murine myeloma cell line. If desired, rats or other mammals besides can be immunized instead of mice and B cells from such animals can be fused with the murine myeloma cell line to form hybridomas. Alternatively, a myeloma cell line from a source other than mouse may be used. Fusion procedures for making hybridomas also are well known.

The single chain antibodies that arc provided may be formed by linking heavy and light 15 chain variable domain (Fv region) fragments via an amino acid bridge (short peptide linker), resulting in a single polypeptide chain. Such single-chain Fvs (scFvs) maybe prepared by fusing DNA encoding a peptide linker between DNAs encoding the two variable domain polypeptides (Vl and Vn). The resulting polypeptides can fold back on themselves to form antigen-binding monomers, or they can form multimers (e.g., dimers, trimers, or tetramers), depending on the length of a flexible linker between the two variable domains (Kortt et at., 1997, Prot, Eng. 10:423; Kortt et al., 2001, Biomol. Eng. 18:95-108). By combining different V_L and Vn -comprising polypeptides, one can form multimeric scFvs that bind to different epitopes (Kriangkum et al., 2001, Biomol. Eng. 18:31-40). Techniques developed for the production of single chain antibodies include those described in U.S. Pat. No. 4,946,778; Bird, 25 1988, Science 242:423; Huston et a!., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:5879; Ward et al.,

1989, Nature 334:544, dc Graaf et al., 2002, Methods Mol Biol. 178:379-387. Single chain antibodies derived from antibodies provided herein include, but are not limited to scFvs comprising the variable domain combinations of the heavy and light chain variable regions depicted in Table 3, or combinations of light and heavy chain variable domains which include 30 CDRs depicted in Tables 4A and 4B.

Antibodies provided herein that are of one subclass can be changed to antibodies from a different subclass using subclass switching methods. Thus, IgG antibodies may be derived from an IgM antibody, for example, and vice versa. Such techniques allow the preparation of new antibodies that possess the antigen binding properties of a given antibody (the parent

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2018203471 16 May 2018 antibody), but also exhibit biological properties associated with an antibody isotype or subclass different from that of the parent antibody. Recombinant DNA techniques may be employed. Cloned DNA encoding particular antibody polypeptides may be employed in such procedures, e.g., DNA encoding the constant domain of an antibody of the desired isotype. See, e.g., Lantto 5 et a!., 2002, Methods Mol. Biot. 178:303-316.

Accordingly, the antibodies that arc provided include those comprising, for example, the variable domain combinations described, supra., having a desired isotype (for example, IgA, IgGl, tgG2, lgG3, lgG4, IgE, and IgD) as well as Fab or F(ab’)_z fragments thereof. Moreover, if an lgG4 is desired, it may also be desired to introduce a point mutation (CPSCP10 >CPPCP) in the hinge region as described in Bloom et al., 1997, Protein Science 6:407, incorporated by reference herein) to alleviate a tendency to form intra-H chain disulfide bonds that can lead to heterogeneity in the IgG4 antibodies.

Moreover, techniques for deriving antibodies having different properties (i.e., varying affinities for the antigen to which they bind) are also known. One such technique, referred to 15 as chain shuffling, involves displaying immunoglobulin variable domain gene repertoires on the surface of filamentous bacteriophage, often referred to as phage display. Chain shuffling has been used to prepare high affinity antibodies to the hapten 2-phenyloxazol-5-one, as described by Marks et al., 1992, BioTechnology 10:779.

Conservative modifications may be made to the heavy and light chain variable regions 20 described in Table 3, or the CDRs described in Tables 4A and 4B (and corresponding modifications to the encoding nucleic acids) to produce a CGRP R binding protein having certain desirable functional and biochemical characteristics. Methods for achieving such modifications are described above.

CGRP antigen binding proteins may be further modified in various ways. For example, 25 if they arc to be used for therapeutic purposes, they may be conjugated with polyethylene glycol (pegylatcd) to prolong the serum half-life or to enhance protein delivery. Alternatively, the V region of the subject antibodies or fragments thereof may be fused with the Fc region of a different antibody molecule. The Fc region used for this purpose may be modified so that it does not bind complement, thus reducing the likelihood of inducing cell lysis in the patient when the fusion protein is used as a therapeutic agent. In addition, the subject antibodies or functional fragments thereof may be conjugated with human serum albumin to enhance the serum half-life of the antibody or antigen binding fragment thereof. Another useful fusion partner for the antigen binding proteins or fragments thereof is transthyretin (TTR). TTR has

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2018203471 16 May 2018 the capacity to form a tetramer, thus an antibody-TTR fusion protein can form a multivalent antibody which may increase its binding avidity.

Alternatively, substantial modifications in the functional and/or biochemical characteristics of the antigen binding proteins described herein may be achieved by creating 5 substitutions in the amino acid sequence of die heavy and light chains that differ significantly in their effect on maintaining (a) the structure of the molecular backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulkiness of the side chain, A “conservative amino acid substitution” may involve a substitution of a native amino acid residue with a nonnative 10 residue that has little or no effect on the polarity or charge of the amino acid residue at that position. See, Table 4, supra. Furthermore, any native residue in the polypeptide may also be substituted with alanine, as has been previously described for alanine scanning mutagenesis.

Amino acid substitutions (whether conservative or non-conservative) of the subject antibodies can be implemented by those skilled in the art by applying routine techniques.

Amino acid substitutions can be used to identify important residues of the antibodies provided herein, or to increase or decrease the affinity of these antibodies for human CGRP R or for modify ing the binding affinity of other antigen-binding proteins described herein.

Methods Of Expressing Antigen Binding Proteins

Expression systems and constructs in the form of plasmids, expression vectors, transcription or expression cassettes that comprise at least one polynucleotide as described above are also provided herein, as well host cells comprising such expression systems or constructs.

The antigen binding proteins provided herein may be prepared by any of a number of conventional techniques. For example, CGRP R antigen binding proteins may be produced by recombinant expression systems, using any technique known in the art. See, e.g.. Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Rennet et al. (eds.) Plenum Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988).

Antigen binding proteins can be expressed in hybridoma cell lines (e.g., in particular antibodies may be expressed in hybridomas) or in cell lines other than hybridomas. Expression constructs encoding the antibodies can be used to transform a mammalian, insect or microbial host cell. Transformation can be performed using any known method for introducing polynucleotides into a host cell, including, for example packaging the polynucleotide in a virus or bacteriophage and transducing a host cell with the construct by transfection procedures

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2018203471 16 May 2018 known in the art, as exemplified by United States Patent No. 4,399,216; No. 4,912,040;

No. 4,740,461; No. 4,959,455. The optimal transformation procedure used will depend upon which type of host cell is being transformed, Methods for introduction of heterologous polynucleotides into mammalian cells are well known in the art and include, but are not limited 5 to, dextran-mediated transfection, calcium phosphate precipitation, polybrcne mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotidc(s) in liposomes, mixing nucleic acid with positively-charged lipids, and direct microinjcction of the DNA into nuclei.

Recombinant expression constructs typically comprise a nucleic acid molecule 10 encoding a polypeptide comprising one or more of the following: one or more CDRs provided herein; a light chain constant region; a light chain variable region; a heavy chain constant region (e.g., ChL C_S12 and/or Cr3); and/or another scaffold portion of a CGRP R antigen binding protein. These nucleic acid sequences are inserted into an appropriate expression vector using standard ligation techniques. In one embodiment, the heavy or light chain 15 constant region is appended to the C-terminus of the anti-CGRP R-specific heavy or light chain variable region and is ligated into an expression vector. The vector is typically selected to be functional in the particular host cell employed (i.e., the vector is compatible with the host cell machinery, permitting amplification and/or expression of the gene can occur). In some embodiments, vectors are used that employ protein-fragment complementation assays using 20 protein reporters, such as dihydrofolatc reductase (see, for example, U.S. Pat. No. 6,270,964, which is hereby incorporated by reference). Suitable expression vectors can be purchased, for example, from lnvitrogen Life Technologies or BD Biosciences (formerly Clontech). Other useful vectors for cloning and expressing the antibodies and fragments include those described in Bianchi and McGrew, 2003, Biotech. Biotechnol. Bioeng. 84:439-44, which is hereby 25 incorporated by reference. Additional suitable expression vectors are discussed, for example, in Methods Enzymol., vol. 185 (D. V. Goeddel, cd.), 1990, New York: Academic Press.

Typically, expression vectors used in any of the host cells will contain sequences for plasmid maintenance and for cloning and expression of exogenous nucleotide sequences. Such sequences, collectively referred to as “flanking sequences” in certain embodiments will 30 typically include one or more of the following nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcriptional termination sequence, a complete intron sequence containing a donor and acceptor splice site, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a

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2018203471 16 May 2018 polylinker region for inserting the nucleic acid encoding the polypeptide to be expressed, and a selectable marker element. Each of these sequences is discussed below.

Optionally, the vector may contain a tag’’-encoding sequence, i.e., an oligonucleotide molecule located at the 5' or 3' end of the CGRP R binding protein coding sequence; the 5 oligonucleotide sequence encodes polyHis (such as hexaHis), or another “tag” such as FLAG®, HA (hcmaglutinin influenza virus), or myc, for which commercially available antibodies exist. This tag is typically fused to the polypeptide upon expression of the polypeptide, and can serve as a means for affinity purification or detection of the CGRP R binding protein from the host cell. Affinity purification can be accomplished, for example, 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 means such as using certain peptidases for cleavage.

Flanking sequences may be homologous (i.e., from the same species and/or strain as the host cell), heterologous (i.e., from a species other than the host cell species or strain), hybrid 15 (i.e., a combination of flanking sequences from more than one source), synthetic or native. As such, the source of a flanking sequence may be any prokaryotic or eukaryotic organism, any vertebrate or invertebrate organism, or any plant, provided that the flanking sequence is functional in, and can be activated by, the host cell machinery.

Flanking sequences useful in the vectors may be obtained by any of several methods 20 well known in the art. Typically, flanking sequences useful herein will have been previously identified by mapping and/or by restriction endonuclease digestion and can thus be isolated from the proper tissue source using the appropriate restriction endonucleases. In some cases, the full nucleotide sequence of a flanking sequence may be known. Here, the flanking sequence may be synthesized using the methods described herein for nucleic acid synthesis 25 or cloning.

Whether all or only a portion of the flanking sequence is known, it may be obtained using polymerase chain reaction (PCR) and/or by screening a genomic library with a suitable probe such as an oligonucleotide and/or flanking sequence fragment from the same or another species. Where the flanking sequence is not known, a fragment of DNA containing a flanking sequence may be isolated from a larger piece of DNA that may contain, for example, a coding sequence or even another gene or genes. Isolation may be accomplished by restriction endonuclease digestion to produce the proper DNA fragment followed by isolation using agarose gel purification, Qiagen” column chromatography (Chatsworth, CA), or other methods

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2018203471 16 May 2018 known to the skil led artisan. The selection of suitable enzymes to accomplish this purpose will be readily apparent to one of ordinary skill in the art.

An origin of replication is typically a part of those prokaryotic expression vectors purchased commercially, and the origin aids in the amplification of the vector in a host cell. If 5 the vector of choice does not contain an origin of replication site, one may be chemically synthesized based on a known sequence, and ligated into the vector. For example, the origin of replication from the plasmid pBR.322 (New England Biolabs, Beverly, MA) is suitable for most gram-negative bacteria, and various viral origins (e.g., SV40, polyoma, adenovirus, vesicular stomatitus virus (VSV), or papillomaviruses such as HPV or BPV) are useful for 10 cloning vectors in mammalian cells. Generally, the origin of replication component is not needed for mammalian expression vectors (for example, the SV40 origin is often used only because it also contains the virus early promoter).

A transcription termination sequence is typically located 3' to the end of a polypeptide coding region and serves to terminate transcription. Usually, a transcription termination 15 sequence in prokaryotic cells is a G-C rich fragment followed by a poly-T sequence. While the sequence is easily cloned from a library or even purchased commercially as part of a vector, it can also be readily synthesized using methods for nucleic acid synthesis such as those described herein.

A selectable marker gene encodes a protein necessary for the survival and growth of a host cell grown in a selective culture medium. Typical selection marker genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, tetracycline, or kanamyein for prokaryotic host cells; (b) complement auxotrophic deficiencies of the cell; or (c) supply critical nutrients not available from complex or defined media. Specific selectable markers are the kanamyein resistance gene, the ampicillin resistance gene, and the tetracycline resistance gene. Advantageously, a neomycin resistance gene may also be used for selection in both prokaryotic and eukaryotic host cells.

Other selectable genes may be used to amplify the gene that will be expressed, Amplification is the process wherein genes that are required for production of a protein critical for growth or cell survival are reiterated in tandem within the chromosomes of successive generations of recombinant cells. Examples of suitable selectable markers for mammalian cells include dihydrofolate reductase (DHFR) and promoterless thymidine kinase genes. Mammalian cell transformants are placed under selection pressure wherein only the transformants are uniquely adapted to survive by virtue of the selectable gene present in the vector. Selection pressure is imposed by culturing the transformed cells under conditions in

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2018203471 16 May 2018 which the concentration of selection agent in the medium is successively increased, thereby leading to the amplification of both the selectable gene and the DNA that encodes another gene, such as an antigen binding protein that binds to CGRP R. As a result, increased quantities of a polypeptide such as an antigen binding protein are synthesized from the 5 amplified DNA.

A ribosome-binding site is usually necessary for translation initiation of mRNA and is characterized by a Shine-Dal garno sequence (prokaryotes) or a Kozak sequence (eukaryotes). The element is typically located 3' to the promoter and 5' to the coding sequence of the polypeptide to be expressed.

In some cases, such as where glycosylation is desired in a eukaryotic host cell expression system, one may manipulate the various pre- or pro-sequences to improve glycosylation or yield. For example, one may alter the peptidase cleavage site of a particular signal peptide, or add prosequenccs, which also may affect glycosylation. The final protein product may have, in the -1 position (relative to the first amino acid of the mature protein), one or more additional amino acids incident to expression, which may not have been totally removed. For example, the final protein product may have one or two amino acid residues found in the peptidase cleavage site, attached to the amino-terminus. Alternatively, use of some enzyme cleavage sites may result in a slightly truncated form of the desired polypeptide, if the enzyme cuts at such area within the mature polypeptide.

Expression and cloning will typically contain a promoter that is recognized by the host organism and operably linked to the molecule encoding a CGRP R binding protein. Promoters are untranscribed sequences located upstream (i.e., 5') to the start codon of a structural gene (generally within about 100 to 1000 bp) that control transcription of the structural gene. Promoters are conventionally grouped into one of two classes: inducible promoters and constitutive promoters. Inducible promoters initiate increased levels of transcription from

DNA under their control in response to some change in culture conditions, such as the presence or absence of a nutrient or a change in temperature. Constitutive promoters, on the other hand, uniformly transcribe a gene to which they are operably linked, that is, with little or no control over gene expression. A large number of promoters, recognized by a variety of potential host cells, are well known. A suitable promoter is operably linked to the DNA encoding heavy chain or light chain comprising a CGRP R binding protein by removing the promoter from the source DNA by restriction enzyme digestion and inserting the desired promoter sequence into the vector.

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Suitable promoters for use with yeast hosts are also well known in the art. Yeast enhancers are advantageously used with yeast promoters. Suitable promoters for use with mammalian host cells are well known and include, but are not limited to, those obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 5 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, retroviruses, hepatitis-B virus, and Simian Virus 40 (SV40). Other suitable mammalian promoters include heterologous mammalian promoters, for example, heat-shock promoters and the actin promoter.

Additional promoters which may be of interest include, but are not limited to: SV40 early promoter (Benoist and Chambon, 1981, Nature 290:304-310); CMV promoter (Thomsen 10 et al, 1984, Proc. Natl Acad. U.S.A. 81.:659-663); the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto etal, 1980, Cell 22:787-7971: herpes thymidine kinase promoter (Wagner et al, 1981, Proc. Natl. Acad. Sci. U.S.A. 78:1444-1445 ): promoter and regulatory sequences from the metallothionine gene (Prinster et al, 1982, Nature 296:39-42): and prokaryotic promoters such as the beta-lactamase promoter (Vilta-Kamaroff et 15 al, 1978, Proc. Natl Acad. Scl U.S.A. 75:3727-3731); or the tac promoter (DeBoer et al,

1983, Proc. Natl. Acad. Sci. U.S.A. 80:21-25). Also of interest arc the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: the elastase 1 gene control region that is active in pancreatic acinar cells (Swift et al, 1984, Cell 38:639-646; Ornitz et al, 1986, Cold Spring Harbor Syrup. Quant.

Biol 50:399-409; MacDonald, 1987, Hepatology 7:425-515); the insulin gene control region that is active in pancreatic beta cells (Hanahan, 1985, Aatwe 315:115-122); the immunoglobulin gene control region that is active in lymphoid cells (Grosschedl et al, 1984, Cell 38:647-658; Adames et al, 1985, Nature 318:533-538: Alexander etal, \9X7,Mol. Cell Biol 7:1436-1444); the mouse mammary tumor virus control region that is active in testicular, 25 breast, lymphoid and mast cells (Ledcr et al, 1986, Cell 45:485-495); the albumin gene control region that is active in liver (Pinkert et al, 1987, Genes and Devel 1:268-276); the alpha-fetoprotein gene control region that is active in liver (Krumlauf et al , 1985, Mol Cell. Biol 5:1639-1648; Hammer et al, 1987, Science 253:53-58); the alpha 1-antitrypsin gene control region that is active in liver (Kelsey et al, 1987, Genes and Devel 1:161-171); the beta-globin 30 gene control region that is active in myeloid cells (Mogram et al, 1985, Nature 315:338-340: Kollias et al, 1986, Cell 46:89-94); the myelin basic protein gene control region that is active in oligodendrocyte cells in the brain (Readhead et al, 1987, Cell 48:703-712); the myosin light chain-2 gene control region that is active in skeletal muscle (Sani, 1985, Nature 314:283-286):

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2018203471 16 May 2018 and the gonadotropic releasing hormone gene control region that is active in the hypothalamus (Mason et al., 1986, Science 234:1372-1378k

An enhancer sequence may be inserted into the vector to increase transcription of DNA encoding light chain or heavy chain comprising a human CGRP R binding protein by higher 5 eukaryotes. Enhancers are cis-acting elements of DNA, usually about 10-300 bp in length, that act on the promoter to increase transcription. Enhancers are relatively orientation and position independent, having been found at positions both 5' and 3' to the transcription unit. Several enhancer sequences available from mammalian genes are known (e.g., globin, elastase, albumin, alpba-feto-protein and insulin). Typically, however, an enhancer from a virus is used. 10 The SV40 enhancer, the cytomegalovirus early promoter enhancer, the polyoma enhancer, and adenovirus enhancers known in the art are exemplary enhancing elements for the activation of eukaryotic promoters. While an enhancer may be positioned in the vector either 5' or 3' to a coding sequence, it is typically located at a site 5' from the promoter, A sequence encoding an appropriate native or heterologous signal sequence (leader sequence or signal peptide) can be 15 incorporated into an expression vector, to promote extracellular secretion of the antibody. The choice of signal peptide or leader depends on the type of host cells in which the antibody is to be produced, and a heterologous signal sequence can replace the native signal sequence. Examples of signal peptides that are functional in mammalian host cells include the following: the signal sequence for interleukin-7 (IL-7) described in US Patent No. 4,965,195; the signal 20 sequence for interlcukin-2 receptor described in Cosman et al., 1984, Nature 312:768; the interleukin-4 receptor signal peptide described in EP Patent No. 0367 566; the type I interleukin-1 receptor signal peptide described in U.S. Patent No. 4,968,607; the type II interleukin-1 receptor signal peptide described in EP Patent No. 0 460 846.

The expression vectors that are provided may be constructed from a starting vector 25 such as a commercially available vector. Such vectors may or may not contain all of the desired flanking sequences. Where one or more of the flanking sequences described herein arc not already present in the vector, they may be individually obtained and ligated into the vector. Methods used for obtaining each of the flanking sequences are well known to one skilled in the art.

After the vector has been constructed and a nucleic acid molecule encoding light chain, a heavy chain, or a light chain and a heavy chain comprising a CGRP R antigen 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 polypeptide expression. The transformation of an expression vector for an antigen-binding protein into a selected host cell

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2018203471 16 May 2018 may be accomplished by well known methods Including transfection, infection, calcium phosphate co-precipitation, electroporation, microinjection, lipofection, DEAE-dextran mediated transfection, or other known techniques. The method selected will in part be a function of the type of host cell to be used. These methods and other suitable methods are well 5 known to the skilled artisan, and arc set forth, for example, in Sambrook et al., 2001, supra.

A host cell, when cultured under appropriate conditions, synthesizes an antigen binding protein that can subsequently be collected from the culture medium (if the host cell secretes it into the medium) or directly from the host cell producing it (if it is not secreted). The selection of an appropriate host cel l will depend upon various factors, such as desired expression levels, 10 polypeptide modifications that are desirable or necessary for activity (such as glycosylation or phosphorylation) and ease of folding into a biologically active molecule.

Mammalian cell lines available as hosts for expression are well known in the an and include, but arc not limited to, immortalized cell lines available from the American Type Culture Collection (ATCC), including but not limited to Chinese hamster ovary (CHO) cells,

HcLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and a number of other cell lines. In certain embodiments, cell lines may be selected through determining which cell lines have high expression Levels and constitutively produce antigen binding proteins with CGRP R binding properties. In another embodiment, a cell line from the B cell lineage that does not make its 20 own antibody but has a capacity to make and secrete a heterologous antibody can be selected. Use of Human CGRP Antigen Binding Proteins for Diagnostic and Therapeutic Purposes

Antigen binding proteins are useful for detecting CGRP R in biological samples and identification of cells or tissues that produce CGRP R. For instance, the CGRP R antigen binding proteins can be used in diagnostic assays, e.g., binding assays to detect and/or quantify

CGRP R expressed in a tissue or cell. Antigen binding proteins that specifically bind to CGRP R can also be used in treatment of diseases related to CGRP Rina patient in need thereof. In addition, CGRP R antigen binding proteins can be used to inhibit CGRP R from forming a complex with its ligand CGRP, thereby modulating the biological activity of CGRP R in a cell or tissue. Examples of activities that can be modulated include, but are not limited to, inhibiting vasodialation and/or decrease neurogenic inflammation. Antigen binding proteins that bind to CGRP R thus can modulate and/or block interaction with other binding compounds and as such may have therapeutic use in ameliorating diseases related to CGRP R.

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Indications

A disease or condition associated with human CGRP R includes any disease or condition whose onset in a patient is caused by, at least in part, the interaction of CGRP R with its ligand, CGRP. The severity ofthe disease or condition can also be increased or decreased 5 by the interaction of CGRP R with CGRP. Examples of diseases and conditions that can be treated with the antigen binding proteins described herein include headaches, such as cluster headaches, migraine, including migraine headaches, chronic pain, type II diabetes mellitus, inflammation, e.g., neurogenic inflammation, cardiovascular disorders, and hemodynamic derangement associated with endotoxemia and sepsis.

In particular, antigen binding proteins described herein can be used to treat migraine, either as an acute treatment commencing after a migraine attack has commenced, and/or as a prophylactic treatment administered, e.g., daily, weekly, biweekly, monthly, bimonthly, biannual ly, etc.) to prevent or reduce the frequency and/or severity of symptoms, e.g., pain symptoms, associated with migraine attacks.

Diagnostic Methods

The antigen binding proteins described herein can be used for diagnostic purposes to detect, diagnose, or monitor diseases and/or conditions associated with CGRP R. Also provided are methods for the detection of the presence of CGRP R in a sample using classical immunohisto logical methods known to those of skill in the art (e.g., Tijssen, 1993, Practice and Theory of Enzyme Immunoassays, Vol 15 (Eds R.H. Burdon and P.H. van Knippenberg, Elsevier, Amsterdam); Zola, 1987, Monoclonal Antibodies: A Manual of Techniques, pp. 147158 (CRC Press, Inc.); Jalkanen et al., 1985,7. Celt. Biol. 101:976-985; Jalkanen et a!., 1987, J. Cell Biol. 105:3087-3096). The detection of CGRP R can be performed in vivo or in vitro.

Diagnostic applications provided herein include use of the antigen binding proteins to detect expression of CGRP R and binding of the ligands to CGRP R. Examples of methods useful in the detection of the presence of CGRP R include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA).

For diagnostic applications, the antigen binding protein typically will be labeled with a detectable labeling group. Suitable labeling groups include, but are not limited to, the following: radioisotopes or radionuclides (e.g., ³H, ¹⁴C, ^l5N, ³⁵S, ^WY, Tc,^lf 'in, ¹²⁵I, ¹³¹1), fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic groups (e.g,, horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent groups, biotinyl groups, or predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal

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2018203471 16 May 2018 binding domains, epitope tags). In some embodiments, the labeling group is coupled to the antigen binding protein via spacer arms of various lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art and may be used.

In another aspect, an antigen binding protein can be used to identify a cell or cells that 5 express CGRP R. In a specific embodiment, the antigen binding protein is labeled with a labeling group and the binding of the labeled antigen binding protein to CGRP R is detected.

In a further specific embodiment, the binding of the antigen binding protein to CGRP R detected in vivo. In a further specific embodiment, the CGRP R antigen binding protein is isolated and measured using techniques known in the art. See, for example, Harlow and Lane, 10 1988, Antibodies: A Laboratory Manual, New York: Cold Spring Harbor (ed. 1991 and periodic supplements); John E. Coligan, ed., 1993, Current Protocols In Immunology New York: John Wiley & Sons.

Another aspect provides for detecting the presence of a test molecule that competes for binding to CGRP R with the antigen binding proteins provided. An example of one such assay 15 would involve detecting the amount of free antigen binding protein in a solution containing an amount of CGRP R in the presence or absence of the test molecule. An increase in the amount of free antigen binding protein (i.e., the antigen binding protein not bound to CGRP R) would indicate that the test molecule is capable of competing for CGRP R binding with the antigen binding protein. In one embodiment, the antigen binding protein is labeled with a labeling 20 group. Alternatively, the test molecule is labeled and the amount of free test molecule is monitored in the presence and absence of an antigen binding protein.

Methods of Treatment: Pharmaceutical Formulations, Routes of Administration

Methods of using the antigen binding proteins are also provided. In some methods, an antigen binding protein is provided to a patient. The antigen binding protein inhibits binding 25 of CGRP to human CGRP R.

Pharmaceutical compositions that comprise a therapeutically effective amount of one or a plurality of the antigen binding proteins and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant are also provided. In addition, methods of treating a patient, e.g., for migraine, by administering such pharmaceutical composition are included. The term “patient” includes human patients.

Acceptable formulation materials are nontax ic to recipients at the dosages and concentrations employed. In specific embodiments, pharmaceutical compositions comprising a therapeutically effective amount of human CGRP R antigen binding proteins are provided.

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In certain embodiments, acceptable formulation materials preferably are non toxic to recipients at the dosages and concentrations employed. In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, 5 stability, rate of dissolution or release, adsorption or penetration ofthe composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or 10 glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-betacyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as 15 polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such 20 as pluronics, PEG, sorbitan esters, polysorbates such as poly sorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and/or pharmaceutical adjuvants. See, REMINGTON’S PHARMACEUTICAL SCIENCES, 18”

Edition, (A.R. Genrmo, ed.), 1990, Mack Publishing Company,

In certain embodiments, the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format and desired dosage. See, for example, REMINGTON’S

PHARMACEUTICAL SCIENCES, supra. In certain embodiments, such compositions may 30 influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antigen binding proteins disclosed. In certain embodiments, the primary vehicle or carrier in a pharmaceutical composition may be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for

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2018203471 16 May 2018 parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In specific embodiments, pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, and may further include sorbitol or a suitable substitute. In certain embodiments, human CGRP R antigen binding 5 protein compositions may be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (REMINGTON’S

PHARMACEUTICAL SCIENCES, supra) in the form of a lyophilized cake or an aqueous solution. Further, in certain embodiments, the human CGRP R antigen binding protein may be formulated as a lyophilizate using appropriate excipients such as sucrose.

The pharmaceutical compositions can be selected for parenteral delivery.

Alternatively, the compositions may be selected for inhalation or for delivery through the digestive tract, such as orally. Preparation of such pharmaceutically acceptable compositions is within the skill of the art.

The formulation components are present preferably in concentrations that are acceptable to the site of administration. In certain embodiments, buffers arc used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8,

When parenteral administration is contemplated, the therapeutic compositions may be provided in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the desired human CGRP R binding protein in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which the human CGRP R antigen binding protein is formulated as a sterile, isotonic solution, properly preserved. In certain embodiments, the preparation can involve the formulation of the desired molecule with an agent, such as injectable microspberes, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that may provide controlled or sustained release of the product which can be delivered via depot injection. In certain embodiments, hyaluronic acid may also be used, having the effect of promoting sustained duration in the circulation. In certain embodiments, implantable drug delivery devices may be used to introduce the desired antigen binding protein.

Certain pharmaceutical compositions are formulated for inhalation. In some embodiments, human CGRP R antigen binding proteins are formulated as a dry, inhalable powder. In specific embodiments, human CGRP R antigen binding protein inhalation solutions may also be formulated with a propellant for aerosol delivery. In certain embodiments, solutions may be nebulized. Pulmonary administration and formulation

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2018203471 16 May 2018 methods therefore are further described in International Patent Application No. PCT/US94/001875, which is incorporated by reference and describes pulmonary delivery of chemically modified proteins. Some formulations can be administered orally. Human CGRP R antigen binding proteins that are administered in this fashion can be formulated with or 5 without earners customarily used in the compounding of solid dosage forms such as tablets and capsules. In certain embodiments, a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional agents can be included to facilitate absorption of the human CGRP R antigen binding protein. Diluents, flavorings, low melting 10 point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.

Some pharmaceutical compositions comprise an effective quantity of one or a plurality of human CGRP R antigen binding proteins in a mixture with non-toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another 15 appropriate vehicle, solutions may be prepared in unit-dose form. Suitable excipients include, but arc not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

Additional pharmaceutical compositions will be evident to those skilled in the art, including formulations involving human CGRP R antigen binding proteins in sustained- or contra I led-deli very formulations. Techniques for formulating a variety of other sustained- or control led-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. See, for example. International Patent Application No. PCT/US93/00829, which is incorporated by reference and 25 describes controlled release of porous polymeric microparticles for delivery of pharmaceutical compositions. Sustained-release preparations may include scmipermcable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactidcs (as disclosed in U.S. Patent No. 3,773,919 and European Patent Application Publication No. EP 058481, each of which is incorporated by 30 reference), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., 1983, Biopolymers 2:547-556), poly (2-hydroxyethyl-inethacrylate) (Langer et al., 1981, J. Biomed. Mater. Res. 15:167-277 and Langer, 1982, Chem. Tech. 12:98-105), ethylene vinyl acetate (Langer et al., 1981, supra) or poly-D(-)-3-hydroxybutyric acid (European Patent Application Publication No. EP 133,988). Sustained release compositions may also include liposomes that

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2018203471 16 May 2018 can be prepared by any of several methods known in the art. See, e.g., Eppstein et al., 1985, Pmc, Natl. Acad. Set. N.S.A. 82:3688-3692; European Patent Application Publication Nos. EP 036,676; EP 088,046 and EP 143,949, incorporated by reference.

Pharmaceutical compositions used for in vivo administration are typically provided as sterile preparations. Sterilization can be accomplished by filtration through sterile filtration membranes. When the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. Compositions for parenteral administration can be stored in lyophilized form or in a solution. Parenteral compositions generally are placed into a container having a sterile access port, for example, an 10 intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. In certain embodiments, cells expressing a recombinant antigen binding protein as disclosed herein is encapsulated for delivery (see, Invest. Ophthalmol Vis Sci 43:3292-3298, 2002 and Proc. Natl. Acad, Sciences 103:3896-3901,2006).

In certain formulations, an antigen binding protein has a concentration of at least 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ ml or 150 mg/ml. Some formulations contain a buffer, sucrose and polysorbate. An example of a formulation is one containing 50-100 mg/ml of antigen binding protein, 5-20 mM sodium acetate, 5-10% w/v sucrose, and 0.002 - 0.008% w/v poly sorbate. Certain, formulations, for instance, contain 65-75 mg/ml of an antigen binding protein in 9-11 mM sodium acetate buffer, 8-10% w/v sucrose, and 0.005-0.006% w/v polysorbate. The pH of certain such formulations is in the range of 4.5-6. Other formulations have a pH of 5.0-5,5 (e.g., pH of 5.0, 5.2 or 5.4),

Once the pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, crystal, or as a dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration. Kits for producing a single-dose administration unit arc also provided. Certain kits contain a first container having a dried protein and a second container having an aqueous formulation. In certain embodiments, kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are provided. The therapeutically effective amount of a human CGRP R antigen binding protein-containing pharmaceutical composition to be employed will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will vary depending, in part, upon the molecule delivered, the indication for which the human CGRP R antigen binding protein is being used,

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2018203471 16 May 2018 the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and genera] health) of the patient. In certain embodiments, the clinician may titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.

A typical dosage may range from about ] pg/kg to up to about 30 mg/kg or more, depending on the factors mentioned above. In specific embodiments, the dosage may range from 10 pg/kg up to about 30 mg/kg, optionally from 0.1 mg/kg up to about 30 mg/kg, alternatively from 0.3 mg/kg up to about 20 mg/kg. In some applications, the dosage is from 0.5 mg/kg to 20 mg/kg. In some instances, an antigen binding protein is dosed at 0.3 mg/kg, 10 0.5mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, or 20 mg/kg. The dosage schedule in some treatment regimes is at a dose of 0,3 mg/kg qW, 0.5mg/kg qW, 1 mg/kg qW, 3 mg/kg qW, 10 mg/kg qW₃ or 20 mg/kg qW.

Dosing frequency will depend upon the pharmacokinetic parameters of the particular human CGRP R antigen binding protein in the formulation used. Typically, a clinician 15 administers the composition until a dosage is reached that achieves the desired effect. The composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Appropriate dosages may be ascertained through use of appropriate dose-response data. In certain embodiments, the 20 antigen binding proteins can be administered to patients throughout an extended time period. Chronic administration of an antigen binding protein minimizes the adverse immune or allergic response commonly associated with antigen binding proteins that are not fully human, for example an antibody raised against a human antigen in a non-human animal, for example, a non-fully human antibody or non-human antibody produced in a non-human species.

The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally, through injection by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, or intralesional routes; by sustained release systems or by implantation devices. In certain embodiments, the compositions may be administered by bolus injection or continuously by 30 infusion, or by implantation device.

The composition also may be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. In certain embodiments, where an implantation device is used, the device may

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2018203471 16 May 2018 be implanted into any suitable tissue or organ, and delivery of the desired molecule may be via diffusion, timed-release bolus, or continuous administration.

It also may be desirable to use human CGRP R antigen binding protein pharmaceutical compositions ex vivo. In such instances, cells, tissues or organs that have been removed from 5 the patient are exposed to human CGRP R antigen binding protein pharmaceutical compositions after which the cells, tissues and/or organs are subsequently implanted back into the patient.

In particular, human CGRP R antigen binding proteins can be delivered by implanting certain cells that have been genetically engineered, using methods such as those described 10 herein, to express and secrete the polypeptide. In certain embodiments, such cells may be animal or human cells, and may be autologous, heterologous, or xenogeneic. In,-certain embodiments, the cells may be immortalized. In other embodiments, in order to decrease the chance of an immunological response, the cells may be encapsulated to avoid infiltration of surrounding tissues. In further embodiments, the encapsulation materials are typically 15 biocompatible, semi-permeable polymeric enclosures or membranes that allow the release of the protein product(s) but prevent the destruction of the cells by the patient’s immune system or by other detrimental factors from the surrounding tissues.

The following examples, including the experiments conducted and Hie results achieved, are provided for illustrative purposes only and are not to be construed as limiting the scope of 20 the appended claims,

EXAMPLE 1

GENERATION OF CGRP RECEPTOR AS ANTIGENS

A. Molecular cloning of human CRLR and RAMP1

Human CRLR cDNA (GenBank Accession No. U17473; SEQ ID NOT) and RAMP1 25 cDNA (GenBank Accession No. AJ001014; SEQ ID NO:3) were cloned into the mammalian cell expression vectors pcDNA3.I-Zco and pcDNA3.1-Hyg (Invitrogen, Carlsbad, CA), respectively, for transfections of HEK 293EBNA cells (Invitrogen) as described below. The hCRLR cDNA and hRAMPl cDNA were also cloned into the pDSRo24 vector (Kim, Η. Y. et al. J. Inv. Derm. Symp. Proc. (2007) 12: 48-49) for transfections of AM-1 CHO cells (U.S.

Patent Number 6,210,924).

B. Stably-Transfected Cell Lines

1. Stable expression of human CGRP R in 293EBNA cells

HEK 293EBNA cells (available from ATCC or Invitrogen) were seeded at a density of 1.5x1 {/' cells per 100mm dish. After 24 hours, the cells were co-transfccted with 6qg

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2018203471 16 May 2018 linearized DMAs of huRAM.Pl/pcDNA3.1-Hyg and huCRLR/pcDNA3.1-Zeo with FuGene6 (Invitrogen, Carlsbad, CA) following instructions supplied by Invitrogen. After two days, the cells were trypsinized and subcultured into growth medium containing 400ug/ml hygromycin + 250pg/ml zeocin. After two weeks, the resulting drug resistant colonies were trypsinized and 5 combined into pools. The pools were subjected to four rounds of FACS sorting an Alexa 647labeled CGRPg-37 peptide analog (described below). The highest 5% of expressing cells were collected at each round.

2. Stable expression of human CGRP R in AM-1 CHO cells

AM-1 CHO cells (a serum-free growth media-adapted variant from the CHO DHFR10 deficient cell line described in Urlaub and Chasin, Proc. Natl. Acad. Sci. ΊΊ, 4216 (1980), were seeded at 1.5xl0⁶ cells per J 00mm dish. After 24 hours, the cells were co-transfected with linearized 4 gg DNAs each of pDSRa24/huRAMPl and pDSRrx24/huCRLR with FuGeneb (Invitrogen, Carlsbad, CA) following instructions supplied by Invitrogen. The transfected cells were trypsinized 2 days after transfection and seeded into CHO DHFR selective growth 15 medium containing 10% dialyzed FBS and without hypoxanthine/thymidtnc supplement. After 2 weeks, the resulting transfected colonics were trypsinized and pooled. The pools were subjected to FACS sorting analysis.

3. Stable expression of human adrenomedullin (AM 1) in HEK 293EBNA celts

293EBNA cells were seeded in 100mm dishes at 1.5x10⁶ cells/dish in DMEM (high 20 glucose) + 5% FBS + 1% MEM non-essential amino acids + 1% sodium pyruvate. The following day the cells were co-transfected using FuGENE 6 transfection reagent (Roche) with pcDNA3.1/zeocin/huCRLR plus pcDNA3.1/hygromycin/huRAMP2. Both DNA constructs were linearized with Fspl. After 48 hours the cells were subcultured into tOOmm dishes at 3 cell densities (8x10', 3.2x10⁵, and 8xl0⁴ cells/dish) in growth medium containing 200gg/ml zeocin. The medium was changed twice weekly. After one week the plates were fed with medium containing 200gg/mI hygromycin + 200gg/ml zeocin. After two weeks, 96 colonies were isolated with cloning rings. The remaining colonies were collected into a single pool culture. The clones and pools were assayed for their response to stimulation by receptor agonist or forskolin. Several clones showed a good response, and one was selected for use in subsequent experiments.

4. Stable expression of cyno CGRP R in HEK 293EBNA cells

293EBNA cells were seeded in 100mm dishes at 1.5x10⁶ cells/dish in DMEM (high glucose) + 5% FBS + 1% MEM non-essential amino acids + 1% sodium pyruvate. The following day the ceils were co-transfected using FuGENE 6 with

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2018203471 16 May 2018 pcDNA3.1/zeocin/cynoCRLR plus pcDNA3.I/hygromycin/cynoRAMPl. Both constructs were linearized with Fspl. After 48 hours the cells were subcultured into growth medium containing 200gg/ml zeocin + 400gg/ml hygromycin at dilutions of 1:20, 1:40, 1:100, and 1:200. The medium was changed twice weekly. After two weeks, 96 transfected colonies 5 were isolated using cloning rings. The clones were assayed for their response to stimulation by CGRP ligand. Several clones showed similar high levels of response and one was selected for use in subsequent experiments.

C. Isolation of high-expressing CGRP receptor cells

A CGRPaj? peptide analog was synthesized (Midwest Bio-Tech Inc. Fishers, IN) with the sequence below:

AC-WVTHRLAGLLSRSGGVVRCNFVPTDVGPFAF-NH2 (SEQ ID NO:9)

The peptide was labeled with Alexa 647-NHS following the manufacturer’s instructions (Molecular Probes, Inc. Cat A 2006). The Alexa 647-labeled CGRPg-.v showed specific staining of CGRP receptor transfected cells and not the non-transfected parental cells 15 and was used as the FACS reagent.

The huCGRP receptor-transfected 293EBNA and AM-1 CHO cell pools (generated as above) were sorted repeatedly up to four times pools using with Alexa 647-labeled CGRPg-v? peptide. High expressing cells were collected at each sort, expanded and after the final sorting frozen into vials. The AM-1 CHO/huCGRP R cells were used for immunization as described below, and the 293EBNA/huCGRP R cells were used for titering mouse sera after immunization and in binding screens of the hybridoma supernatants,

D. Generation of soluble CGRP receptor

Soluble CGRP receptor polypeptides containing the N-terminal extracellular domains (ECDs) of human CRLR (SEQ ID NO:6) and human RAMP1 (SEQ ID NO:8) were generated by transiently co-transfecting 293 6E cells (Durocher, etal.. Nucleic Acids Res. 30:E9 (2002)) with vectors containing the corresponding cDNAs (SEQ ID NO:5 or SEQ ID NO:7) as described below. Commonly used tags (polyHis, Flag, HA and/or Fc) were employed to facilitate secretion and/or subsequent purification.

A soluble heterodimeric CGRP R ECD fused to Fc was prepared by PCR cloning with the appropriate primers into the transient expression vector pTT5 (Durocher, et al., supra).

The CRLR N-terminal ECD-Fc consisted of the N-terminal extracellular domain of CRLR (SEQ ID NO:6) fused to human IgG I Fc. The RAMP1 ECD-Fe contains the extracellular domain of RAMP! (SEQ ID NO:8) fused to human IgGl Fc. In both cases, there was a linker consisting of five consecutive glycines between the ECD domain and Fc.

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The soluble heterodimeric CGRP receptor was expressed by co-transfecting the two constructs as follows. 293-6E cells at lxl0⁶ cells/ml in shake flasks were transfected with 0.5mg/L DNA (hCRLRN-ter ECD-Fc/pTT5 and huRAMPl ECD-Fc/pTT5) with 3ml PEI/mg DNA in FreeStyle 293 media (lnvitrogen). Cells were grown in suspension in FreeStyle 293 5 expression medium supplemented with 0.1% Pluronic F68 and 50 gg/ml Gencticin for 7 days and harvested for purification.

Purifications from conditioned media (“CM”) were performed by buffering the CM with the addition of 50mM Tris, 400mM sodium citrate, and adjusting the pH to 8.5. The buffered CM was then passed over a Protein A affinity column equilibrated in 50mM Tris,

400mM sodium citrate and pH adjusted to pH 8.5. The Protein A column was washed with

PBS and the Fc fusion protein eluted with 0.1 N HOAc. The eluted peak contained both CRLR and RAM Pl components when tested by western blot using individual antibodies specific to cither CRLR. or RAMPL Further LC-MS and N-terminal sequencing confirmed the presence of both CRLR:RAMP1 heterodimcr and CRLR:CRLR homodimer in approximately 15 (2:3) ratio. This “soluble CGRP receptor” was shown to compete in Alcxa647 labeled CGRPs.

₃7 binding to CGRP receptor expressing recombinant cells in the FMAT analysis, although· it failed to bind CGRP ligand as determined using Biacore testing. The material was used as an immunogen as described in Example, despite, inter alia, its heterogeneity and tack of CGRP ligand binding.

E. Generation of membrane extracts from recombinant CGRP receptor expressing ceils

Membrane extracts were prepared from CGRP receptor expressing cells using a method described by Bosse, R. et a!., (Journal of Biomolecular Screening, 3(4): 285-292 (1998)). Briefly, approximately 5 grams of cell paste were pelleted in 50 ml of PBS at 3,000 rpm for 10 min at 4^UC and re-suspended in 30 m l of cold lysis buffer (25 mM HEPES, pH 7.4, 3 mM

MgCL plus one Roche protease inhibitor cocktail tablet/ 50mL). The lysate was homogenized with Gias-Col (Teflon-glass homogenizer) with -20 strokes at 5,000 rpm and spun in a JA21 rotor at 20,000 rpm for 15 min at 4°C. This process was repeated once more and the final pellet was re-suspended in -1-5 ml ‘final pellet’ buffer (25 mM HEPES, pH 7.4,3 mM MgCL,

10 % (w/v) sucrose plus one Roche protease inhibitor cocktail tablet/ 50mL). The membrane extracts were sheared by passing through 16 G and 25 G needles 2-3 times. Total membrane protein concentration was determined with a Microplate BCA Protein Assay (Pierce).

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EXAMPLE 2

2018203471 16 May 2018

GENERATION OF ANTIBODIES TO CGRP RECEPTOR

A. Immunization

Immunizations were conducted using the following forms of CGRP receptor antigens, prepared as described in Example 1:

(i) AM-1 CHO transfectants expressing full length human CRLR and RAMP1 at the cell surface, obtained by co-transfecting CHO cells with human full length CRLR cDNA (SEQ ID NO:1) encoding a polypeptide having the sequence SEQ ID NO;2, and RAMP1 cDNA (SEQ ID NO:3) encoding a polypeptide having the sequence SEQ ID NO:4 (ii) membrane extract from the cells described in (i) above; and (iii) soluble CGRP receptor obtained by co-expressing and purifying the N-terminal ECD of CRLR (SEQ ID NO:6) and the extracellular domain (ECD) of RAMPI (SEQ ID NO:8) as described in Example 1.

XENOMOUSE animals were immunized with purified soluble CGRP receptor protein 15 and purified CGRP R membranes prepared from AM-1 CHO cells stably expressing CGRP R in the same manner using doses of 10 gg/mousc and 150 gg/mouse respectively. CGRP membranes were prepared using methods described above.

Subsequent boosts were administered at doses of ten gg/mouse of soluble CGRP R or 75 gg of purified CGRP R membranes, XENOMOUSE animals were also immunized with

CGRP receptor-expressing cells using doses of 3.4 x I0^e CGRP R transfected eells/mousc and subsequent boosts were of 1.7 x 10⁶ CGRP R transfected cells/mouse. Injection sites used were combinations of subcutaneous base-of-tail and intraperitoneal. Immunizations were performed in accordance with methods disclosed in U.S. Patent Number 7,064,244, filed February 19, 2002, the disclosure of which is hereby incorporated by reference. Adjuvants TiterMax Gold (Sigma; cat. # T2684), Alum (E.M. Sergent Pulp and Chemical Co., Clifton, NJ, cat. # 1452250) were prepared according to manufacturers’ instructions and mixed in a Ll ratio of adjuvant emulsion to antigen solution.

Sera were collected 4-6 weeks after the first injection and specific titers were determined by FACs staining of recombinant CGRP receptor-expressing 293EBNA cells.

Mice were immunized with either cells/membranes expressing full length CGRP R cells or soluble CGRP R extracellular domain, with a range of 11 - 17 immunizations over a period of approximatelyone to three and one-half months. Mice with the highest sera titer were identified and prepared for hybridoma generation. The immunizations were performed in

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2018203471 16 May 2018 groups of multiple mice, typically ten. Popliteal and inguinal lymph nodes and spleen tissues were typically pooled from each group for generating fusions.

B, Preparation of Monoclonal Antibodies

Animals exhibiting suitable titers were identified, and lymphocytes were obtained from draining lymph nodes and, if necessary, pooled for each cohort. Lymphocytes were dissociated from lymphoid tissue in a suitable medium (for example, Dulbecco’s Modified Eagle Medium; DMEM; obtainable from Invitrogcn, Carlsbad, CA) to release the cells from the tissues, and suspended In DMEM. B cells were selected and/or expanded using a suitable method, and fiised with suitable fusion partner, for example, nonsecretory myeloma 10 P3X63Ag8.653 cells (American Type Culture Collection CRL 1580; Kearney et al, J.

Immunol. 123, 1979, 1548-1550),

Lymphocytes were mixed with fusion partner cells at a ratio of 1:4. The cell mixture was gently pelleted by centrifugation at 400 x g for 4 minutes, the supernatant decanted, and the cell mixture gently mixed by using a I ml pipette. Fusion was induced with PEG/DMSO 15 (polyethylene glycol/dimctbyl sulfoxide; obtained from Sigma-Aldrich, St. Louis MO; 1 ml per million of lymphocytes). PEG/DMSO was slowly added with gentle agitation over one minute followed, by one minute of mixing. IDMEM (DMEM without glutamine; 2 mJ per million of B cells), was then added over 2 minutes with gentle agitation, followed by additional IDMEM (8 ml per million B-cells) which was added over 3 minutes.

The fused cells were gently pelleted (400 x g 6 minutes) and resuspended in 20 ml

Selection media (for example, DMEM containing Azaserine and Hypoxanthine [HA] and other supplemental materials as necessary) per million B-celis. Cells were incubated for 20-30 minutes at 37°C and then resuspended in 200 ml Selection media and cultured for three to four days in T175 flasks prior to 96-well plating.

Cells were distributed into 96-well plates using standard techniques to maximize clonality of the resulting colonics. After several days of culture, the hybridoma supernatants were collected and subjected to screening assays as detailed in the examples below, including confirmation of binding to human CGRP receptor, identification of blocking antibodies by a ligand binding competition assay and evaluation of cross-reactivity with other receptors related to CGRP receptor (for example, human Adrenomedullin receptor). Positive cells were further selected and subjected to standard cloning and subeloning techniques. Clonal lines were expanded in vitro, and the secreted human antibodies obtained for analysis.

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C. Sequence Analysis of Selected Monoclonal Antibodies

Selected subcloned monoclonal antibodies were sequenced using standard RT-PCR methods. Table 2A shows the amino acid sequences of the light chains of exemplary antibodies disclosed herein. Table 2B shows the amino acid sequences of the heavy chains of 5 exemplary antibodies disclosed herein.

Amino acid sequences corresponding to CDR regions of sequenced antibodies were aligned and the alignments were used to group the clones by similarity.

Sequence alignments of light chain CDRs from clones having kappa light chains, and certain corresponding consensus sequences, are shown in Figs 3A and 3B.

Sequence alignments of light chain CDRs from clones having lambda light chains, and certain corresponding consensus sequences, are shown in Fig. 4.

Sequence alignments of heavy chain CDRs of exemplary antibodies disclosed herein, and certain corresponding consensus sequences, are shown in Figs. 5A, 5B, 5C, 5D and 5E.

Certain consensus sequences of exemplary heavy chain CDRs disclosed herein are 15 shown in Fig. 5F.

EXAMPLE 3

IDENTIFICATION OF CGRP RECEPTOR SPECIFIC ANTIBODIES A. Selection of CGRP receptor specific binding antibodies by FMAT

After 14 days of culture, hybridoma supernatants were screened for CGRP R-specific 20 monoclonal antibodies by Fluorometric Microvolume Assay Technology (FMAT) (Applied

Biosystems, Foster City, CA). The supernatants were screened against either the AM-1 CHO huCGRP R cells or recombinant HEK 293 cells that were transfected with human CGRP R and counter-screened against parental HEK293 cells (prepared as described in Example I).

Briefly, the cells in Freestyle media (Invitrogen, Carlsbad, CA) were seeded into 38425 well FMAT plates in a volume of 50 gL/well at a density of approximately 4000 cells/well for the stable transfcctants, and at a density of approximately 16,000 cclls/well for the parental cells, and cells were incubated overnight at 37°C, Then, 10 gL/well'of supernatant was added and plates were incubated for approximately one hour at 4°C, after which 10 gL/well of antihuman IgG-Cy5 secondary antibody (Jackson Immunoresearcb, West Grove, PA) was added at a concentration of 2.8 pg/ml (400ng/ml final concentration). Plates were then incubated for one hour at 4°C, and fluorescence was read using an FMAT macroconfocal scanner (Applied Biosystems, Foster City, CA).

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For counter screens, the parental AM-1 CHO cells or HEK 293 cells were seeded similarly and supernatants screened by FMAT on these cells in parallel to differentiate and eliminate hybridomas binding to cellular proteins, but not to the CGRP receptor.

B. Identification of blocking antibodies by ligand binding competition assay through FMAT

A ligand binding competition method was developed to identify antibodies (in the hybridoma supernatants) that bind CGRP receptor and block CGRP ligand binding. 384-wells plates (Corning Costar, Cat:#3712) were prepared with 5,000 AM-1 huCGRP R Pool 2 cells and 20,000 untransfected CHO-S cells in each well. 20 μ I of anti-CGRP R hybridoma 10 supernatant were added to each well, and the plates were incubated for 1 hr at room temperature. 10μ1 of 2.8pg/ml Alexa647-CGRPg_₃7 peptide were then added to each well and the plates were incubated for a further 3 hours at room temperature. The amount of Alexa647CGRPs-37bound to the cells was assayed on a FMAT 8200 Cellular Detection System (Applied Biosystems). Output data were both a numerical FL1 value of signal intensity (higher FL1 15 values indicate higher signal intensity) and also an image of the cells.

The experiments included negative control hybridoma supernatants. The average FL I value observed in these negative control experiments was adopted as the maximum possible signal for the assay. Experimental supernatants were compared to this maximum signal and a percent inhibition was calculated for each well (% Inhibition = (I -(FL 1 of the anti-CGRP R 20 hybridoma supematant/Maximum FL1 signal)).

An overview of the data is shown in Fig. 6, In this experiment, 1092 anti-CGRP R supernatants were tested using the receptor ligand assay. The data were rank ordered using the average percent inhibition. Ninety supernatants had >25% average inhibition, 31 of these were >50% and 7 were >70% average inhibition.

An abbreviated data set is shown in Table 10, below. Sample ID Nos. 1 -5 illustrate examples of anti-CGRP R hybridoma supernatants which inhibited the binding Alcxa647CGRPs-37 peptide to CGRP receptor and Sample ID Nos 536 - 540 illustrate examples of antiCGRP R hybridoma supernatants which did not inhibit the binding of the Alexa647-CGRP§.₃7 peptide to the CGRP receptor.

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Table 10 - Exemplary data from FMAT ligand binding competition assay

Sample ID	FL1	Expt. #1 Image	% inhibition	PL1	Expt. #2 Image	% inhibits
1	2264		84%	2585		88%
2	3007	1	77%	2804	1 vd	85%
3	3460		72%	2929	fu'J	84%
4	3650		70%	3294		79%
5	3764	H	69%	3246	\ *	80%
536	10412	H	0%	11142	Hi	-17%
537	10413		0%	9388	B	5%
538	10414	ggj	0%	9420	B	4%
539	10415	H	0%	10943	H	-14%
540	10415	||	0%	10561	B	-10%

Based on the binding competition assays, approximately 30 supernatants were selected 5 for further characterization.

EXAMPLE 4

ACTIVITY OF CGRP RECEPTOR SPECIFIC BLOCKING MONOCLONAL

ANTIBODIES IN A cAMP FUNCTIONAL ASSAY A. CGRP receptor antibody activity.

Selected CGRP receptor antibodies were screened in an in vitro CGRP receptor mediated cAMP assay to determine intrinsic potency. The in vitro cAMP assay employed a

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2018203471 16 May 2018 human neuroblastoma-derived cell line (SK-N-MC; Spengler, et al., (1973) In Vitro 8: 410) obtained from ATCC (ATCC Number HTB-10; “HTB-10 cells”). HTB-10 cells express CRLR and RAMP1, which form CGRP receptor (L. M. McLatchie et al, 1998). A 293EBNA cell line expressing recombinant cynomolgus CGRP R was generated as described in Example 5 1, and a rat L6 cell line expressing rat CGRP receptor was obtained from the ATCC (CRL1458).

The LANCE cAMP assay kit (PerkinElmer, Boston, MA) was used in the screening. The assays were performed in white 96-well plates in a total volume of 60 μΕ. Briefly, on the day of the assay, the frozen HTB-10 celts were thawed at 37°C, cells were washed once with 10 assay buffer and 12 μΐ. of cell suspension containing 10000 cells mixed with Alexa-labeled anti-cAMP antibody was added into 96 half-area white plates. After adding I2pL CGRP receptor antibody, the mixture was incubated for 30 min at room temperature. Then 12μΕ CGRP receptor agonist human α-CGRP (InM final concentration) was added and further incubated for 15 min at room temperature. After human α-CGRP stimulation, 24 μΕ of 15 detection mix was added and incubated for 60 minutes at room temperature and the plates were red on EnVision instrument (PerkinElmer, Boston, MA) at Em665nM. Data were processed and analyzed by Prizm (GraphPad Software Inc.) or ActivityBase (IDBS).

Fig. 7A shows exemplary data obtained as described above using the hCGRP receptorexpressing cell line HTB-10 for three antibodies - 3C8, 13H2 and I El 1. The data are plotted 20 as percentage over control (POC”) as a function of antibody (3C8, I3H2 or 1E11) concentration, and are fitted with standard nonlinear regression curves to yield the 1C50 values shown at the bottom of the figure,

B. Lack of antibody activity in related receptors.

Cells expressing related receptors AMI (HEK 293 cells expressing hCRLR+hRAMP2; 25 D. R. Poyner, et al. Pharmacological review, 54:233-246, 2002), AM2 (CHO cells expressing hCRLR+hRAMP3; D. R. Poyner, et al, Pharmacological review, 54:233-246, 2002) or human amylin AMY I receptor (MCF-7 cells hCTR+hRAMPI; Wen-Ji Chen, et al, Molecular pharmacology, 52: 1164-1175, 1997) were used to determine the selectivity of the tested antibodies. The AMI-expressing HEK 293 cell line was generated as described in Example 1, 30 above. The AM2-expressing CHO cell line was purchased from EuroScreen (now

PerkinElmer, Inc.); and the human amylin AMY1 receptor-expressing MCF-7 cell tine (Zimmermann, et al, Journal of Endocrinology, 423-431, 1997), was obtained from the ATCC (ΉΤΒ-22). Exemplary results, plotted as described above, arc shown in Figs. 7B (hAMl-HEK cells), 7C (hAM2-CHO cells) and 7D (hAMY-MCF-7 cells). Note that none of the tested

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2018203471 16 May 2018 antibodies had significant inhibitory activity against hAMl, bAM2 or liAMY I receptors over the range tested.

Similar experiments were performed using recombinant HEK cells expressing cynomolgus CGRP receptors and rat L6 cells expressing rat CGRP receptor (ATCC). Data 5 from these studies, as well as additional IC50 data obtained as described in part A of this Example, arc shown in the “cAMP” columns in Table 11, below. Note that the IC50 values against the human and eyno CGRP receptors arc in the nanomolar range, whereas activities against rat CGRP receptor, and human AMI, AM2 and AMY 1 receptors, as well as MCF7 cells expressing calcitonin (data not shown) are all greater than 1 micromolar. The difference 10 in IC50 between human CGRP receptor and human AM 1, AM2, amylin and calcitonin receptors illustrates the high selectivity of the these antibodies for the CGRP receptor over related receptors formed in part of the same receptor components. IC50 obtained using human and cynomolgus CGRP receptors were similar, whereas the tested antibodies did not appear to cross-react with rat CGRP receptor.

Table II

Clone	cAMP assay	l2yI assay
hCGRP R 1C50 (nM)	Cyno CGRP R IC50 (nM)	Rat CGRP R IC50 (nM)	hAmylin 1 IC50 (nM)	hAMl IC50 (nM)	hAM2 IC50 (nM)	Human CGRP Ki (nM)
01E11.2	1.77	2.79	>1000	>1000	>1000	>1000	0.030
01H7.2	3.27	4.74	>1000	>1000	>1000	>1000	0.079
02A10.1	11.83	17.6	>1000	>1000	>1000	>1000	0.291
02E7.2	6.30	5.51	>1000	>1000	>1000	>1000	0.117
03A5.I	9.89	28.9	>1000	>1000	>1000	>1000	0.093
03B6.2	2.74	2.22	>1000	>1000	>1000	>1000	0,033
03C8.2	6.66	5.32	>1000	>1000	>1000	>1000	0.044
03H8.2	10.84	10.6	>1000	>1000	>1000	>1000	0.111
04E4.2	2.38	3.52	>1000	>1000	>1000	>1000	0.015
04H6.1	3.78	5.59	>1000	>1000	>1000	>1000	0.052
05F5.1	4.79	4.78	>1000	>1000	>1000	>1000	0.147
07B2.I	8.96	27.7	>1000	>1000	>1000	>1000	0,116
07B3.1	10.2	14.1	>1000	>1000	>1000	>1000	0.127
07FI.1	8.92	10.5	>1000	>1000	>1000	>1000	0.140
ORB 11.2	10.7	17.0	>1000	>1000	>1000	>1000	0.118

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09D4.2	1.40	2.46	>1000	>1000	>1000	>1000	0.023
09F5.2	3.06	4.44	>1000	>1000	>1000	>1000	0.043
10E4.2	3.08	3.23	>1000	>1000	>1000	>1000	0.100
11A9.1	16.1	47.8	>1000	>1000	>1000	>1000	0.157
11OI1.1	4.93	3.85	>1000	>1000	>1000	>1000	0.044
11H9.1	4,56	5.07	>1000	>1000	>1000	>1000	0.057
12E8.2	2.93	4.13	>1000	>1000	>1000	>1000	0.097
12G8.2	2.14	2.74	>1000	>1000	>1000	>1000	0.017
13D6.2	8.23	11.8	>1000	>1000	>1000	>1000	0.055
13E2.2	18.3	49.2	>1000	>1000	>1000	>1000	0.128
I3H2.2	1.95	8.41	>1000	>1000	>1000	>1000	0.033
32H7.1G		1.93		>1000	>1000	>1000

EXAMPLE 5

RADIOLIGAND CGRP BINDING ASSAY FOR Ki DETERMINATION

RECEPTOR BLOCKING ANTIBODIES ^l23I-labcled CGRP (Amersham Biosciences, Piscataway, NJ) and cell membranes from

HTB-10 cells (PerkinElmer Inc., Waltham, Massachusetts) were used for radioligand binding experiment in the presence of various concentrations of the test antibodies to determine the corresponding Ki values. The CGRP binding assay was set up at room temperature in 96-well plates containing: 110 μΙ binding buffer (20 mM Tris-HCl, pH7.5, 5.0 mM MgSO4, 0.2% BSA (Sigma), I tablet of CompleteTM/50 ml buffer (a protease inhibitor)); 20 μΙ test compound (10X); 20 μΐ ^l25l-haCGRP (Amersham Bioscienccs; I OX); and 50 μΐ human neuroblastoma cell (HTB-10) membrane suspension (10 pg per well, PerkinElmer). The plates were incubated at room temperature for 2 hours with shaking at 60 rpm, and then the contents of each well were filtered over 0.5% polyethyleneimine (PEI)-treated (for at least one hour) GF/C 96-well filter plates. The GF/C filter plates were washed six times with ice-cold 50 mM Tris, pH 7.5 and dried in an oven at 55°C for 1 hour. The bottoms of the GF/C plates were then sealed. 40 μΐ M icroscint^1M 20 was added to each well, the tops of the GF/C plates were sealed with TopSeal^r‘^M-A (a press-on adhesive sealing film), and the GF/C plates were counted with TopCount NXT (Packard), The data were analyzed using Prizm (GraphPad Software Inc.)

Exemplary data and Ki values obtained using antibodies 3C8, I2H2 and 1E11 are shown in Fig. 8.

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The right-most column in Table 11, above, lists the KJ values of the indicated mAbs in the radiolabeled ^l25T-CGRP competition binding assay to HTB-IO cell membranes. The data demonstrate that the CGRP receptor antibodies were highly competitive (all sub-nanomolar range) against CGRP binding.

EXAMPLE 6

FACS BINDING ASSAY FOR KP DETERMINATION OF CGRP RECEPTOR

BLOCKING ANTIBODIES

The affinities of anti-CGRP R mAbs for CGRP receptors expressed on cells were determined using a FACS method. Briefly, AM-1 CHO huCGRP R-expressing cells, prepared 10 as described above, were plated in 96-well plates at densities of 16,000 or 160,000 cells per well in DMEM medium containing 10%FBS, NEAA, PS, L Glut, NaPyr and 0.05% sodium azide. CGRP receptor antibodies were titrated in the same medium from 50 nM to 1 pM and incubated with cells. After an overnight incubation at 4°C in a total volume of 120 μΙ, on a plate shaker, the cells were washed 2X with PBS+2%FBS, centrifuging and discarding 15 supernatant each time. 100 μΐ/ well of G anti-Hu Fc Cy5 (5pg/mL; Jackson ImmunoResearch Laboratories Inc., West Grove, PA, USA) containing 7AAD (5gl/well)was then added and incubated at 4°C for 40 min. The cells were washed 2X with PBS+2%FBS, centrifuging and discarding the supernatant each time. 100 μΐ PBS+2%FBS buffer was then added and analyzed by FACS to determined the binding geomean. The Kd was calculated using KinExA 20 software by taking the negative geomean at each antibody concentration as the amount of free Ab present Rathanaswami, et ah, Biochemical and Biophysical Research Communications 334 (2005) 1004-1013. The data obtained at the two different cell concentrations were analyzed by n-eurve analysis to determine the Kd and the 95% confidence interval as described in Rathanaswami, et al., Biochemical and Biophysical Research Communications 334 (2005)

1004-1013.

Exemplary data with corresponding curve fits arc shown in Fig. 10 for antibody 12G8.2. The data of eight blocking antibodies generated in support of the present disclosure are shown in Table 12. One of the antibodies (3B6) was analyzed on two different days. The ratio of 0.9 obtained for the experiment with 16K cells indicates that the antigen concentration is predicted as 0.9X the Kd and hence the curve obtained by this experiment is a Kd controlled curve. It can be appreciated that the Kd values obtained in this manner were in the low singledigit nanomolar range for all tested antibodies.

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Table 12

	N curve analysis
	Kd(oM)	Kdtow (nM) :	Kd High (»M)	% error	Ratio ί 16K
1H7	1.9	1.5	3	3.8	0.001
2E7	1.5	0.7	3.4	6.3	0.19
3B6 (a)	1.7	1.1	2.7	5.3	0.060
3B6 (b)	2.0	1.6	2.6	3.2	0.21
4E4	1.3	0.9	2.05	3.9	0.16
4H6	2.4	1.78	4.35	3.8	0.070
9D4	2.5	1.8	4.39	4.3	0.060
12E8	2.3	1.58	3.36	3.7	0.55
12G8	1.4	0.92	2.21	3.6	0.94

EXAMPLE 7

BINNING OF CGRP RECEPTOR BLOCKING ANTIBODIES BV BtCORE

BINDING COMPETITION

Biacore analyses (Karlsson, R. et al., Methods', A Companion to Methods in Enzymology, 6: 99-110(1994) were carried out as follows. Immobilization of anti-CGRP receptor antibodies to the CMS sensor chip surface was performed according to manufacturer’s instructions, using a continuous flow of lOmM HEPES, 0.15M NaCI, 3,4mM EDTA, 0.005%

P-20, pH 7.4 (HBS-EP buffer). Carboxyl’groups on the sensor chip surfaces were activated by injecting 60 gL of a mixture containing 0.2 M N-ethyl-N’ (dimethylaminopropyl)carbodiimide (EDC) and 0.05 M N-hydroxysuccinimide (NHS). Specific surfaces were obtained by injecting 180 gil of anti-CGRP receptor antibody diluted in 10 mM acetate, pH 4.0 at a concentration of 30 gg/mL. Excess reactive groups on the surfaces were deactivated by injecting 60 gL of 1 M ethanolamine. Final immobilized levels for the individual antibodies were as follows:

Antibody Resonance Units (RU)

Dll -5,900

3B6 -7,200

4H6 -8,000

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12G8 -7,800

9F5 -6,600

34E3 -3,700

A blank, mock-coupled reference surface was also prepared on the sensor chip. Soluble 5 huCGRP receptor at a concentration of 100n.M was captured on sensor chips having one of the six immobilized antibodies referenced above (11 DI I, 3B6, 4H6, 12G8, 9F5 or 34E3). Each of the 20 test anti-CGRP R antibodies was then injected over the captured huCGRP receptor. If the injected antibody recognized a distinct epitope relative to that recognized by the immobilized antibody, a second binding event would be observed. If the antibodies recognize 10 the same or very similar epitopes, only the binding of the huCGRP receptor would be observed.

Exemplary data obtained using a sensor chip coated with immobilized antibody 3B6 are shown in Fig. 9A. The four traces are data obtained using antibodies I El 1,4E4, 2E7 and 12G8 in the injected solution. Events during the experiment are represented by letters, with 15 “A” corresponding to injection of huCGRP R-Fc, “B” corresponding to end of the huCGRP RFc injection, “C” corresponding to injection of second mAb, and “D” corresponding to end second mAb injection and start of the buffer wash. Note that there is no indication of any binding signal from any of the injected antibody on the immobilized antibody surface, indicating that the four injected antibodies apparently recognize the same or very similar 20 epitopc(s) as the immobilized antibody. Essentially the same results were observed with all tested blocking antibodies washed over each the five immobilized neutralizing antibody surfaces, indicating that all tested anti-huCGRP receptor blocking antibodies recognize the same or very similar and strongly overlapping epitope(s).

In contrast, as shown in part in Figs. 9B, 9C and 9D, the four tested non-blocking,

CGRP receptor specific antibodies 32H8, 33B5, 33E4 and 34E3 failed to compete with 11D11 (data not shown), 3B6 (Fig. 9B), 12G8 (Fig. 9C) and 9F5 (data not shown) although 34E3 was able to compete with 4H6 (Fig, 9D) and weakly with 32H7 (data not shown). 32H8 failed to compete with 3B6, 4H6, 12G8, 9F5 or the non-blocking antibody 34E3, but 33B5 and 33E4 could compete with the non-blocking antibody 34E3. The data for all blocking and non30 blocking antibodies are summarized in Table 13, below. “NB” indicates no binding; “+” indicates significant binding; and “Weak” indicates weak binding.

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Table 13

	Immobilized Antibodies
Ab in Solution	1IDI1	3B6	4H6	12G8	9F5	34E3
1 El 1	NB	NB	NB	NB	NB	+
IH7	NB	NB	NB	NB	NB	+
2E7	NB	NB	NB	NB	NB	+
3B6	NB	NB	NB	NB	NB	+
3C8	NB	NB	NB	NB	NB	+
4E4	NB	NB	NB	NB	NB	+
4H6	NB	NB	NB	NB	NB	NB
5F5	NB	NB	NB	NB	NB	+
9D4	NB	NB	NB	NB	NB	+
9F5	NB	NB	NB	NB	NB	+
10E4	NB	NB	NB	NB	NB	+
11DU	NB	NB	NB	NB	NB	+
11H9	NB	NB	NB	NB	NB
12E8	NB	NB	NB	NB	NB	+
12G8	NB	NB	NB	NB	NB	+
13H2	NB	NB	NB	NB	NB	-I-
32H7	NB	NB	NB	NB	NB	Weak
32H8	+	+	-(-	+	+	+
33B5						NB
33E4	+	+	+	+	+	NB

As can be appreciated from the data, all the tested blocking or neutralizing antibodies bind to the same region as the five immobilized blocking antibodies; i.e., all of the tested neutralizing antibodies bind the same region of the CGRP R molecule. On the other hand, the non-blocking antibodies did not generally compete with the immobilized blocking antibodies, indicating that the non-blocking antibodies primarily bind a different region of CGRP R.

EXAMPLE 8

BINDING OF CGRP RECEPTOR ANTIBODIES TO SOLUBLE CGRP

RECEPTOR. IN WESTERN BLOT

Three representative CGRP receptor blocking antibodies were tested using Western blots for binding to a soluble CGRP receptor-muFc fusion protein.

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100ng of purified CGRP R-muFc (produced and purified as described above for the CGRP R-huFc except the mouse Fc was used and the linker between RAM Pl or CRLR ECD and muFc was changed to “GGGGGVDGGGGGV” (SEQ ID NO:213)) was diluted in PBS with PAGE sample buffer with (reduced) or without (non-reduced) beta-mercaptoethanol 5 (βΜΕ) at 13.3% concentration. The sample containing βΜΕ was then boiled for 4 min. Reduced and non-reduccd samples were loaded onto separate 4-20% Tris-glycine gels (Invitrogen) with alternating lanes of CGRP R-Fc protein and molecular weight markers (Invitrogen). Gels were electroblotted onto 0.2gm nitrocellulose filters (Invitrogen). The blots were washed with Tris-buffered saline + 1% Tween 20 (TBST) and then blocked with TBST + 10 5% powered dry milk for 30min. The blots were cut into strips along the molecular weight marker lanes. One strip each with reduced and non-reduced CGRP R-muFc were incubated with purified huCGRP R antibodies 4E4, 9F5, or 3B6 (1:500 dilution in TBST + 5% milk), goat anti-huRAMPI N-20 (1:500; Santa Cruz Biotechnology, Inc), rabbit anti-mouse IgG-FcHRP (1:10,000) (Pierce), or goat anti-human IgG-Fc-HRP (1:10,000) (Pierce). Blots were 15 incubated with the antibodies for one hour followed by 3x 1 Omin washes with TBST + 1 % milk. The blots treated with the huCGRP R antibodies were then incubated with goat antimouse IgG-Fc-HRP (1:10,000 in TBST + 1% milk) and the blots treated with anti-huRAMPI (N-20 anti-RAMPl goat polyclonal antibody, Santa Cruz Biotech, CA) were incubated with rabbit anti-goat IgG-Fc-HRP (1:10,000) for 20min. Blots were washed 3xl5min with TBST.

The huCGRP R and anti-huRAMPI antibody blots were treated with Pierce Supcrsignal West Pico Detection reagent, and the anti-mouse and anti-human IgG-Fc-HRP blots were treated with Pierce standard Detection Reagent (1 min.). Blots were then exposed with Kodak Biomax MS X-ray film.

All of the three CGRP receptor antibodies, 4E4, 9F5 and 3B6 were able to detect the 25 soluble CGRP R-muFc (containing RAMP 1-ECD and CRLR ECD) under non-reduced condition but not under reduced condition indicating that the binding epitope of these CGRP R antibodies was conformational and sensitive to the disulfide linkages (3 pairs in RAMP1-ECD and 3 pairs in CRLR N-ter ECD). In contrast, the commercial anti-RAMPl antibody N-20 (Santa Cruz Biotech) bound RAMP! under both reduced and no reduced conditions indicating that the binding site for N-20 antibody was primarily linear and not sensitive to disulfide linkages.

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EXAMPLE 9

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BINDING OF CGRP RECEPTOR BLOCKING ANTIBODIES TO CHIMERIC

RECEPTORS

CGRP receptors formed of either native RAMP1 with chimeric CRLR, or native CRLR with chimeric RAMP I, were used to identify CGRP receptor sequences involved in antibody binding. Since all of the human CGRP receptor blocking antibodies tested failed to show functional activity to the rat CGRP receptor, the chimeric components contained regions of rat sequence in a human sequence background. The following chimeras were generated for binding analysis by FACS;

RAMP1 chimera#! (028 to A34): SEQ ID NO:217

Amino acid residues Q28 to A34 in the human RAMP1 were replaced with the corresponding sequences from rat RAMP 1. This stretch included five amino acid residues that arc different between human and rat RAMP 1,

RAMP! chimera#2 (Q43 to E53); SEQ ID NO:218

Amino acid residues Q43 to E53 in the human RAMP1 were replaced with the corresponding sequences from rat RAMP1. This stretch included six amino acid residues that are different between human and rat RAMP I.

RAMP1 chimera#3 (R67 to E78); SEQ ID NO:219

Amino acid residues R67 to E78 in the human RAMP I were replaced with the corresponding sequences from rat RAMP1. This stretch included seven amino acid residues that are different between human and rat RAMP1,

CRLR chimera#! (L24 to Q33k SEQ ID NO:223

Amino acid residues L24 to Q33 in the human CRLR were replaced with the corresponding sequences from rat CRLR. This stretch included eight amino acid residues that are different between human and rat CRLR.

Fig. 11 shows an alignment of RAMP 1 amino acid sequences from cynomolgus monkey (SEQ ID NO:215), human (SEQ ID NO:4), rat (SEQ I D NO:214) and rhesus monkey (SEQ ID NO:216), together with sequences of RAM PI chimera#! (SEQ ID NO:217),chimera #2 (SEQ ID NO:218) and chimera #3 (SEQ ID NO:219), Figs. 12A and I2B show an alignment of CRLR amino acid sequences from human (SEQ ID NO:2), cynomolgus monkey (SEQ ID NO:221), rhesus monkey (SEQ ID NO:222), rat (SEQ ID NO:220) and, as well as the amino acid sequence of CRLR chimera #1 (SEQ ID NO:223).

293-6E cells were transiently transfected with CGRP R chimera DNA constructs (CRLR wt+ RAMP1 Q28-A34; CRLR wt + RAMP I Q43-E53; CRLR wt + RAM Pl R67155

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E78; CRLR L24-Q33 + RAMP wt; CRLR wt + RAMPI wt; pTT5 vector control). Cells were harvested after 72hr, washed with PBS + 0,5% BSA, and counted. Each transfected cell line was resuspended at a dilution of 5xl0⁵ cells per ΙΟΟμΙ PBS/BSA. ΙΟΟμΙ of cell suspension was aliquot per well in a 96-well round-bottom plate (Falcon). The cells were pelleted at 5 1200rpm for 5 min. The supernatant was removed and replaced with ΙΟΟμΙ containing 0.5gg purified huCGRPRantibodies 1H7, 2E7, 3B6, 9F5,4H6, 12G8,3C8, 10E4, 11 DI 1,32H8, or 33B5. Control wells were treated with anti-DNP hu!gG2 (0.5gg), Alexa647-CGRP peptide (0.5gg), or PBS/BSA alone. Cells were incubated on ice for I hr, and then washed twice with PBS/BSA. The cells were resuspended in ΙΟΟμΙ/well PBS/BSA containing anti-hug-Fc-FITC 10 (0.5gg) (except for Alexa647-CGRP treated cells). Cells were incubated on ice in the dark for

I hr, and then washed twice with PBS/BSA. Cells were resuspended in 200μΐ PBS/BSA and analyzed using a FACS Calibur.

Ten representative blocking antibodies (3B6, 9F5, 4H6, 12G8, 3C8, 10E4, 32H7, 4E4,

II DI I and 1H7) and two non-blocking antibody (32H8 and 33B5) were tested. Representative data (9F5 antibody) are shown in Figs. 13A, I3B and 13C. Fig. 13A shows binding to the wild-type CGRP receptor; Fig. 13B show binding to CGRP receptors containing the CRLR L24-Q33 chimera, and Fig. 13C show binding to CGRP receptors containing the RAMPI Q28A34 chimera. The FACS analysis showed that all 12 antibodies bind wild type human CGRP receptor control as expected. All 12 antibodies showed significantly reduced binding to any of the three RAMPI chimera RAMPI (Q28-A34), (Q43-E53) and (R67 - E78). This could result from (I) the expression level of the chimera receptor was much lower, (2) the RAMPI chimera impaired the folding with human CRLR and altered the conformation of the receptor complex, and/or (3) these three selected regions on RAMPI are directly involved in the binding of these antibodies to CGRP receptor.

When the FACS tracing were gated to include only the very small “expressing” cell populations, the non-blocking antibodies 33B5 and 32H8 appeared to consistently bind less well (lower Geo Means) to the RAMPI Q43-E53 chimera as compared to the blocking antibodies, suggesting binding to the RAMPI Q43-E53 region may be more important for the non-blocking antibodies. On the other hand, 33B5 and 32H8 consistently bound better to the

RAMP I R67-E78 chimera than the blocking antibodies, suggesting the RAMP 1 R67-E78 sequence may be more important for the blocking antibodies.

AU CGRP receptor antibodies tested bound reasonably well to the CRLR chimera (L24-Q33), suggesting this site is not essential for binding of blocking antibodies.

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In summary, the data show that three discontinuous regions on RAMP 1 — (Q28-A34), (Q43 — E53) and (R67-E78) — could be involved in CGRP receptor antibody binding, with (R67-E78) more important to the blocking antibodies. The N-terminal sequences (L24-Q33) of CRLR did not appear to be critically involved in binding for the CGRP receptor antibodies 5 as analyzed by this method. This approach does not rule out additional binding sites that share identical or similar sequences between human and rat CGRP receptors which were not targeted in the analysis.

EXAMPLE 10

IDENTIFICATION OF HUMAN CGRP R EPITOPES FOR ΑΝΤΙ-CGRP R 10 NEUTRALIZING ANTIBODIES BY PROTEASE PROTECTION ASSAY

The CRLR portion in the mature form of the CRLR-Fc fusion molecule (with signal peptide removed; disclosed herein as SEQ ID NO: 10) contains 116 amino acids (preceding the glycine linker) and has three large loop structures created by formation of three disulfide bonds. The three disulfide bonds in CRLR arc Cysl at sequence position 26 (all CRLR 15 sequence positions listed in this paragraph are with respect to the mature sequence presented as SEQ ID NO: 10) linked to Cys3 at sequence position 52 (referred to as CRLR Cl-C3), Cys2 at sequence position 43 linked to Cys5 at sequence position 83 (referred to as CRLR C2-C5), Cys4 at sequence position 66 linked to Cys6 at sequence position 105 (referred to as CRLR C4-C6). RAMP1 portion in mature form of RAMPl-Fc fusion molecule contains 91 amino 20 acids (SEQ ID NO: 11) preceding the glycine linker, which also forms three intramolecular disulfide bonds. The three disulfide bonds in RAMP1 are Cysl at sequence position 1 (all RAMP1 sequence positions listed in this paragraph are with respect to the mature sequence presented as SEQ ID NO:11) linked to Cys5 at sequence position 56 (referred to as RAMP! C1-C5), Cys2 at sequence position 14 linked to Cys4 at sequence position 46 (referred to as 25 RAMP I C2-C4), Cys3 at sequence position 31 linked to Cys6 at sequence position 78 (referred toasRAMPl C3-C6).

Regions of the human CGRP receptor protein bound by anti-CGRP neutralizing monoclonal antibodies were identified by fragmenting h CGRP R into peptides with specific proteases, and determining the sequence of the resulting h CGRP R peptides (i.e., both disulfide- and non-disulfide-containing peptide fragments for CRLR and RAMP1 portions). A protease protection assay was then performed to determine the proteolytic digestion of hCGRP R in the presence of binding monoclonal antibodies. The general principle of this assay is that binding of a mAh to CGRP R can result in protection of certain specific protease cleavage sites

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2018203471 16 May 2018 and this information can be used to determine the region or portion of CGRP R where the mAh binds to.

Briefly, the peptide digests were subjected to HPLC peptide mapping; the individual peaks were collected, and the peptides identified and mapped by on-line electrospray 5 ionization LC-MS (ESI-LC-MS) analyses and/or by N-terminal sequencing. All HPLC analyses for these studies were performed using a narrow bore reverse-phase C18 column (2.1 mm i.d. x 15 cm length; Zorbax 30QSB, 5 gm, Agilent Technologies) for off-line analysis and using a capillary reverse phase C18 column (0.5mm i.d, x 25 cm Vydae CIS MS, 5 gm; The Separation Group) for LC-MS. HPLC peptide mapping was performed with a linear gradient 10 from 0.05% trifluoroacetic acid (mobile phase A) to 90% acetonitrile in 0.05% trifluoroacetic acid. Columns were developed over 90 minutes at a flow rate of 0,25 mJ/min for narrow bore HPLC for off-line or on-line LC-MS analyses, and 0.018 ml/min for capillary HPLC for online LC-MS analyses.

Mature form human CGRP R was digested with AspN (which cleaves after aspartic 15 acid and some glutamic acid residues at the amino end) by incubating about 100 gg of CGRP

R at 1.0 mg/ml in 0.1 M sodium phosphate (pH 6.5) for 20 hrs at 37°C with 2 gg of AspN.

HPLC chromatography of the AspN digests generated a peptide profile as shown in Fig. 14 (each sample 30gg injected), chromatogram labeled A for CGRP R alone (concentration 1 mg/ml), while a control digestion with a similar amount of CGRP R neutralizing antibody, clone 12G8, shows that the antibody is essentially resistant to AspN endoproteinasc (chromatogram labeled B; CGRP R: antibody ratio, 100:2; 100:7;

100:20,weight by weight, respectively). Sequence analyses were conducted by on-line LCMS/MS and by Edman sequencing on the peptide peaks recovered from HPLC. On-line ESI LC-MS analyses of the peptide digest were performed to determine the precise mass and sequence of the peptides that were separated by HPLC. The identities of several peptides present in the peptide peaks from the AspN digestion were thus determined (indicated as numbered peaks in Fig. 14). Table 14, below, shows the locations of these peptide sequences in the corresponding component (CRLR or RAMP 1) of the hCGRP R. A capital tetter C followed by a number or X represents a peptide identified as a CRLR peptide; a capital letter R followed by a number or X is a RAMP1 peptide and “Fc” represents the large, undigested Fc fragment released from the CRLR-Fc and RAMPl-Fc fusion molecules.

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Table 14

CRLR and RAMP1 peptides identified by peptide mapping of CGRP R AspN digestion

Peptide	Sequence Disulfide (#) location	Intact mass	Origin
Cl	Ell 1-V122	0	1059	CRLR
C2	D33-A38	0	670	CRLR
C3	D55-M63	0	880	CRLR
C4	D68-Q71	0	571	CRLR
C5	D55-P67/D86-H110		n.d.	CRLR
C6	D8-Y24	0	1938	CRLR
C7	E25-Q32/D48-N54	1	1933	CRLR
C-X		3	n.d.	CRLR
Rl	D32-A44	0	1622	RAMP1
R2	E12-V20/D45-A51	1	1939	RAMPt
R-X	C1-R86	3	10049	RAM Pl
Fc			20500	RAMP1/CRLR

Fig. 15 shows a comparison of an AspN digestion experiment (each sample 30gg injected) with CGRP R alone (chromatogram labeled A) with one performed in the presence of neutralizing antibody 12G8 (chromatogram labeled B), The weight ratio of CGRP R;antibody was 1:1. Several peaks (C5, C6, and C7) show a decreased in peak height in chromatogram B relative to chromatogram A, while two other peaks (C-X and R-X) show an increase in peak height in chromatogram B relative to chromatogram A. A similar peptide map pattern was also observed if a different neutralizing anti-CGRP R antibody (10E4, 3B6, 3C8 or 4E4 ) at a similar quantity was present in the digestion sample as seen in the chromatogram labeled C. Both C6 and C7 are disulfide linked peptides which cover a major portion of the CRLR molecule while C5 is a CRLR non-disulfide containing peptide residing at the N-terminal end of the molecule and is penultimate to the C7 disulfide peptide. Peak C-X contains three CRLR disulfide bonds with multiple sequences, indicating at least two to three peptides arc linked

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2018203471 16 May 2018 together by disulfide bonds. The fact that peak C-X has increased peak height in a CGRP R digest in the presence of CGRP neutralizing antibody indicates that the antibody has protected CGRP R from AspN digestion at several cleavage sites related to Glu25 andAsp55, The antibody does not appear to have a significant protective effect on Asp33 and Asp72 as peak 5 intensity for peptides C2 and C4 did not decrease at all. Therefore the antibody appears to bind to a region of CRLR which includes the CRLR Cl -C3 and CRLR C4-C6 disulfide region together with the loop region between Cys53 and Cys66.

The AspN mapping of hCGRP R also identified a RAM Pl disulfide peptide (R2) and a RAMP 1 non-disulfide peptide (R1) (see Table 14 and Fig. 14), In the presence of any of the 10 above-mentioned neutralizing antibodies (12G8, 10E4, 4E4, 3B6 or 3C8), peptide R-X was recovered at a significantly higher peak intensity than what was obtained from the digestion with no antibody in the sample. Mass and sequence analyses showed that R-x contains a single polypeptide chain corresponding to the RAMP1 sequence between Cys I and Arg86. These experiments indicate that CGRP R neutralizing antibody can protect a significant region of 15 RAMP I from AspN proteolytic digestion.

To assess whether the protective effect of CGRP R AspN proteolysis is specific to CORP R-neutralizing (blocking) antibodies (as compared with anti-CGRP R non-neutralizing antibodies), an AspN digestion of CGRP R was performed in the presence of an unrelated control monoclonal antibody which does not neutralize CGRP R activity. The results are 20 shown in Fig. 15 in chromatogram D. The non-neutralizing antibody docs not show any significant blocking effect on CGRP R AspN proteolysis; indeed, the peptide map profile (chromatogram D) is nearly indistinguishable in the relevant aspects to the profile derived from digestion of CGRP R alone (chromatogram A).

The proteolysis protection effect was dependent on the concentration added to the 25 digestion sample. As seen in Fig. 16, a fixed CGRP R quantity in the sample (lOOpg) with variable amounts of anti-CGRP R neutralizing antibody 4E4 (CGRP R:antibody ratio in micrograms, 100:2; 100:7; 100:20,weight by weight, respectively) was performed for Aspen proteolysis. The protection profile can be observed and the protection is antibody concentration-dependent.

Taken together, these data demonstrate that blocking or neutralizing anti-CGRP R antibodies disclosed herein can block CGRP R (on both CRLR and RAMP1 components) from AspN proteolysis, suggesting that the blocking antibodies bind to both CRLR and RAMP1 when these antibodies bind to the CGRP receptor. Further, the protection effect is antibody160

2018203471 16 May 2018 concentration dependent. These results also indicate that CGRP R neutralizing antibodies bind to common regions on human CGRP R which are close the Asp N cleavage sites.

EXAMPLE 11

COMMERCIALLY-AVAILABLE ANTI-RAMP 1 AND ANTI-CRLR 5 ANTIBODIES IN A cAMP FUNCTIONAL ASSAY

Commercially-available antibodies directed against one or the other components (RAMP1 or CRLR) of the human CGRP receptor were screened in the CGRP receptor mediated cAMP assay using HTB-10 cells as described in Example 4, above, to determine whether the antibodies had biological activity. The data are presented in Table 15, below. The 10 antibodies had either no detectable {“ND”), very weak (“VW”) or weak (“W”) biological activity over a concentration range where the exemplary antibodies disclosed herein had strong biological activity.

Table 15 Commercially-available antibody activity

Name	Source	Antigen or epitope	Vendor	HTB-10 activity
CRLR antibody (ahi 3164)	Rabbit polyclonal Ab	N-terminal ECD ofhCRLR	Abeam Inc., Cambridge, MA	ND
CALCRL antibody	Rabbit polyclonal Ab	N-terminal ECD ofhCRLR	GenWay Biotech, Inc., San Diego, CA	ND
CRLR (N-18)	Goat polyclonal Ab	epitope mapping near N-terminus ofhCRLR	Santa Cruz Biotech	VW
CRLR (H42)	Rabbit polyclonal Ab	aa23-64 of hCRLR	Santa Cruz Biotech	ND
CALCRL Antibody (A01)	Mouse polyclonal Ab	aa23-133 of hCRLR	Novus Biologicals, Inc.	VW
RAMP1 (N- 20)	Goat polyclonal Ab	epitope mapping at N-terminus of hCRLR	Santa Cruz Biotech	ND
RAMPI Antibody	Mouse polyclonal Ab	aa27-118 of hRAMPI	Novus Biologicals,	W

161

(M01)			Inc., Littleton, CO
RAMP1 Antibody (1F1)	Mouse monoclonal Ab	aa27-118 hRAMPt	of	Novus Biologicals, Inc.	ND
RAMP1 antibody (ab67l51)	Mouse polyclonal Ab	frill-length hRAMPl	of	Abeam, Inc.	W
RAMP1 (FL- 148)	Rabbit polyclonal Ab	full hRAMPl	length	Santa Cruz Biotech, Santa Cruz, CA	ND

2018203471 16 May 2018

EXAMPLE 12

Immunohistochemistry Staining of Cells Expressing Different Receptor

Components

2-4x10⁶ cells were injected per colla plug (Integra LifeSciences Co., Plainsboro, NJ).

Colla plugs were embedded in OCT medium (Sakura Finetek Inc., Torrance, CA), frozen at 20°C and cut into 20 pm sections using a cryostat. Sections were fixed with 4% paraformaldehyde for J hour at room temperature (RT) and subsequently washed in phosphatebuffered saline (PBS). Endogenous peroxidase was blocked with 3% LbOyPBS for 15 min and sections were incubated in blocking solution (PBS with 3% normal goat serum (Vector Labs, BurLingame, CA) and 0.3% triton X-100) for 1 hour. Subsequently, sections were incubated in human anti-CGRP receptor primary antibody (32H7, 0.03 - 0.1 pg/rnl) at 4°C over night, washed in PBS and incubated in secondary antibody (biotinylated goat anti-human IgG Fc fragment, 1:800, Jackson lmmunoresearch. West Grove, PA) in 1% normal goat xerumPBS for 1 hour at RT. Immunoreactivity was amplified using the Vector Elite Kit according to the manufacturer’s instructions (Vector Labs, Burlingame, CA) and staining was developed using 3,3'-diaminobenzidine-nickel as chromogen (Sigma-Aldrich, St. Louis, MO). Sections were cleared with xylene and cover slipped with Permount (Fisher Chemicals, Fair Lawn, NJ). Immunoreactivity was analyzed using a Nikon E-800 microscope and associated software (Nikon, Melville, NY).

Data from cells expressing different receptor components (as identified below) using antibody 32H7 as described above revealed pronounced staining of CHO cells expressing recombinant human CGRP receptor (CRUR+RAMP1; “CHO/CGRP R cells”) and weaker staining of SK-N-MC cells that endogenously express CGRP receptors (due to much lower

162

2018203471 16 May 2018 receptor density). No staining was observed in the parent CHO cell line, CHO cells expressing an unrelated recombinant protein (TRPM8), CHO/CGRP R cells after preabsorption with the corresponding 32H7 antigen, CHO cells expressing recombinant human adrenomedullin receptor 2 (CRLR+RAMP3), MCF-7 cells endogenously expressing amylin receptors, HEK cells expressing recombinant human adrenomedullin receptor I (CRLR+RAMP2), or the parent HEK cells. The data from these experiments are summarized in Table 16, below.

Table 16 Immunohistochemical staining intensity of indicated cells

Cell line	Staining intensity (visual score)
CGRP/CHO	4+
SK-N-MC	1+
CHO	0
TRPM8/CHO	0
CGRP/CHO preadsorbed	0
AM2/CHO	0
MCF-7	0
AMI/HEK	0
HEK	0

All patents and other publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the subject matter disclosed herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and docs not constitute any admission as to the correctness of the dates or contents of these documents.

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2018203471 16 May 2018

Claims (17)

1. WHAT IS CLAIMED IS:

   1. An isolated antigen-binding protein, wherein the isolated antigen binding protein selectively inhibits the human CGRP receptor.
2. 2. The isolated antigen binding protein of claim 1, wherein the isolated antigen 5 binding protein selectively inhibits the human CGRP receptor with a selectivity ratio of 100 or more.
3. 3. The isolated antigen binding protein of claim 2, wherein the isolated antigen binding protein selectively inhibits the human CGRP receptor with a selectivity ratio of 500 or more .

   10 4. The isolated antigen binding protein of claim 1, wherein the isolated antigen binding protein specifically binds to human CGRP R with a Ko <100 nM.

   5. The isolated antigen binding protein of claim 4, wherein the isolated antigen binding protein specifically binds to human CGRP R with a Ko <10 nM as determined using a FACS binding assay.

   15 6. The isolated antigen binding protein of claim 1, wherein the isolated antigen binding protein has a Ki of less than 10 nM in a CGRP binding competition assay.

   7. The isolated antigen binding protein of claim 6, wherein the isolated antigen binding protein has a Ki of less than 1 nM in a radiolabeled ¹²⁵I-CGRP binding competition assay to membranes from cells expressing human CGRP R.

   20 8. The isolated antigen-binding protein of claim 1, wherein the isolated antigen binding protein competes for binding to human CGRP R with a reference antibody, said reference antibody comprising (i) a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs: 161, 163, 164, 166 and 168; and (ii) a light chain variable region comprising a sequence selected from the group consisting of SEQ ID

   25 NOs: 140, 143, 146, 148 and 150.

   9. The isolated antigen binding protein of claim 8, wherein the reference antibody comprises (i) a heavy chain defined by a sequence selected from the group consisting of SEQ ID NOs:32, 34, 35, 37 and 39; and (ii) a light chain defined by a sequence selected from the group consisting of SEQ ID NOs: 15, 18, 21, 23 and 25.

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   2018203471 16 May 2018

   10. The isolated antigen binding protein of claim 9, wherein the reference antibody comprises a heavy chain and a light chain defined by one of the following pairs of sequences:

   SEQ ID NO: 32 and SEQ ID NO; 15;

   SEQ ID NO: 34 and SEQ ID NO: 18;

   5 SEQ ID NO: 35 and SEQ ID NO: 21;

   SEQ ID NO: 37 and SEQ ID NO: 23; and

   SEQ ID NO: 39 and SEQ ID NO: 25.

   11. An isolated antigen-binding protein comprising (A) one or more heavy chain complementary determining regions (CDRHs) selected

   10 from the group consisting of: (i) a CDRH1 having SEQ ID NO: 134; (ii) a CDRH2 having SEQ

   ID NO: 135; (iii) a CDRH3 having SEQ ID NO:136; and (iv) a CDRH of (i), (ii) or (iii) that contains one, two, three or four amino acid substitutions, deletions or insertions;

   (B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRL] selected from the group consisting of SEQ ID

   15 NOs:107, 111 and 118; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 108,

   112 and 119; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 109, 113 and 120; and optionally (iv) a CDRL of (i), (ii) and (iii) that contains one, two, three or four amino acid substitutions, deletions or insertions;

   or (C) one or more heavy chain CDRHs of (A) and one or more light chain CDRLs of

   20 (B)

   12. The isolated antigen binding protein of claim II, wherein the CDRHs are further selected from the group consisting of: (i) a CDRH1 having SEQ ID NO: 131; (ii) a CDRH2 having SEQ ID NO: 132; (iii) a CDRH3 having SEQ ID NO: 133; and (iv) a CDRH of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions.

   25 13. The isolated antigen binding protein of claim 12, wherein the CDRHs are further selected from the group consisting of: (i) a CDRH I selected from the group consisting of SEQ ID NO:76, 88, 100, 121, 125 and 128; (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 89, 101, 122, 124, 126, and 129; (iii) a CDRHS selected from the group

   165

   2018203471 16 May 2018 consisting of SEQ ID NO: 78, 90, 102, 123, 127, and 130; and (iv) a CDRH of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions.

   14. The isolated antigen binding protein of claim 13, wherein the CDRHs are further selected from the group consisting of: (i) a CDRH1 selected from the group consisting 5 of SEQ ID NO: 73, 76, 79, 82, 85, 88, 92, 97, and 100; (ii) a CDRH2 selected from the group consisting of SEQ ID NO: 74, 77, 80, 83, 86, 89, 91, 93, 95, 98, 101, and 129; (iii) a CDRH3 selected from the group consisting of SEQ ID NO: 75, 78, 81, 84, 87, 90, 96, 99, 102, and 123; and (iv) a CDRH of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions

   10 15. The isolated antigen binding protein of claim 11, wherein the CDRLs are further selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs: 107, 111 and 115; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 108, 112 and 116; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 109, 113 and 117; and (iv) a CDRL of (i), (ii) and (iii) that contains one, two, three, or four

   15 amino acid substitutions, deletions or insertions.

   16. The isolated antigen binding protein of claim 15, wherein the CDRLs arc further selected from the group consisting of: (i) a CDRL1 selected from the group consisting of SEQ ID NOs: 42, 45, 51, 57, 62, 69, 103, and 110; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 43, 52, 55, 58, 63, 70, 104, 108, and 114; (iii) a CDRL3 selected

   20 from the group consisting of SEQ ID NOs: 44, 47, 53, 56, 59, 64, 105, and 106; and (iv) a CDRL of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions.

   17. The isolated antigen binding protein of claim 16, wherein the CDRLs are further selected from the group consisting of: (i) a CDRL1 selected from the group consisting

   25 of SEQ ID NOs: 42, 45, 48, 51, 54, 57, 62, 65, 66, and 69; (ii) a CDRL2 selected from the group consisting of SEQ ID NOs: 43, 46, 49, 52, 55, 58, 61, 63, 67, and 70; (iii) a CDRL3 selected from the group consisting of SEQ ID NOs: 44, 47, 50, 53, 56, 59, 64, 68, 71, and 72; and (iv) a CDRL of (i), (ii) and (iii) that contains one, two or three amino acid substitutions, deletions or insertions.

   30 18. The isolated antigen binding protein of any of claims 11 - 17, wherein the isolated antigen-binding protein comprises at least one CDRH and at least one CDRL.

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   2018203471 16 May 2018

   19. The isolated antigen binding protein of claim 18, wherein the isolated antigenbinding protein comprises at least two CDRH and at least two CDRL.

   20. The isolated antigen binding protein of any of claims 11 - 19, wherein the isolated antigen-binding protein comprises a CDRH1, a CDRH2, a CDRH3, a CDRL1, a

   5 CDRL2 and a CDRL3.

   21. An isolated antigen-binding protein comprising a heavy chain variable region (V_H) sequence that has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 158-170.

   22. An isolated antigen-binding protein comprising a light chain variable region 10 (Vl) sequence that has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:137-153.

   23. An isolated antigen-binding protein comprising a V_H sequence that has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: :158, 159, and 162-172, and a Vl sequence that has at least 90% sequence identity

   15 with an amino acid sequence selected from the group consisting of SEQ ID NOs: 137, 138, 140-145, 148-151, and 153-157.

   24. The isolated antigen binding protein of any of claims t - 23, wherein the isolated antigen-binding protein is selected from the group consisting of a monoclonal antibody, a Fab fragment, an Fab' fragment, an F(ab')₂ fragment, an Fv fragment, a diabody,

   20 and a single chain antibody.

   25. The isolated antigen binding protein of claim 24, wherein the isolated antigenbinding protein is a monoclonal antibody selected from the group consisting of a fully human antibody, a humanized antibody and a chimeric antibody.

   26. The isolated antigen binding protein of claim 25, wherein the monoclonal 25 antibody is an IgGl-, IgG2-, IgG3-, or lgG4-type antibody.

   27. The isolated antigen binding protein of claim 26, wherein the monoclonal antibody is an IgGl or lgG2 antibody.

   28. An isolated nucleic acid polynucleotide that encodes an antigen-binding protein of any of claims 1-27.

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   2018203471 16 May 2018

   29. The isolated nucleic acid polynucleotide of claim 28, wherein the polynucleotide comprises a sequence that is 80% or more identical with a sequence selected from the group consisting of SEQ ID NOs:175, 176, 178, 179, 180, 181, 182, 183, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 197, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209

   5 and 210.

   30. The isolated nucleic acid polynucleotide of claim 28, wherein the polynucleotide comprises a sequence that is 80% or more identical with a sequence selected from the group consisting of SEQ ID NOs :224-258.

   31. The isolated nucleic acid polynucleotide of claim 28, wherein the 10 polynucleotide comprises a sequence capable of hybridizing under stringent hybridization conditions with a sequence selected from the group consisting of SEQ ID NOs:224-258.

   32. An expression vector comprising an isolated polynucleotide of any of claims

   28-31.

   33. A cell line transformed with expression vector of claim 32.

   15 34. A method of making an antigen-binding protein of any of claims 1-27, comprising preparing the antigen binding protein from a host cell that secretes the antigenbinding protein.

   35. The method of claim 34, wherein said antigen binding protein is generated using an immunogen comprising soluble CGRP receptor.

   20 36. The method of claim 35, wherein said soluble CGRP receptor is obtained by coexpressing and purifying an N-terminal extracellular domain (ECD) of human CRLR and an ECD of human RAMP1.

   37. The method of claim 36, wherein said ECD of human CRLR comprises SEQ ID NO: 6 and said ECD of RAMP 1 comprises SEQ ID NO: 8.

   25 38. A pharmaceutical composition comprising an antigen binding protein of any of claims 1-27 and a pharmaceutically acceptable excipient.

   39. A method for treating a condition associated with CGRP R in a patient, comprising administering to a patient an effective amount of an isolated antigen-binding protein of any of claims 1-27.

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   2018203471 16 May 2018

   40. The method of claim 39, wherein the condition is headache.

   41. The method of claim 40, wherein the condition is migraine.

   42. The method of any of claims 39 to 41, wherein the method comprises prophylactic treatment.

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   1/17

   OO

   2018203471 16 May 201

   CYNO_RAMP1 Π) HGMAN_RAMP1 (1) RAT_RAMP1 m CYNO__RAMP1 (55) HUMAIt_RAMPl (55) RATJtAMPl (55) CYNG~RAKP1 (1095 ί-Γϋ1ίΑί4_ΕΑΜΡΙ (109} EAT_RAJ4P1 (109)

   1 10

   2 0 3 0' 4 0

   MARAIjCRLPQRGLWLLI.AHHLFMATACQEAKYGAL1<QEIjCI.TQFQVDMEAVGET

   MARALCRLPRRGliWLLLAHHLFMTTACQEANYGAIiLRELCLTQFQVDMEAVGET

   MAPGLRGLPRRGLWLLI.AHHLFMVTACRDPDYGTLIQELCLSRFKEDMETXGKT

   SO 70 80 90 100

   LWCDWGRTXGSYREIADCTWHMAEKLGCFStfPKABVDRFFLAVHGHYFRACPISG LWCDWGRTXRSYRBLADCTWKMAEitLGCFiiPNAEVDRFFLAVKGRYFRSCPISG LWCDWGKTXGSYGELTHCTKLVANKIGCFWPNPEVDKFFXAVHHRYFSKCPVSG

   110 120 130 140

   RAVRDPPGSVLYF FI WPITVTLLVl’ALVWQS KHTEGIV RAVRDPPGSILYPFIWPITVTLLVTALWWQSKRTEGIV RALS.DPPNS ILCPFXVLPITVTLLMTALWWRS KRTEGXV

   2/17

   2018203471 16 May 2018

   CYNOCRLR (1) HUCRLR U) RATCRLR (1)

   CYNOCRLR {57) HUCRLR ¢57) RATCRLR ¢57)

   CYNOCR.LR (114 ) HUCRLR ¢114} RATCRLR (114}

   CYNOCRLR{171} HUCRLR ¢171) RATCRLR ¢171)

   1 IQ 20 30 40 50

   -KBKKCTLYFLVLLPFFHXFVTAELEBSPEDSXQLGVTRNKIMTAQYECYQKXMQDP -MEKKCTLYFLVLLPFFHXLVTAELESSPSDSIQLGVTRNKXMTAQYECYQKIMQDP MMDKKCTLCFLFLLLLNMALIAAESEEGAKQT-DLGVTRNKXMTAQYECYQKIMQDP

   60 70 80 90 100 110

   XQQASGVYCMRTWDGWLCWNNVAAGTESMQLC PDYFQDFDPSEKVTKICDQDGNWFR IQQAEGVYCKRTWDGWLCWlSiDVAAGTESMqLCPDYFQDFDPSEKVTKICDQDGKWFR XQQGEGLYCHRTWDGWLCWKDVAAGTESMQYCPDYFQDFDPSEKVTKICDQDGRWFR

   120 130 140 150 150 170

   HPASNRTWTNYTQCWVNTHE KVKTALHLFYLTX1GHGLSXASLLISLGIFRYFKSLS HPASNRTWTNYTQCHVNTHEKVXSALNLFYLTXXGHGLSXASLLISLGIFFYFKSLS HPDSNRTrTNYTLCHJSISTHE KVKTALNLFYLT1X GHGLS XASLXISLIX FFYFKSLS

   180 190 200 210 220

   CQRITLHKNLFFSFVCNSWTXXHLTAVANNQALVATNPVSCKVSQPXHLYLMGCNY

   C^RXTLHKXiliFFSFVCNSVVTXXHLTAVANNQALVATNPVSCKVSQFXHLYLMGCRfY

   CQRXTLHKJfoFFSFVCNSXVTIIHLTAVANNQALVATNPVSCKVSQFXHLYLMGCNY

   CYNOCRLR(228) HUCRLR ¢228} RATCRLR ¢228)

   230 240 250 260 270 280

   FWMLCEGIYLHTLXWAVFAEi^JHLMWYYFLGWGFPLIPACXHAXARSLYYNDiiCWI

   FWLCEGXYLHTLXWAVFAEK^HLMWYYFLGWGFPLXPACXHAIARSLYYNISiCWI

   FWMLCEGXYLHTLIWAVFAEKQHLMWYYFLGWGFPLLPACXKAXARSLYYNDNCWX

   CYNOCRLR¢285) HUCRLR ¢285) RATCRLR (285}

   290 300 310 320 330 340

   SSDTHLLYIXHGPXCAALLVNLFFLLNIVRVLITKLKVTHQABSNLYMKAVRATLXL SSDTHLLYIXHGPICAALLVNLFFLLKIVRVLITKLKVTHQASSNLYMKAVRATLIL SSDTHLLYIIHGPICAALLVNLFFLLKIVRVLITKLKVTHQABSNLYMKAVRATLIL

   CYNOCRLR{342}

   HUCRLR (342) RATCRLR (342)

   350 350 370 380 390

   VPLLGISFVLIPWRPEGKIAEBVYDYIMHILKHFQGLLVSTXFCFFiiGEVQAXLRRN VPLLGISFVLIP'WRPBGKIAEEVYDYIMHILMKFQGLLVSTIFCFFNGEVQAILRRN VPLLGISFVLFPWRPEGKVAEEVYDYVKHILNHYQGLLVSTIFCFFNGEVQAILRRN

   40 0

   410

   420

   430

   440

   450

   CYNOCRLR¢399) HUCRLR ¢399) RATCRLR ¢339)

   WNQYKIQFGNSFSNSEALRSASYTVSTISDGPGYSHDCPSEHLNGKSXHDIEN'WLK

   WNQYKIQFGNSFSNSEALRSASYTVSTISDGPGYSHDCPSEHLNGKSXHDISlsE’LLK

   WNQYKIQFGNGFSKSDALRSASYTVSTISDVQGYSHDCPTEHI^fGKSIQDIBNVALK

   CYNOCRLR(456} HUCRLR (456} RATCRLR (456}

   460

   PENLYN--PEMLYN--PSKMYDLVM

   3/17

   2018203471 16 May 2018

   Kappa X1 SEQ SEQ SEQ CDR1 5D NO: CDR2 ID MO: CDRS IO NO; 2E7 RASQG i RNOLG 48 AAS S LQS 49 LQY«IYPWT 50 13H2 RASQGi R K D I G 58 G A S S L Q S 67 LGYNSFPWT 68 K1 Consensus RASOGI R S D L G 103 AASS LQS 104 LQYN 3YPWT 105 K G SF Kappa K4 SEQ SEQ SEQ COR1 10 NO: COR2 SO NO: CQR3 SO NG: 32H7 R A S Q S V S S G Y L T 59 GASSRAT 70 QQYGNSLCR 71 32H7a RASQSVSSGYLT 69 6 A S S R A T 70 QQYGNSLSR 72 K4 Consensus RASQSVSSGYLT 69 GASSRAT 70 QQYGNSLSR C 106 SEQ SEQ SEQ CORI 3D NO: CDR2 ID NO: COR3 (0 NO: Kappa K1,4 Cons RASQSVSSGYLT 107 GASSRAT 10S QQYGNS LCR 109 G 5 RN 0 G A LQS L KTYPWT

   K F S

   Kappa K2 SEQ ID NO: 57 CDR2 L G SNR /1S SEQ IO NO: 58 CDRS MQALQTPFT SEQ © NO; 59 4HS CDRI RSSQSLLHSFGYNYLD Kappa K3 SEQ SEQ SEQ CORI ID NO; CDR2 ID NO: CDRS ID NO: SC8 KSSQSLLHSAGKTYLY 34 E V S N R F S 55 MQSFPLPLT 56 SFS KSSQSLLHSDGKTYLY SO E V S N R F S 55 MQSFPLPLT 56 12E3 KSSQSLLHSDGRNYLY 85 E V S N R F S 55 MQSFPLPLT 56 K3 Consensus KSSQSLLHSDGRNYLY 110 E V S N R F $ 55 MQSFPLPLT 56 A KT SEQ SEQ SEQ CDRI ID NO: COR2 IO NO: CDRS © NO; Kappa K2,3 Cons RSSQSLLHSFGYNYLD 111 L G S R R A S 112 HQALQTPFT 113 K D R T Y E V F SFPL L

   A X
4. 4/17

   2018203471 16 May 2018

   Lambda LI SEQ SEQ SEQ CDR1 ID TO: CDR2 ID NO: CDRS ID NO: 1E11 SGSSSN5 GNNYVS 42 S N N K R P S 43 GTWDSRLSAVV 44 4E4 SGSSSNIGNNYVS 42 O N N K R P S 43 GTWDSRLSAVV 44 904 SGSSSNiGNNYVS 42 G N N K R P S 43 GTWOSRL SAW 44 1203 SGSSSNIGNNYVS 42 DNNKRPS 43 GTWOSRLSAVV 44 L1 Consensus S G S S S 54 I G14 N Y V S 42 0 N N K R P S 43 GTWOSRLSAVV 44 Lambda L2 SEQ SEQ SEQ CDR1 ID NO: CDR2 IO NO: CDRS ID NO: 10Ξ4 SGSSSNIGSNTVN 52 TNNQRPS 63 AARDESLNGW 64 Lambda L3 SEQ SEQ SEQ CDR1 ID NO: CDR2 IO NO: CDRS ID NO: 11 011 S G S S S N I G S N Y V Y 45 RNRQRPS 61 AAWDDS L SGWV 47 11HS SGSSSNIGSNYVY 45 R N N Q R P S 61 AAWDDSL SGWV 47 1H7 S G S S S N i G S N Y V Y 45 R S N Q R P S 46 AAWDDS LSGWV 47 SFS SGSSSNIGSMYVY 45 R N N Q R P S 61 AAWDDS L SGWV 47 L3 Consensus SGSSSNIGSKYVY 45 RNNQRPS S 114 AAWDDS L SGWV 47 Lambda L4 SEQ SEQ SEQ CORI ID NG: CDR2 ID TO: CDR3 ID NO: 386 QG DS LRSFYAS 51 G K N N R P S 52 NSRDSSVYHLV 53 SEQ SEQ SEQ CDR1 ID NO: COR2 ID NO: CDRS ID NO: Lam LI,2,3 Cons SGSSSNIGNNYVS 115 DNNKRPS 116 GTWOSRLSAVV 117 5 T N T S Q AAR DS NG Y R SEQ SEQ SEQ CDR1 ID NO: COR2 ID NG: CDRS ID NO: Lambda AU Cons SGSSSNIGNNYVS 118 ONNKRPS 119 GTWOSRLSAVV 120 Q - D - LRSHAfi GK H MSP DSVYNL Y TS Q A A NG

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   2018203471 16 May 2018 cAMP content in cels expressing hCGRP R stimulated with 1nM hCGRP ¹²⁵I-CGRP binding to human CGRP receptor

   Fig 8
9. 9/17

   2018203471 16 May 2018

   120 cAKF content in hAMl-HEK ceils
10. 10£H T

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    Fig 7B cAMP content In hAM2-CHQ cells

    3C8 13H2 1 El 1

    Fig 7C cAMP content in MCF-7 ceils (expressing human amylin receptors) °»13 42.....-11.....40.....ί ί.......»7.......»$.....-5 concentration, log M

    10/17

    2018203471 16 May 2018

    Time (sec)

    Time (sec)
11. 11/17

    2018203471 16 May 2018

    Time (sec)
12. 12/17

    FAGS Kd determination mAh 12GS

    OO

    2018203471 16 May 201

    Log concentration of mAb (M)

    Fig 10

    CRLR: RA^P1 Wild Type pjg 1 3A

    CRLR L24-Q33: RAIVIP1

    CRLR: RAMPi Q28-A34

    Fig 13C
13. 13/17

    2018203471 16 May 2018 cyna__RAMFl huEnan_RAMP 1 hyRAMPl(Q28-A34)) huRAMPl{Q4 3-E53} hyRAMPliS6?’K73} rat_RAMPX rhesus_RAMPl

    CyBO_RAMPX huraan_RAMPl huRAMPlί Q28-A3 4)) huRAMPl(Q43-S53) huRAMP1(SS 7 -E78) rat_RAMPl rhesus RAMP1 cyno_RAMPl human_RAMPl huRAMPl{$28-A34) ) huRAMPl{Q43-E535 hyRAMPl(R67-E785 rat_RAMPl rhesus_RAMPl

    1 SO

    MARALCRLPQ RGLWLLLAHH LFMATACQEA 1TYGALLQELC LTQFQVDMEA MASALCRLPR RGLWLLLAHH LFMTTACQBA NYGALLRSLC LTQFQVDMEA MARALCKLPR RGLKLLLAHH LFMTTACRDP DYGTLLR2LC LTQFQVDMEA MARALCRLPR RGLWLLLAHH LFMTTACQEA NYGALLRSLC LTRFKEDMET MASALCRLPR RGLWLLLAHH LFMTTACQEA NYGALLRSLC LTQFQVDMEA MAPGLRGLPR RGLWLLLAHH LFMVTACRDP DYGTLIQELC LSRFKEDMET MARALCRLPQ RGLWLLLA.HK LFMATACQEA NYGALLQELC LTQFQVDKEA

    31 100

    VGETLWCDWG RTXGSYRELA DCTWHMAEKL GCFWPMABVD RFFLAVHGHY VGETLWCDWG RTIRSYRBLA DCTWHMAEKL GCFWPNAEVD RFFLAVHGRY VGETLWCDWG RTIRSYRELA DCTWHMAEKL GCFWPNAEVD RFFLAVHGRY IGKTLWCDWG RTIRSYRELA DCTWHMAEKL GCFWPNAEVD RFFLAVHGRY VGSTLWCDWG RTIRSYGELT HCTKLVANKL GCFWPMAEVD RFFLAn-lGRY IGKTLWCDWG KTIOSYGELT HCTKLVANKI GCFWPNPEVD KFFIAVHHRY VGETLWCDWG RTIGSYRELA. DCTWHMAEKL GCFWPNABVD RFFLAVHGHY

    101 148

    FRACPISGRA VRDPPGSVLY PFIWPITVT LLVTALWWQ SKKTEGIV FRSCPISGRA VRDPPGSILY PFIWPITVT LLVTALWWQ SKRTEGIV FRSCPISGRA VRDPPGSILY PFIWPITVT LLVTALWWQ SKRTEGIV FRSCPISGRA VRDPPGSILY PFIWPITVT LLVTALWWQ SKRTEGIV FRSCPISGRA VRDPPGSILY PFIWFITVT LLVTALWWQ SKRTEGIV FSKCPVSGRA IRDPPNSILC PFIVLPITVT LLMTALWWR SKRTEGIV FRACPISGRA VRDPPGSVLY PFIWPITVT LLVTALWWQ SKHTEGIV
14. 14/17

    2018203471 16 May 2018 huCRLR cynoCRLR rhesusCRLR ratCRLR huCRLR(L24-Q33)

    Consensus huCRLR.

    cyr.oCRLR rhesusCRLR ratCRLR huCRLR (1.24-Q33)

    Co nsen huCRLR cynoCRLR rhesusCRLR ratCRLR huCRLR(L24“Q33}

    Consensus huCRLR cynoCRLR rhesusCRLR ratCRLR huCRLR(L24-Q33)

    Consensus huCRLR cynoCRLR rhesusCRLR ratCRLR huCRLR(L24-Q33)

    Consensus

    1 50

    MEKKCTLYF LVLLPFFMXL VTAELEESPB DSXQLGVTRK KXMTAQYECY MEKKCTLYF LVLLPFFMXF VTAELEESPE DSXQLGVTRN KXMTAQYECY MEKKCTLYF LVLLPFFMXF VTAELEESPE DSXQLGVTRK KXMTAQYECY

    KMDKKCTLCF LFLLLLSMAL XAAESEEGAN QT-DLGVTRN KXMTAQYECY M2KKCTLYF LVLLPFFMXL VTAESEEGAN QT-DLGVTRN kxmtaqyecy MeKKCTLyF LvLLpffMil -tAE-BE---------LGVTRN KXMTAQYECY

    SI 1-00

    QKIMQOPIQQ AEGVYCMRTW DGWLCWKDVA AGTESMQLC? DYFQDFDPSE QKIMQDPIQQ AEGVYCMRTK DGWLCKMNVA AGTESMQLCP DYFQDFDPSE QKIMQDPIQQ ABGVYCNRTSf DGWLCKNNVA AGTESMQLCP DYFQDFDPSE QKIMQDPIQQ GSGLYCNRTW DGWLCWMDVA AGTSSMQYCP DYFQDFDPSE QKIMQDPIQQ AEGVYCMRTK DGMLCWNDVA AGTESMQLCP DYFQDFDPSE QKIMQDPIQQ aEG-YCNETW DGWLCMM-VA AGTESMQ1CP DYFQDFDPSE

    101 150

    KVTKICDQDG JWFRKPASKR TWTSYTQCUV NTHEJCVKTAL NLFYLTXIGH KVTKICDQDG WFRKPASKR WXSYTQCKV MTHBKVKTAL NLFYLTXXGH KVTKICDQDG WFSHPASNR TWTMYTQCW NTHEKVKTAL NLFYLTXXGH KVTKICDQDG WFRKPDSKR TWTNYTLCMN STHEKVKTAL NLFYLTIXGH KVTKICDQDG NWFRHPASNR TMTMYTQCKV MTHEKVKTAL NLFYLTIXGH KVTKICDQDG NNFRKPaSNR TWTNYTqCNv nTHBKVKTAL NLFYLTIXGH

    151 200

    GLSIASLLIS LGIFFYFKSL SCQRXTLHKN LFFSFVCNSV VTIXHLTAVA GLSIASLLIS LGIFFYFKSL SCQRITLHKN LFFSFVCKSV VTIXHLTAVA GLSIASLLIS LGIFFYFKSL SCQSITLKKN LFFSFVCKSV VTIXHLTAVA GLSXASLIIS LXXFFYFKSL SCQRITLHKN LFFSFVCNSI VTIXHLTAVA GLSIASLLIS LGIFFYFKSL SCQRITLHKN LFFSFVCKSV VTIXHLTAVA GLSXASL-IS LglFFYFKSL SCQRITLHKN LFFSFVCNS- VTXXHLTAVA

    201 250

    NNQALVATNP VSCXVSQFTH LYLMGCNYFW MLCEGXYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCEGXYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCWYFW MLCEGIYLKT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCEGXYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCEGXYLHT LXWAVFAEK NNQALVATNP VSCKVSQFIH LYLMGCNYFW MLCEGIYLKT LXWAVFAEK huCRLR cynoCRLR rhesusCRLR ratCRLR huCRLR(L24-Q335

    Consensus

    251

    QHLMWYYFLG

    QHLMWYYFI.G

    QHLMMYYFLG

    QKLMWYYPLG

    QHLMWYYFLG

    QHLMWYYFLG

    W3FPLIPACI WGFPLX PACT WGFPLIPACX WGFPLLPACI MGFPLIPACX WGFPL-PACX

    HAIARSLYYN

    HAIARSLYYN

    HAIARSLYYN

    HAIARSLYYN

    HAIARSLYYN

    HAIARSLYYN

    DNCMXSSDTH

    DHCWISSDTH

    DNCWISSDTH

    DNCWISSDTH

    DNCWISSDTH

    DNCWISSDTH

    300

    LLYIIHGPIC

    LLYIIHGPIC

    LLYIIHGPIC

    X.LYIIHGPIC

    LLYXI.RGPIC

    LLYIIHGPIC
15. 15/17

    2018203471 16 May 2018

    301 350 huCRLR AALLVNLFFL W'IVSVLITK LKVTHQAESN LYMKAVRATL ILVPLLGISF

    cynoCRLR rbesusCRLR ratCRLR buCRLR{L24-Q33) Consensus AALLVKLFFL LSXVRVLXTK LXVTHQASSB AALLVNLFFL LNXVRVLXTK XjKVTHQABSN Mt,LW,PPL LNIVRVLITK LKVTKQASSN AALLWAFFL LNIVRVLITK LKVTKQAESN LYMK.AVRATL LYMKAVRATL LYMK.WRATL LYTSKAVEATL LYMKAVRATL ILVPLLGXSF ILVPLLGISP XLVPLLGIEF XLVPLLGIEF ILVPLLGIEF AftLLVNLFFL LKIVRVLITK LKVTHQAESN 351 4 00 huCRLR VLXPWREEGK XASEVYDYXM HILMHFQGLL VSTIFCFFNG EVQAILRKW cynoCRLR VL1FWKPEGK lASEVYLYIM HILMHFQSLL VSTIFCFFHG EVQATLRWW rheeusCRLR VL1PSSFEGK IASEVYDYIM HILMHFQGLL VSTIF'CFFNG EVQATLRRNN ratCRLS VLPPWRPEGK VASEVYDYVM HILMHYQSLL VSTXPCFFNG EVQAILREW huCRLR(L24~Q33) VLIFKKPEGK IA3EVY0YIM HILMHFQSLL VSTXFCFFNG EVQAXLRRNW Consensus VLiPWRREGK -AEEVYDY-M HILKH-QGLL VSTXFCFFNG EVQAILRRNN 4 Cl 450 buCRI.R HQYKJQFGMS FSNSSALRSA SYTVSTXSDG PGYSHDCPSS HLNGKSIHDI cynoCRLR NQYKIQFGNS FSNSEALRSA SYTVSTXSDG PGYSKDCPSE HLNGKSIHDX rhesusCRLR MQYRIQFGNS FSNSEALRSA SYTVSTXSDG PGYSKDCPSE HLNGKSIHDI ratCRLR NQYKXQFGNG FSHSDALRSA SYTVSTISDV QGYSBDCPTE BLKGKSXQDI buCRLR(L24-Q33i NQYKIQFGSSS FSNSEALRSA SYTVSTXSDG PGYSKDCPSE HLNGKSIHDI Consensus NQYKXQFGNS FSnSeALRSA SYTVSTXSDg pGY3HDCP-E HLNGKSIbDX 451 45 5 huCSLR ENVLLKPEKL YR·..... cynoCRLR BNYVLKPERL YN--- rhesusCRLR EWVLRPSNL YN- _ . rafcCSLR ENVALKPEKM YDLVK buCRLR(L24-Q335 SKVLLKPSKL YN--- Consensus ENY-LKPEn- y----
16. 16/17

    2018203471 16 May 2018

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17. 17/17

    2018203471 16 May 2018

    ...........__Λτ, ί___________

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    2018203471 16 May 2018

    A1472PCT

    SEQUENCE LI STI NG <110> AMGEN I NC.

    <120> HUMAN CGRP RECEPTOR BI NDI NG PROTEI NS <130> A- 1472-WD-PCT <140>

    <141>

    <150> 61/264, 622 <151> 2009-11-25 <150> 61/203, 569 <151> 2008- 12-23 <160> 261 <170> Pat ent I n version 3.5 <210> 1 <211> 1419 <212> DNA <213> Homo sapi ens <400> 1

    at gt t at aca gcat at t t ca 1111 ggct t a at gat ggaga aaaagt gt ac cct gt at t t t 60 ct ggt t ct ct t gcct 11111 t at gat t ct t gt t acagcag aat t agaaga gagt cct gag 120 gact caat t c agt t gggagt t act agaaat aaaat cat ga cagct caat a t gaat gt t ac 180 caaaagat t a t gcaagaccc cat t caacaa gcagaaggcg t t t act gcaa cagaacct gg 240 gat ggat ggc t ct gct ggaa cgat gt t gca gcaggaact g aat caat gca gct ct gccct 300 gat t act t t c aggact t t ga t ccat cagaa aaagt t acaa agat ct gt ga ccaagat gga 360 aact ggt 11 a gacat ccagc aagcaacaga acat ggacaa at t at accca gt gt aat gt t 420 aacacccacg agaaagt gaa gact gcact a aat t t gt t t t acct gaccat aat t ggacac 480 ggat t gt ct a 11 gcat cact gct t at ct cg ct t ggcat at t ct t t t at t t caagagcct a 540 agt t gccaaa ggat t acct t acacaaaaat ct gt t ct t ct cat t t gt t t g t aact ct gt t 600 gt aacaat ca 11 cacct cac t gcagt ggcc aacaaccagg cct t agt agc cacaaat cct 660 gt t agt t gca aagt gt ccca gt t cat t cat ct t t acct ga t gggct gt aa 11 act 111 gg 720 at gct ct gt g aaggcat t t a cct acacaca ct cat t gt gg t ggccgt gt t t gcagagaag 780 caacat 11 aa tgtggt at t a t t t t ct t ggc tggggatttc Page 1 cact gat t cc t gct t gt at a 840

    2018203471 16 May 2018

    A1472PCT catgccattg ctagaagctt at at t acaat gacaattgct ggatcagttc t gat acccat 900 ct cct ct aca 11 at ccat gg cccaat 11 gt gctgctttac t ggt gaat ct 111111 ct t g 960

    11 aaat at t g tacgcgttct cat caccaag 11 aaaagt t a cacaccaagc ggaat ccaat 1020 ct gt acat ga aagct gt gag agctactctt atcttggtgc cattgcttgg cat t gaat tt 1080 gtgctgattc cat ggcgacc t gaaggaaag attgcagagg aggtatatga ct acat cat g 1140 cacat cct t a tgcacttcca gggt ct 111 g gt ct ct acca ttttctgctt ctttaatgga 1200 gaggttcaag caattctgag aagaaact gg aat caat aca aaat ccaat t t ggaaacagc 1260 ttttccaact cagaagctct tcgtagtgcg tcttacacag tgtcaacaat cagtgatggt 1320 ccaggt t at a gt cat gact g t cct agt gaa cact t aaat g gaaaaagcat ccat gat att 1380 gaaaat gt t c t ct t aaaacc agaaaat t t a t at aat t ga 1419 <210> 2 <211> 472 <212> PRT <213> Homo sapi ens

    <400> 2 Hi s Phe Gl y Leu 10 Met Met Gl u Lys Lys 15 Cy s Met 1 Leu Tyr Ser Ile 5 Phe Thr Leu Tyr Phe 20 Leu Val Leu Leu Pr o 25 Phe Phe Met Ile Leu 30 Val Thr Al a Gl u Leu 35 Gl u Gl u Ser Pr o Gl u 40 As p Ser I l e Gl n Leu 45 Gl y Val Thr Ar g As n 50 Lys I l e Met Thr Al a 55 Gl n Ty r Gl u Cy s Ty r 60 Gl n Lys Ile Met Gl n 65 As p Pr o Ile Gl n Gl n 70 Al a Gl u Gl y Val Ty r 75 Cy s As n Ar g Thr Tr p 80 As p Gly Tr p Leu Cy s 85 Tr p As n As p Val Al a 90 Al a Gl y Thr Gl u Ser 95 Met Gl n Leu Cys Pr o 100 As p Ty r Phe Gl n As p 105 Phe As p Pr o Ser Gl u 110 Lys Val

    Page 2

    2018203471 16 May 2018

    A1472PCT

    Thr Lys I l e 115 Cys Asp G n Asp G y Asn Trp Phe Arg 120 Hi s 125 Pr o Al a Ser Asn Ar g Thr Tr p Thr As n Tyr Thr Gl n Cys As n Val As n Thr Hi s Gl u 130 135 140 Lys Val Lys Thr Al a Leu As n Leu Phe Tyr Leu Thr Ile Ile Gl y Hi s 145 150 155 160 Gly Leu Ser Ile Al a Ser Leu Leu I l e Ser Leu Gl y Ile Phe Phe Tyr 165 170 175 Phe Lys Ser Leu Ser Cys Gl n Ar g I l e Thr Leu Hi s Lys As n Leu Phe 180 185 190 Phe Ser Phe Val Cys As n Ser Val Val Thr I l e Ile Hi s Leu Thr Al a 195 200 205 Val Al a As n As n Gl n Al a Leu Val Al a Thr As n Pr o Val Ser Cys Lys 210 215 220 Val Ser Gl n Phe Ile Hi s Leu Tyr Leu Met Gl y Cys As n Tyr Phe Tr p 225 230 235 240 Met Leu Cys Gl u Gl y Ile Tyr Leu Hi s Thr Leu Ile Val Val Al a Val 245 250 255 Phe Al a Gl u Lys Gl n Hi s Leu Met Tr p Tyr Tyr Phe Leu Gl y Tr p Gl y 260 265 270 Phe Pr o Leu Ile Pr o Al a Cys Ile Hi s Al a I l e Al a Ar g Ser Leu Tyr 275 280 285 Tyr As n Asp As n Cys Tr p Ile Ser Ser As p Thr Hi s Leu Leu Tyr Ile 290 295 300 I l e Hi s Gl y Pr o Ile Cys Al a Al a Leu Leu Val As n Leu Phe Phe Leu 305 310 315 320

    Page 3

    2018203471 16 May 2018

    Leu As n I l e Val Ar g 325 Val Leu Ile Thr Lys 330 Leu Lys Val Thr Hi s 335 Gl n Al a Gl u Ser As n Leu Tyr Met Lys Al a Val Ar g Al a Thr Leu Ile Leu 340 345 350 Val Pr o Leu Leu Gl y Ile Gl u Phe Val Leu I l e Pr o Tr p Ar g Pr o Gl u 355 360 365 Gly Lys I l e Al a Gl u Gl u Val Tyr As p Tyr I l e Met Hi s Ile Leu Met 370 375 380 Hi s Phe Gl n Gl y Leu Leu Val Ser Thr I l e Phe Cys Phe Phe As n Gl y 385 390 395 400 Gl u Val Gl n Al a Ile Leu Ar g Ar g As n Tr p As n Gl n Ty r Lys Ile Gl n 405 410 415 Phe Gl y As n Ser Phe Ser As n Ser Gl u Al a Leu Ar g Ser Al a Ser Ty r 420 425 430 Thr Val Ser Thr Ile Ser As p Gl y Pr o Gl y Tyr Ser Hi s As p Cy s Pr o 435 440 445 Ser Gl u Hi s Leu As n Gl y Lys Ser I l e Hi s As p Ile Gl u As n Val Leu 450 455 460 Leu Lys Pr o Gl u As n Leu Tyr As n 465 470

    <210> 3 <211> 447 <212> DNA <213> Homo sapi ens <400> 3 at ggcccggg ccctgtgccg cct cccgcgg cgcggcct ct ggct gct cct ggcccat cac 60 ctcttcatga ccact gcct g ccaggaggct aact acggt g ccct cct ccg ggagct ct gc 120 ctcacccagt tccaggtaga catggaggcc gtcggggaga cgctgtggtg tgactggggc 180 aggaccat ca ggagct acag ggagct ggcc gact gcacct ggcacat ggc ggagaagct g 240

    Page 4

    2018203471 16 May 2018

    A1472PCT ggctgcttct ggcccaat gc agaggt ggac aggt t ct t cc t ggcagt gca t ggccgct ac 300 ttcaggagct gccccatctc aggcagggcc gtgcgggacc cgcccggcag catcctctac 360 ccct t cat cg t ggt ccccat cacggt gacc ct gct ggt ga cggcact ggt ggt ct ggcag 420 agcaagcgca ct gagggcat t gt gt ag 447 <210> 4 <211> 148 <212> PRT <213> Homo sapi ens <400> 4

    Met 1 Al a Ar g Al a Leu 5 Cys Ar g Leu Pr o Ar g 10 Ar g Gl y Leu Tr p Leu 15 Leu Leu Al a Hi s Hi s Leu Phe Met Thr Thr Al a Cys Gl n Gl u Al a As n Tyr 20 25 30 Gl y Al a Leu Leu Ar g Gl u Leu Cys Leu Thr Gl n Phe Gl n Val As p Met 35 40 45 Gl u Al a Val Gl y Gl u Thr Leu Tr p Cys As p Tr p Gl y Ar g Thr Ile Ar g 50 55 60 Ser Tyr Ar g Gl u Leu Al a As p Cys Thr Tr p Hi s Met Al a Gl u Lys Leu 65 70 75 80 Gl y Cys Phe Tr p Pr o As n Al a Gl u Val As p Ar g Phe Phe Leu Al a Val 85 90 95 Hi s Gl y Ar g Tyr Phe Ar g Ser Cys Pr o I l e Ser Gl y Ar g Al a Val Ar g 100 105 110 As p Pr o Pr o Gl y Ser Ile Leu Tyr Pr o Phe I l e Val Val Pr o Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Gl n Ser Lys Ar g Thr 130 135 140

    Gl u Gl y I l e Val 145

    Page 5

    A1472PCT

    2018203471 16 May 2018 <210> 5 <211> 414 <212> DNA <213> Homo <400> 5 at ggagaaaa acagcagaat at cat gacag gaaggcgt t t ggaact gaat gt t acaaaga t ggacaaat t

    sapi ens agt gt accct gt at t t t ct g gt t ct ct t gc ct t t t t t t at gat t ct t gt t 60 t agaagagag t cct gaggac t caat t cagt tgggagttac t agaaat aaa 120 ct caat at ga at gt t accaa aagat t at gc aagaccccat t caacaagca 180 act gcaacag aacct gggat ggat ggct ct gct ggaacga t gt t gcagca 240 caat gcagct ct gccct gat t act 11 cagg act t t gat cc at cagaaaaa 300 t ct gt gacca agat ggaaac t ggt 11 agac at ccagcaag caacagaaca 360 at acccagt g t aat gt t aac acccacgaga aagt gaagac t gca 414

    <210> 6 <211> 138 <212> PRT <213> Homo sapi ens <400> 6

    Met G u Lys Lys Cys Thr Leu Tyr Phe Leu Val Leu Leu Pro Phe Phe 1 5 10 15

    Met I l e Leu Val Thr Al a Gl u Leu Gl u Gl u Ser Pr o Gl u Asp Ser I l e 20 25 30

    G n Leu G y Val Thr Arg Asn Lys I l e Met Thr Al a G n Tyr G u Cys 35 40 45

    Tyr G n Lys I l e Met G n Asp Pro I l e G n G n Al a G u Gy Val Tyr 50 55 60

    Cys Asn Arg Thr Trp Asp Gly Trp Leu Cys Trp Asn Asp Val Ala Ala 65 70 75 80

    G y Thr G u Ser Met G n Leu Cys Pro Asp Tyr Phe G n Asp Phe Asp 85 90 95

    Pro Ser G u Lys Val Thr Lys I l e Cys Asp G n Asp G y Asn Trp Phe 100 105 110

    Page 6

    A1472PCT

    2018203471 16 May 2018

    Arg Hi s Pr o 115 Al a Ser As n Ar g Thr 120 Tr p Thr Asn Tyr Thr Gl n Cys Asn 125 Val As n Thr Hi s Gl u Lys Val Lys Thr Al a 130 135

    <210> 7 <211> 351 <212> DNA <213> Homo sapi ens <400> 7 at ggcccggg ccctgtgccg cct cccgcgg cgcggcct ct ggct gct cct ggcccat cac 60 ctcttcatga ccact gcct g ccaggaggct aact acggt g ccct cct ccg ggagct ct gc 120 ctcacccagt tccaggtaga catggaggcc gtcggggaga cgctgtggtg tgactggggc 180 aggaccat ca ggagct acag ggagct ggcc gact gcacct ggcacat ggc ggagaagct g 240 ggct gct tct ggcccaat gc agaggt ggac aggt t ct t cc t ggcagt gca t ggccgct ac 300 ttcaggagct gccccatctc aggcagggcc gtgcgggacc cgcccggcag c 351 <210> 8 <211> 117 <212> PRT <213> Homo sapi ens

    <400> 8 Met 1 Al a Arg Al a Leu Cys 5 Ar g Leu Pr o Ar g 10 Ar g Gl y Leu Tr p Leu 15 Leu Leu Al a Hi s Hi s Leu Phe 20 Met Thr Thr 25 Al a Cy s Gl n Gl u Al a 30 As n Ty r Gly Al a Leu Leu Ar g Gl u 35 Leu Cy s 40 Leu Thr Gl n Phe Gl n Val 45 As p Met Gl u Al a Val Gl y Gl u Thr 50 Leu 55 Tr p Cy s As p Tr p Gl y 60 Ar g Thr I l e Ar g Ser 65 Tyr Arg Gl u Leu Al a 70 As p Cy s Thr Tr p Hi s 75 Met Al a Gl u Lys Leu 80

    Page 7

    A1472PCT

    2018203471 16 May 2018

    G y Cys Phe Tr p Pr o 85 As n Al a Gl u Val As p Ar g 90 Phe Phe Leu Al a 95 Val Hi s Gy Arg Tyr Phe 100 Asp Pro Pro G y Ser 115 <210> 9 <211> 31 <212> PRT <213> Homo sapi ens <400> 9 Ar g Ser Cys Pro 105 I l e Ser Gl y Ar g Al a 110 Val Ar g Trp Val 1 Thr Hi s Ar g 5 Leu Al a Gl y Leu Leu Ser 10 Ar g Ser Gl y Gl y 15 Val Val Arg Cys Asn Phe 20 <210> 10 <211> 116 <212> PRT <213> Homo sapi ens <400> 10 Val Pr o Thr As p 25 Val Gl y Pr o Phe Al a 30 Phe G u Leu 1 Gl u Gl u Ser 5 Pr o Gl u Asp Ser I l e Gl n 10 Leu Gl y Val Thr 15 Ar g Asn Lys I l e Met Thr 20 Al a G n Tyr G u 25 Cys Tyr Gl n Lys I l e 30 Met Gl n As p Pr o I l e Gl n Gl n 35 Al a Gl u Gl y Val 40 Tyr Cys As n Ar g Thr 45 Tr p As p Gl y Tr p 50 Leu Cy s Tr p As n Asp Val Al a 55 Al a Gl y Thr Gl u Ser 60 Met Gl n Leu Cy s 65 Pro Asp Tyr Phe 70 Gl n As p Phe As p Pr o 75 Ser Gl u Lys Val Thr 80 Lys I l e Cys Asp G n As p Gl y As n Tr p Phe Ar g Page 8 Hi s Pr o Al a Ser As n

    2018203471 16 May 2018

    A1472PCT

    85 90 95

    Arg Thr Trp Thr Asn Tyr Thr Gl n Cys Asn Val Asn Thr His Glu Lys 100 105 110

    Val Lys Thr Al a 115 <210> 11 <211> 91 <212> PRT <213> Homo sapi ens <400> 11

    Cy s 1 Gl n Gl u Al a As n Ty r 5 Gl y Al a Leu Leu 10 Ar g Gl u Leu Cy s Leu 15 Thr Gl n Phe Gl n Val As p Met Gl u Al a Val Gl y Gl u Thr Leu Tr p Cy s As p 20 25 30 Tr p Gl y Ar g Thr Ile Ar g Ser Ty r Ar g Gl u Leu Al a As p Cy s Thr Tr p 35 40 45 Hi s Met Al a Gl u Lys Leu Gl y Cy s Phe Tr p Pr o As n Al a Gl u Val As p 50 55 60 Ar g Phe Phe Leu Al a Val Hi s Gl y Ar g Ty r Phe Ar g Ser Cy s Pr o Ile 65 70 75 80 Ser Gl y Ar g Al a Val Ar g As p Pr o Pr o Gl y Ser

    85 90 <210> 12 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 12

    Met Asp Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 Page 9 15

    A1472PCT

    2018203471 16 May 2018

    Leu Ar g Gl y Al a 20 Ar g Cys Gl n Ser Val 25 Leu Thr Gl n Pr o Pr o 30 Ser Val Ser Gl u Al a 35 Pr o Gl y Gl n Lys Val 40 Thr I l e Ser Cys Ser 45 Gl y Ser Ser Ser As n 50 I l e Gl y As n As n Tyr 55 Val Ser Tr p Tyr Gl n 60 Gl n Leu Pr o Gl y Thr 65 Al a Pr o Lys Leu Leu 70 Ile Tyr As p As n As n 75 Lys Ar g Pr o Ser Gl y 80 I l e Pr o As p Ar g Phe 85 Ser Gl y Ser Lys Ser 90 Gl y Thr Ser Al a Thr 95 Leu Gl y I l e Thr Gl y 100 Leu Gl n Thr Gl y As p 105 Gl u Al a As p Tyr Tyr 110 Cys Gl y Thr Tr p As p 115 Ser Ar g Leu Ser Al a 120 Val Val Phe Gl y Gl y 125 Gl y Thr Lys Leu Thr 130 Val Leu Gl y Gl n Pr o 135 Lys Al a As n Pr o Thr 140 Val Thr Leu Phe Pr o 145 Pr o Ser Ser Gl u Gl u 150 Leu Gl n Al a As n Lys 155 Al a Thr Leu Val Cys 160 Leu I l e Ser As p Phe 165 Tyr Pr o Gl y Al a Val 170 Thr Val Al a Tr p Lys 175 Al a As p Gl y Ser Pr o 180 Val Lys Al a Gl y Val 185 Gl u Thr Thr Lys Pr o 190 Ser Lys Gl n Ser As n 195 As n Lys Tyr Al a Al a 200 Ser Ser Tyr Leu Ser 205 Leu Thr Pr o Gl u Gl n 210 Tr p Lys Ser Hi s Ar g 215 Ser Tyr Ser Cys Gl n 220 Val Thr Hi s Gl u

    Page 10

    2018203471 16 May 2018

    A1472PCT Gl y Ser Thr Val Gl u Lys Thr Val Al a Pro Thr G u Cys Ser 225 230 235 <210> 13 <211> 238 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic

    pol ypept i de <400> 13

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a 20 Ar g Cy s Gl n Ser Val 25 Leu Thr Gl n Pr o Pr o 30 Ser Al a Ser Gl y Thr 35 Pr o Gl y Gl n Ar g Val 40 Thr I l e Ser Cy s Ser 45 Gl y Ser Ser Ser As n 50 I l e Gl y Ser As n Ty r 55 Val Ty r Tr p Ty r Gl n 60 Gl n Leu Pr o Gl y Al a 65 Al a Pr o Lys Leu Leu 70 Ile Phe Ar g Ser As n 75 Gl n Ar g Pr o Ser Gl y 80 Val Pr o As p Ar g Phe 85 Ser Gl y Ser Lys Ser 90 Gl y Thr Ser Al a Ser 95 Leu Al a I l e Ser Gl y 100 Leu Ar g Ser Gl u As p 105 Gl u Al a As p Ty r Ty r 110 Cy s Al a Al a Tr p As p 115 As p Ser Leu Ser Gl y 120 Tr p Val Phe Gl y Gl y 125 Gl y Thr Lys Leu Thr 130 Val Leu Gl y Gl n Pr o 135 Lys Al a As n Pr o Thr 140 Val Thr Leu Phe Pr o 145 Pr o Ser Ser Gl u Gl u 150 Leu Gl n Al a As n Lys 155 Al a Thr Leu Val Cy s 160

    Page 11

    2018203471 16 May 2018

    Leu I l e Ser A1472PCT As p Phe Ty r 165 Pr o Gl y Al a Val 170 Thr Val Al a Tr p Lys 175 Al a As p Gl y Ser Pr o Val Lys Al a Gl y Val Gl u Thr Thr Lys Pr o Ser Lys 180 185 190 Gl n Ser Asn As n Lys Tyr Al a Al a Ser Ser Ty r Leu Ser Leu Thr Pr o 195 200 205 Gl u Gl n Tr p Lys Ser Hi s Arg Ser Tyr Ser Cy s Gl n Val Thr Hi s Gl u 210 215 220 Gl y Ser Thr Val Gl u Lys Thr Val Al a Pr o Thr Gl u Cy s Ser 225 230 235 <210> 14 <211> 236 <212> PRT <213> Art i fi ci al Sequenc e

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 14

    Met Asp Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15

    Leu Arg G y Al a Arg Cys Asp I l e G n Met Thr G n Ser Pro Ser Ser 20 25 30

    Leu Ser Al a Ser Val 35

    Gl y Asp Ar g Val 40

    Thr I l e Thr Cys Arg Al a Ser 45

    Gl n Gl y 50

    I l e Ar g As n As p Leu 55

    Gl y Tr p Phe Gl n Gl n 60

    Lys

    Pr o Gl y

    Lys

    Al a Pr o Lys Ar g 65

    Leu I l e Tyr 70

    Al a Al a Ser

    Ser

    Leu Gl n Ser Gl y Val 80

    Pr o Ser Ar g Phe Ser 85

    Gl y Ser Gl y Ser

    Gl y Thr G u Phe Thr 90

    Leu Thr 95

    Page 12

    A1472PCT

    2018203471 16 May 2018

    I l e Ser Ser Leu 100 Gl n Pr o Gl u As p Leu Al a Thr 105 Tyr Tyr Cys 110 Leu Gl n Tyr As n I l e Tyr Pr o Tr p Thr Phe Gl y Gl n Gl y Thr Lys Val Gl u Ile 115 120 125 Lys Ar g Thr Val Al a Al a Pr o Ser Val Phe I l e Phe Pr o Pr o Ser As p 130 135 140 Gl u Gl n Leu Lys Ser Gl y Thr Al a Ser Val Val Cys Leu Leu As n As n 145 150 155 160 Phe Tyr Pr o Ar g Gl u Al a Lys Val Gl n Tr p Lys Val As p As n Al a Leu 165 170 175 Gl n Ser Gl y As n Ser Gl n Gl u Ser Val Thr Gl u Gl n As p Ser Lys As p 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a As p Tyr 195 200 205 Gl u Lys Hi s Lys Val Tyr Al a Cys Gl u Val Thr Hi s Gl n Gl y Leu Ser 210 215 220 Ser Pr o Val Thr Lys Ser Phe As n Ar g Gl y Gl u Cys 225 230 235

    <210> 15 <211> 236 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 15

    Met Asp Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15

    Leu Arg Gl y Al a Arg Cys Ser Ser Gl u Leu Thr Gl n Asp Pro Thr Val Page 13

    2018203471 16 May 2018

    20 A1472PCT 25 30 Ser Val Al a Leu Gl y Gl n Thr Val Lys I l e Thr Cys Gl n Gl y As p Ser 35 40 45 Leu Ar g Ser Phe Tyr Al a Ser Tr p Tyr Gl n Gl n Lys Pr o Gl y Gl n Al a 50 55 60 Pr o Val Leu Val Phe Tyr Gl y Lys As n As n Ar g Pr o Ser Gl y Ile Pr o 65 70 75 80 As p Ar g Phe Ser Gl y Ser Ser Ser Gl y As n Thr Al a Ser Leu Thr Ile 85 90 95 Thr Gl y Al a Gl n Al a Gl u As p Gl u Al a As p Tyr Tyr Cys As n Ser Ar g 100 105 110 As p Ser Ser Val Tyr Hi s Leu Val Leu Gl y Gl y Gl y Thr Lys Leu Thr 115 120 125 Val Leu Gl y Gl n Pr o Lys Al a As n Pr o Thr Val Thr Leu Phe Pr o Pr o 130 135 140 Ser Ser Gl u Gl u Leu Gl n Al a As n Lys Al a Thr Leu Val Cys Leu Ile 145 150 155 160 Ser As p Phe Tyr Pr o Gl y Al a Val Thr Val Al a Tr p Lys Al a As p Gl y 165 170 175 Ser Pr o Val Lys Al a Gl y Val Gl u Thr Thr Lys Pr o Ser Lys Gl n Ser 180 185 190 As n As n Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o Gl u Gl n 195 200 205 Tr p Lys Ser Hi s Ar g Ser Tyr Ser Cys Gl n Val Thr Hi s Gl u Gl y Ser 210 215 220 Thr Val Gl u Lys Thr Val Al a Pr o Thr Gl u Cys Ser 225 230 235

    Page 14

    A1472PCT

    2018203471 16 May 2018 <210> 16 <211> 241 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 16

    Met 1 Asp Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a Ar g Cy s As p Ile I l e Leu Al a Gl n Thr Pr o Leu Ser 20 25 30 Leu Ser Val Thr Pr o Gl y Gl n Pr o Al a Ser I l e Ser Cy s Lys Ser Ser 35 40 45 Gl n Ser Leu Leu Hi s Ser Al a Gl y Lys Thr Ty r Leu Ty r Tr p Ty r Leu 50 55 60 Gl n Lys Pr o Gl y Gl n Pr o Pr o Gl n Leu Leu I l e Ty r Gl u Val Ser As n 65 70 75 80 Ar g Phe Ser Gl y Val Pr o As p Ar g Phe Ser Gl y Ser Gl y Ser Gl y Thr 85 90 95 As p Phe Thr Leu Lys Ile Ser Ar g Val Gl u Al a Gl u As p Val Gl y Ile 100 105 110 Ty r Ty r Cy s Met Gl n Ser Phe Pr o Leu Pr o Leu Thr Phe Gl y Gl y Gl y 115 120 125 Thr Lys Val Gl u Ile Lys Ar g Thr Val Al a Al a Pr o Ser Val Phe Ile 130 135 140 Phe Pr o Pr o Ser As p Gl u Gl n Leu Lys Ser Gl y Thr Al a Ser Val Val 145 150 155 160 Cy s Leu Leu As n As n Phe Ty r Pr o Ar g Gl u Al a Lys Val Gl n Tr p Lys

    165 170 175

    Page 15

    A1472PCT

    2018203471 16 May 2018

    Val As p As n Al a 180 Leu Gl n Ser Gl y Gl n As p Ser 195 Lys As p Ser Thr Ty r 200 Ser Lys 210 Al a As p Ty r Gl u Lys 215 Hi s Hi s 225 Gl n Gl y Leu Ser Ser 230 Pr o Val

    As n 185 Ser Gl n Gl u Ser Val 190 Thr Gl u Ser Leu Ser Ser Thr 205 Leu Thr Leu Lys Val Ty r Al a 220 Cy s Gl u Val Thr Thr Lys Ser 235 Phe As n Ar g Gl y Gl u 240

    Cys <210> 17 <211> 238 <212> PRT <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Arti pol ypept i de <400> 17 ficial Sequence: Synthetic

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Ar g Gl y Al a 20 Ar g Cy s Gl n Ser Ser Al a Al a 35 Pr o Gl y Gl n Lys Val 40 Ser As n 50 I l e Gl y As n As n Ty r 55 Val Thr 65 Al a Pr o Lys Leu Leu 70 Ile Ty r I l e Pr o As p Ar g Phe Ser Gl y Ser

    Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Val 25 Leu Thr Gl n Pr o Pr o 30 Ser Val Thr I l e Ser Cy s Ser 45 Gl y Ser Ser Ser Tr p Ty r Gl n 60 Gl n Leu Pr o Gl y As p As n As n 75 Lys Ar g Pr o Ser Gl y 80 Lys Ser Gl y Thr Ser Thr Thr Leu

    Page 16

    2018203471 16 May 2018

    85 90 95 Gl y I l e Thr Gl y Leu Gl n Thr Gl y As p Gl u Al a As p Ty r Ty r Cy s Gl y 100 105 110 Thr Tr p As p Ser Ar g Leu Ser Al a Val Val Phe Gl y Gl y Gl y Thr Lys 115 120 125 Leu Thr Val Leu Gl y Gl n Pr o Lys Al a As n Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser Gl u Gl u Leu Gl n Al a As n Lys Al a Thr Leu Val Cy s 145 150 155 160 Leu I l e Ser As p Phe Ty r Pr o Gl y Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 As p Gl y Ser Pr o Val Lys Al a Gl y Val Gl u Thr Thr Lys Pr o Ser Lys 180 185 190 Gl n Ser As n As n Lys Ty r Al a Al a Ser Ser Ty r Leu Ser Leu Thr Pr o 195 200 205 Gl u Gl n Tr p Lys Ser Hi s Ar g Ser Ty r Ser Cy s Gl n Val Thr Hi s Gl u 210 215 220 Gl y Ser Thr Val Gl u Lys Thr Val Al a Pr o Thr Gl u Cy s Ser 225 230 235

    <210> 18 <211> 241 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 18

    Met Asp Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15

    Page 17

    A1472PCT

    2018203471 16 May 2018

    Leu Ar g Gl y Al a 20 Ar g Cys As p Ile Val 25 Met Thr Gl n Ser Pr o 30 Leu Ser Leu Pr o Val 35 Thr Pr o Gl y Gl u Pr o 40 Al a Ser I l e Ser Cys 45 Ar g Ser Ser Gl n Ser 50 Leu Leu Hi s Ser Phe 55 Gl y Tyr As n Tyr Leu 60 As p Tr p Tyr Leu Gl n 65 Lys Pr o Gl y Gl n Ser 70 Pr o Gl n Leu Leu I l e 75 Tyr Leu Gl y Ser As n 80 Ar g Al a Ser Gl y Val 85 Pr o As p Ar g Phe Ser 90 Gl y Ser Gl y Ser Gl y 95 Thr As p Phe Thr Leu 100 Lys Ile Ser Ar g Val 105 Gl u Al a Gl u As p Val 110 Gl y Val Tyr Tyr Cys 115 Met Gl n Al a Leu Gl n 120 Thr Pr o Phe Thr Phe 125 Gl y Pr o Gl y Thr Lys 130 Val As p Ile Lys Ar g 135 Thr Val Al a Al a Pr o 140 Ser Val Phe Ile Phe 145 Pr o Pr o Ser As p Gl u 150 Gl n Leu Lys Ser Gl y 155 Thr Al a Ser Val Val 160 Cys Leu Leu As n As n 165 Phe Tyr Pr o Ar g Gl u 170 Al a Lys Val Gl n Tr p 175 Lys Val As p As n Al a 180 Leu Gl n Ser Gl y As n 185 Ser Gl n Gl u Ser Val 190 Thr Gl u Gl n As p Ser 195 Lys As p Ser Thr Tyr 200 Ser Leu Ser Ser Thr 205 Leu Thr Leu Ser Lys 210 Al a As p Tyr Gl u Lys 215 Hi s Lys Val Tyr Al a 220 Cys Gl u Val Thr Hi s 225 Gl n Gl y Leu Ser Ser 230 Pr o Val Thr Lys Ser 235 Phe As n Ar g Gl y Gl u 240

    Page 18

    A1472PCT

    2018203471 16 May 2018

    Cy s <210> 19 <211> 241 <212> PRT <213> Ar t i f i ci al Sequence

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 19

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a 20 Ar g Cy s As p Ile I l e 25 Leu Thr Gl n Thr Pr o 30 Leu Ser Leu Ser Val 35 Thr Pr o Gl y Gl n Pr o 40 Al a Ser I l e Ser Cy s 45 Lys Ser Ser Gl n Ser 50 Leu Leu Hi s Ser As p 55 Gl y Lys Thr Ty r Leu 60 Ty r Tr p Ty r Leu Gl n 65 Lys Pr o Gl y Gl n Pr o 70 Pr o Gl n Leu Leu I l e 75 Ty r Gl u Val Ser As n 80 Ar g Phe Ser Gl y Gl u 85 Pr o As p Ar g Phe Ser 90 Gl y Ser Gl y Ser Gl y 95 Thr As p Phe Thr Leu 100 Lys Ile Ser Ar g Val 105 Gl u Al a Gl u As p Val 110 Gl y Thr Ty r Ty r Cy s 115 Met Gl n Ser Phe Pr o 120 Leu Pr o Leu Thr Phe 125 Gl y Gl y Gl y Thr Lys 130 Val Gl u Ile Lys Ar g 135 Thr Val Al a Al a Pr o 140 Ser Val Phe Ile Phe Pr o Pr o Ser As p Gl u Gl n Leu Lys Ser Gl y Page 19 Thr Al a Ser Val Val

    A1472PCT

    2018203471 16 May 2018

    145 150 155 160 Cys Leu Leu As n As n Phe Ty r 165 Pr o Ar g Gl u Al a Lys Val 170 Gl n Tr p Lys 175 Val Asp Asn Al a Leu Gl n Ser 180 Gl y Asn Ser Gl n Gl u Ser 185 Val Thr Gl u 190 Gl n As p Ser Lys Asp Ser Thr 195 Tyr Ser Leu Ser Ser Thr 200 205 Leu Thr Leu Ser Lys 210 Al a Asp Tyr Gl u Lys 215 Hi s Lys Val Tyr Al a Cys 220 Gl u Val Thr Hi s Gl n Gl y Leu Ser Ser Pr o 225 230 Cy s <210> 20 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce Val Thr Lys Ser Phe Asn 235 Ar g Gl y Gl u 240 <223> / not e= Descr i pt i on of pol ypept i de <400> 20 Artificial Sequence: Synthetic Met Asp 1 Met Ar g Val Pr o Al a 5 Gl n Leu Leu Gl y Leu Leu 10 Leu Leu Tr p 15 Leu Ar g Gl y Al a Ar g Cy s Gl n 20 Ser Val Leu Thr Gl n Pr o 25 Pr o Ser Val 30 Ser Al a Al a Pr o Gl y Gl n Lys 35 Val Thr I l e Ser Cys Ser 40 45 Gl y Ser Ser Ser Asn 50 I l e Gl y As n As n Ty r 55 Val Ser Trp Tyr Gl n Gl n 60 Phe Pr o Gl y

    Page 20

    2018203471 16 May 2018

    Thr 65 Al a Pr o Lys Leu Leu 70 Ile Tyr As p As n As n 75 Lys Ar g Pr o Ser Gl y 80 I l e Pr o As p Ar g Phe Ser Gl y Ser Lys Ser Gl y Thr Ser Al a Thr Leu 85 90 95 Gl y I l e Thr Gl y Leu Gl n Thr Gl y As p Gl u Al a As p Tyr Tyr Cys Gl y 100 105 110 Thr Tr p As p Ser Ar g Leu Ser Al a Val Val Phe Gl y Gl y Gl y Thr Lys 115 120 125 Leu Thr Val Leu Gl y Gl n Pr o Lys Al a As n Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser Gl u Gl u Leu Gl n Al a As n Lys Al a Thr Leu Val Cys 145 150 155 160 Leu I l e Ser As p Phe Tyr Pr o Gl y Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 As p Gl y Ser Pr o Val Lys Al a Gl y Val Gl u Thr Thr Lys Pr o Ser Lys 180 185 190 Gl n Ser As n As n Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 Gl u Gl n Tr p Lys Ser Hi s Ar g Ser Tyr Ser Cys Gl n Val Thr Hi s Gl u 210 215 220 Gl y Ser Thr Val Gl u Lys Thr Val Al a Pr o Thr Gl u Cys Ser 225 230 235

    <210> 21 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    Page 21

    A1472PCT <400> 21

    2018203471 16 May 2018

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a 20 Ar g Cys Gl n Ser Val 25 Leu Thr Gl n Ser Pr o 30 Ser Al a Ser Gl y Thr 35 Pr o Gl y Gl n Ar g Val 40 Thr I l e Ser Cys Ser 45 Gl y Ser Ser Ser As n 50 I l e Gl y Ser As n Tyr 55 Val Tyr Tr p Tyr Gl n 60 Gl n Leu Pr o Gl y Al a 65 Al a Pr o Lys Leu Leu 70 Ile Leu Ar g As n As n 75 Gl n Ar g Pr o Ser Gl y 80 Val Pr o As p Ar g Phe 85 Ser Gl y Ser Lys Ser 90 Gl y Thr Ser Al a Ser 95 Leu Thr I l e Ser Gl y 100 Leu Ar g Ser Gl u As p 105 Gl u Al a As p Tyr Tyr 110 Cys Al a Al a Tr p As p 115 As p Ser Leu Ser Gl y 120 Tr p Val Phe Gl y Gl y 125 Gl y Thr Lys Leu Thr 130 Val Leu Gl y Gl n Pr o 135 Lys Al a As n Pr o Thr 140 Val Thr Leu Phe Pr o 145 Pr o Ser Ser Gl u Gl u 150 Leu Gl n Al a As n Lys 155 Al a Thr Leu Val Cys 160 Leu I l e Ser As p Phe 165 Tyr Pr o Gl y Al a Val 170 Thr Val Al a Tr p Lys 175 Al a As p Gl y Ser Pr o 180 Val Lys Al a Gl y Val 185 Gl u Thr Thr Lys Pr o 190 Ser Lys Gl n Ser As n 195 As n Lys Tyr Al a Al a 200 Ser Ser Tyr Leu Ser 205 Leu Thr Pr o Gl u Gl n Tr p Lys Ser Hi s Ar g Ser Tyr Ser Cys Gl n Val Thr Hi s Gl u

    Page 22

    2018203471 16 May 2018

    210 A1472PCT 215 220 Gl y Ser Thr Val Gl u Lys Thr Val Al a Pro Thr Gl u Cys Ser 225 230 235

    <210> 22 <211> 238 <212> PRT <213> Ar t i f i ci al Sequence

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 22

    Met 1 Asp Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a Ar g Cy s Gl n Ser Val Leu Thr Gl n Pr o Pr o Ser Al a 20 25 30 Ser Gl y Thr Pr o Gl y Gl n Ar g Val Thr I l e Ser Cy s Ser Gl y Ser Ser 35 40 45 Ser As n I l e Gl y Ser As n Thr Val As n Tr p Ty r Gl n Gl n Leu Pr o Gl y 50 55 60 Thr Al a Pr o Lys Leu Leu Ile Ty r Thr As n As n Gl n Ar g Pr o Ser Gl y 65 70 75 80 Val Pr o As p Ar g Phe Ser Gl y Ser Lys Ser Gl y Thr Ser Al a Ser Leu 85 90 95 Al a I l e Ser Gl y Leu Gl n Ser Gl u As p Gl u Al a As p Phe Ty r Cy s Al a 100 105 110 Al a Ar g As p Gl u Ser Leu As n Gl y Val Val Phe Gl y Gl y Gl y Thr Lys 115 120 125 Leu Thr Val Leu Gl y Gl n Pr o Lys Al a As n Pr o Thr Val Thr Leu Phe 130 135 140

    Page 23

    A1472PCT

    2018203471 16 May 2018

    Pr o 145 Pr o Ser Ser Gl u Gl u 150 Leu Gl n Al a As n Lys 155 Al a Thr Leu Val Cy s 160 Leu I l e Ser As p Phe Ty r Pr o Gl y Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 As p Gl y Ser Pr o Val Lys Al a Gl y Val Gl u Thr Thr Lys Pr o Ser Lys 180 185 190 Gl n Ser As n As n Lys Ty r Al a Al a Ser Ser Ty r Leu Ser Leu Thr Pr o 195 200 205 Gl u Gl n Tr p Lys Ser Hi s Ar g Ser Ty r Ser Cy s Gl n Val Thr Hi s Gl u 210 215 220 Gl y Ser Thr Val Gl u Lys Thr Val Al a Pr o Thr Gl u Cy s Ser 225 230 235 <210> 23 <211> 238 <212> PRT <213> Art i f i ci al Sequenc e

    <220>

    <221> sour ce

    <223> / n ot e Des c r i pt i on of Ar t i f i ci al Sequence: Sy nt het ic po l ypept i de <400> 23 Met As p Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15 Leu Ar g Gl y Al a Ar g Cy s Gl n Ser Val Leu Thr Gl n Pr o Pr o Ser Al a 20 25 30 Ser Gl y Thr Pr o Gl y Gl n Ar g Val Thr I l e Ser Cy s Ser Gl y Ser Ser 35 40 45 Ser As n I l e Gl y Ser As n Ty r Val Ty r Tr p Ty r Gl n Gl n Leu Pr o Gl y 50 55 60 Al a Al a Pr o Lys Leu Leu Ile Phe Ar g As n As n Gl n Ar g Pr o Ser Gl y 65 70 75 80

    Page 24

    A1472PCT

    2018203471 16 May 2018

    Val Pr o As p Ar g Phe 85 Ser Gl y Ser Lys Ser 90 Gl y Thr Ser Al a Ser 95 Leu Al a I l e Ser Gl y Leu Ar g Ser Gl u As p Gl u Al a As p Ty r Ty r Cy s Al a 100 105 110 Al a Tr p As p As p Ser Leu Ser Gl y Tr p Val Phe Gl y Gl y Gl y Thr Lys 115 120 125 Leu Thr Val Leu Gl y Gl n Pr o Lys Al a As n Pr o Thr Val Thr Leu Phe 130 135 140 Pr o Pr o Ser Ser Gl u Gl u Leu Gl n Al a As n Lys Al a Thr Leu Val Cy s 145 150 155 160 Leu I l e Ser As p Phe Ty r Pr o Gl y Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 As p Gl y Ser Pr o Val Lys Al a Gl y Val Gl u Thr Thr Lys Pr o Ser Lys 180 185 190 Gl n Ser As n As n Lys Ty r Al a Al a Ser Ser Ty r Leu Ser Leu Thr Pr o 195 200 205 Gl u Gl n Tr p Lys Ser Hi s Ar g Ser Ty r Ser Cy s Gl n Val Thr Hi s Gl u 210 215 220 Gl y Ser Thr Val Gl u Lys Thr Val Al a Pr o Thr Gl u Cy s Ser 225 230 235

    <210> 24 <211> 241 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 24

    Met Asp Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15 Page 25

    A1472PCT

    2018203471 16 May 2018

    Leu Ar g Gl y Al a 20 Ar g Cys As p Ile Thr 25 Leu Thr Gl n Thr Pr o 30 Leu Ser Leu Ser Val 35 Ser Pr o Gl y Gl n Pr o 40 Al a Ser I l e Ser Cys 45 Lys Ser Ser Gl n Ser 50 Leu Leu hi s Ser As p 55 Gl y Ar g As n Tyr Leu 60 Tyr Tr p Tyr Leu Gl n 65 Lys Pr o Gl y Gl n Pr o 70 Pr o Gl n Leu Leu I l e 75 Tyr Gl u Val Ser As n 80 Arg Phe Ser Gl y Leu 85 Pr o As p Ar g Phe Ser 90 Gy Ser Gl y Ser Gl y 95 Thr Asp Phe Thr Leu 100 Lys Ile Ser Ar g Val 105 Gl u Al a Gl u As p Val 110 Gl y Ile Tyr Tyr Cys 115 Met Gl n Ser Phe Pr o 120 Leu Pr o Leu Thr Phe 125 Gl y Gl y Gl y Thr Lys 130 Val Gl u I l e Lys Ar g 135 Thr Val Al a Al a Pr o 140 Ser Val Phe Ile Phe 145 Pr o Pr o Ser As p Gl u 150 Gl n Leu Lys Ser Gl y 155 Thr Al a Ser Val Val 160 Cys Leu Leu As n As n 165 Phe Tyr Pr o Ar g Gl u 170 Al a Lys Val Gl n Tr p 175 Lys Val As p As n Al a 180 Leu Gl n Ser Gl y As n 185 Ser Gl n Gl u Ser Val 190 Thr Gl u Gl n As p Ser 195 Lys As p Ser Thr Tyr 200 Ser Leu Ser Ser Thr 205 Leu Thr Leu Ser Lys 210 Al a As p Tyr Gl u Lys 215 Hi s Lys Val Tyr Al a 220 Cys Gl u Val Thr

    Page 26

    2018203471 16 May 2018

    Hi s Gl 225 Cy s n Gl y A1472PCT Leu Ser Ser Pr o Val 230 Thr Ly s Ser Phe As n Ar g Gl y Gl u 235 240 <210> 25 <211> 238 <212> PRT <213> Ar t i f i ci al Sequenc e

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 25

    Met 1 Asp Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a Ar g Cy s Gl n Ser Val Leu Thr Gl n Pr o Pr o Ser Val 20 25 30 Ser Al a Al a Pr o Gl y Gl n Lys Val Thr I l e Ser Cy s Ser Gl y Ser Ser 35 40 45 Ser As n I l e Gl y As n As n Ty r Val Ser Tr p Ty r Gl n Gl n Leu Pr o Gl y 50 55 60 Thr Al a Pr o Lys Leu Leu Ile Ty r As p As n As n Lys Ar g Pr o Ser Gl y 65 70 75 80 I l e Pr o As p Ar g Phe Ser Gl y Ser Lys Ser Gl y Thr Ser Al a Thr Leu 85 90 95 Gl y I l e Thr Gl y Leu Gl n Thr Gl y As p Gl u Al a As p Ty r Ty r Cy s Gl y 100 105 110 Thr Tr p As p Ser Ar g Leu Ser Al a Val Val Phe Gl y Gl y Gl y Thr Lys 115 120 125 Leu Thr Val Leu Gl y Gl n Pr o Lys Al a As n Pr o Thr Val Thr Leu Phe 130 135 140

    Page 27

    A1472PCT

    2018203471 16 May 2018

    Pr o 145 Pr o Ser Ser Gl u Gl u 150 Leu Gl n Al a As n Lys 155 Al a Thr Leu Val Cys 160 Leu I l e Ser As p Phe Tyr Pr o Gl y Al a Val Thr Val Al a Tr p Lys Al a 165 170 175 As p Gl y Ser Pr o Val Lys Al a Gl y Val Gl u Thr Thr Lys Pr o Ser Lys 180 185 190 Gl n Ser As n As n Lys Tyr Al a Al a Ser Ser Tyr Leu Ser Leu Thr Pr o 195 200 205 Gl u Gl n Tr p Lys Ser Hi s Ar g Ser Tyr Ser Cys Gl n Val Thr Hi s Gl u 210 215 220 Gl y Ser Thr Val Gl u Lys Thr Val Al a Pr o Thr Gl u Cys Ser 225 230 235

    <210> 26 <211> 236 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 26

    Met As p Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15 Leu Ar g Gl y Al a Ar g Cys As p Il e Gl n Met Thr Gl n Ser Pr o Ser Ser 20 25 30 Leu Ser Al a Ser Val Gl y As p Ar ^g Val Thr I l e Thr Cys Ar g Al a Ser 35 40 45 Gl n Gl y I l e Ar g Lys As p Leu Gl ^y Tr p Tyr Gl n Gl n Lys Pr o Gl y Lys 50 55 60 Al a Pr o Lys Ar g Leu Ile Tyr Gl ^y Al a Ser Ser Leu Gl n Ser Gl y Val 65 70 75 80

    Page 28

    A1472PCT

    2018203471 16 May 2018

    Pr o Ser Ar g Phe Ser 85 Gl y Ser Gl y Ser Gl y 90 Thr Gl u Phe Thr Leu 95 Thr I l e Ser Ser Leu Gl n Pr o Gl u As p Phe Al a Thr Ty r Ty r Cy s Leu Gl n 100 105 110 Ty r As n Ser Phe Pr o Tr p Thr Phe Gl y Gl n Gl y Thr Lys Val Gl u Ile 115 120 125 Lys Ar g Thr Val Al a Al a Pr o Ser Val Phe I l e Phe Pr o Pr o Ser As p 130 135 140 Gl u Gl n Leu Lys Ser Gl y Thr Al a Ser Val Val Cy s Leu Leu As n As n 145 150 155 160 Phe Ty r Pr o Ar g Gl u Al a Lys Val Gl n Tr p Lys Val As p As n Al a Leu 165 170 175 Gl n Ser Gl y As n Ser Gl n Gl u Ser Val Thr Gl u Gl n As p Ser Lys As p 180 185 190 Ser Thr Ty r Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a As p Ty r 195 200 205 Gl u Lys Hi s Lys Val Ty r Al a Cy s Gl u Val Thr Hi s Gl n Gl y Leu Ser 210 215 220 Ser Pr o Val Thr Lys Ser Phe As n Ar g Gl y Gl u Cy s 225 230 235

    <210> 27 <211> 235 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 27

    Met Gl u Thr Pr o Al a Gl n Leu Leu Phe Leu Leu Leu Leu Tr p Leu Pr o Page 29

    2018203471 16 May 2018

    1 5 A1472PCT 10 15 Asp Thr Thr Gl y 20 Gl u Ile Val Leu Thr 25 Gl n Ser Pr o Gl y Thr 30 Leu Ser Leu Ser Pr o 35 Gl y Gl u Ar g Al a Thr 40 Leu Ser Cys Ar g Al a 45 Ser Gl n Ser Val Ser 50 Ser Gl y Tyr Leu Thr 55 Tr p Tyr Gl n Gl n Lys 60 Pr o Gl y Gl n Al a Pr o 65 Ar g Leu Leu I l e Tyr 70 Gl y Al a Ser Ser Ar g 75 Al a Thr Gl y Ile Pr o 80 As p Ar g Phe Ser Gl y 85 Ser Gl y Ser Gl y Thr 90 As p Phe Thr Leu Thr 95 Ile Ser Ar g Leu Gl u 100 Pr o Gl u As p Phe Al a 105 Val Tyr Tyr Cys Gl n 110 Gl n Tyr Gly As n Ser 115 Leu Cys Ar g Phe Gl y 120 Gl n Gl y Thr Lys Leu 125 Gl u Ile Lys Ar g Thr 130 Val Al a Al a Pr o Ser 135 Val Phe I l e Phe Pr o 140 Pr o Ser As p Gl u Gl n 145 Leu Lys Ser Gl y Thr 150 Al a Ser Val Val Cys 155 Leu Leu As n As n Phe 160 Tyr Pr o Ar g Gl u Al a 165 Lys Val Gl n Tr p Lys 170 Val As p As n Al a Leu 175 Gl n Ser Gl y As n Ser 180 Gl n Gl u Ser Val Thr 185 Gl u Gl n As p Ser Lys 190 As p Ser Thr Tyr Ser 195 Leu Ser Ser Thr Leu 200 Thr Leu Ser Lys Al a 205 As p Tyr Gl u Lys Hi s 210 Lys Val Tyr Al a Cys 215 Gl u Val Thr Hi s Gl n 220 Gl y Leu Ser Ser

    Page 30

    2018203471 16 May 2018

    A1472PCT Pr o Val Thr Lys Ser Phe Asn Arg Gl y Gl u Cys 225 230 235

    <210> 28 <211> 235 <212> PRT <213> Ar t i f i ci al Sequence

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 28

    Met 1 Gl u Thr Pr o Al a 5 Gl n Leu Leu Phe Leu 10 Leu Leu Leu Tr p Leu 15 Pr o As p Thr Thr Gl y Gl u Ile Val Leu Thr Gl n Ser Pr o Gl y Thr Leu Ser 20 25 30 Leu Ser Pr o Gl y Gl u Ar g Al a Thr Leu Ser Cys Ar g Al a Ser Gl n Ser 35 40 45 Val Ser Ser Gl y Tyr Leu Thr Tr p Tyr Gl n Gl n Lys Pr o Gl y Gl n Al a 50 55 60 Pr o Ar g Leu Leu Ile Tyr Gl y Al a Ser Ser Ar g Al a Thr Gl y Ile Pr o 65 70 75 80 As p Ar g Phe Ser Gl y Ser Gl y Ser Gl y Thr As p Phe Thr Leu Thr Ile 85 90 95 Ser Ar g Leu Gl u Pr o Gl u As p Phe Al a Val Tyr Tyr Cys Gl n Gl n Tyr 100 105 110 Gl y As n Ser Leu Ser Ar g Phe Gl y Gl n Gl y Thr Lys Leu Gl u Ile Lys 115 120 125 Ar g Thr Val Al a Al a Pr o Ser Val Phe I l e Phe Pr o Pr o Ser As p Gl u 130 135 140 Gl n Leu Lys Ser Gl y Thr Al a Ser Val Val Cys Leu Leu As n As n Phe 145 150 155 160 Page 31

    A1472PCT

    2018203471 16 May 2018

    Tyr Pr o Ar g Gl u Al a 165 Lys Val Gl n Ser Gl y As n Ser 180 Gl n Gl u Ser Val Thr Tyr Ser 195 Leu Ser Ser Thr Leu 200 Lys Hi s 210 Lys Val Tyr Al a Cys 215 Gl u Pr o 225 Val Thr Lys Ser Phe 230 As n Ar g

    Tr p Lys 170 Val As p As n Al a Leu 175 Gl n Thr 185 Gl u Gl n As p Ser Lys 190 As p Ser Thr Leu Ser Lys Al a 205 As p Tyr Gl u Val Thr Hi s Gl n 220 Gl y Leu Ser Ser Gl y Gl u Cys

    235 <210> 29 <211> 478 <212> PRT <213> Artificial Sequence <220>

    <221> sour ce <223> / note= Descri ption of Arti pol ypept i de <400> 29 ficial Sequence: Synthetic

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Ar g Gl y Al a 20 Ar g Cys Gl n Val Val Val Gl n 35 Pr o Gl y Ar g Ser Leu 40 Phe Thr 50 Phe Ser Ser Phe Gl y 55 Met Lys 65 Gl y Leu Gl u Tr p Val 70 Al a Val Tyr Ser Val As p Ser Val Lys Gl y

    Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Gl n 25 Leu Val Gl u Ser Gl y 30 Gl y Gl y Ar g Leu Ser Cys Al a 45 Al a Ser Gl y Hi s Tr p Val Ar g 60 Gl n Al a Pr o Gl y I l e Ser Phe 75 As p Gl y Ser Ile Lys 80 Ar g Phe Thr Ile Ser Ar g As p As n

    Page 32

    2018203471 16 May 2018

    85 A1472PCT 90 95 Ser Lys As n Thr 100 Leu Phe Leu Gl n Met 105 As n Ser Leu Ar g Al a 110 Gl u As p Thr Al a Val 115 Ty r Ty r Cy s Al a Ar g 120 As p Ar g Leu As n Ty r 125 Ty r As p Ser Ser Gl y 130 Ty r Ty r Hi s Ty r Lys 135 Ty r Ty r Gl y Met Al a 140 Val Tr p Gl y Gl n Gl y 145 Thr Thr Val Thr Val 150 Ser Ser Al a Ser Thr 155 Lys Gl y Pr o Ser Val 160 Phe Pr o Leu Al a Pr o 165 Cy s Ser Ar g Ser Thr 170 Ser Gl u Ser Thr Al a 175 Al a Leu Gl y Cy s Leu 180 Val Lys As p Ty r Phe 185 Pr o Gl u Pr o Val Thr 190 Val Ser Tr p As n Ser 195 Gl y Al a Leu Thr Ser 200 Gl y Val Hi s Thr Phe 205 Pr o Al a Val Leu Gl n 210 Ser Ser Gl y Leu Ty r 215 Ser Leu Ser Ser Val 220 Val Thr Val Pr o Ser 225 Ser As n Phe Gl y Thr 230 Gl n Thr Ty r Thr Cy s 235 As n Val As p Hi s Lys 240 Pr o Ser As n Thr Lys 245 Val As p Lys Thr Val 250 Gl u Ar g Lys Cy s Cy s 255 Val Gl u Cy s Pr o Pr o 260 Cy s Pr o Al a Pr o Pr o 265 Val Al a Gl y Pr o Ser 270 Val Phe Leu Phe Pr o 275 Pr o Lys Pr o Lys As p 280 Thr Leu Met Ile Ser 285 Ar g Thr Pr o Gl u Val 290 Thr Cy s Val Val Val 295 As p Val Ser Hi s Gl u 300 As p Pr o Gl u Val

    Page 33

    A1472PCT

    2018203471 16 May 2018

    Gl n 305 Phe As n Tr p Ty r Val 310 As p Gl y Val Gl u Val 315 Hi s As n Al a Lys Thr 320 Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser Val 325 330 335 Leu Thr Val Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Ty r Lys Cy s 340 345 350 Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o I l e Gl u Lys Thr Ile Ser 355 360 365 Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Ty r Thr Leu Pr o Pr o 370 375 380 Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cy s Leu Val 385 390 395 400 Lys Gl y Phe Ty r Pr o Ser As p Ile Al a Val Gl u Tr p Gl u Ser As n Gl y 405 410 415 Gl n Pr o Gl u As n As n Ty r Lys Thr Thr Pr o Pr o Met Leu As p Ser As p 420 425 430 Gl y Ser Phe Phe Leu Ty r Ser Lys Leu Thr Val As p Lys Ser Ar g Tr p 435 440 445 Gl n Gl n Gl y As n Val Phe Ser Cy s Ser Val Met Hi s Gl u Al a Leu Hi s 450 455 460 As n Hi s Ty r Thr Gl n Lys Ser Leu Ser Leu Ser Pr o Gl y Lys

    465 470 475 <210> 30 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    Page 34

    A1472PCT

    2018203471 16 May 2018

    <400> 30 Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Met 1 Asp Met Ar g Leu Ar g Gl y Al a Ar g Cy s Gl u Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y 20 25 30 Leu Val Lys Pr o Gl y Gl y Ser Leu Ar g Leu Ser Cy s Al a Al a Ser Gl y 35 40 45 Phe Thr Phe Ser As n Al a Tr p Met Ser Tr p Val Ar g Gl n Al a Pr o Gl y 50 55 60 Lys Gl y Leu Gl u Tr p Val Gl y Ar g I l e Lys Ser Thr Thr As p Gl y Gl y 65 70 75 80 Thr Thr As p Ty r Al a Al a Pr o Val Lys Gl y Ar g Phe Thr Ile Ser Ar g 85 90 95 As p As p Ser Lys As n Thr Leu Ty r Leu Gl n Met As n Ser Leu Lys Thr 100 105 110 Gl u As p Thr Al a Val Ty r Ty r Cy s Thr Thr As p Ar g Thr Gl y Ty r Ser 115 120 125 I l e Ser Tr p Ser Ser Ty r Ty r Ty r Ty r Ty r Gl y Met As p Val Tr p Gl y 130 135 140 Gl n Gl y Thr Thr Val Thr Val Ser Ser Al a Ser Thr Lys Gl y Pr o Ser 145 150 155 160 Val Phe Pr o Leu Al a Pr o Cy s Ser Ar g Ser Thr Ser Gl u Ser Thr Al a 165 170 175 Al a Leu Gl y Cy s Leu Val Lys As p Ty r Phe Pr o Gl u Pr o Val Thr Val 180 185 190 Ser Tr p As n Ser Gl y Al a Leu Thr Ser Gl y Val Hi s Thr Phe Pr o Al a 195 200 205

    Page 35

    2018203471 16 May 2018

    Val Leu 210 Gl n Ser Ser A1472PCT Gl y Leu 215 Ty r Ser Leu Ser Ser 220 Val Val Thr Val Pr o Ser Ser As n Phe Gl y Thr Gl n Thr Ty r Thr Cy s As n Val As p Hi s 225 230 235 240 Lys Pr o Ser As n Thr Lys Val As p Lys Thr Val Gl u Ar g Lys Cy s Cy s 245 250 255 Val Gl u Cy s Pr o Pr o Cy s Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val 260 265 270 Phe Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr 275 280 285 Pr o Gl u Val Thr Cy s Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u 290 295 300 Val Gl n Phe As n Tr p Ty r Val As p Gl y Val Gl u Val Hi s As n Al a Lys 305 310 315 320 Thr Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser 325 330 335 Val Leu Thr Val Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Ty r Lys 340 345 350 Cy s Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o Ile Gl u Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Ty r Thr Leu Pr o 370 375 380 Pr o Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cy s Leu 385 390 395 400 Val Lys Gl y Phe Ty r Pr o Ser As p I l e Al a Val Gl u Tr p Gl u Ser As n 405 410 415 Gl y Gl n Pr o Gl u As n As n Ty r Lys Thr Thr Pr o Pr o Met Leu As p Ser 420 425 430

    Page 36

    A1472PCT

    2018203471 16 May 2018

    As p Gl y Ser 435 Phe Phe Leu Tyr Ser 440 Tr p Gl n 450 Gl n Gl y As n Val Phe 455 Ser Hi s As n Hi s Tyr Thr Gl n Lys Ser

    465 470

    Lys Leu Thr Val As p 445 Lys Ser Ar g Cys Ser Val Met 460 Hi s Gl u Al a Leu Leu Ser Leu 475 Ser Pr o Gl y Lys

    <210> 31 <211> 478 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Ar t i pol ypept i de <400> 31 ficial Sequence: Synthetic

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Ar g Gl y Al a 20 Ar g Cys Gl u Val Leu Val Gl n 35 Pr o Gl y Gl u Ser Leu 40 Phe Thr 50 Phe Ser Ser Tyr Al a 55 Met Lys 65 Gl y Leu Gl u Tr p Val 70 Ser Al a Tyr Tyr Al a As p Ser 85 Val Lys Gl y Ser Lys As n Thr 100 Leu Tyr Leu Gl n Thr Al a Val Tyr Tyr Cys Al a Lys

    Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Gl n 25 Leu Leu Gl u Ser Gl y 30 Gl y Gl y Ar g Leu Ser Cys Al a 45 Al a Ser Gl y Ser Tr p Val Ar g 60 Gl n Al a Pr o Gl y I l e Ser Gl y 75 Ser Gl y Gl y Ar g Thr 80 Ar g Phe 90 Thr Ile Ser Ar g As p 95 As n Met 105 As n Ser Leu Ar g Al a 110 Gl u As p As p Gl n Ar g Gl u Val Gl y Pr o Tyr

    Page 37

    2018203471 16 May 2018

    A14 72PC T 115 120 125 Ser Ser Gl y Tr p Tyr As p Tyr Tyr Tyr Gl y Met As p Val Tr p Gl y Gl n 130 135 140 Gl y Thr Thr Val Thr Val Ser Ser Al a Ser Thr Lys Gl y Pr o Ser Val 145 150 155 160 Phe Pr o Leu Al a Pr o Cys Ser Ar g Ser Thr Ser Gl u Ser Thr Al a Al a 165 170 175 Leu Gl y Cys Leu Val Lys As p Tyr Phe Pr o Gl u Pr o Val Thr Val Ser 180 185 190 Tr p As n Ser Gl y Al a Leu Thr Ser Gl y Val Hi s Thr Phe Pr o Al a Val 195 200 205 Leu Gl n Ser Ser Gl y Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pr o 210 215 220 Ser Ser As n Phe Gl y Thr Gl n Thr Tyr Thr Cys As n Val As p Hi s Lys 225 230 235 240 Pr o Ser As n Thr Lys Val As p Lys Thr Val Gl u Ar g Lys Cys Cys Val 245 250 255 Gl u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val Phe 260 265 270 Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr Pr o 275 280 285 Gl u Val Thr Cys Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u Val 290 295 300 Gl n Phe As n Tr p Tyr Val As p Gl y Val Gl u Val Hi s As n Al a Lys Thr 305 310 315 320 Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser Val 325 330 335

    Page 38

    A1472PCT

    2018203471 16 May 2018

    Leu Thr Val Val 340 Hi s Gl n Asp Tr p Leu 345 As n Gl y Lys Gl u Ty r 350 Lys Cy s Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o I l e Gl u Lys Thr Ile Ser 355 360 365 Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Ty r Thr Leu Pr o Pr o 370 375 380 Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cy s Leu Val 385 390 395 400 Lys Gl y Phe Ty r Pr o Ser As p Ile Al a Val Gl u Tr p Gl u Ser As n Gl y 405 410 415 Gl n Pr o Gl u As n As n Ty r Lys Thr Thr Pr o Pr o Met Leu As p Ser As p 420 425 430 Gl y Ser Phe Phe Leu Ty r Ser Lys Leu Thr Val As p Lys Ser Ar g Tr p 435 440 445 Gl n Gl n Gl y As n Val Phe Ser Cy s Ser Val Met Hi s Gl u Al a Leu Hi s 450 455 460 As n Hi s Ty r Thr Gl n Lys Ser Leu Ser Leu Ser Pr o Gl y Lys 465 470 475

    <210> 32 <211> 478 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 32

    Met Asp Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15

    Leu Ar g Gl y Al a Ar g Cy s Gl n Val Gl n Leu Val Gl n Ser Gl y Al a Gl u 20 25 30

    Page 39

    A1472PCT

    2018203471 16 May 2018

    Val Lys Lys 35 Pr o Gl y Al a Ser Val 40 Lys Val Ser Cys Lys 45 Al a Ser Gl y Tyr Thr 50 Phe Thr Gl y Tyr Tyr 55 Met Hi s Tr p Val Ar g 60 Gl n Al a Pr o Gl y Gl n 65 Gl y Leu Gl u Tr p Met 70 Gl y Tr p I l e As n Pr o 75 As n Ser Gl y Gl y Thr 80 As n Tyr Al a Gl n Lys 85 Phe Gl n Gl y Ar g Val 90 Thr Met Thr Ar g As p 95 Thr Ser I l e Ser Thr 100 Al a Tyr Met Gl u Leu 105 Ser Ar g Leu Ar g Ser 110 As p As p Thr Al a Val 115 Tyr Phe Cys Al a Ar g 120 As p Gl n Met Ser Ile 125 Ile Met Leu Ar g Gl y 130 Val Phe Pr o Pr o Tyr 135 Tyr Tyr Gl y Met As p 140 Val Tr p Gl y Gl n Gl y 145 Thr Thr Val Thr Val 150 Ser Ser Al a Ser Thr 155 Lys Gl y Pr o Ser Val 160 Phe Pr o Leu Al a Pr o 165 Cys Ser Ar g Ser Thr 170 Ser Gl u Ser Thr Al a 175 Al a Leu Gl y Cys Leu 180 Val Lys As p Tyr Phe 185 Pr o Gl u Pr o Val Thr 190 Val Ser Tr p As n Ser 195 Gl y Al a Leu Thr Ser 200 Gl y Val Hi s Thr Phe 205 Pr o Al a Val Leu Gl n 210 Ser Ser Gl y Leu Tyr 215 Ser Leu Ser Ser Val 220 Val Thr Val Pr o Ser 225 Ser As n Phe Gl y Thr 230 Gl n Thr Tyr Thr Cys 235 As n Val As p Hi s Lys 240

    Page 40

    A1472PCT

    2018203471 16 May 2018

    Pr o Ser As n Thr Lys 245 Val Asp Lys Thr Val 250 Gl u Ar g Lys Cys Cys 255 Val Gl u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val Phe 260 265 270 Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr Pr o 275 280 285 Gl u Val Thr Cys Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u Val 290 295 300 Gl n Phe As n Tr p Tyr Val As p Gl y Val Gl u Val Hi s As n Al a Lys Thr 305 310 315 320 Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser Val 325 330 335 Leu Thr Val Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Tyr Lys Cys 340 345 350 Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o I l e Gl u Lys Thr Ile Ser 355 360 365 Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Tyr Thr Leu Pr o Pr o 370 375 380 Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cys Leu Val 385 390 395 400 Lys Gl y Phe Tyr Pr o Ser As p Ile Al a Val Gl u Tr p Gl u Ser As n Gl y 405 410 415 Gl n Pr o Gl u As n As n Tyr Lys Thr Thr Pr o Pr o Met Leu As p Ser As p 420 425 430 Gl y Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val As p Lys Ser Ar g Tr p 435 440 445 Gl n Gl n Gl y As n Val Phe Ser Cys Ser Val Met Hi s Gl u Al a Leu Hi s 450 455 460

    Page 41

    A1472PCT

    2018203471 16 May 2018

    Asn Hi s Tyr Thr Gl n Lys Ser Leu 465 470

    <210> 33 <211> 477 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / note= Descri ption of Arti pol ypept i de <400> 33

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Ar g Gl y Al a 20 Ar g Cys Gl n Val Val Val Gl n 35 Pr o Gl y Ar g Ser Leu 40 Phe Thr 50 Phe Ser Ser Tyr Gl y 55 Met Lys 65 Gl y Leu Gl u Tr p Val 70 Al a Val Ser Tyr Al a As p Ser 85 Val Lys Gl y Ser Lys As n Thr 100 Leu Tyr Leu Gl n Thr Al a Val 115 Tyr Phe Cys Al a Ar g 120 Thr Leu 130 Tyr Tyr Tyr Phe Tyr 135 Tyr Thr Thr Val Thr Val Ser Ser Al a

    Ser Leu Ser Pr o Gl y Lys 475 ficial Sequence: Synthetic

    Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Gl n 25 Leu Val Gl u Ser Gl y 30 Gl y Gl y Ar g Leu Ser Cys Al a 45 Al a Ser Gl y Hi s Tr p Val Ar g 60 Gl n Al a Pr o Gl y I l e Ser Tyr 75 As p Gl y Ser Hi s Gl u 80 Ar g Phe 90 Thr Ile Ser Ar g As p 95 Ile Met 105 As n Ser Leu Ar g Al a 110 Gl u As p Gl u Ar g Lys Ar g Val 125 Thr Met Ser Gl y Met As p Val 140 Tr p Gl y Gl n Gl y Ser Thr Lys Gl y Pr o Ser Val Phe

    Page 42

    2018203471 16 May 2018

    A1472PCT

    145 150 155 160

    Pr o Leu Al a Pr o Cy s 165 Ser Ar g Ser Thr Ser 170 Gl u Ser Thr Al a Al a 175 Leu Gl y Cy s Leu Val 180 Lys As p Ty r Phe Pr o 185 Gl u Pr o Val Thr Val 190 Ser Tr p As n Ser Gl y 195 Al a Leu Thr Ser Gl y 200 Val Hi s Thr Phe Pr o 205 Al a Val Leu Gl n Ser 210 Ser Gl y Leu Ty r Ser 215 Leu Ser Ser Val Val 220 Thr Val Pr o Ser Ser 225 As n Phe Gl y Thr Gl n 230 Thr Ty r Thr Cy s As n 235 Val As p Hi s Lys Pr o 240 Ser As n Thr Lys Val 245 As p Lys Thr Val Gl u 250 Ar g Lys Cy s Cy s Val 255 Gl u Cy s Pr o Pr o Cy s 260 Pr o Al a Pr o Pr o Val 265 Al a Gl y Pr o Ser Val 270 Phe Leu Phe Pr o Pr o 275 Lys Pr o Lys As p Thr 280 Leu Met I l e Ser Ar g 285 Thr Pr o Gl u Val Thr 290 Cy s Val Val Val As p 295 Val Ser Hi s Gl u As p 300 Pr o Gl u Val Gl n Phe 305 As n Tr p Ty r Val As p 310 Gl y Val Gl u Val Hi s 315 As n Al a Lys Thr Lys 320 Pr o Ar g Gl u Gl u Gl n 325 Phe As n Ser Thr Phe 330 Ar g Val Val Ser Val 335 Leu Thr Val Val Hi s 340 Gl n As p Tr p Leu As n 345 Gl y Lys Gl u Ty r Lys 350 Cy s Lys Val Ser As n 355 Lys Gl y Leu Pr o Al a 360 Pr o I l e Gl u Lys Thr 365 Ile Ser Lys

    Page 43

    A1472PCT

    2018203471 16 May 2018

    Thr Lys 370 Gl y Gl n Pr o Ar g Gl u 375 Pr o Ar g 385 Gl u Gl u Met Thr Lys 390 As n Gl n Gl y Phe Ty r Pr o Ser 405 As p Ile Al a Pr o Gl u As n As n 420 Ty r Lys Thr Thr Ser Phe Phe 435 Leu Ty r Ser Lys Leu 440 Gl n Gl y 450 As n Val Phe Ser Cy s 455 Ser Hi s 465 Ty r Thr Gl n Lys Ser 470 Leu Ser

    Gl n Val Ty r Thr 380 Leu Pr o Pr o Ser Val Ser Leu 395 Thr Cy s Leu Val Lys 400 Val Gl u 410 Tr p Gl u Ser As n Gl y 415 Gl n Pr o 425 Pr o Met Leu As p Ser 430 As p Gl y Thr Val As p Lys Ser 445 Ar g Tr p Gl n Val Met Hi s Gl u 460 Al a Leu Hi s As n Leu Ser Pr o 475 Gl y Lys

    <210> 34 <211> 469 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Ar t i pol ypept i de ficial Sequence: Synthetic

    <400> 34 Ar g Val 5 Pr o Al a Gl n Met 1 As p Met Leu Ar g Gl y Al a 20 Ar g Cy s Gl u Val Leu Val Lys 35 Pr o Gl y Ar g Ser Leu 40 Phe Thr 50 Phe Gl y As p Ty r Al a 55 Met

    Leu Leu Gl y Leu Leu Leu Leu Tr p 10 15

    Gl n Leu Val Gl u Ser Gl y Gl y Gl y 25 30

    Arg Leu Ser Cys Thr Al a Ser Gl y 45

    Ser Tr p Phe Ar g Gl n Al a Pr o Gl y 60

    Page 44

    A1472PCT

    2018203471 16 May 2018

    Lys 65 Gl y Leu Gl u Tr p I l e 70 Gl y Phe I l e Ar g Ser 75 Ar g Al a Tyr Gl y Gl y 80 Thr Pr o Gl u Tyr Al a Al a Ser Val Lys Gl y Ar g Phe Thr Ile Ser Ar g 85 90 95 As p As p Ser Lys Thr Ile Al a Tyr Leu Gl n Met As n Ser Leu Lys Thr 100 105 110 Gl u As p Thr Al a Val Tyr Phe Cys Al a Ar g Gl y Ar g Gl y Ile Al a Al a 115 120 125 Ar g Tr p As p Tyr Tr p Gl y Gl n Gl y Thr Leu Val Thr Val Ser Ser Al a 130 135 140 Ser Thr Lys Gl y Pr o Ser Val Phe Pr o Leu Al a Pr o Cys Ser Ar g Ser 145 150 155 160 Thr Ser Gl u Ser Thr Al a Al a Leu Gl y Cys Leu Val Lys As p Tyr Phe 165 170 175 Pr o Gl u Pr o Val Thr Val Ser Tr p As n Ser Gl y Al a Leu Thr Ser Gl y 180 185 190 Val Hi s Thr Phe Pr o Al a Val Leu Gl n Ser Ser Gl y Leu Tyr Ser Leu 195 200 205 Ser Ser Val Val Thr Val Pr o Ser Ser As n Phe Gl y Thr Gl n Thr Tyr 210 215 220 Thr Cys As n Val As p Hi s Lys Pr o Ser As n Thr Lys Val As p Lys Thr 225 230 235 240 Val Gl u Ar g Lys Cys Cys Val Gl u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o 245 250 255 Val Al a Gl y Pr o Ser Val Phe Leu Phe Pr o Pr o Lys Pr o Lys As p Thr 260 265 270

    Page 45

    A1472PCT

    2018203471 16 May 2018

    Leu Met I l e 275 Ser Ar g Thr Pr o Gl u 280 Val Thr Cy s Val Val 285 Val As p Val Ser Hi s 290 Gl u As p Pr o Gl u Val 295 Gl n Phe As n Tr p Ty r 300 Val As p Gl y Val Gl u 305 Val Hi s As n Al a Lys 310 Thr Lys Pr o Ar g Gl u 315 Gl u Gl n Phe As n Ser 320 Thr Phe Ar g Val Val 325 Ser Val Leu Thr Val 330 Val Hi s Gl n As p Tr p 335 Leu As n Gl y Lys Gl u 340 Ty r Lys Cy s Lys Val 345 Ser As n Lys Gl y Leu 350 Pr o Al a Pr o I l e Gl u 355 Lys Thr Ile Ser Lys 360 Thr Lys Gl y Gl n Pr o 365 Ar g Gl u Pr o Gl n Val 370 Ty r Thr Leu Pr o Pr o 375 Ser Ar g Gl u Gl u Met 380 Thr Lys As n Gl n Val 385 Ser Leu Thr Cy s Leu 390 Val Lys Gl y Phe Ty r 395 Pr o Ser As p Ile Al a 400 Val Gl u Tr p Gl u Ser 405 As n Gl y Gl n Pr o Gl u 410 As n As n Ty r Lys Thr 415 Thr Pr o Pr o Met Leu 420 As p Ser As p Gl y Ser 425 Phe Phe Leu Ty r Ser 430 Lys Leu Thr Val As p 435 Lys Ser Ar g Tr p Gl n 440 Gl n Gl y As n Val Phe 445 Ser Cy s Ser Val Met 450 Hi s Gl u Al a Leu Hi s 455 As n Hi s Ty r Thr Gl n 460 Lys Ser Leu Ser

    Leu Ser Pr o Gl y Ly s 465 <210> 35 <211> 479

    Page 46

    2018203471 16 May 2018

    A1472PCT <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    <400> 35 Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu Tr p 15 Met 1 As p Met Leu Ar g Gl y Al a Ar g Cy s Gl u Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y 20 25 30 Leu Val Lys Pr o Gl y Gl y Ser Leu Ar g Leu Ser Cy s Al a Al a Ser Gl y 35 40 45 Phe Thr Phe Ser As n Al a Tr p Met Ser Tr p Val Ar g Gl n Al a Pr o Gl y 50 55 60 Lys Gl y Leu Gl u Tr p Val Gl y Ar g I l e Lys Ser Lys Thr As p Gl y Gl y 65 70 75 80 Thr Thr As p Ty r Thr Al a Pr o Val Lys Gl y Ar g Phe Thr Ile Ser Ar g 85 90 95 As p As p Ser Lys As n Thr Leu Ty r Leu Gl n Met As n Ser Leu Lys Al a 100 105 110 Gl u As p Thr Al a Val Ty r Ty r Cy s Thr Thr As p Ar g Thr Gl y Ty r Ser 115 120 125 I l e Ser Tr p Ser Ser Ty r Ty r Ty r Ty r Ty r Gl y Met As p Val Tr p Gl y 130 135 140 Gl n Gl y Thr Thr Val Thr Val Ser Ser Al a Ser Thr Lys Gl y Pr o Ser 145 150 155 160 Val Phe Pr o Leu Al a Pr o Cy s Ser Ar g Ser Thr Ser Gl u Ser Thr Al a 165 170 175 Al a Leu Gl y Cy s Leu Val Lys As p Ty r Phe Pr o Gl u Pr o Val Thr Val Page 47

    2018203471 16 May 2018

    A1472PCT 180 185 190 Ser Tr p As n Ser Gl y Al a Leu Thr Ser Gl y Val Hi s Thr Phe Pr o Al a 195 200 205 Val Leu Gl n Ser Ser Gl y Leu Ty r Ser Leu Ser Ser Val Val Thr Val 210 215 220 Pr o Ser Ser As n Phe Gl y Thr Gl n Thr Ty r Thr Cy s As n Val As p Hi s 225 230 235 240 Lys Pr o Ser As n Thr Lys Val As p Lys Thr Val Gl u Ar g Lys Cy s Cy s 245 250 255 Val Gl u Cy s Pr o Pr o Cy s Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val 260 265 270 Phe Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr 275 280 285 Pr o Gl u Val Thr Cy s Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u 290 295 300 Val Gl n Phe As n Tr p Ty r Val As p Gl y Val Gl u Val Hi s As n Al a Lys 305 310 315 320 Thr Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser 325 330 335 Val Leu Thr Val Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Ty r Lys 340 345 350 Cy s Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o Ile Gl u Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Ty r Thr Leu Pr o 370 375 380 Pr o Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cy s Leu 385 390 395 400

    Page 48

    A1472PCT

    2018203471 16 May 2018

    Val Lys Gl y Phe Tyr 405 Pr o Ser As p I l e Al a 410 Val Gl u Tr p Gl u Ser 415 As n Gly Gl n Pr o Gl u 420 As n As n Tyr Lys Thr 425 Thr Pr o Pr o Met Leu 430 As p Ser As p Gl y Ser 435 Phe Phe Leu Tyr Ser 440 Lys Leu Thr Val As p 445 Lys Ser Ar g Tr p Gl n 450 Gl n Gl y As n Val Phe 455 Ser Cys Ser Val Met 460 Hi s Gl u Al a Leu Hi s 465 As n Hi s Tyr Thr Gl n 470 Lys Ser Leu Ser Leu 475 Ser Pr o Gl y Lys

    <210> 36 <211> 475 <212> PRT <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 36

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a Ar g Cy s Gl n Val Gl n Leu Val Gl n Ser Gl y Al a Gl u 20 25 30 Val Lys Lys Pr o Gl y Al a Ser Val Lys Val Ser Cy s Lys Al a Ser Gl y 35 40 45 Ty r Thr Phe Thr As p Ty r Ty r Met Ty r Tr p Val Ar g Gl n Al a Pr o Gl y 50 55 60 Gl n Gl y Leu Gl u Tr p Met Gl y Tr p I l e Ser Pr o As n Ser Gl y Gl y Thr 65 70 75 80 As n Ty r Al a Gl n Lys Phe Gl n Gl y Ar g Val Thr Met Thr Ar g As p Thr 85 90 95

    Page 49

    A1472PCT

    2018203471 16 May 2018

    Ser I l e Ser Thr 100 Al a Tyr Met Gl u Leu 105 Ser Ar g Leu Ar g Ser 110 As p As p Thr Al a Val 115 Tyr Tyr Cys Val Ar g 120 Gl y Gl y Tyr Ser Gl y 125 Tyr Al a Gl y Leu Tyr 130 Ser Hi s Tyr Tyr Gl y 135 Met As p Val Tr p Gl y 140 Gl n Gl y Thr Thr Val 145 Thr Val Ser Ser Al a 150 Ser Thr Lys Gl y Pr o 155 Ser Val Phe Pr o Leu 160 Al a Pr o Cys Ser Ar g 165 Ser Thr Ser Gl u Ser 170 Thr Al a Al a Leu Gl y 175 Cys Leu Val Lys As p 180 Tyr Phe Pr o Gl u Pr o 185 Val Thr Val Ser Tr p 190 As n Ser Gl y Al a Leu 195 Thr Ser Gl y Val Hi s 200 Thr Phe Pr o Al a Val 205 Leu Gl n Ser Ser Gl y 210 Leu Tyr Ser Leu Ser 215 Ser Val Val Thr Val 220 Pr o Ser Ser As n Phe 225 Gl y Thr Gl n Thr Tyr 230 Thr Cys As n Val As p 235 Hi s Lys Pr o Ser As n 240 Thr Lys Val As p Lys 245 Thr Val Gl u Ar g Lys 250 Cys Cys Val Gl u Cys 255 Pr o Pr o Cys Pr o Al a 260 Pr o Pr o Val Al a Gl y 265 Pr o Ser Val Phe Leu 270 Phe Pr o Pr o Lys Pr o 275 Lys As p Thr Leu Met 280 I l e Ser Ar g Thr Pr o 285 Gl u Val Thr Cys Val 290 Val Val As p Val Ser 295 Hi s Gl u As p Pr o Gl u 300 Val Gl n Phe As n

    Page 50

    2018203471 16 May 2018

    Tr p 305 Tyr Val As p Gl y A1472PCT Val 310 Gl u Val Hi s As n Al a 315 Lys Thr Lys Pr o Ar g 320 Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser Val Leu Thr Val 325 330 335 Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Tyr Lys Cys Lys Val Ser 340 345 350 As n Lys Gl y Leu Pr o Al a Pr o Ile Gl u Lys Thr Ile Ser Lys Thr Lys 355 360 365 Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Tyr Thr Leu Pr o Pr o Ser Ar g Gl u 370 375 380 Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cys Leu Val Lys Gl y Phe 385 390 395 400 Tyr Pr o Ser As p Ile Al a Val Gl u Tr p Gl u Ser As n Gl y Gl n Pr o Gl u 405 410 415 As n As n Tyr Lys Thr Thr Pr o Pr o Met Leu As p Ser As p Gl y Ser Phe 420 425 430 Phe Leu Tyr Ser Lys Leu Thr Val As p Lys Ser Ar g Tr p Gl n Gl n Gl y 435 440 445 As n Val Phe Ser Cys Ser Val Met Hi s Gl u Al a Leu Hi s As n Hi s Tyr 450 455 460 Thr Gl n Lys Ser Leu Ser Leu Ser Pr o Gl y Lys

    465 470 475 <210> 37 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    Page 51

    A1472PCT <400> 37

    2018203471 16 May 2018

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a 20 Ar g Cys Gl u Val Gl n 25 Leu Val Gl u Ser Gl y 30 Gl y Gl y Leu Val Lys 35 Pr o Gl y Gl y Ser Leu 40 Ar g Leu Ser Cys Al a 45 Al a Ser Gl y Phe Thr 50 Phe Gl y As n Al a Tr p 55 Met Ser Tr p Val Ar g 60 Gl n Al a Pr o Gl y Lys 65 Gl y Leu Gl u Tr p Val 70 Gl y Ar g I l e Lys Ser 75 Lys Thr As p Gl y Gl y 80 Thr Thr As p Tyr Al a 85 Al a Pr o Val Lys Gl y 90 Ar g Phe Thr Ile Ser 95 Ar g As p As p Ser Lys 100 As n Thr Leu Tyr Leu 105 Gl n Met As n Ser Leu 110 Lys Thr Gl u As p Thr 115 Al a Val Tyr Phe Cys 120 Thr Thr As p Ar g Thr 125 Gl y Tyr Ser I l e Ser 130 Tr p Ser Ser Tyr Tyr 135 Tyr Tyr Tyr Gl y Met 140 As p Val Tr p Gl y Gl n 145 Gl y Thr Thr Val Thr 150 Val Ser Ser Al a Ser 155 Thr Lys Gl y Pr o Ser 160 Val Phe Pr o Leu Al a 165 Pr o Cys Ser Ar g Ser 170 Thr Ser Gl u Ser Thr 175 Al a Al a Leu Gl y Cys 180 Leu Val Lys As p Tyr 185 Phe Pr o Gl u Pr o Val 190 Thr Val Ser Tr p As n 195 Ser Gl y Al a Leu Thr 200 Ser Gl y Val Hi s Thr 205 Phe Pr o Al a Val Leu Gl n Ser Ser Gl y Leu Tyr Ser Leu Ser Ser Val Val Thr Val

    Page 52

    2018203471 16 May 2018

    A1472PCT

    210 215 220

    Pr o 225 Ser Ser As n Phe Gl y Thr 230 Gl n Thr Tyr Thr 235 Cys Asn Val As p Hi s 240 Lys Pr o Ser As n Thr Lys Val As p Lys Thr Val Gl u Ar g Lys Cys Cys 245 250 255 Val Gl u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val 260 265 270 Phe Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr 275 280 285 Pr o Gl u Val Thr Cys Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u 290 295 300 Val Gl n Phe As n Tr p Tyr Val As p Gl y Val Gl u Val Hi s As n Al a Lys 305 310 315 320 Thr Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser 325 330 335 Val Leu Thr Val Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Tyr Lys 340 345 350 Cys Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o Ile Gl u Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Tyr Thr Leu Pr o 370 375 380 Pr o Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cys Leu 385 390 395 400 Val Lys Gl y Phe Tyr Pr o Ser As p I l e Al a Val Gl u Tr p Gl u Ser As n 405 410 415 Gl y Gl n Pr o Gl u As n As n Tyr Lys Thr Thr Pr o Pr o Met Leu As p Ser 420 425 430

    Page 53

    A1472PCT

    2018203471 16 May 2018

    As p Gl y Ser 435 Phe Phe Leu Ty r Ser 440 Lys Leu Thr Val As p 445 Lys Ser Ar g Tr p Gl n Gl n Gl y As n Val Phe Ser Cy s Ser Val Met Hi s Gl u Al a Leu 450 455 460 Hi s As n Hi s Ty r Thr Gl n Lys Ser Leu Ser Leu Ser Pr o Gl y Lys 465 470 475

    <210> 38 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 38

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a Ar g Cy s Gl u Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y 20 25 30 Leu Val Lys Pr o Gl y Gl y Ser Leu Ar g Leu Ser Cy s Al a Al a Ser Gl y 35 40 45 Phe Thr Phe Gl y As n Al a Tr p Met Ser Tr p Val Ar g Gl n Al a Pr o Gl y 50 55 60 Lys Gl y Leu Gl u Tr p Val Gl y Ar g I l e Lys Ser Lys Thr As p Gl y Gl y 65 70 75 80 Thr Thr As p Ty r Al a Al a Pr o Val Lys Gl y Ar g Phe Thr Ile Ser Ar g 85 90 95 As p As p Ser Lys As n Thr Leu Ty r Leu Gl n Met As n Ser Leu Lys Thr 100 105 110 Gl u As p Thr Al a Val Ty r Ty r Cy s Thr Thr As p Ar g Thr Gl y Ty r Ser 115 120 125

    Page 54

    A1472PCT

    2018203471 16 May 2018

    I l e Ser 130 Tr p Ser Ser Ty r Ty r 135 Ty r Ty r Ty r Gl y Met 140 As p Val Tr p Gl y Gl n Gl y Thr Thr Val Thr Val Ser Ser Al a Ser Thr Lys Gl y Pr o Ser 145 150 155 160 Val Phe Pr o Leu Al a Pr o Cy s Ser Ar g Ser Thr Ser Gl u Ser Thr Al a 165 170 175 Al a Leu Gl y Cy s Leu Val Lys As p Ty r Phe Pr o Gl u Pr o Val Thr Val 180 185 190 Ser Tr p As n Ser Gl y Al a Leu Thr Ser Gl y Val Hi s Thr Phe Pr o Al a 195 200 205 Val Leu Gl n Ser Ser Gl y Leu Ty r Ser Leu Ser Ser Val Val Thr Val 210 215 220 Pr o Ser Ser As n Phe Gl y Thr Gl n Thr Ty r Thr Cy s As n Val As p Hi s 225 230 235 240 Lys Pr o Ser As n Thr Lys Val As p Lys Thr Val Gl u Ar g Lys Cy s Cy s 245 250 255 Val Gl u Cy s Pr o Pr o Cy s Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val 260 265 270 Phe Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr 275 280 285 Pr o Gl u Val Thr Cy s Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u 290 295 300 Val Gl n Phe As n Tr p Ty r Val As p Gl y Val Gl u Val Hi s As n Al a Lys 305 310 315 320 Thr Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser 325 330 335

    Page 55

    2018203471 16 May 2018

    Val Leu Thr Val 340 A1472PCT Val Hi s Gl n As p Tr p 345 Leu As n Gl y Lys Gl u 350 Ty r Lys Cy s Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o Ile Gl u Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Ty r Thr Leu Pr o 370 375 380 Pr o Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cy s Leu 385 390 395 400 Val Lys Gl y Phe Ty r Pr o Ser As p I l e Al a Val Gl u Tr p Gl u Ser As n 405 410 415 Gl y Gl n Pr o Gl u As n As n Ty r Lys Thr Thr Pr o Pr o Met Leu As p Ser 420 425 430 As p Gl y Ser Phe Phe Leu Ty r Ser Lys Leu Thr Val As p Lys Ser Ar g 435 440 445 Tr p Gl n Gl n Gl y As n Val Phe Ser Cy s Ser Val Met Hi s Gl u Al a Leu 450 455 460 Hi s As n Hi s Ty r Thr Gl n Lys Ser Leu Ser Leu Ser Pr o Gl y Lys

    465 470 475 <210> 39 <211> 478 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 39

    Met Asp Met Ar g Val Pr o Al a Gl n Leu Leu Gl y Leu Leu Leu Leu Tr p 1 5 10 15

    Leu Ar g Gl y Al a Ar g Cy s Gl n Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y 20 25 30

    Page 56

    A1472PCT

    2018203471 16 May 2018

    Val Val Gl n 35 Pr o Gl y Ar g Ser Leu 40 Ar g Leu Ser Cys Al a 45 Al a Ser Gl y Phe Thr 50 Phe Ser Ser Phe Gl y 55 Met Hi s Tr p Val Ar g 60 Gl n Al a Pr o Gl y Lys 65 Gl y Leu Gl u Tr p Val 70 Al a Val I l e Ser Phe 75 As p Gl y Ser Ile Lys 80 Tyr Ser Val As p Ser 85 Val Lys Gl y Ar g Phe 90 Thr Ile Ser Ar g As p 95 As n Ser Lys As n Thr 100 Leu Phe Leu Gl n Met 105 As n Ser Leu Ar g Al a 110 Gl u As p Thr Al a Val 115 Tyr Tyr Cys Al a Ar g 120 As p Ar g Leu As n Tyr 125 Tyr As p Ser Ser Gl y 130 Tyr Tyr Hi s Tyr Lys 135 Tyr Tyr Gl y Leu Al a 140 Val Tr p Gl y Gl n Gl y 145 Thr Thr Val Thr Val 150 Ser Ser Al a Ser Thr 155 Lys Gl y Pr o Ser Val 160 Phe Pr o Leu Al a Pr o 165 Cys Ser Ar g Ser Thr 170 Ser Gl u Ser Thr Al a 175 Al a Leu Gl y Cys Leu 180 Val Lys As p Tyr Phe 185 Pr o Gl u Pr o Val Thr 190 Val Ser Tr p As n Ser 195 Gl y Al a Leu Thr Ser 200 Gl y Val Hi s Thr Phe 205 Pr o Al a Val Leu Gl n 210 Ser Ser Gl y Leu Tyr 215 Ser Leu Ser Ser Val 220 Val Thr Val Pr o Ser 225 Ser As n Phe Gl y Thr 230 Gl n Thr Tyr Thr Cys 235 As n Val As p Hi s Lys 240 Pr o Ser As n Thr Lys Val As p Lys Thr Val Gl u Ar g Lys Cys Cys Val

    Page 57

    2018203471 16 May 2018

    245 A1472PCT 250 255 Gl u Cy s Pr o Pr o Cy s Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val Phe 260 265 270 Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr Pr o 275 280 285 Gl u Val Thr Cy s Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u Val 290 295 300 Gl n Phe As n Tr p Ty r Val As p Gl y Val Gl u Val Hi s As n Al a Lys Thr 305 310 315 320 Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser Val 325 330 335 Leu Thr Val Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Ty r Lys Cy s 340 345 350 Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o I l e Gl u Lys Thr Ile Ser 355 360 365 Lys Thr Lys Gl y Gl n Pr o Ar g Gl u Pr o Gl n Val Ty r Thr Leu Pr o Pr o 370 375 380 Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cy s Leu Val 385 390 395 400 Lys Gl y Phe Ty r Pr o Ser As p Ile Al a Val Gl u Tr p Gl u Ser As n Gl y 405 410 415 Gl n Pr o Gl u As n As n Ty r Lys Thr Thr Pr o Pr o Met Leu As p Ser As p 420 425 430 Gl y Ser Phe Phe Leu Ty r Ser Lys Leu Thr Val As p Lys Ser Ar g Tr p 435 440 445 Gl n Gl n Gl y As n Val Phe Ser Cy s Ser Val Met Hi s Gl u Al a Leu Hi s 450 455 460

    Page 58

    2018203471 16 May 2018

    A1472PCT

    Asn His Tyr Thr G n Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <210> 40 <211> 479 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 40

    Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a Ar g Cy s Gl u Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y 20 25 30 Leu Val Lys Pr o Gl y Gl y Ser Leu Ar g Leu Ser Cy s Al a Al a Ser Gl y 35 40 45 Ty r Thr Phe Ser Thr Ty r Ser Met As n Tr p Val Ar g Gl n Al a Pr o Gl y 50 55 60 Lys Gl y Leu Gl u Tr p Val Ser Ser I l e Ser Ser Ser Ser Ser Ty r Ar g 65 70 75 80 Ty r Ty r Al a As p Ser Val Lys Gl y Ar g Phe Thr Ile Ser Ar g As p As n 85 90 95 Al a Lys As n Ser Leu Ty r Leu Gl n Met Ser Ser Leu Ar g Al a Gl u As p 100 105 110 Thr Al a Val Ty r Ty r Cy s Al a Ar g Gl u Gl y Val Ser Gl y Ser Ser Pr o 115 120 125 Ty r Ser I l e Ser Tr p Ty r As p Ty r Ty r Ty r Gl y Met As p Val Tr p Gl y 130 135 140 Gl n Gl y Thr Thr Val Thr Val Ser Ser Al a Ser Thr Lys Gl y Pr o Ser 145 150 155 160

    Page 59

    A1472PCT

    2018203471 16 May 2018

    Val Phe Pr o Leu Al a 165 Pr o Cys Ser Ar g Ser 170 Thr Ser Gl u Ser Thr 175 Al a Al a Leu Gl y Cys Leu Val Lys As p Tyr Phe Pr o Gl u Pr o Val Thr Val 180 185 190 Ser Tr p As n Ser Gl y Al a Leu Thr Ser Gl y Val Hi s Thr Phe Pr o Al a 195 200 205 Val Leu Gl n Ser Ser Gl y Leu Tyr Ser Leu Ser Ser Val Val Thr Val 210 215 220 Pr o Ser Ser As n Phe Gl y Thr Gl n Thr Tyr Thr Cys As n Val As p Hi s 225 230 235 240 Lys Pr o Ser As n Thr Lys Val As p Lys Thr Val Gl u Ar g Lys Cys Cys 245 250 255 Val Gl u Cys Pr o Pr o Cys Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val 260 265 270 Phe Leu Phe Pr o Pr o Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr 275 280 285 Pr o Gl u Val Thr Cys Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u 290 295 300 Val Gl n Phe As n Tr p Tyr Val As p Gl y Val Gl u Val Hi s As n Al a Lys 305 310 315 320 Thr Lys Pr o Ar g Gl u Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser 325 330 335 Val Leu Thr Val Val Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Tyr Lys 340 345 350 Cys Lys Val Ser As n Lys Gl y Leu Pr o Al a Pr o Ile Gl u Lys Thr Ile 355 360 365

    Page 60

    A1472PCT

    2018203471 16 May 2018

    Ser Lys 370 Thr Lys Gl y Gl n Pr o 375 Ar g Gl u Pr o Gl n Val 380 Tyr Thr Leu Pr o Pr o Ser Ar g Gl u Gl u Met Thr Lys As n Gl n Val Ser Leu Thr Cys Leu 385 390 395 400 Val Lys Gl y Phe Tyr Pr o Ser As p I l e Al a Val Gl u Tr p Gl u Ser As n 405 410 415 Gl y Gl n Pr o Gl u As n As n Tyr Lys Thr Thr Pr o Pr o Met Leu As p Ser 420 425 430 As p Gl y Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val As p Lys Ser Ar g 435 440 445 Tr p Gl n Gl n Gl y As n Val Phe Ser Cys Ser Val Met Hi s Gl u Al a Leu 450 455 460 Hi s As n Hi s Tyr Thr Gl n Lys Ser Leu Ser Leu Ser Pr o Gl y Lys 465 470 475 <210> 41 <211> 474 <212> PRT <213> Art i f i ci al Sequenc e

    <220>

    <221> sour ce

    <223> / not e= Descr i pt i or pol ypept i de <400> 41 of Ar t i f i ci al Sequence: Sy nt het i c Met 1 As p Met Ar g Val 5 Pr o Al a Gl n Leu Leu 10 Gl y Leu Leu Leu Leu 15 Tr p Leu Ar g Gl y Al a 20 Ar g Cys Gl n Val Gl n 25 Leu Val Gl u Ser Gl y 30 Gl y Gl ^y Val Val Gl n 35 Pr o Gl y Ar g Ser Leu 40 Ar g Leu Ser Cys Al a 45 Al a Ser Gl ^y Phe Thr 50 Phe Ser Ser Tyr Gl y 55 Met Hi s Tr p Val Ar g 60 Gl n Al a Pr o Gl ^y

    Page 61

    A1472PCT

    2018203471 16 May 2018

    Lys 65 Gl y Leu Gl u Tr p Val 70 Al a Val I l e Tr p Ty r 75 As p Gl y Ser As n Lys 80 Ty r Ty r Al a As p Ser Val Lys Gl y Ar g Phe I l e Ile Ser Ar g As p Lys 85 90 95 Ser Lys As n Thr Leu Ty r Leu Gl n Met As n Ser Leu Ar g Al a Gl u As p 100 105 110 Thr Al a Val Ty r Ty r Cy s Al a Ar g Al a Gl y Gl y Ile Al a Al a Al a Gl y 115 120 125 Leu Ty r Ty r Ty r Ty r Gl y Met As p Val Tr p Gl y Gl n Gl y Thr Thr Val 130 135 140 Thr Val Ser Ser Al a Ser Thr Lys Gl y Pr o Ser Val Phe Pr o Leu Al a 145 150 155 160 Pr o Cy s Ser Ar g Ser Thr Ser Gl u Ser Thr Al a Al a Leu Gl y Cy s Leu 165 170 175 Val Lys As p Ty r Phe Pr o Gl u Pr o Val Thr Val Ser Tr p As n Ser Gl y 180 185 190 Al a Leu Thr Ser Gl y Val Hi s Thr Phe Pr o Al a Val Leu Gl n Ser Ser 195 200 205 Gl y Leu Ty r Ser Leu Ser Ser Val Val Thr Val Pr o Ser Ser As n Phe 210 215 220 Gl y Thr Gl n Thr Ty r Thr Cy s As n Val As p Hi s Lys Pr o Ser As n Thr 225 230 235 240 Lys Val As p Lys Thr Val Gl u Ar g Lys Cy s Cy s Val Gl u Cy s Pr o Pr o 245 250 255 Cy s Pr o Al a Pr o Pr o Val Al a Gl y Pr o Ser Val Phe Leu Phe Pr o Pr o 260 265 270 Lys Pr o Lys As p Thr Leu Met Ile Ser Ar g Thr Pr o Gl u Val Thr Cy s

    Page 62

    2018203471 16 May 2018

    275 280 285 Val Val Val As p Val Ser Hi s Gl u As p Pr o Gl u Val Gl n Phe As n Tr p 290 295 300 Tyr Val As p Gl y Val Gl u Val Hi s As n Al a Lys Thr Lys Pr o Ar g Gl u 305 310 315 320 Gl u Gl n Phe As n Ser Thr Phe Ar g Val Val Ser Val Leu Thr Val Val 325 330 335 Hi s Gl n As p Tr p Leu As n Gl y Lys Gl u Tyr Lys Cys Lys Val Ser As n 340 345 350 Lys Gl y Leu Pr o Al a Pr o Ile Gl u Lys Thr I l e Ser Lys Thr Lys Gl y 355 360 365 Gl n Pr o Ar g Gl u Pr o Gl n Val Tyr Thr Leu Pr o Pr o Ser Ar g Gl u Gl u 370 375 380 Met Thr Lys As n Gl n Val Ser Leu Thr Cys Leu Val Lys Gl y Phe Tyr 385 390 395 400 Pr o Ser As p Ile Al a Val Gl u Tr p Gl u Ser As n Gl y Gl n Pr o Gl u As n 405 410 415 As n Tyr Lys Thr Thr Pr o Pr o Met Leu As p Ser As p Gl y Ser Phe Phe 420 425 430 Leu Tyr Ser Lys Leu Thr Val As p Lys Ser Ar g Tr p Gl n Gl n Gl y As n 435 440 445 Val Phe Ser Cys Ser Val Met Hi s Gl u Al a Leu Hi s As n Hi s Tyr Thr 450 455 460 Gl n Lys Ser Leu Ser Leu Ser Pr o Gl y Lys 465 470

    <210> 42 <211> 13 <212> PRT

    Page 63

    A1472PCT

    2018203471 16 May 2018

    <213> Art i f i ci al Sequence <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de Ar t i f i ci al Sequence <400> 42 Ser Gl y Ser Ser Ser As n I l e Gl y As n As n Tyr Val 1 5 10

    Synt het i c

    Ser

    <210> 43 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence pept i de <400> 43

    Asp Asn Asn Lys Arg Pro Ser

    1 5 <210> 44 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence pept i de <400> 44

    Gl y Thr Tr p Asp Ser Ar g Leu Ser Al a Val Val 1 5 10 <210> 45 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence pept i de <400> 45

    Ser Gl y Ser Ser Ser Asn I l e Gl y Ser Asn Tyr Val

    Page 64

    Synt het i c

    Synt het i c

    Synt het i c

    Tyr

    Ar t i f i ci al Sequence

    Synt het i c

    2018203471 16 May 2018 <210> 46 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of pept i de <400> 46

    Arg Ser Asn Gn Arg Pro Ser 1 5 <210> 47 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of pept i de <400> 47

    Al a Al a Tr p Asp Asp Ser Leu 1 5 <210> 48 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of pept i de <400> 48

    Ar g Al a Ser Gl n Gl y I l e Ar g 1 5 <210> 49 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence

    A1472PCT

    Ar t i f i ci al Sequence

    Ser Gl y Tr p Val 10

    Ar t i f i ci al Sequence

    Asn Asp Leu Gl y 10

    Synt het i c

    Synt het i c <220>

    Page 65

    A1472PCT

    2018203471 16 May 2018

    <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i ci pept i de <400> 49 Al a Al a Ser Ser Leu Gl n Ser 1 5 <210> 50 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i ci pept i de <400> 50 Leu Gl n Ty r As n I l e Ty r Pr o Tr p Thr 1 5 <210> 51 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i ci pept i de <400> 51 Gl n Gl y Asp Ser Leu Ar g Ser Phe Ty r 1 5 <210> 52 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i ci pept i de <400> 52

    Synt het i c

    Synt het i c

    Synt het i c

    Synt het i c

    Gly Lys Asn Asn Arg Pro Ser

    1 5

    Page 66

    A1472PCT

    2018203471 16 May 2018

    <210> 53 <211> 11 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 53 Asn Ser Arg Asp Ser Ser Val 1 5 <210> 54 <211> 16 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 54 Lys Ser Ser Gl n Ser Leu Leu 1 5 <210> 55 <211> 7 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 55

    Gl u Val Ser Asn Arg Phe Ser 1 5 <210> 56 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de

    Page 67

    A1472PCT

    2018203471 16 May 2018 <400> 56

    Met Gl n Ser Phe Pr o Leu Pr o Leu Thr 1 5 <210> 57 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 57

    Arg Ser Ser G n Ser Leu Leu Hi s Ser Phe G y Tyr Asn Tyr Leu Asp 1 5 10 15 <210> 58 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 58

    Leu Gl y Ser As n Ar g Al a Ser

    1 5 <210> 59 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce

    <223> / not e= Des c r i pt i on of Artificial Sequence: Synthetic pept i de <400> 59 Met Gl n Al a Leu Gl n Thr Pr o Phe Thr 1 5 <210> 60 <211> 16 <212> PRT

    Page 68

    2018203471 16 May 2018

    A1472PCT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 60

    Lys Ser Ser Gl n Ser Leu Leu Hi s Ser Asp Gl y Lys Thr Tyr Leu Tyr 1 5 10 15 <210> 61 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 61

    Arg Asn Asn Gn Arg Pro Ser

    1 5 <210> 62 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 62

    Ser Gl y Ser Ser Ser Asn I l e Gl y Ser Asn Thr Val Asn 1 5 10 <210> 63 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 63

    Thr Asn Asn Gl n Arg Pro Ser

    Page 69

    A1472PCT

    2018203471 16 May 2018

    1 5 <210> 64 <211> 11 <212> PRT <213> Art i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Descr i pt i on of pept i de <400> 64 Al a Al a Ar g As p Gl u Ser Leu 1 5 <210> 65 <211> 16 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 65 Lys Ser Ser G n Ser Leu Leu 1 5 <210> 66 <211> 11 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 66 Ar g Al a Ser Gl n Gl y I l e Ar g 1 5 <210> 67 <211> 7 <212> PRT <213> Ar t i f i ci al Sequenc e

    <220>

    Page 70

    2018203471 16 May 2018

    A1472PCT <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: pept i de

    Synt het i c

    <400> 67 Gl y Al a Ser Ser Leu Gl n Ser 1 5 <210> 68 <211> 9 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence pept i de <400> 68 Leu Gl n Ty r As n Ser Phe Pr o Tr p Thr 1 5 <210> 69 <211> 12 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i ci al Sequence pept i de <400> 69 Ar g Al a Ser Gl n Ser Val Ser Ser Gl y Ty r Leu Thr 1 5 10 <210> 70 <211> 7 <212> PRT <213> Ar t i f i ci al Sequenc e

    Synt het i c

    Synt het i c <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: pept i de <400> 70

    Gl y Al a Ser Ser Ar g Al a Thr

    1 5

    Synt het i c

    Page 71

    A1472PCT

    Synt het i c

    2018203471 16 May 2018

    <210> 71 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i ci pept i de <400> 71 Gl n Gl n Ty r Gl y As n Ser Leu Cy s Ar g 1 5 <210> 72 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Des c r i pt i on of Ar t i f i ci pept i de <400> 72 Gl n Gl n Ty r Gl y As n Ser Leu Ser Ar g 1 5 <210> 73 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Des c r i pt i on of Ar t i f i ci pept i de <400> 73 Ser Phe Gl y Met hi s 1 5 <210> 74 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Des c r i pt i on of Ar t i f i ci pept i de

    Synt het i c

    Synt het i c

    Synt het i c

    Page 72

    A1472PCT

    2018203471 16 May 2018 <400> 74

    Val I l e Ser Phe Asp Gl y Ser I l e Lys Tyr Ser Val Asp Ser Val Lys 1 5 10 15

    Gl y <210> 75 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 75

    Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gl y Tyr Tyr Hi s Tyr Lys Tyr 1 5 10 15

    Tyr Gl y Met Al a Val 20 <210> 76 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 76

    Asn Al a Tr p Met Ser

    1 5 <210> 77 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de

    Page 73

    2018203471 16 May 2018

    A1472PCT <400> 77 Ar g I l e Lys Ser Thr Thr Asp Gy Gy Thr Thr Asp Tyr Al a Al a Pr o 1 5 10 15

    Val Lys G y <210> 78 <211> 20 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce

    <223> / not e= Descr i pt i on of pept i de Ar t i f i ci al Sequence: Synt het i c <400> 78 Asp Arg Thr G y Tyr Ser I l e 1 5 Ser Tr p Ser 10 Ser Ty r Ty r Ty r Ty r Ty r 15 G y Met Asp Val 20

    <210> 79 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 79

    Ser Tyr Al a Met Ser

    1 5 <210> 80 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 80

    Page 74

    2018203471 16 May 2018

    A1472PCT

    Al a I l e Ser Gl y Ser Gl y Gl y Arg Thr Tyr Tyr Al a Asp Ser Val Lys 1 5 10 15

    Gl y <210> 81 <211> 21 <212> PRT <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 81

    Asp Gl n Arg Gl u Val Gl y Pro Tyr Ser Ser Gl y Trp Tyr Asp Tyr Tyr 1 5 10 15

    Tyr Gl y Met Asp Val 20 <210> 82 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 82

    Gl y Tyr Tyr Met Hi s

    1 5 <210> 83 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 83

    Trp I l e Asn Pro Asn Ser Gl y Gl y Thr Asn Tyr Al a Gl n Lys Phe Gl n Page 75

    2018203471 16 May 2018

    1 5 Gl y <210> 84 <211> 21 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 84 As p Gl n Met Ser I l e I l e Met 1 5 Tyr Gl y Met As p Val 20 <210> 85 <211> 5 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 85 Ser Tyr Gl y Met Hi s 1 5 <210> 86 <211> 17 <212> PRT <213> Ar t i f i ci al Sequenc e <220> <221> sour ce <223> / not e= Des c r i pt i on of pept i de <400> 86 Val I l e Ser Ty r Asp Gl y Ser 1 5

    A1472PCT

    Page 76

    A1472PCT

    2018203471 16 May 2018

    Gly <210> 87 <211> 20 <212> PRT <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 87

    G u Arg Lys Arg Val Thr Met Ser Thr Leu Tyr Tyr Tyr Phe Tyr Tyr 1 5 10 15

    Gl y Met Asp Val 20 <210> 88 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 88

    Asp Tyr Al a Met Ser

    1 5 <210> 89 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 89

    Phe I l e Ar g Ser Arg Al a Tyr G y G y Thr Pro G u Tyr Al a Al a Ser 1 5 10 15

    Page 77

    A1472PCT

    2018203471 16 May 2018

    Val Lys Gl y <210> 90 <211> 10 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 90

    Gly Arg Gly Ile Ala Ala Arg Trp Asp Tyr

    1 5 10 <210> 91 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 91

    Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Thr Ala Pro 1 5 10 15

    Val Lys Gl y <210> 92 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 92

    Asp Tyr Tyr Met Tyr

    1 5

    Page 78

    2018203471 16 May 2018

    A1472PCT <210> 93 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 93

    Trp Ile Ser Pro Asn Ser Gl y Gl y Thr As n Ty r Al a Gl n Lys Phe Gl n 1 5 10 15

    Gl y <210> 94 <211> 18 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 94

    Gl y Gl y Tyr Ser Gl y Tyr Al a Gl y Leu Tyr Ser Hi s Tyr Tyr Gl y Met 1 5 10 15

    Asp Val <210> 95 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 95

    Ar g I l e Lys Ser Lys Thr As p Gl y Gl y Thr Thr As p Ty r Al a Al a Pr o 1 5 10 15

    Val Lys Gl y

    Page 79

    A1472PCT

    2018203471 16 May 2018 <210> 96 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 96

    Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gl y Tyr Tyr Hi s Tyr Lys Tyr 1 5 10 15

    Tyr Gl y Leu Al a Val 20 <210> 97 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 97

    Thr Tyr Ser Met Asn

    1 5 <210> 98 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 98

    Ser I l e Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Al a Asp Ser Val Lys 1 5 10 15 Gl y

    Page 80

    A1472PCT

    Artificial Sequence: Synthetic

    2018203471 16 May 2018 <210> 99 <211> 22 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of pept i de <400> 99

    Gl u Gl y Val Ser Gl y Ser Ser 1 5

    Pro Tyr Ser Ile Ser Trp Tyr Asp Tyr 10 15

    Tyr Tyr G y Met Asp Val 20 <210> 100 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of pept i de <400> 100

    Ser Tyr G y Met Hi s 1 5

    Artificial Sequence: Synthetic <210> 101 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of pept i de <400> 101

    Val Ile Trp Tyr Asp Gly Ser 1 5

    Artificial Sequence: Synthetic

    Asn Lys Tyr Tyr Al a Asp Ser Val Lys 10 15

    Gl y

    Page 81

    A1472PCT

    2018203471 16 May 2018 <210> 102 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 102

    Ala Gly Gly Ile Ala Ala Ala Gly Leu Tyr Tyr Tyr Tyr Gl y Met Asp 1 5 10 15

    Val <210> 103 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> (8) . . (8) <223> / r epl ace= Lys <220>

    <221> mi sc_f eat ure <222> ( 8) . . ( 8) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 103

    Arg Al a Ser Gn Gly Ile Arg Asn Asp Leu Gl y

    1 5 10 <210> 104 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce

    Page 82

    2018203471 16 May 2018

    A1472PCT <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARIANT <222> (1)..(1) <223> / repl ace= G y <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <400> 104

    Al a Al a Ser Ser Leu Gl n Ser

    1 5 <210> 105 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> (6) . . (6) <223> / repl ace= Phe <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 6) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 105

    Leu G n Tyr Asn Ile Tyr Pro Trp Thr

    1 5 <210> 106 <211> 9

    Page 83

    2018203471 16 May 2018

    A1472PCT <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARIANT <222> (8) . . (8) <223> / repl ace=Cys <220>

    <221> mi sc_f eat ure <222> ( 8) . . ( 8) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 106

    Gl n Gl n Tyr Gl y Asn Ser Leu Ser Arg

    1 5 <210> 107 <211> 12 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARIANT <222> ( 5) . . ( 5) <223> / r epl ace= Gl y <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / r epl ace= I l e <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Ar g <220>

    <221> VARI ANT <222> ( 8) . . ( 8)

    Page 84

    2018203471 16 May 2018

    A1472PCT <223> / repl ace=Asn or Lys <220>

    <221> mi sc_f eat ure <222> (5) . . (8) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 10) . . ( 10) <223> / r epl ace= Asp <220>

    <221> mi sc_f eat ure <222> ( 10) . . ( 10) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / repl ace=G y <220>

    <221> mi sc_f eat ure <222> ( 12) . . ( 12) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 107

    Ar g Al a Ser Gl n Ser Val Ser Ser Gl y Tyr Leu Thr 1 5 10

    <210> 108 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / repl ace=Al a <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1)

    Page 85

    2018203471 16 May 2018

    A1472PCT <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARIANT <222> (5) . . (5) <223> / r epl ace= Leu <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / r epl ace= Gl n <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 7) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 108

    Gl y Al a Ser Ser Ar g Al a Thr

    1 5 <210> 109 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Leu <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARI ANT <222> ( 4) . . ( 4)

    Page 86

    2018203471 16 May 2018

    A1472PCT <223> / r epl ace= Asn <220>

    <221> VARIANT <222> (5) . . (5) <223> / repl ace=Thr <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / repl ace=Tyr or Phe <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Pr o <220>

    <221> VARI ANT <222> ( 8) . . ( 8) <223> / r epl ace= Tr p or Ser <220>

    <221> VARI ANT <222> ( 9) . . ( 9) <223> / repl ace=Thr <220>

    <221> mi sc_f eat ure <222> ( 4) . . ( 9) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <400> 109

    G n G n Tyr G y Asn Ser Leu Cys Arg

    1 5 <210> 110 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 10) . . ( 10) <223> / r epl ace= Al a

    Page 87

    2018203471 16 May 2018

    A1472PCT <220>

    <221> m sc_feat ure <222> (10) . . (10) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARIANT <222> ( 12) . . ( 12) <223> / r epl ace=Lys <220>

    <221> VARIANT <222> ( 13) . . ( 13) <223> / repl ace=Thr <220>

    <221> m sc_feat ure <222> ( 12) . . ( 13) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 110

    Ly s Ser Ser Gl n Ser Leu Leu Hi s Ser As p Gl y Ar g As n Ty r Leu Ty r

    1 5 10 15 <210> 111 <211> 16 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Lys <220>

    <221> m sc_feat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARI ANT <222> ( 10) . . ( 10) <223> / r epl ace= Asp or Al a

    Page 88

    2018203471 16 May 2018

    A1472PCT <220>

    <221> mi sc_f eat ure <222> (10) . . (10) <223> / not e= Resi due given in the sequence has no preference with respect to those in the annotations for said position <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / r epl ace= Ar g or Lys <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> /repl ace=Thr <220>

    <221> mi sc_f eat ure <222> ( 12) . . ( 13) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 16) . . ( 16) <223> /repl ace=Tyr <220>

    <221> mi sc_f eat ure <222> ( 16) . . ( 16) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <400> 111

    Arg Ser Ser Gl n Ser Leu Leu Hi s Ser Phe Gl y Tyr Asn Tyr Leu Asp 1 5 10 15 <210> 112 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Gl u

    Page 89

    2018203471 16 May 2018

    A1472PCT <220>

    <221> VARI ANT <222> (2) . . (2) <223> / r epl ace= Val <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 2) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / r epl ace= Phe <220>

    <221> mi sc_f eat ure <222> ( 6) . . ( 6) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 112

    Leu Gl y Ser As n Ar g Al a Ser

    1 5 <210> 113 <211> 9 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / r epl ace= Phe <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Pr o <220>

    Page 90

    2018203471 16 May 2018

    A1472PCT <221> VARIANT <222> (6) . . (6) <223> / r epl ace= Leu <220>

    <221> mi sc_f eat ure <222> ( 3) . . ( 6) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARIANT <222> ( 8) . . ( 8) <223> / r epl ace= Leu <220>

    <221> mi sc_f eat ure <222> ( 8) . . ( 8) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 113

    Met Gl n Al a Leu Gl n Thr Pr o Phe Thr

    1 5 <210> 114 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 2) . . ( 2) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 114

    Arg Asn Asn Gn Arg Pro Ser

    1 5 <210> 115

    Page 91

    2018203471 16 May 2018

    A1472PCT <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> (9) . . (9) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 9) . . ( 9) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARI ANT <222> ( 11) . . ( 11) <223> /repl ace=Thr <220>

    <221> mi sc_f eat ure <222> ( 11) . . ( 11) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> / repl ace= Asn or Tyr <220>

    <221> mi sc_f eat ure <222> ( 13) . . ( 13) <223> / not e= Resi due given in the sequence has no preference with respect to those in the annotation for said position <400> 115

    Ser G y Ser Ser Ser Asn Ile Gy Asn Asn Tyr Val Ser

    1 5 10 <210> 116 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    Page 92

    2018203471 16 May 2018

    A1472PCT <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> (1)..(1) <223> / repl ace=Thr or Arg <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 2) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / r epl ace= Gl n <220>

    <221> mi sc_f eat ure <222> ( 4) . . ( 4) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <400> 116

    Asp Asn Asn Lys Arg Pro Ser

    1 5 <210> 117 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 2) <223> / r epl ace= Al a <220>

    Page 93

    2018203471 16 May 2018

    A1472PCT <221> VARIANT <222> (3) . . (3) <223> / r epl ace= Ar g <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 3) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Asp <220>

    <221> VARI ANT <222> (6) . . (6) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 6) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 8) . . ( 8) <223> / r epl ace= Asn <220>

    <221> VARI ANT <222> (9) . . (9) <223> / r epl ace= Gl y <220>

    <221> mi sc_f eat ure <222> ( 8) . . ( 9) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 117

    Gl y Thr Tr p As p Ser Ar g Leu Ser Al a Val Val 1 5 10 <210> 118 <211> 13 <212> PRT <213> Ar t i f i ci al Sequenc e

    <220>

    <221> sour ce

    Page 94

    2018203471 16 May 2018

    A1472PCT <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> (1)..(1) <223> / r epl ace= Gl n <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / r epl ace= Asp <220>

    <221> mi sc_f eat ure <222> ( 3) . . ( 4) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> (6) . . (6) <223> / r epl ace= <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Leu <220>

    <221> VARI ANT <222> (8) . . (8) <223> / r epl ace= Ar g <220>

    <221> VARI ANT <222> (9) . . (9) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 10) . . ( 10)

    Page 95

    2018203471 16 May 2018

    A1472PCT <223> / r epl ace= Phe <220>

    <221> VARI ANT <222> ( 11) . . ( 11) <223> / repl ace=Thr <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / r epl ace= Al a <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> / repl ace= Asn or Tyr <220>

    <221> mi sc_f eat ure <222> ( 6) . . ( 13) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 118

    Ser Gl y Ser Ser Ser Asn Ile Gl y Asn Asn Tyr Val Ser

    1 5 10 <210> 119 <211> 7 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / repl ace=G y or Thr or Arg <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> /repl ace= Lys or Ser <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 2) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions

    Page 96

    A1472PCT

    2018203471 16 May 2018 <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / repl ace= Asn or Gn <220>

    <221> mi sc_f eat ure <222> ( 4) . . ( 4) <223> / not e= Resi due given in the sequence has no preference with respect t o t hose i n t he annot at i ons f or sai d posi t i on <400> 119

    Asp Asn Asn Lys Arg Pro Ser

    1 5 <210> 120 <211> 11 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / repl ace= Asn or Ala <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> / r epl ace= Ser or Al a <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Ar g <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 3) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Asp

    Page 97

    2018203471 16 May 2018

    A1472PCT <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Val <220>

    <221> VARI ANT <222> ( 8) . . ( 8) <223> / repl ace=Tyr or Asn <220>

    <221> VARI ANT <222> ( 9) . . ( 9) <223> / r epl ace= Hi s or Gl y <220>

    <221> VARI ANT <222> ( 10) . . ( 10) <223> / r epl ace= Leu <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 10) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 120

    Gl y Thr Tr p Asp Ser Ar g Leu Ser Al a Val Val

    1 5 10 <210> 121 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Asp <220>

    <221> mi sc_f eat ure

    Page 98

    2018203471 16 May 2018

    A1472PCT <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / repl ace=Tyr <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 5) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <400> 121

    G y Tyr Tyr Met hi s

    1 5 <210> 122 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 3) . . ( 3) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <400> 122

    Trp I l e Asn Pro Asn Ser Gy Gy Thr Asn Tyr Al a G n Lys Phe G n 1 5 10 15

    Gl y <210> 123 <211> 21 <212> PRT

    Page 99

    2018203471 16 May 2018

    A1472PCT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 2) <223> / repl ace=G y <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / repl ace=Tyr <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 3) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / repl ace=G y <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / repl ace=Tyr <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / repl ace=Al a <220>

    <221> VARI ANT <222> (8) . . (9) <223> / repl ace= <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 9) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 11) . . ( 11) <223> / r epl ace= Leu

    Page 100

    A1472PCT

    2018203471 16 May 2018 <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / repl ace=Tyr <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 14) . . ( 14) <223> / r epl ace= Hi s <220>

    <221> mi sc_f eat ure <222> ( 11) . . ( 14) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 17) . . ( 17) <223> / r epl ace= <220>

    <221> mi sc_f eat ure <222> ( 17) . . ( 17) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 123

    Asp Gl n Met Ser Ile Ile Met Leu Arg Gly Val Phe Pro Pro Tyr Tyr 1 5 10 15

    Tyr Gl y Met Asp Val 20 <210> 124 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    Page 101

    2018203471 16 May 2018

    A1472PCT <221> VARI ANT <222> ( 5) . . ( 5) <223> / repl ace=Thr <220>

    <221> m sc_feat ure <222> ( 5) . . ( 5) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARI ANT <222> ( 14) . . ( 14) <223> / r epl ace= Al a <220>

    <221> m sc_feat ure <222> ( 14) . . ( 14) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 124

    Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Thr Ala Pro 1 5 10 15

    Val Lys Gl y <210> 125 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Ser <220>

    <221> m sc_feat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARI ANT

    Page 102

    2018203471 16 May 2018

    A1472PCT <222> ( 3) . . ( 3) <223> / r epl ace= Al a <220>

    <221> mi sc_f eat ure <222> ( 3) . . ( 3) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARIANT <222> ( 5) . . ( 5) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 5) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <400> 125

    Thr Tyr Ser Met Asn

    1 5 <210> 126 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARIANT <222> ( 1) . . ( 1) <223> / r epl ace= Al a <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / r epl ace= Gl y <220>

    <221> mi sc_f eat ure

    Page 103

    2018203471 16 May 2018

    A1472PCT <222> ( 4) . . ( 4) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARI ANT <222> ( 6) . . ( 7) <223> / r epl ace= Gl y <220>

    <221> VARI ANT <222> ( 8) . . ( 8) <223> / r epl ace= Ar g <220>

    <221> VARI ANT <222> ( 9) . . ( 9) <223> / repl ace=Thr <220>

    <221> mi sc_f eat ure <222> ( 6) . . ( 9) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 126

    Ser I l e Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Al a Asp Ser Val Lys 1 5 10 15

    Gl y <210> 127 <211> 22 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Asp <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> / r epl ace= Gl n

    Page 104

    A1472PCT

    2018203471 16 May 2018 <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Ar g <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / r epl ace= Gl u <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Val <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / r epl ace= Gl y <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 7) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 11) . . ( 11) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / r epl ace= Gl y <220>

    <221> mi sc_f eat ure <222> ( 11) . . ( 12) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions

    <400> 127 Gl u Gl y Val Ser Gl y Ser Ser Pro Tyr Ser I l e Ser Tr p Ty r As p Ty r 1 5 10 15 Ty r Ty r Gl y Met As p Val

    Page 105

    A1472PCT

    2018203471 16 May 2018 <210> 128 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> / repl ace=Tyr <220>

    <221> mi sc_f eat ure <222> ( 2) . . ( 2) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 128

    Ser Phe Gl y Met Hi s

    1 5 <210> 129 <211> 17 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / repl ace=Tyr <220>

    <221> mi sc_f eat ure <222> ( 4) . . ( 4) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <220>

    <221> VARI ANT

    Page 106

    2018203471 16 May 2018

    A1472PCT <222> ( 8) . . ( 8) <223> / r epl ace= Hi s <220>

    <221> mi sc_f eat ure <222> ( 8) . . ( 8) <223> / not e= Resi due given in the sequence has no preference with respect to that in the annotation for said position <220>

    <221> VARI ANT <222> ( 11) . . ( 11) <223> / repl ace=Tyr <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / r epl ace= Al a <220>

    <221> mi sc_f eat ure <222> ( 11) . . ( 12) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <400> 129

    Val Ile Ser Phe Asp Gl y Ser I l e Lys Tyr Ser Val Asp Ser Val Lys 1 5 10 15

    Gl y <210> 130 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Gl u <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with Page 107

    2018203471 16 May 2018

    A1472PCT respect to that in the annotation for said position <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Lys <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / r epl ace= Ar g <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Val <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / repl ace=Thr <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Met <220>

    <221> mi sc_f eat ure <222> ( 3) . . ( 7) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 9) . . ( 9) <223> / repl ace=Thr <220>

    <221> VARI ANT <222> ( 10) . . ( 10) <223> / r epl ace= Leu <220>

    <221> mi sc_f eat ure <222> ( 9) . . ( 10) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> / repl ace=Tyr

    Page 108

    2018203471 16 May 2018

    A1472PCT <220>

    <221> VARIANT <222> ( 14) . . ( 14) <223> / r epl ace= <220>

    <221> VARI ANT <222> ( 15) . . ( 15) <223> / r epl ace= Phe <220>

    <221> mi sc_f eat ure <222> ( 13) . . ( 15) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 19) . . ( 19) <223> / r epl ace= Leu <220>

    <221> VARI ANT <222> ( 20) . . ( 20) <223> / r epl ace= Asp <220>

    <221> mi sc_f eat ure <222> ( 19) . . ( 20) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <400> 130

    Asp Arg Leu Asn Tyr Tyr Asp Ser Ser G y Tyr Tyr Hi s Tyr Lys Tyr 1 5 10 15

    Tyr G y Met Al a Val 20 <210> 131 <211> 5 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT

    Page 109

    2018203471 16 May 2018

    A1472PCT <222> ( 1) . . ( 1) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> / repl ace=Tyr or Phe <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Al a or Gl y <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 3) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Hi s <220>

    <221> mi sc_f eat ure <222> ( 5) . . ( 5) <223> / not e= Resi due given in the sequence has no preference with respect t o t hat i n t he annot at i on f or sai d posi t i on <400> 131

    Asn Al a Tr p Met Ser

    1 5 <210> 132 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Al a or Val <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1)

    Page 110

    2018203471 16 May 2018

    A1472PCT <223> / not e= Resi due given in the sequence has no preference with respect t o t hose i n t he annot at i ons f or sai d posi t i on <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Ser or Tr p <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / repl ace=G y or Phe or Tyr <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / repl ace=Thr or <220>

    <221> VARI ANT <222> ( 6) . . ( 6) <223> / r epl ace= <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 3) . . ( 7) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 9) . . ( 9) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 10) . . ( 10) <223> / repl ace= Arg or I l e or Asn or His <220>

    <221> VARI ANT <222> ( 11) . . ( 11) <223> / r epl ace= Lys <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / repl ace=Tyr

    Page 111

    2018203471 16 May 2018

    A1472PCT <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> / r epl ace= Ser <220>

    <221> VARI ANT <222> ( 14) . . ( 14) <223> / r epl ace= Al a or Val <220>

    <221> VARI ANT <222> ( 15) . . ( 15) <223> / r epl ace= Asp <220>

    <221> VARI ANT <222> ( 16) . . ( 16) <223> / r epl ace= Ser <220>

    <221> mi sc_f eat ure <222> ( 9) . . ( 16) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 132

    Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Thr Ala Pro 1 5 10 15

    Val Lys Gl y <210> 133 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / r epl ace= Al a or Gl u <220>

    <221> VARI ANT <222> ( 2) . . ( 2)

    Page 112

    A1472PCT

    2018203471 16 May 2018 <223> / repl ace=G n or Gly <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / r epl ace= Ar g or Leu or <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / repl ace=G u or Asn or <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Val or Al a <220>

    <221> VARI ANT <222> (6) . . (6) <223> / repl ace=G y or Tyr or

    Gl y or Lys

    I l e or Ar g

    Ala or Thr <220>

    <221> VARI ANT <222> ( 7) . . ( 7) <223> / r epl ace= Pr o or Asp or <220>

    <221> VARI ANT <222> ( 8) . . ( 8) <223> / r epl ace= Tyr or <220>

    <221> VARI ANT <222> ( 9) . . ( 9) <223> / repl ace= Ser or Thr or <220>

    <221> VARI ANT <222> ( 10) . . ( 10) <223> / r epl ace= Gl y or Leu <220>

    <221> VARI ANT <222> ( 11) . . ( 11) <223> / r epl ace= Gl y or Leu or

    Al a or Met

    Tyr <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / r epl ace= Tyr or <220>

    <221> VARI ANT

    Page 113

    2018203471 16 May 2018

    A1472PCT <222> ( 13) . . ( 13) <223> / r epl ace= Hi s <220>

    <221> VARI ANT <222> ( 14) . . ( 14) <223> / r epl ace= Asp or <220>

    <221> VARI ANT <222> ( 15) . . ( 15) <223> / r epl ace= Lys or Phe <220>

    <221> VARI ANT <222> ( 16) . . ( 17) <223> / r epl ace= <220>

    <221> m sc_feat ure <222> ( 1) . . ( 17) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> (19) . . (19) <223> / r epl ace= Leu <220>

    <221> VARI ANT <222> ( 20) . . ( 20) <223> / r epl ace= Al a <220>

    <221> m sc_feat ure <222> ( 19) . . ( 20) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions

    <400> 133 As p Ar g Thr G y Tyr Ser I l e Ser Tr p Ser Ser Trp Tyr Tyr Tyr Tyr 1 5 10 15

    Tyr G y Met As p 20 Val <210> 134 <211> 5 <212> PRT <213> Ar t i f i ci al Sequenc e

    Page 114

    2018203471 16 May 2018

    A1472PCT <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    <221> VARI ANT <222> ( 1) . . ( 1) <223> / repl ace=G y or Asp or Ser or Ala <220>

    <221> VARI ANT <222> ( 2) . . ( 2) <223> /repl ace= Phe or Tyr <220>

    <221> VARI ANT <222> ( 3) . . ( 3) <223> / repl ace= Tyr or Ala or Gy <220>

    <221> VARI ANT <222> ( 4) . . ( 4) <223> / r epl ace= Leu <220>

    <221> VARI ANT <222> ( 5) . . ( 5) <223> / r epl ace= Hi s <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 5) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 134

    Asn Al a Tr p Met Ser

    1 5 <210> 135 <211> 19 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <220>

    Page 115

    A1472PCT

    2018203471 16 May 2018 <221> VARIANT <222> ( 1) . . ( 1) <223> / repl ace=Trp or Ala or Val or Ser or Phe <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 1) <223> / not e= Resi due given in the sequence has no preference with respect to those in the annotations for said position <220>

    <221> VARIANT <222> ( 3) . . ( 3)

    <223> / r epl ace= Asn or Ser or Tr p or Ar g <220> <221> VARI ANT <222> (4). . (4) <223> / r epl ace= Pr o or Gl y or Phe or Tyr <220> <221> VARI ANT <222> (5). . (5) <223> / r epl ace= Thr or Ar g or II II <220> <221> VARI ANT <222> (6). . (6) <223> / r epl ace= Al a or II II <220> <221> VARI ANT <222> (7). . (7) <223> / r epl ace= Asn or Hi s or Ser or Tyr <220> <221> VARI ANT <222> (8). . (9) <223> / r epl ace= Ser <220> <221> VARI ANT <222> (10). . (10) <223> / r epl ace= Gl y or Ar g or I l e or As n <220> <221> VARI ANT <222> (11)..(11) <223> / r epl ace= Lys or Ar g or Pr o <220> <221> VARI ANT <222> (12). . (12) <223> / r epl ace= Asn or Tyr or Gl u

    Page 116 or

    His or

    Tyr

    A1472PCT

    2018203471 16 May 2018 <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> / repl ace=Ser <220>

    <221> VARI ANT <222> ( 14) . . ( 14) <223> / repl ace=Al a or Val <220>

    <221> VARI ANT <222> ( 15) . . ( 15) <223> / repl ace=G n or Asp <220>

    <221> VARI ANT <222> ( 16) . . ( 16) <223> /repl ace= Lys or Ser <220>

    <221> VARI ANT <222> ( 17) . . ( 17) <223> / repl ace= Phe <220>

    <221> VARI ANT <222> ( 18) . . ( 18) <223> / repl ace=G n <220>

    <221> mi sc_f eat ure <222> ( 3) . . ( 18) <223> / note= Residues given in the sequence have no preference with respect to those in the annotations for said positions <400> 135

    Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Thr Ala Pro 1 5 10 15

    Val Lys Gl y <210> 136 <211> 21 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic Page 117

    2018203471 16 May 2018

    A1472PCT pept i de

    <220> <221> VARI ANT Al a or Gl u <222> <223> (1)..(1) / r epl ace= Gl y or <220> <221> VARI ANT <222> (2). . (2) <223> / r epl ace= Gl y or Gl n <220> <221> VARI ANT <222> (3). . (3) <223> / r epl ace= Met or Tyr or Ar g <220> <221> VARI ANT <222> (4). . (4) <223> / r epl ace= Ser or Gl u or As n <220> <221> VARI ANT <222> (5). . (5) <223> / r epl ace= I l e or Gl y or Val <220> <221> VARI ANT <222> (6). . (6) <223> / r epl ace= I l e or Tyr or Gl y <220> <221> VARI ANT <222> (7). . (7) <223> / r epl ace= Met or Al a or Pr o <220> <221> VARI ANT <222> (8). . (8) <223> / r epl ace= Leu or Tyr or II II <220> <221> VARI ANT <222> (9). . (9) <223> / r epl ace= Ar g or Ser or Thr <220> <221> VARI ANT <222> (10). . (10) <223> / r epl ace= Gl y or Leu

    or or or or or or

    Leu

    I l e

    Al a

    Al a

    Asp

    II II or or or

    Gly or Lys

    Ar g

    Thr <220>

    Page 118

    2018203471 16 May 2018

    A1472PCT <221> VARI ANT <222> ( 11) . . ( 11) <223> / repl ace= Val or Leu or Gly or Tyr <220>

    <221> VARI ANT <222> ( 12) . . ( 12) <223> / repl ace=Tyr or Trp or <220>

    <221> VARI ANT <222> ( 13) . . ( 13) <223> / r epl ace= Pr o or Ser or Hi s <220>

    <221> VARI ANT <222> ( 14) . . ( 14) <223> / r epl ace= Pr o or Asp or Hi s or <220>

    <221> VARI ANT <222> ( 15) . . ( 15) <223> / r epl ace= Lys or Phe <220>

    <221> VARI ANT <222> ( 16) . . ( 17) <223> / r epl ace= <220>

    <221> mi sc_f eat ure <222> ( 1) . . ( 17) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <220>

    <221> VARI ANT <222> ( 19) . . ( 19) <223> / r epl ace= Leu <220>

    <221> VARI ANT <222> ( 20) . . ( 20) <223> / r epl ace= Al a <220>

    <221> mi sc_f eat ure <222> ( 19) . . ( 20) <223> / not e= Resi dues given in the sequence have no preference with respect to those in the annotations for said positions <400> 136

    Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Phe Tyr Tyr Tyr Tyr 1 5 10 15

    Page 119

    A1472PCT

    2018203471 16 May 2018

    Tyr Gl y Met As p 20 Val <210> 137 <211> 110 <212> PRT <213> Ar t i f i ci al Sequenc e

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 137

    Gl n 1 Ser Val Leu Thr 5 Gl n Pr o Pr o Ser Val 10 Ser Gl u Al a Pr o Gl y 15 Gl n Lys Val Thr Ile Ser Cy s Ser Gl y Ser Ser Ser As n Ile Gl y As n As n 20 25 30 Ty r Val Ser Tr p Ty r Gl n Gl n Leu Pr o Gl y Thr Al a Pr o Lys Leu Leu 35 40 45 I l e Ty r As p As n As n Lys Ar g Pr o Ser Gl y I l e Pr o As p Ar g Phe Ser 50 55 60 Gl y Ser Lys Ser Gl y Thr Ser Al a Thr Leu Gl y Ile Thr Gl y Leu Gl n 65 70 75 80 Thr Gl y As p Gl u Al a As p Ty r Ty r Cy s Gl y Thr Tr p As p Ser Ar g Leu 85 90 95 Ser Al a Val Val Phe Gl y Gl y Gl y Thr Lys Leu Thr Val Leu

    100 105 110 <210> 138 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    Page 120

    A1472PCT

    2018203471 16 May 2018 <400> 138

    Gl n 1 Ser Val Leu Thr 5 Gl n Pr o Pr o Ar g Val Thr Ile 20 Ser Cys Ser Gl y Tyr Val Tyr 35 Tr p Tyr Gl n Gl n Leu 40 I l e Phe 50 Ar g Ser As n Gl n Ar g 55 Pr o Gl y 65 Ser Lys Ser Gl y Thr 70 Ser Al a Ser Gl u As p Gl u Al a 85 As p Tyr Tyr Ser Gl y Tr p Val 100 Phe Gl y Gl y Gl y

    Ser Al a 10 Ser Gl y Thr Pr o Gl y 15 Gl n Ser 25 Ser Ser As n Ile Gl y 30 Ser As n Pr o Gl y Al a Al a Pr o 45 Lys Leu Leu Ser Gl y Val Pr o 60 As p Ar g Phe Ser Ser Leu Al a 75 Ile Ser Gl y Leu Ar g 80 Cys Al a 90 Al a Tr p As p As p Ser 95 Leu Thr 105 Lys Leu Thr Val Leu 110

    <210> 139 <211> 107 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Ar t i pol ypept i de <400> 139 ficial Sequence: Synthetic

    As p 1 I l e Gl n Met Thr 5 Gl n Ser Pr o As p Ar g Val Thr 20 Ile Thr Cys Ar g Leu Gl y Tr p 35 Phe Gl n Gl n Lys Pr o 40 Tyr Al a Al a Ser Ser Leu Gl n Ser

    Ser Ser 10 Leu Ser Al a Ser Val 15 Gl y Al a 25 Ser Gl n Gl y Ile Ar g 30 As n As p Gl y Lys Al a Pr o Lys 45 Ar g Leu Ile Gl y Val Pr o Ser Ar g Phe Ser Gl y

    Page 121

    A1472PCT

    2018203471 16 May 2018

    50 55 60 Ser Gl y Ser Gl ^y Thr Gl u Phe Thr Leu Thr I l e Ser Ser Leu Gl n Pr o 65 70 75 80 Gl u As p Leu Al a Thr Tyr Tyr Cys Leu Gl n Tyr As n Ile Tyr Pr o Tr p 85 90 95 Thr Phe Gl y Gl n Gl y Thr Lys Val Gl u I l e Lys 10 0 105

    <210> 140 <211> 108 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 140

    Ser 1 Ser Gl u Leu Thr 5 Gl n As p Pr o Thr Val 10 Ser Val Al a Leu Gl y 15 Gl n Thr Val Lys Ile Thr Cys Gl n Gl y As p Ser Leu Ar g Ser Phe Tyr Al a 20 25 30 Ser Tr p Tyr Gl n Gl n Lys Pr o Gl y Gl n Al a Pr o Val Leu Val Phe Tyr 35 40 45 Gl y Lys As n As n Ar g Pr o Ser Gl y I l e Pr o As p Ar g Phe Ser Gl y Ser 50 55 60 Ser Ser Gl y As n Thr Al a Ser Leu Thr I l e Thr Gl y Al a Gl n Al a Gl u 65 70 75 80 As p Gl u Al a As p Tyr Tyr Cys As n Ser Ar g As p Ser Ser Val Tyr Hi s 85 90 95 Leu Val Leu Gl y Gl y Gl y Thr Lys Leu Thr Val Leu 100 105

    Page 122

    2018203471 16 May 2018

    A1472PCT <210> 141 <211> 112 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 141

    As p 1 I l e I l e Leu Al a 5 Gl n Thr Pr o Leu Ser 10 Leu Ser Val Thr Pr o 15 Gl y Gl n Pr o Al a Ser Ile Ser Cy s Lys Ser Ser Gl n Ser Leu Leu Hi s Ser 20 25 30 Al a Gl y Lys Thr Ty r Leu Ty r Tr p Ty r Leu Gl n Lys Pr o Gl y Gl n Pr o 35 40 45 Pr o Gl n Leu Leu Ile Ty r Gl u Val Ser As n Ar g Phe Ser Gl y Val Pr o 50 55 60 As p Ar g Phe Ser Gl y Ser Gl y Ser Gl y Thr As p Phe Thr Leu Lys Ile 65 70 75 80 Ser Ar g Val Gl u Al a Gl u As p Val Gl y I l e Ty r Ty r Cy s Met Gl n Ser 85 90 95 Phe Pr o Leu Pr o Leu Thr Phe Gl y Gl y Gl y Thr Lys Val Gl u Ile Lys 100 105 110

    <210> 142 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce

    <223> / not e= Descr i pt i on pol ypept i de of Ar t i f i ci al Sequence: Synt het i c <400> 142 Gl n Ser Val Leu Thr Gl n Pr o Pr o Ser Val Ser Al a Al a Pr o Gl y Gl n 1 5 10 15

    Page 123

    A1472PCT

    2018203471 16 May 2018

    Lys Val Thr Ile Ser Cy s Ser Gl y Ser Ser Ser As n Ile Gl y As n As n 20 25 30 Tyr Val Ser Tr p Ty r Gl n Gl n Leu Pr o Gl y Thr Al a Pr o Lys Leu Leu 35 40 45 I l e Ty r As p As n As n Lys Ar g Pr o Ser Gl y I l e Pr o As p Ar g Phe Ser 50 55 60 Gl y Ser Lys Ser Gl y Thr Ser Thr Thr Leu Gl y Ile Thr Gl y Leu Gl n 65 70 75 80 Thr Gl y As p Gl u Al a As p Ty r Ty r Cy s Gl y Thr Tr p As p Ser Ar g Leu 85 90 95 Ser Al a Val Val Phe Gl y Gl y Gl y Thr Lys Leu Thr Val Leu 100 105 110 <210> 143 <211> 112 <212> PRT <213> Art i fi ci al Sequenc e

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 143

    Asp I l e Val Met Thr Gl n Ser Pr o Leu Ser Leu Pr o Val Thr Pr o Gl y 1 5 10 15

    G u Pro Al a Ser I l e Ser Cys Arg Ser Ser G n Ser Leu Leu Hi s Ser 20 25 30

    Phe Gl y Ty r As n Ty r 35

    Leu As p Tr p Ty r 40

    Leu Gl n Lys Pr o Gl y Gl n Ser 45

    Pr o Gl n Leu Leu 50

    I l e Tyr

    Leu Gl y Ser 55

    Asn Arg Al a Ser 60

    Gl y Val

    Pr o

    Asp Ar g Phe Ser Gl y Ser 65 70

    Gl y Ser

    Gl y

    Thr As p Phe 75

    Thr Leu Lys I l e 80

    Page 124

    2018203471 16 May 2018

    A1472PCT Ser Ar g Val Gl u Al a Gl u As p Val Gl y Val Ty r Ty r Cys Met Gl n Al a 85 90 95 Leu Gl n Thr Pr o Phe Thr Phe Gl y Pr o Gl y Thr Lys Val As p Ile Lys 100 105 110 <210> 144 <211> 112 <212> PRT <213> Ar t i f i ci al Sequenc e

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 144

    As p 1 I l e I l e Leu Thr 5 Gl n Thr Pr o Leu Ser 10 Leu Ser Val Thr Pr o 15 Gl y Gl n Pr o Al a Ser 20 Ile Ser Cy s Lys Ser 25 Ser Gl n Ser Leu Leu 30 Hi s Ser As p Gl y Lys 35 Thr Ty r Leu Ty r Tr p 40 Ty r Leu Gl n Lys Pr o 45 Gl y Gl n Pr o Pr o Gl n 50 Leu Leu Ile Ty r Gl u 55 Val Ser As n Ar g Phe 60 Ser Gl y Gl u Pr o As p 65 Ar g Phe Ser Gl y Ser 70 Gl y Ser Gl y Thr As p 75 Phe Thr Leu Lys Ile 80 Ser Ar g Val Gl u Al a 85 Gl u As p Val Gl y Thr 90 Ty r Ty r Cy s Met Gl n 95 Ser Phe Pr o Leu Pr o 100 Leu Thr Phe Gl y Gl y 105 Gl y Thr Lys Val Gl u 110 Ile Lys

    <210> 145 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

    Page 125

    2018203471 16 May 2018

    A1472PCT <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 145

    Gl n 1 Ser Val Leu Thr 5 Gl n Pr o Pr o Ser Val 10 Ser Al a Al a Pr o Gl y 15 Gl n Lys Val Thr Ile Ser Cy s Ser Gl y Ser Ser Ser As n Ile Gl y As n As n 20 25 30 Ty r Val Ser Tr p Ty r Gl n Gl n Phe Pr o Gl y Thr Al a Pr o Lys Leu Leu 35 40 45 I l e Ty r As p As n As n Lys Ar g Pr o Ser Gl y I l e Pr o As p Ar g Phe Ser 50 55 60 Gl y Ser Lys Ser Gl y Thr Ser Al a Thr Leu Gl y Ile Thr Gl y Leu Gl n 65 70 75 80 Thr Gl y As p Gl u Al a As p Ty r Ty r Cy s Gl y Thr Tr p As p Ser Ar g Leu 85 90 95 Ser Al a Val Val Phe Gl y Gl y Gl y Thr Lys Leu Thr Val Leu 100 105 110

    <210> 146 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 146

    Gl n 1 Ser Val Leu Thr 5 Gl n Ser Pr o Ser Al a Ser 10 Gl y Thr Pr o Gl y 15 Gl n Ar g Val Thr Ile Ser Cy s Ser Gl y Ser Ser Ser As n Ile Gl y Ser As n 20 25 30 Ty r Val Ty r Tr p Ty r Gl n Gl n Leu Pr o Gl y Al a Al a Pr o Lys Leu Leu 35 40 45

    Page 126

    A1472PCT

    2018203471 16 May 2018

    I l e Leu 50 Ar g As n As n Gl n Ar g 55 Pr o Gl y 65 Ser Lys Ser Gl y Thr 70 Ser Al a Ser Gl u As p Gl u Al a 85 As p Tyr Tyr Ser Gl y Tr p Val Phe Gl y Gl y Gl y

    100

    Ser Gl y Val Pr o 60 As p Ar g Phe Ser Ser Leu Thr 75 Ile Ser Gl y Leu Ar g 80 Cys Al a 90 Al a Tr p As p As p Ser 95 Leu Thr 105 Lys Leu Thr Val Leu 110

    <210> 147 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Ar t i pol ypept i de <400> 147 ficial Sequence: Synthetic

    Gl n 1 Ser Val Leu Thr 5 Gl n Pr o Pr o Ar g Val Thr Ile 20 Ser Cys Ser Gl y Thr Val As n 35 Tr p Tyr Gl n Gl n Leu 40 I l e Tyr 50 Thr As n As n Gl n Ar g 55 Pr o Gl y 65 Ser Lys Ser Gl y Thr 70 Ser Al a Ser Gl u As p Gl u Al a 85 As p Phe Tyr

    Ser Al a 10 Ser Gl y Thr Pr o Gl y 15 Gl n Ser 25 Ser Ser As n Ile Gl y 30 Ser As n Pr o Gl y Thr Al a Pr o 45 Lys Leu Leu Ser Gl y Val Pr o 60 As p Ar g Phe Ser Ser Leu Al a 75 Ile Ser Gl y Leu Gl n 80 Cys Al a 90 Al a Ar g As p Gl u Ser 95 Leu

    Asn Gl y Val Val

    Phe Gl y Gl y Gl y Thr

    Lys Leu Thr Val Page 127

    Leu

    2018203471 16 May 2018

    A1472PCT 100 105 110 <210> 148 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 148

    Gl n Ser 1 Val Leu Thr 5 Gl n Pr o Pr o Ser Al a 10 Ser Gl y Thr Pr o Gl y 15 Gl n Ar g Val Thr Ile Ser Cys Ser Gl y Ser Ser Ser As n Ile Gl y Ser As n 20 25 30 Tyr Val Tyr Tr p Tyr Gl n Gl n Leu Pr o Gl y Al a Al a Pr o Lys Leu Leu 35 40 45 I l e Phe Ar g As n As n Gl n Ar g Pr o Ser Gl y Val Pr o As p Ar g Phe Ser 50 55 60 Gl y Ser Lys Ser Gl y Thr Ser Al a Ser Leu Al a Ile Ser Gl y Leu Ar g 65 70 75 80 Ser Gl u As p Gl u Al a As p Tyr Tyr Cys Al a Al a Tr p As p As p Ser Leu 85 90 95 Ser Gl y Tr p Val Phe Gl y Gl y Gl y Thr Lys Leu Thr Val Leu

    100 105 110 <210> 149 <211> 112 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 149

    Asp I l e Thr Leu Thr Gl n Thr Pr o Leu Ser Leu Ser Val Ser Pr o Gl y Page 128

    2018203471 16 May 2018

    1 A1472PCT 5 10 15 Gl n Pr o Al a Ser Ile Ser Cys Lys Ser Ser Gl n Ser Leu Leu Hi s Ser 20 25 30 As p Gl y Ar g As n Tyr Leu Tyr Tr p Tyr Leu Gl n Lys Pr o Gl y Gl n Pr o 35 40 45 Pr o Gl n Leu Leu Ile Tyr Gl u Val Ser As n Ar g Phe Ser Gl y Leu Pr o 50 55 60 As p Ar g Phe Ser Gl y Ser Gl y Ser Gl y Thr As p Phe Thr Leu Lys Ile 65 70 75 80 Ser Ar g Val Gl u Al a Gl u As p Val Gl y I l e Tyr Tyr Cys Met Gl n Ser 85 90 95

    Phe Pr o Leu

    Pr o 100

    Leu Thr Phe Gl y Gl y 105

    Gl y Thr Lys

    Val

    G u Ile Lys 110 <210> 150 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 150

    Gl n Ser Val Leu Thr Gl n Pr o Pr o Ser Val Ser Al a Al a Pr o Gl y Gl n 1 5 10 15

    Lys Val Thr I l e Ser Cys Ser G y Ser Ser Ser Asn Ile G y Asn Asn 20 25 30

    Tyr Val

    Ser Trp Tyr 35

    Gl n Gl n Leu 40

    Pr o Gl y Thr

    Al a Pr o Lys Leu Leu 45

    I l e Ty r 50

    Asp Asn Asn Lys Arg 55

    Pr o

    Ser

    Gl y I l e Pr o As p Ar g Phe Ser 60

    Page 129

    A1472PCT

    2018203471 16 May 2018

    Gl y 65 Ser Lys Ser Gl y Thr 70 Ser Al a Thr Leu Gl y 75 Ile Thr Gl y Leu Gl n 80 Thr Gl y As p Gl u Al a As p Tyr Tyr Cys Gl y Thr Tr p As p Ser Ar g Leu 85 90 95 Ser Al a Val Val Phe Gl y Gl y Gl y Thr Lys Leu Thr Val Leu 100 105 110

    <210> 151 <211> 107 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 151

    As p 1 I l e Gl n Met Thr 5 Gl n Ser Pr o Ser Ser 10 Leu Ser Al a Ser Val 15 Gl y As p Ar g Val Thr Ile Thr Cys Ar g Al a Ser Gl n Gl y Ile Ar g Lys As p 20 25 30 Leu Gl y Tr p Tyr Gl n Gl n Lys Pr o Gl y Lys Al a Pr o Lys Ar g Leu Ile 35 40 45 Tyr Gl y Al a Ser Ser Leu Gl n Ser Gl y Val Pr o Ser Ar g Phe Ser Gl y 50 55 60 Ser Gl y Ser Gl y Thr Gl u Phe Thr Leu Thr I l e Ser Ser Leu Gl n Pr o 65 70 75 80 Gl u As p Phe Al a Thr Tyr Tyr Cys Leu Gl n Tyr As n Ser Phe Pr o Tr p 85 90 95 Thr Phe Gl y Gl n Gl y Thr Lys Val Gl u I l e Lys 100 105

    <210> 152 <211> 108 <212> PRT

    Page 130

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    A1472PCT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 152

    Gl u 1 I l e Val Leu Thr 5 Gl n Ser Pr o Gl y Thr 10 Leu Ser Leu Ser Pr o 15 Gl y Gl u Ar g Al a Thr Leu Ser Cys Ar g Al a Ser Gl n Ser Val Ser Ser Gl y 20 25 30 Tyr Leu Thr Tr p Tyr Gl n Gl n Lys Pr o Gl y Gl n Al a Pr o Ar g Leu Leu 35 40 45 I l e Tyr Gl y Al a Ser Ser Ar g Al a Thr Gl y I l e Pr o As p Ar g Phe Ser 50 55 60 Gl y Ser Gl y Ser Gl y Thr As p Phe Thr Leu Thr Ile Ser Ar g Leu Gl u 65 70 75 80 Pr o Gl u As p Phe Al a Val Tyr Tyr Cys Gl n Gl n Tyr Gl y As n Ser Leu 85 90 95 Cys Ar g Phe Gl y Gl n Gl y Thr Lys Leu Gl u I l e Lys 100 105

    <210> 153 <211> 108 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 153

    Gl u I l e Val Leu Thr Gl n Ser Pr o Gl y Thr Leu Ser Leu Ser Pr o Gl y 1 5 10 15

    Gl u Ar g Al a Thr Leu Ser Cys Arg Al a Ser Gl n Ser Val Ser Ser Gl y 20 25 30

    Page 131

    A1472PCT

    2018203471 16 May 2018

    Ty r Leu Thr 35 Tr p Ty r Gl n Gl n Lys 40 Pr o Gl y Gl n Al a Pr o Ar g 45 Leu Leu I l e Ty r Gl y Al a Ser Ser Ar g Al a Thr Gl y I l e Pr o As p Ar g Phe Ser 50 55 60 Gl y Ser Gl y Ser Gl y Thr As p Phe Thr Leu Thr Ile Ser Ar g Leu Gl u 65 70 75 80 Pr o Gl u As p Phe Al a Val Ty r Ty r Cy s Gl n Gl n Ty r Gl y As n Ser Leu 85 90 95 Ser Ar g Phe Gl y Gl n Gl y Thr Lys Leu Gl u I l e Lys 100 105

    <210> 154 <211> 113 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 154

    Asp I l e Val 1 Met Thr 5 Gl n Ser Pr o As p Ser 10 Leu Al a Val Ser Leu 15 Gl y Gl u Ar g Al a Thr Ile As n Cy s Lys Ser Ser Gl n Ser Ile Leu As p Ser 20 25 30 Ser As n As n As p As n Ty r Leu Al a Tr p Ty r Gl n Gl n Lys Pr o Gl y Gl n 35 40 45 Pr o Pr o Lys Leu Leu Ile Ty r Tr p Al a Ser Thr Ar g Gl u Ser Gl y Val 50 55 60 Pr o As p Ar g Phe Ser Gl y Ser Gl y Ser Gl y Thr As p Phe Thr Leu Thr 65 70 75 80 I l e Ser Ser Leu Gl n Al a Gl u As p Val Al a Val Ty r Ty r Cy s Gl n Gl n 85 90 95

    Page 132

    A1472PCT

    2018203471 16 May 2018

    Tyr Tyr Asn Thr Pro Phe Thr Phe Gl y Pro Gl y Thr Lys Val Asp Ile 100 105 110

    Lys <210> 155 <211> 107 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 155

    As p 1 I l e Gl n Met Thr 5 Gl n Ser Pr o Ser Ser 10 Leu Ser Al a Ser Val 15 Gl y As p Ar g Val Thr Ile Thr Cy s Ar g Al a Ser Gl n Gl y Ile Ar g As n As p 20 25 30 Leu Gl y Tr p Ty r Gl n Gl n Lys Pr o Gl y Lys Al a Pr o Lys Ar g Leu Ile 35 40 45 Ty r Val Al a Ser Ser Leu Gl n Ser Gl y Val Pr o Ser Ar g Phe Ser Gl y 50 55 60 Ser Gl y Ser Gl y Thr Gl u Phe Thr Leu Thr I l e Ser Ser Leu Gl n Pr o 65 70 75 80 Gl u As p Phe Al a Thr Ty r Ty r Cy s Leu Gl n Ty r As n Thr Ty r Pr o Leu 85 90 95 Thr Phe Gl y Gl y Gl y Thr Lys Val Gl u I l e Lys 100 105

    <210> 156 <211> 108 <212> PRT <213> Ar t i f i ci al Sequence

    Page 133

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    A1472PCT <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 156

    Gl u 1 I l e Val Met Thr 5 Gl n Ser Pr o Al a Thr 10 Leu Ser Val Ser Pr o 15 Gl y Gl u Ar g Al a Thr Leu Ser Cys Ar g Al a Ser Gl n Ser Val Ar g Ser As n 20 25 30 Leu Al a Tr p Tyr Gl n Gl n Lys Pr o Gl y Gl n Al a Pr o Ar g Leu Leu Ile 35 40 45 Hi s As p Al a Ser Pr o Ar g Thr Al a Gl y I l e Pr o Al a Ar g Phe Ser Gl y 50 55 60 Ser Gl y Ser Gl y Thr Gl u Phe Thr Leu Thr I l e As n Ser Leu Gl n Ser 65 70 75 80 Gl u As p Phe Al a Val Tyr Tyr Cys Gl n Gl n Tyr As n Tyr Tr p Thr Pr o 85 90 95 I l e Thr Phe Gl y Gl n Gl y Thr Ar g Leu Gl u I l e Lys 100 105

    <210> 157 <211> 110 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 157

    Gl n Ser Val Leu Thr Gl n Pr o Pr o Ser Met Ser Al a Al a Pr o Gl y Gl n 1 5 10 15

    Ly s Val Thr I l e Ser Cy s Ser Gl y Ser Ser Ser As n I l e Gl y As n As n 20 25 30

    Tyr Val

    Ser Trp Tyr

    Gl n Gl n Leu

    Pr o Gl y Thr Al a Page 134

    Pr o Lys

    Leu Leu

    A1472PCT

    2018203471 16 May 2018

    35 40 I l e Tyr As p As n As n Lys Ar g Pr o 50 55 Gl y Ser Lys Ser Gl y Thr Ser Al a 65 70 Thr Gl y As p Gl u Al a As n Tyr Cys 85 Ser Val Tr p Val Phe Gl y Gl y Gl y

    100

    45 Ser Gl y I l e Pr o 60 As p Ar g Phe Ser Thr Leu Gl y 75 Ile Thr Gl y Leu Gl n 80 Cys Gl y 90 Thr Tr p As p Ile Gl y 95 Leu Thr 105 Lys Leu Thr Val Leu 110

    <210> 158 <211> 130 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Ar t i pol ypept i de <400> 158 ficial Sequence: Synthetic

    Gl n 1 Val Gl n Leu Val 5 Gl u Ser Gl y Ser Leu Ar g Leu 20 Ser Cys Al a Al a Gl y Met Hi s 35 Tr p Val Ar g Gl n Al a 40 Al a Val 50 I l e Ser Phe As p Gl y 55 Ser Lys 65 Gl y Ar g Phe Thr Ile 70 Ser Ar g Leu Gl n Met As n Ser Leu Ar g Al a

    Gl y Gl y 10 Val Val Gl n Pr o Gl y 15 Ar g Ser 25 Gl y Phe Thr Phe Ser 30 Ser Phe Pr o Gl y Lys Gl y Leu 45 Gl u Tr p Val I l e Lys Tyr Ser 60 Val As p Ser Val As p As n Ser 75 Lys As n Thr Leu Phe 80 Gl u As p 90 Thr Al a Val Tyr Tyr 95 Cys

    Page 135

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    Al a Ar g As p Ar g 100 Leu As n Ty r Ty r Lys Ty r Ty r 115 Gl y Met Al a Val Tr p 120 Ser Ser 130

    As p 105 A1472PCT Ser Ser Gl y Ty r Ty r 110 Hi s Ty r Gl y Gl n Gl y Thr Thr 125 Val Thr Val

    <210> 159 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 159

    Gl u Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y Leu Val Lys Pr o Gl y Gl y 1 5 10 15

    Ser Leu Ar g Leu Ser Cys Al a Al a Ser Gl y Phe Thr Phe Ser Asn Al a 20 25 30

    Tr p Met Ser Tr p Val 35

    Ar g Gl n Al a Pr o Gl y 40

    Lys

    Gl y Leu Gl u Tr p Val 45

    Gl y Ar g I l e Lys Ser 50

    Thr

    Thr As p Gl y Gl y Thr 55

    Thr As p Ty r Al a Al a 60

    Pr o Val 65

    Lys Gl y Ar g Phe Thr 70

    I l e Ser Ar g As p As p Ser 75

    Lys Asn Thr 80

    Leu Tyr Leu Gl n Met 85

    Asn Ser

    Leu Lys Thr 90

    Gl u Asp Thr Al a Val 95

    Ty r

    Ty r Cy s Thr Thr As p Ar g Thr 100

    Gl y Tyr Ser 105

    I l e Ser Tr p Ser Ser Ty r 110

    Ty r Ty r Ty r Ty r 115

    Gl y Met

    Asp Val 120

    Tr p

    Gl y Gl n Gl y

    Thr Thr Val 125

    Thr

    Page 136

    A1472PCT

    2018203471 16 May 2018

    Val Ser Ser 130 <210> 160 <211> 130 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 160

    Gl u 1 Val Gl n Leu Leu Gl u 5 Ser Gl y Gl y Gl y 10 Leu Val Gl n Pr o Gl y 15 Gl u Ser Leu Ar g Leu Ser Cys Al a Al a Ser Gl y Phe Thr Phe Ser Ser Tyr 20 25 30 Al a Met Ser Tr p Val Ar g Gl n Al a Pr o Gl y Lys Gl y Leu Gl u Tr p Val 35 40 45 Ser Al a I l e Ser Gl y Ser Gl y Gl y Ar g Thr Tyr Tyr Al a As p Ser Val 50 55 60 Lys Gl y Ar g Phe Thr Ile Ser Ar g As p As n Ser Lys As n Thr Leu Tyr 65 70 75 80 Leu Gl n Met As n Ser Leu Ar g Al a Gl u As p Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Lys As p Gl n Ar g Gl u Val Gl y Pr o Tyr Ser Ser Gl y Tr p Tyr As p 100 105 110 Tyr Tyr Tyr Gl y Met As p Val Tr p Gl y Gl n Gl y Thr Thr Val Thr Val 115 120 125

    Ser Ser 130 <210> 161 <211> 130

    Page 137

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    A1472PCT <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 161

    Gl n 1 Val Gl n Leu Val 5 Gl n Ser Gl y Al a Gl u Val 10 Lys Lys Pr o Gl y 15 Al a Ser Val Lys Val Ser Cy s Lys Al a Ser Gl y Ty r Thr Phe Thr Gl y Ty r 20 25 30 Ty r Met Hi s Tr p Val Ar g Gl n Al a Pr o Gl y Gl n Gl y Leu Gl u Tr p Met 35 40 45 Gl y Tr p I l e As n Pr o As n Ser Gl y Gl y Thr As n Ty r Al a Gl n Lys Phe 50 55 60 Gl n Gl y Ar g Val Thr Met Thr Ar g As p Thr Ser Ile Ser Thr Al a Ty r 65 70 75 80 Met Gl u Leu Ser Ar g Leu Ar g Ser As p As p Thr Al a Val Ty r Phe Cy s 85 90 95 Al a Ar g As p Gl n Met Ser Ile Ile Met Leu Ar g Gl y Val Phe Pr o Pr o 100 105 110 Ty r Ty r Ty r Gl y Met As p Val Tr p Gl y Gl n Gl y Thr Thr Val Thr Val 115 120 125

    Ser Ser 130 <210> 162 <211> 129 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    Page 138

    A1472PCT

    2018203471 16 May 2018 <400> 162

    Gl n Val 1 Gl n Leu Val 5 Gl u Ser Gl y Gl y Gl y Val 10 Val Gl n Pr o Gl y 15 Ar g Ser Leu Ar g Leu Ser Cy s Al a Al a Ser Gl y Phe Thr Phe Ser Ser Ty r 20 25 30 Gl y Met Hi s Tr p Val Ar g Gl n Al a Pr o Gl y Lys Gl y Leu Gl u Tr p Val 35 40 45 Al a Val I l e Ser Ty r As p Gl y Ser Hi s Gl u Ser Ty r Al a As p Ser Val 50 55 60 Lys Gl y Ar g Phe Thr Ile Ser Ar g As p I l e Ser Lys As n Thr Leu Ty r 65 70 75 80 Leu Gl n Met As n Ser Leu Ar g Al a Gl u As p Thr Al a Val Ty r Phe Cy s 85 90 95 Al a Ar g Gl u Ar g Lys Ar g Val Thr Met Ser Thr Leu Ty r Ty r Ty r Phe 100 105 110 Ty r Ty r Gl y Met As p Val Tr p Gl y Gl n Gl y Thr Thr Val Thr Val Ser 115 120 125 Ser

    <210> 163 <211> 121 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    <400> 163 Gl u 1 Val Gl n Leu Val 5 Gl u Ser Gl y Gl y Gl y 10 Leu Val Lys Pr o Gl y Ar g 15 Ser Leu Ar g Leu Ser Cy s Thr Al a Ser Gl y Phe Thr Phe Gl y As p Ty r Page 139

    A1472PCT

    2018203471 16 May 2018

    20 25 30 Al a Met Ser Tr p Phe Ar g Gl n Al a Pr o Gl y Lys Gl y Leu Gl u Tr p Ile 35 40 45 Gl y Phe I l e Ar g Ser Ar g Al a Ty r Gl y Gl y Thr Pr o Gl u Ty r Al a Al a 50 55 60 Ser Val Lys Gl y Ar g Phe Thr Ile Ser Ar g As p As p Ser Lys Thr Ile 65 70 75 80 Al a Ty r Leu Gl n Met As n Ser Leu Lys Thr Gl u As p Thr Al a Val Ty r 85 90 95 Phe Cy s Al a Ar g Gl y Ar g Gl y Ile Al a Al a Ar g Tr p As p Ty r Tr p Gl y 100 105 110 Gl n Gl y Thr Leu Val Thr Val Ser Ser 115 120 <210> 164 <211> 131 <212> PRT <213> Art i f i ci al Sequenc e

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 164

    Gl u Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y Leu Val Lys Pro Gl y Gl y 1 5 10 15

    Ser Leu Arg Leu Ser Cys Al a Al a Ser Gl y Phe Thr Phe Ser Asn Al a 20 25 30

    Tr p Met Ser Tr p Val Ar g Gl n Al a Pr o Gl y Lys Gl y Leu Gl u Tr p Val 35 40 45

    Gl y Ar g I l e Lys Ser 50

    Lys Thr Asp 55

    Gl y

    Gl y Thr Thr 60

    As p Ty r Thr Al a

    Page 140

    A1472PCT

    2018203471 16 May 2018

    Pr o Val 65 Lys Gl y Ar g Phe Thr 70 Ile Ser Ar g As p As p 75 Ser Ly s As n Thr 80 Leu Tyr Leu Gl n Met Asn Ser Leu Lys Al a Gl u As p Thr Al a Val Tyr 85 90 95 Tyr Cys Thr Thr As p Ar g Thr Gl y Tyr Ser I l e Ser Tr p Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gl y Met Asp Val Tr p Gl y Gl n Gl y Thr Thr Val Thr 115 120 125 Val Ser Ser 130 <210> 165 <211> 127 <212> PRT <213> Art i fi ci al Sequence

    <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 165

    Gl n Val Gl n Leu Val Gl n Ser Gl y Al a Gl u Val Lys Lys Pr o Gl y Al a 1 5 10 15

    Ser Val Lys Val Ser Cys Lys Al a Ser Gl y Tyr Thr Phe Thr Asp Tyr 20 25 30

    Tyr Met Tyr Trp Val 35

    Ar g Gl n Al a Pr o Gl y 40

    Gl n

    Gl y Leu Gl u Tr p Met 45

    Gl y Tr p I l e Ser 50

    Pro Asn Ser 55

    Gl y Gl y Thr Asn Tyr 60

    Al a Gl n Lys Phe

    Gl n Gl y Ar g Val 65

    Thr Met 70

    Thr Ar g Asp Thr Ser 75

    I l e Ser Thr Al a Ty r 80

    Met

    Gl u Leu Ser Ar g Leu Ar g Ser 85

    Asp Asp Thr Al a Val 90

    Tyr Tyr Cys 95

    Page 141

    2018203471 16 May 2018

    A1472PCT

    Val Arg Gl y Gl y Tyr Ser Gl y Tyr Al a Gl y Leu Tyr Ser Hi s Tyr Tyr 100 105 110

    Gl y Met Asp Val Tr p Gl y Gl n Gl y Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 166 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 166

    Gl u 1 Val Gl n Leu Val 5 Gl u Ser Gl y Gl y Gl y 10 Leu Val Lys Pr o Gl y 15 Gl y Ser Leu Ar g Leu 20 Ser Cys Al a Al a Ser 25 Gl y Phe Thr Phe Gl y 30 As n Al a Tr p Met Ser 35 Tr p Val Ar g Gl n Al a 40 Pr o Gl y Lys Gl y Leu 45 Gl u Tr p Val Gl y Ar g 50 I l e Lys Ser Lys Thr 55 As p Gl y Gl y Thr Thr 60 As p Tyr Al a Al a Pr o 65 Val Lys Gl y Ar g Phe 70 Thr Ile Ser Ar g As p 75 As p Ser Lys As n Thr 80 Leu Tyr Leu Gl n Met 85 As n Ser Leu Lys Thr 90 Gl u As p Thr Al a Val 95 Tyr Phe Cys Thr Thr 100 As p Ar g Thr Gl y Tyr 105 Ser I l e Ser Tr p Ser 110 Ser Tyr Tyr Tyr Tyr 115 Tyr Gl y Met As p Val 120 Tr p Gl y Gl n Gl y Thr 125 Thr Val Thr

    Val Ser Ser

    130

    Page 142

    A1472PCT

    2018203471 16 May 2018 <210> 167 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 167

    Gl u 1 Val Gl n Leu Val 5 Gl u Ser Gl y Gl y Gl y 10 Leu Val Lys Pr o Gl y 15 Gl y Ser Leu Ar g Leu 20 Ser Cys Al a Al a Ser 25 Gl y Phe Thr Phe Gl y 30 As n Al a Tr p Met Ser 35 Tr p Val Ar g Gl n Al a 40 Pr o Gl y Lys Gl y Leu 45 Gl u Tr p Val Gl y Ar g 50 I l e Lys Ser Lys Thr 55 As p Gl y Gl y Thr Thr 60 As p Tyr Al a Al a Pr o 65 Val Lys Gl y Ar g Phe 70 Thr Ile Ser Ar g As p 75 As p Ser Lys As n Thr 80 Leu Tyr Leu Gl n Met 85 As n Ser Leu Lys Thr 90 Gl u As p Thr Al a Val 95 Tyr Tyr Cys Thr Thr 100 As p Ar g Thr Gl y Tyr 105 Ser I l e Ser Tr p Ser 110 Ser Tyr Tyr Tyr Tyr 115 Tyr Gl y Met As p Val 120 Tr p Gl y Gl n Gl y Thr 125 Thr Val Thr

    Val Ser Ser 130 <210> 168 <211> 130 <212> PRT <213> Ar t i f i ci al Sequence

    Page 143

    2018203471 16 May 2018

    A1472PCT <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 168

    Gl n 1 Val Gl n Leu Val 5 Gl u Ser Gl y Gl y Gl y Val 10 Val Gl n Pr o Gl y 15 Ar g Ser Leu Ar g Leu Ser Cys Al a Al a Ser Gl y Phe Thr Phe Ser Ser Phe 20 25 30 Gl y Met Hi s Tr p Val Ar g Gl n Al a Pr o Gl y Lys Gl y Leu Gl u Tr p Val 35 40 45 Al a Val I l e Ser Phe As p Gl y Ser I l e Lys Tyr Ser Val As p Ser Val 50 55 60 Lys Gl y Ar g Phe Thr Ile Ser Ar g As p As n Ser Lys As n Thr Leu Phe 65 70 75 80 Leu Gl n Met As n Ser Leu Ar g Al a Gl u As p Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Ar g As p Ar g Leu As n Tyr Tyr As p Ser Ser Gl y Tyr Tyr Hi s Tyr 100 105 110 Lys Tyr Tyr Gl y Leu Al a Val Tr p Gl y Gl n Gl y Thr Thr Val Thr Val 115 120 125

    Ser Ser 130 <210> 169 <211> 131 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 169

    Gl u Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y Leu Val Lys Pro Gl y Gl y Page 144

    2018203471 16 May 2018

    Ser Leu Ar g Leu 20 Ser Cy s Al a Al a Ser Met As n 35 Tr p Val Ar g Gl n Al a 40 Ser Ser 50 I l e Ser Ser Ser Ser 55 Ser Lys 65 Gl y Ar g Phe Thr Ile 70 Ser Ar g Leu Gl n Met Ser Ser 85 Leu Ar g Al a Al a Ar g Gl u Gl y 100 Val Ser Gl y Ser As p Ty r Ty r 115 Ty r Gl y Met As p Val 120 Val Ser 130 Ser

    A1472PCT 10 15 Ser 25 Gl y Ty r Thr Phe Ser 30 Thr Ty r Pr o Gl y Lys Gl y Leu 45 Gl u Tr p Val Ty r Ar g Ty r Ty r 60 Al a As p Ser Val As p As n Al a 75 Lys As n Ser Leu Ty r 80 Gl u As p 90 Thr Al a Val Ty r Ty r 95 Cy s Ser 105 Pr o Ty r Ser Ile Ser 110 Tr p Ty r Tr p Gl y Gl n Gl y Thr 125 Thr Val Thr

    <210> 170 <211> 126 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 170

    Gl n Val Gl n Leu Val Gl u Ser Gl y Gl y Gl y Val Val Gl n Pr o Gl y Ar g 1 5 10 15

    Ser Leu Ar g Leu Ser Cys Al a Al a Ser Gl y Phe Thr Phe Ser Ser Tyr 20 25 30

    Page 145

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    Gl y Met Hi s Tr p Val Ar g Gl n Al a 35 40

    Al a Val I l e Tr p Ty r As p Gl y Ser 50 55

    Pr o A1472PCT Gl y Lys Gl y Leu 45 Gl u Tr p Val As n Lys Tyr Tyr 60 Al a As p Ser Val

    Lys 65 Gl y Ar g Phe Ile Ile 70 Ser Ar g As p Lys Ser 75 Lys As n Thr Leu Tyr 80 Leu Gl n Met As n Ser 85 Leu Ar g Al a Gl u As p 90 Thr Al a Val Tyr Tyr 95 Cys Al a Ar g Al a Gl y 100 Gl y Ile Al a Al a Al a 105 Gl y Leu Tyr Tyr Tyr 110 Tyr Gl y Met As p Val 115 Tr p Gl y Gl n Gl y Thr 120 Thr Val Thr Val Ser 125 Ser

    <210> 171 <211> 118 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 171

    Gl n Val 1 Gl n Leu Val 5 Gl n Ser Gl y Al a Gl u Val 10 Lys Lys Pr o Gl y 15 Al a Ser Val Lys Val Ser Cys Lys Al a Ser Gl y Tyr Thr Phe Thr Al a Tyr 20 25 30 Tyr Leu Hi s Tr p Val Ar g Gl n Al a Pr o Gl y Gl n Gl y Leu Gl u Tr p Met 35 40 45 Gl y Tr p I l e As n Pr o Hi s Ser Gl y Gl y Thr As n Tyr Al a Gl n Lys Phe 50 55 60 Gl n Gl y Ar g Val Thr Met Thr Ar g As p Thr Ser Ile Ser Thr Al a Tyr 65 70 75 80

    Page 146

    A1472PCT

    2018203471 16 May 2018

    Met Gl u Leu Ser Ar g 85 Leu Ar g Ser As p As p 90 Thr Al a Val Phe Ty r 95 Cy s Al a Ar g Gl y Ar g Gl n Tr p Leu Gl y Phe As p Ty r Tr p Gl y Gl n Gl y Thr 100 105 110 Leu Val Thr Val Ser Ser

    115 <210> 172 <211> 117 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 172

    Gl n 1 Val Gl n Leu Gl n Gl n Tr p Gl y Al a Gl y Leu Leu Lys Pr o Ser 15 Gl u 5 10 Thr Leu Ser Leu Ser Cy s Al a Val Ty r Gl y Gl y Ser Phe Gl y Gl y Ty r 20 25 30 Ty r Tr p Ser Tr p Ile Ar g Gl n Pr o Pr o Gl y Lys Gl y Leu Gl u Tr p Ile 35 40 45 Gl y Gl u I l e As n Hi s Ser Gl y Gl y Thr Lys Ty r As n Pr o Ser Leu Lys 50 55 60 Ser Ar g Val Thr Ile Ser Val As p Thr Ser Lys As n Gl n Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Al a Al a As p Thr Al a Val Ty r Phe Cy s Al a 85 90 95 Ar g Gl y As p Val Val Gl y Phe Phe As p Ty r Tr p Gl y Gl n Gl y Thr Leu 100 105 110

    Val Thr Val Ser Ser

    115

    Page 147

    A1472PCT

    2018203471 16 May 2018 <210> 173 <211> 120 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 173

    Gl n Val 1 Gl n Leu Val 5 Gl n Ser Gl y Al a Gl u Val 10 Lys Lys Ser Gl y 15 Al a Ser Val Lys Val Ser Cys Lys Al a Ser Gl y Tyr Thr Phe Thr Gl y Tyr 20 25 30 Tyr Met Hi s Tr p Val Ar g Gl n Al a Pr o Gl y Gl n Gl y Leu Gl u Tr p Met 35 40 45 Gl y Tr p I l e As n Pr o As n Ser Gl y Gl y Thr As n Tyr Val Gl n Lys Phe 50 55 60 Gl n Gl y Ar g Val Thr Met Thr Ar g As p Thr Ser Ile Ser Thr Al a Tyr 65 70 75 80 Met Gl u Leu Ser Ar g Leu Ar g Ser As p As p Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Ar g As n Gl u Tyr Ser Ser Al a Tr p Pr o Leu Gl y Tyr Tr p Gl y Gl n 100 105 110 Gl y Thr Leu Val Thr Val Ser Ser 115 120

    <210> 174 <211> 118 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

    Page 148

    2018203471 16 May 2018

    A1472PCT <400> 174

    Gl n 1 I l e Thr Leu Lys 5 Gl u Ser Gl y Pr o Thr 10 Leu Val Lys Pr o Thr 15 Gl n Thr Leu Thr Leu Thr Cy s Thr Phe Ser Gl y Phe Ser Leu Ser Thr Ser 20 25 30 Gl y Val Gl y Val Al a Tr p Ile Ar g Gl n Pr o Pr o Gl y Lys Al a Leu Gl u 35 40 45 Tr p Leu Al a Leu Ile Ty r Tr p Thr As p As p Lys Ar g Ty r Ser Pr o Ser 50 55 60 Leu Lys Ser Ar g Leu Thr Ile Thr Lys As p Thr Ser Lys As n Gl n Val 65 70 75 80 Val Leu Ar g Met Thr As n Met As p Pr o Leu As p Thr Al a Thr Ty r Phe 85 90 95 Cys Al a Hi s Ar g Pr o Gl y Gl y Tr p Phe As p Pr o Tr p Gl y Gl n Gl y Thr 100 105 110 Leu Val Thr Val Ser Ser

    115 <210> 175 <211> 321 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 175 gacat ccaga t gacccagt c t ccat cct cc ct gt ct gcat ct gt aggaga cagagt cacc 60 atcacttgcc gggcaagt ca gggcattaga aatgatttag gctggtttca gcagaaacca 120 gggaaagccc ct aagcgcct gat ct at gct gcatccagtt tgcaaagtgg ggt cccat ca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240 gaagatttag caact t at t a ct gt ct acag t at aat at 11 acccgt ggac gttcggccaa 300

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    A1472PCT gggaccaagg t ggaaat caa a 321 <210> 176 <211> 321 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 176

    gacat ccaga t gacccagt c t ccat cct cc ct gt ct gcat ct gt aggaga cagagt cacc 60 at cact t gcc gggcaagt ca gggcatt aga aaggat t t ag gct ggt at ca gcagaaacca 120 gggaaagccc ct aagcgcct gat ct at gga gcat ccagt t tgcaaagtgg ggt cccat ca 180 aggt t cagcg gcagt ggat c t gggacagaa 11 cact ct ca caat cagcag cct gcagcct 240 gaagat t t t g caact t at t a ct gt ct acag t at aat agt t t cccgt ggac gt t cggccaa 300 gggaccaagg t ggaaat caa a 321 <210> 177 <211> 359 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 177 aggt gcagct ggt gcagt ct ggggctgagg t gaagaagt c t ggggcct ca gt gaaggt ct 60 cct gcaaggc t t ct ggat ac acct t caccg gct act at at gcact gggt g cgacaggccc 120 ct ggacaagg gct t gagt gg at gggat gga t caaccct aa cagt ggt ggc acaaact at g 180 t acagaagt t t cagggcagg gt caccat ga ccagggacac gt ccat cagc acagcct aca 240 t ggagct gag caggct gaga t ct gacgaca cggccgt gt a t t act gt gcg agaaat gagt 300 at agcagt gc ct ggccct t g gggt at t ggg gccagggaac cct ggt cacc gt ct ct agt 359

    <210> 178 <211> 336

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    A1472PCT <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 178 gat at t gt ga t gact cagt c t ccact ct cc ct gcccgt ca cccct ggaga gccggcct cc 60 at ct cct gca ggt ct agt ca gagcct cct g cat agt t t t g ggt acaact a tttggattgg 120 t acct gcaga agccagggca gt ct ccacag ct cct gat ct at t t gggt t c t aat cgggcc 180 t ccggggt cc ct gacaggt t cagt ggcagt ggat caggca cagat t t t ac act gaaaat c 240 agcagagt gg aggct gagga tgttggggtt t at t act gca t gcaagct ct acaaact cca 300 t t cact t t cg gccct gggac caaagt ggat at caaa 336

    <210> 179 <211> 336 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i c i al Sequenc e: Sy nt het i c pol ynucl eot i de <400> 179 gat at t at ac t ggcccagac t ccact t t ct ct gt ccgt ca cccct ggaca gccggcct cc 60 at ct cct gca agt ct agt ca gagcct cct g cacagt gct g gaaagacct a tttgtattgg 120 t acct gcaga agccaggcca gcct ccacag ct cct gat ct at gaagt t t c caaccggt t c 180 t ct ggagt gc cagat aggt t cagt ggcagc gggt caggga cagat t t cac act gaaaat c 240 agccgggt gg aggct gagga tgttgggatt t at t act gca t gcaaagt t t t ccgct t ccg 300 ct cact t t cg gcggagggac caaggt ggag at caaa 336

    <210> 180 <211> 336 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic Page 151

    2018203471 16 May 2018

    A1472PCT pol ynucl eot i de <400> 180

    gat at t at t c t gacccagac t ccact t t ct ct gt ccgt ca cccct ggaca gccggcct cc 60 at ct cct gca agt ct agt ca gagcct cct g cacagt gat g gaaagacct a tttgtattgg 120 t acct gcaga agcccggcca gcct ccacag ct cct gat ct at gaagt t t c caaccggt t c 180 t ct ggagagc cagat aggt t cagt ggcagc gggt caggga cagat t t cac act gaaaat c 240 agccgggt gg aggct gagga tgttgggact t at t at t gca t gcaaagt t t t ccgct t ccg 300 ct cact t t cg gcggagggac caaggt ggag at caaa 336

    <210> 181 <211> 336 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 181

    gat at t acac t gacccagac t ccact t t ct ct gt ccgt ct cccct ggaca gccggcct cc 60 at ct cct gca agt ct agt ca gagcct cct g cacagt gat g gaaggaact a tct gt attgg 120 t acct gcaga agccaggcca gcct ccacag ct cct gat ct at gaagt gt c caaccggt t c 180 t ct ggact gc cagat aggt t cagt ggcagc gggt caggga cagat t t cac act gaaaat c 240 agccgggt gg aggct gagga tgtt gggat t t at t act gca t gcaaagt t t t ccgct t ccg 300 ct cact t t cg gcggagggac caaggt ggag at caaa 336

    <210> 182 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 182 gaaattgtgt t gacgcagt c t ccaggcacc ct gt ct 11 gt ct ccagggga aagagccacc 60 ct ct cct gca gggccagt ca gagtgttagc agcggct act t aacct ggt a ccagcagaaa 120

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    cct ggccagg ct cccaggct cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 180 gacaggt t ca gt ggcagt gg gt ct gggaca gact t cact c t caccat cag cagact ggag 240 cct gaagat t t t gcagt gt a 11 act gt cag cagt at ggt a act cact gt g caggt t t ggc 300 caggggacca agct ggagat caaa 324

    <210> 183 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 183

    gaaat t gt gt t gacgcagt c t ccaggcacc ct gt ct t t gt ct ccagggga aagagccacc 60 ct ct cct gca gggccagt ca gagt gt t agc agcggct act t aacct ggt a ccagcagaaa 120 cct ggccagg ct cccagact cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 180 gacaggt t ca gt ggcagt gg gt ct gggacg gact t cact c t caccat cag cagact ggag 240 cct gaagat t t t gcagt gt a 11 act gt cag cagt at ggt a act cact gag caggt t t ggc 300 caggggacca agct ggagat caaa 324 <210> 184 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 184 gaaat agt ga t gacgcagt c t ccagccacc ct gt ct gt gt ct ccagggga aagagccacc 60 ct ct cct gt a gggccagt ca gagt gttcgc agcaat t t ag cct ggt acca gcagaaacct 120 ggccaggct c ccaggct cct cat t cat gat gcat ccccca ggaccgct gg t at cccagcc 180 aggt t cagt g gcagt ggat c t gggacagaa 11 cact ct ca ccat caacag cct gcagt ct 240 gaagat t t t g cagt t t at t a ct gt cagcag t at aat t act ggact ccgat cacct t cggc 300

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    A1472PCT caagggacac gact ggagat t aaa

    324 <210> 185 <211> 339 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 185 gacat cgt ga at caact gca t ggt accagc gaat ccgggg at cagcagcc ccat t cact t t gacccagt c agt ccagcca agaaaccagg t ccct gaccg t gcaggct ga t cggccct gg t ccagact cc gagt at t t t a acagcct cct at t cagt ggc agat gt ggca gaccaaagt g ct ggct gt gt gacagct cca aaact gct ca agcgggt ct g gt t t at t act gat at caaa ct ct gggcga acaat gat aa

    111 act gggc ggacagat t t gt cagcaat a gagggccacc ct act t agct at ct acccgg cact ct cacc

    11 at aat act

    120

    180

    240

    300

    339 <210> 186 <211> 330 <212> DNA <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 186 cagt ct gt gt t cct gct ct g ccaggaacag gaccgat t ct act ggggacg t t cggcggag t gacgcagcc gaagcagct c cccccaaact ct ggct ccaa aggccgat t a ggaccaagct gccct cagt g caacat t ggg cct cat t t at gt ct ggcacg

    11 act gcgga gaccgt cct a t ct gaggccc aat aat t at g gacaat aat a t cagccaccc acat gggat a caggacagaa t at cct ggt a agcgaccct c t gggcat cac gccgcct gag ggt caccat c ccagcagct c agggat t cct cggact ccag tgct gtggtt

    120

    180

    240

    300

    330 <210> 187 <211> 330

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    A1472PCT <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 187 cagt ct gt gt t gacgcagcc gccct cagt g t ct gcggccc caggacagaa ggt caccat c 60 t cct gct ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagct c 120 ccaggaacag cccccaaact cct cat t t at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t caaccaccc t gggcat cac cggact ccag 240 act ggggacg aggccgat t a 11 act gcgga acat gggat a gccgcct gag tgct gtggtt 300 t t cggcggag ggaccaagct gaccgt cct a 330

    <210> 188 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i c i al Sequenc e: Sy nt het i c pol ynucl eot i de <400> 188 cagt ct gt gt t gacgcagcc gccct cagt g t ct gcggccc caggacagaa ggt caccat c 60 t cct gct ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagt t c 120 ccaggaacag cccccaaact cct cat t t at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t cagccaccc t gggcat cac cggact ccag 240 act ggggacg aggccgat t a 11 act gcgga acat gggat a gccgcct gag tgct gtggtt 300 t t cggcggag ggaccaagct gaccgt cct a 330

    <210> 189 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic Page 155

    2018203471 16 May 2018

    A1472PCT pol ynucl eot i de <400> 189

    cagt ct gt gt t gacgcagcc gccct cagt g t ct gcggccc caggacagaa ggt caccat c 60 t cct gct ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagct c 120 ccaggaacag cccccaaact cct cat t t at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t cagccaccc t gggcat cac cggact ccag 240 act ggggacg aggccgat t a 11 act gcgga acat gggat a gccgcct gag tgct gtggtt 300 t t cggcggag ggaccaagct gaccgt cct a 330

    <210> 190 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 190

    cagt ct gt gt t gacgcagcc gccct caat g t ct gcggccc caggacagaa ggt caccat c 60 t cct gct ct g gaagcagct c caacat t ggg aat aat t at g t at cct ggt a ccagcagct c 120 ccaggaacag cccccaaact cct cat t t at gacaat aat a agcgaccct c agggat t cct 180 gaccgat t ct ct ggct ccaa gt ct ggcacg t cagccaccc t gggcat cac cggact ccag 240 act ggggacg aggccaat t a ct gct gcgga acat gggat a t cggcct gag tgtttgggtg 300 tt cggcggag ggaccaaact gaccgt cct a 330 <210> 191 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 191 cagt ct gt gc t gact cagcc accct cagcg t ct gggaccc ccgggcagag ggt caccat c 60 t ct t gt t ct g gaagcagt t c caat at cgga agt aat act g t gaact ggt a ccagcagct c 120

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    ccaggaacgg cccccaaact cct cat ct at act aat aat c agcggccct c aggggt ccct 180 gaccgat t ct ct ggct ccaa gt ct ggcacc t cagcct ccc t ggccat cag t ggact ccag 240 t ct gaggat g aggct gat t t t t act gt gca gcgcgggat g agagcct gaa t ggt gt ggt a 300 t t cggcggag ggaccaagct gaccgt cct a 330

    <210> 192 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 192

    cagt ct gt gc t gact cagcc accct cagcg t ct gggaccc ccgggcagag agt caccat c 60 t ct t gt t ct g gaagcagct c caacat cggc agt aat t at g t at act ggt a ccagcagct c 120 ccaggagcgg cccccaaact cctcatcttt aggaataatc agcggccctc aggggt ccct 180 gaccgcttct ct ggct ccaa gt ct ggcacc t cagcct ccc t ggccat cag t gggct ccgg 240 t ccgaggat g aggctgatta ttactgtgca gcat gggat g acagcct gag t ggt t gggt g 300 ttcggcggag ggaccaagct gaccgtccta <210> 193 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic 330 pol ynucl eot i de <400> 193 cagt ct gt gc t gact cagcc accct cagcg t ct gggaccc ccgggcagag agt caccat c 60 t ct t gt t ct g gaagcagct c caacat cggc agt aat t at g t at act ggt a ccagcagct c 120 ccaggagcgg cccccaaact cctcatcttt aggagtaatc agcggccctc aggggt ccct 180 gaccgattct ct ggct ccaa gt ct ggcacc t cagcct ccc t ggccat cag t gggct ccgg 240 t ccgaggat g aggctgatta ttactgtgca gcat gggat g acagcct gag tggttgggtg 300

    Page 157

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    A1472PCT ttcggcggag ggaccaagct gaccgtccta 330 <210> 194 <211> 330 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 194

    cagt ct gt gc t gact cagt c accct cagcg t ct gggaccc ccgggcagag agt caccat c 60 t ct t gt t ct g gaagcagct c caacat cggc agt aat t at g t at act ggt a ccagcagct c 120 ccaggagcgg cccccaaact cct cat cct t aggaat aat c agcggccct c aggggt ccct 180 gaccgat t ct ct ggct ccaa gt ct ggcacc t cagcct ccc t gaccat cag t gggct ccgg 240 t ccgaggat g aggct gact a 11 at t gt gca gcat gggat g acagcct gag tggttgggtg 300 t t cggcggag ggaccaagct gaccgt cct a 330

    <210> 195 <211> 324 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 195 t ct t ct gagc t gact cagga ccct act gt g t ct gt ggcct t gggacagac agt caaaat c 60 acat gccaag gagacagcct cagaagt t t t t at gcaagct ggt accagca gaagccagga 120 caggcccct g t act t gt ct t ct at ggt aaa aacaaccggc cct cagggat cccagaccga 180 t t ct ct ggct ccagct cagg aaacacagct t cct t gacca t cact ggggc t caggcggaa 240 gat gaggct g act at t at t g t aat t cccgg gacagcagt g t t t accat ct ggt act cggc 300 ggagggacca agct gaccgt cct a 324

    <210> 196 <211> 390

    Page 158

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    A1472PCT <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 196 caggt gcagt t ggt gcagt c t ggggct gag gt gaagaagc ct ggggcct c agt gaaggt c 60 t cct gcaagg ct t ct ggat a cacct t cacc ggct act at a t gcact gggt gcgacaggcc 120 cct ggacaag ggct t gagt g gat gggat gg at caaccct a acagt ggt gg cacaaact at 180 gcacagaagt t t cagggcag ggt caccat g accagggaca cgt ccat cag cacagcct ac 240 at ggagct ga gcaggct gag at ct gacgac acggccgt gt at t t ct gt gc gagagat caa 300 at gagt at t a t t at gct t cg gggagt t t t t ccccct t act at t acggt at ggacgt ct gg 360 ggccaaggga ccacggt cac cgt ct ct agt 390

    <210> 197 <211> 381 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i c i al Sequenc e: Sy nt het i c pol ynucl eot i de <400> 197 caggt gcagc t ggt gcagt c t ggggct gag gt gaagaagc ct ggggcct c agt gaaggt c 60 t cct gcaagg ct t ct ggat a cacct t cacc gact act at a t gt act gggt gcgacaggcc 120 cct ggacaag ggct t gagt g gat gggat gg at cagccct a at agt ggt gg cacaaact at 180 gcccagaagt t t cagggcag ggt caccat g accagggaca cgt ct at cag cacagcct ac 240 at ggagct ga gt aggct gag at ct gacgac acggccgt gt at t act gt gt gagaggagga 300 t at agt ggct acgct gggct ct act cccac t act acggt a t ggacgt ct g gggccaaggg 360 accacggt ca ccgt ct ct ag t 381

    <210> 198 <211> 354 <212> DNA <213> Ar t i f i ci al Sequence

    Page 159

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    A1472PCT <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 198 caggt gcagc t ggt gcagt c t ggggct gag gt gaagaagc ct ggggcct c agt gaaggt c 60 t cct gcaagg ct t ct ggat a cacct t cacc gcct act at t t acact gggt gcgacaggcc 120 cct ggacaag ggct t gagt g gat gggat gg at caaccct c acagt ggt gg cacaaact at 180 gcacagaagt t t cagggcag ggt caccat g accagggaca cgt ccat cag cacagcct ac 240 at ggagct ga gcaggct gag at ct gacgac acggccgt gt t ct act gt gc gagaggaagg 300 cagt ggct gg gct t t gact a ct ggggccag ggaaccct gg t caccgt ct c t agt 354

    <210> 199 <211> 321 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 199

    gacat ccaga t gacccagt c t ccat cct cc ct gt ct gcat ct gt aggaga cagagt t acc 60 at t act t gcc gggcaagt ca gggcatt aga aat gat t t ag gct ggt at ca gcagaaacca 120 gggaaagccc ct aagcgcct gat ct at gt t gcat ccagt t tgcaaagtgg ggt cccat ca 180 aggt t cagcg gcagt ggat c t gggacagaa 11 cact ct ca caat cagcag cct gcagcct 240 gaagat t t t g caact t at t a ct gt ct acag t at aacact t acccgct cac ttt cggcgga 300 gggaccaagg t ggagat caa ^g 321

    <210> 200 <211> 393 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    Page 160

    A1472PCT

    2018203471 16 May 2018 <400> 200 gaggt acagc t cct gt gcag ccagggaagg gact acgct g ct gt at ct gc gat cggaccg t ggggccaag t ggt ggagt c cct ct ggat t ggct ggagt g cacccgt gaa aaat gaacag ggt at agcat ggaccacggt t gggggaggc cact 11 cggt ggttggccgt aggcagat t c cct gaaaacc cagct ggt ct caccgt ct ct

    11 ggt aaagc aacgcct gga at t aaaagca accat ct caa gaggacacag agt t act act agt ct ggggggt c t gagct gggt aaact gat gg gagat gat t c ccgt gt at t t act act acgg cct cagact c ccgccaggct t gggacaaca aaaaaacacg ct gt accaca t at ggacgt c

    120

    180

    240

    300

    360

    393 <210> 201 <211> 393 <212> DNA <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 201 gaggt gcagc t cct gt gcag ccagggaagg gact acact g ct gt at ct gc gat cggaccg t ggggccaag t ggt ggagt c cct ct ggat t ggct ggagt g cacccgt gaa aaat gaat ag ggt at agcat ggaccacggt tgggggaggc cact 11 cagt ggttggccgt aggcagat t c cct gaaagcc cagct ggt ct caccgt ct ct

    11 ggt aaagc aacgcct gga at t aaaagca accat ct caa gaggacacag agt t act act agt ct ggggggt c t gagct gggt aaact gat gg gagat gat t c ccgt gt at t a act act acgg cct t agact c ccgccaggct t gggacaaca aaaaaacacg ct gt accaca t at ggacgt c

    120

    180

    240

    300

    360

    393 <210> 202 <211> 393 <212> DNA <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 202 gaggtacagc t ggt ggagt c tgggggaggc tt ggt aaagc ct ggggggt c cct t agact c Page 161

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    t cct gt gcag cct ct ggat t cact 11 cggt aacgcct gga t gagct gggt ccgccaggct 120 ccagggaagg ggct ggagt g ggttggccgt at t aaaagca aaact gat gg t gggacaaca 180 gact acgct g cacccgt gaa aggcagat t c accat ct caa gagat gat t c aaaaaacacg 240 ct gt at ct gc aaat gaacag cct gaaaacc gaggacacag ccgt gt at t a ct gt accaca 300 gat cggaccg ggt at agcat cagct ggt ct agt t act act act act acgg t at ggacgt c 360 t ggggccaag ggaccacggt caccgt ct ct agt 393

    <210> 203 <211> 393 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i c i al Sequenc e: Sy nt het i c pol ynucl eot i de <400> 203 gaggt gcagc t ggt ggagt c t gggggaggc t t ggt aaagc ct ggggggt c cct t agact c 60 t cct gt gcag cct ct ggat t cact 11 cagt aacgcct gga t gagct gggt ccgccaggct 120 ccagggaagg ggct ggagt g ggttggccgt at t aaaagca caact gat gg t gggacaaca 180 gact acgct g cacccgt gaa aggcagat t c accat ct caa gagat gat t c aaaaaacacg 240 ct gt at ct gc aaat gaacag cct gaaaacc gaggacacag ccgt gt at t a ct gt accaca 300 gat cggaccg gat at agcat cagct ggt ct agt t act act act act acgg t at ggacgt c 360 t ggggccaag ggaccacggt caccgt ct ct agt <210> 204 <211> 393 <212> DNA <213> Artificial Sequence <220> <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic 393 pol ynucl eot i de <400> 204 gaggt gcagc t ggt ggagt c tgggggaggc ct ggt caagc ct ggggggt c cct gagact c 60 t cct gt gcag cct ct ggat a cacct t cagt acct at agca t gaact gggt ccgccaggct 120

    Page 162

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    2018203471 16 May 2018 ccagggaagg gcagact cag ct gcaaat ga gt gt ct ggca t ggggccaag

    ggct ggagt g ggt ct cat cc at t agt agt a gt agt agt t a cagat at t ac 180 t gaagggccg at t caccat c t ccagagaca acgccaagaa ct cact gt at 240 gt agcct gag agccgaggac acggct gt gt at t act gt gc gagagaaggg 300 gt t cgccgt a t agcat cagc t ggt acgact act at t acgg t at ggacgt c 360 ggaccacggt caccgt ct ct agt 393

    <210> 205 <211> 390 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 205

    gaggt gcagc t at t ggagt c tgggggaggc t t ggt acagc ct ggggagt c cct gagact c 60 t cct gt gcag cct ct gggt t cacct t t agc agct at gcca t gagct gggt ccgccaggct 120 ccagggaagg ggct ggagt g ggt ct cagct at t agt ggt a gt ggt ggt cg cacat act ac 180 gcagact ccg t gaagggccg gt t caccat c t ccagagaca at t ccaagaa cacgct gt at 240 ct gcaaat ga at agcct gag agccgaggac acggccgt at at t act gt gc gaaagat caa 300 agggaggt ag ggccgt at ag cagt ggct gg t acgact act act acggt at ggacgt ct gg 360 ggccaaggga ccacggt cac cgt ct ct agt 390

    <210> 206 <211> 387 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 206 caggt gcagc t ggt ggagt c t gggggaggc gt ggt ccagc ct gggaggt c cct gagact c t cct gt gcag cct ct ggat t cacct t cagt agct at ggca t gcact gggt ccgccaggct

    120 ccaggcaagg ggct ggagt g ggtggcagtt at t t cat at g Page 163 at ggaagt ca t gaat cct at

    180

    A1472PCT

    2018203471 16 May 2018

    gcagact ccg t gaagggccg at t caccat c t ccagagaca t t t ccaagaa cacgct gt at 240 ct gcaaat ga acagcct gag agct gaggac acggct gt gt at t t ct gt gc gagagagagg 300 aaacgggt t a cgat gt ct ac ct t at at t ac t act t ct act acggt at gga cgt ct ggggc 360 caagggacca cggt caccgt ct ct agt 387

    <210> 207 <211> 390 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 207

    caggt gcagc t ggt ggaat c t gggggaggc gt ggt ccagc ct gggaggt c cct gagact c 60 t cct gt gcag cctctggatt cacct t cagt agct 11 ggca t gcact gggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt at at cat t t g at ggaagt at t aagt at t ct 180 gtagactccg tgaagggccg attcaccatc t ccagagaca at t caaagaa cacgct gt t t 240 ct gcaaat ga acagcct gcg agccgaggac acggct gt gt at t act gt gc gagagat cgg 300 ct caat t act at gat agt ag t ggt t at t at cact acaaat act acggt at ggccgt ct gg 360 ggccaaggga ccacggt cac cgt ct ct agt <210> 208 <211> 390 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic 390 pol ynucl eot i de <400> 208 caggt gcagc t ggt ggaat c t gggggaggc gt ggt ccagc ct gggaggt c cct gagact c 60 t cct gt gcag cctctggatt cacct t cagt agct 11 ggca tgcattgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt at at cat t t g at ggaagt at t aagt act ct 180 gtagactccg tgaagggccg attcaccatc t ccagagaca at t caaagaa cacgct gt t t 240

    Page 164

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    ct gcaaat ga acagcct gcg agccgaggac acggct gt gt at t act gt gc gagagat cgg 300 ct caat t act at gat agt ag t ggt t at t at cact acaaat act acggt ct ggccgt ct gg 360 ggccaaggga ccacggt cac cgt ct ct agt 390

    <210> 209 <211> 363 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 209

    gaggt gcagc t ggt ggagt c tgggggaggc t t ggt aaagc cagggcggt c cct gagact c 60 t cct gt acag ct t ct ggat t cacct t t ggt gat t at gct a tgagctggtt ccgccaggct 120 ccagggaagg ggct ggagt g gat aggt t t c at t agaagca gagct t at gg t gggacacca 180 gaat acgccg cgt ct gt gaa aggcagat t c accat ct caa gagat gat t c caaaaccat c 240 gcct at ct gc aaat gaacag cct gaaaacc gaggacacag ccgt gt at t t ct gt gct aga 300 ggacggggt a t t gcagct cg 11 gggact ac t ggggccagg gaaccct ggt caccgt ct ct 360

    agt 363 <210> 210 <211> 378 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 210 caggt gcagc t ggt ggagt c t gggggaggc gt ggt ccagc ct gggaggt c cct gagact c 60 t cct gt gcag cgt ct ggat t cacct t cagt agct at ggca t gcact gggt ccgccaggct 120 ccaggcaagg ggct ggagt g ggtggcagtt at at ggt at g at ggaagt aa t aaat act at 180 gcagact ccg t gaagggccg at t cat cat c t ccagagat a aat ccaagaa cacgct gt at 240 ct gcaaat ga acagcct gag agccgaggac acggct gt gt at t act gt gc gagagcgggg 300

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    A1472PCT ggt at agcag cagct ggcct ct act act ac t acggt at gg acgt ct gggg ccaagggacc 360 acggt caccg t ct ct agt 378 <210> 211 <211> 351 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 211

    caggt gcagt t acagcagt g gggcgcagga ct gt t gaagc ct t cggagac cct gt ccct c 60 agct gcgct g t ct at ggt gg gt cct t cggt ggt t act act ggagct ggat ccgccagccc 120 ccagggaagg ggct ggagt g gat t ggggaa at caat cat a gt ggaggcac caagt acaac 180 ccgt ccct ca agagt cgagt caccat at ca gt agacacgt ccaagaacca gt t ct ccct g 240 aagct gagct ct gt gaccgc cgcggacacg gct gt gt at t t ct gt gcgag aggcgat gt a 300 gt aggt t t ct 11 gact at t g gggccaggga accct ggt ca ccgt ct ct ag t 351

    <210> 212 <211> 354 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i on of Ar t i f i c i al Sequenc e: Sy nt het i c pol ynucl eot i de <400> 212 cagat cacct t aaaggagt c t ggt cct acg ct ggt gaaac ccacacagac cct cacgct g 60 acct gcacct t ct ct gggt t ct cact cagc act agt ggt g tgggt gt ggc ct ggat ccgt 120 cagccccccg gaaaggccct ggagtggctt gcact cat 11 at t ggact ga t gat aagcgc 180 t acagt ccat ct ct gaagag caggct cacc at caccaagg acacct ccaa gaaccaggt g 240 gt cct t agaa t gaccaacat ggaccct 11 g gacacagcca ct t at t t ct g t gcacacaga 300 ccagggggct ggt t cgaccc ct ggggccag ggaaccct gg t caccgt ct c t agt 354

    Page 166

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    A1472PCT <210> 213 <211> 13 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pept i de <400> 213

    Gl y Gl y Gl y Gl y Gl y Val Asp Gl y 1 5

    Gl y Gl y Gl y Gl y Val 10 <210> 214 <211> 148 <212> PRT <213> Rat t us sp.

    <400> 214 Met 1 Al a Pr o Gl y Leu 5 Ar g Gl y Leu Leu Al a Hi s Hi s 20 Leu Phe Met Val Gl y Thr Leu 35 Ile Gl n Gl u Leu Cy s 40 Gl u Thr 50 I l e Gl y Lys Thr Leu 55 Tr p Ser 65 Ty r Gl y Gl u Leu Thr 70 Hi s Cy s Gl y Cy s Phe Tr p Pr o 85 As n Pr o Gl u Hi s Hi s Ar g Ty r 100 Phe Ser Lys Cy s As p Pr o Pr o 115 As n Ser Ile Leu Cy s 120 Val Thr Leu Leu Met Thr Al a Leu

    Pr o Ar g Ar g Gl y Leu Tr p Leu Leu 10 15

    Thr Al a Cy s Ar g As p Pr o As p Ty r 25 30

    Leu Ser Ar g Phe Lys Gl u Asp Met 45

    Cys Asp Trp Gly Lys Thr Ile Gly 60

    Thr Lys Leu Val Al a Asn Lys I l e 75 80

    Val Asp Lys Phe Phe I l e Al a Val 90 95

    Pr o Val Ser Gl y Ar g Al a Leu Ar g 105 110

    Pr o Phe I l e Val Leu Pr o I l e Thr 125

    Val Val Tr p Ar g Ser Lys Ar g Thr Page 167

    2018203471 16 May 2018

    A1472PCT

    130 135 140

    Gl u Gl y I l e Val 145 <210> 215 <211> 148 <212> PRT <213> Macaca f asci cul ar i s <400> 215

    Met 1 Al a Ar g Al a Leu 5 Cys Arg Leu Pr o Gl n 10 Ar g Gl y Leu Tr p Leu 15 Leu Leu Al a Hi s Hi s Leu Phe Met Al a Thr Al a Cys Gl n Gl u Al a As n Tyr 20 25 30 Gl y Al a Leu Leu Gl n Gl u Leu Cys Leu Thr Gl n Phe Gl n Val As p Met 35 40 45 Gl u Al a Val Gl y Gl u Thr Leu Tr p Cys As p Tr p Gl y Ar g Thr Ile Gl y 50 55 60 Ser Tyr Ar g Gl u Leu Al a As p Cys Thr Tr p Hi s Met Al a Gl u Lys Leu 65 70 75 80 Gl y Cys Phe Tr p Pr o As n Al a Gl u Val As p Ar g Phe Phe Leu Al a Val 85 90 95 Hi s Gl y Hi s Tyr Phe Ar g Al a Cys Pr o I l e Ser Gl y Ar g Al a Val Ar g 100 105 110 As p Pr o Pr o Gl y Ser Val Leu Tyr Pr o Phe I l e Val Val Pr o Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Gl n Ser Lys Hi s Thr

    130 135 140

    Gl u Gl y I l e Val 145 <210> 216

    Page 168

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    A1472PCT <211> 148 <212> PRT <213> Macaca mulatta <400> 216

    Met 1 Al a Ar g Al a Leu 5 Cy s Ar g Leu Pr o Gl n 10 Ar g Gl y Leu Tr p Leu 15 Leu Leu Al a Hi s Hi s Leu Phe Met Al a Thr Al a Cy s Gl n Gl u Al a As n Ty r 20 25 30 Gl y Al a Leu Leu Gl n Gl u Leu Cy s Leu Thr Gl n Phe Gl n Val As p Met 35 40 45 Gl u Al a Val Gl y Gl u Thr Leu Tr p Cy s As p Tr p Gl y Ar g Thr Ile Gl y 50 55 60 Ser Ty r Ar g Gl u Leu Al a As p Cy s Thr Tr p Hi s Met Al a Gl u Lys Leu 65 70 75 80 Gl y Cy s Phe Tr p Pr o As n Al a Gl u Val As p Ar g Phe Phe Leu Al a Val 85 90 95 Hi s Gl y Hi s Ty r Phe Ar g Al a Cy s Pr o I l e Ser Gl y Ar g Al a Val Ar g 100 105 110 As p Pr o Pr o Gl y Ser Val Leu Ty r Pr o Phe I l e Val Val Pr o Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Gl n Ser Lys Hi s Thr 130 135 140

    Gl u Gl y I l e Val 145 <210> 217 <211> 148 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de

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    <400> 217 Leu Tr p Leu 15 Leu Met 1 Al a Ar g Al a Leu Cys Arg 5 Leu Pr o Ar g 10 Ar g Gl y Leu Al a Hi s Hi s Leu Phe Met Thr Thr Al a Cys Ar g As p Pr o As p Tyr 20 25 30 Gl y Thr Leu Leu Ar g Gl u Leu Cys Leu Thr Gl n Phe Gl n Val As p Met 35 40 45 Gl u Al a Val Gl y Gl u Thr Leu Tr p Cys As p Tr p Gl y Ar g Thr Ile Ar g 50 55 60 Ser Tyr Ar g Gl u Leu Al a As p Cys Thr Tr p Hi s Met Al a Gl u Lys Leu 65 70 75 80 Gl y Cys Phe Tr p Pr o As n Al a Gl u Val As p Ar g Phe Phe Leu Al a Val 85 90 95 Hi s Gl y Ar g Tyr Phe Ar g Ser Cys Pr o I l e Ser Gl y Ar g Al a Val Ar g 100 105 110 As p Pr o Pr o Gl y Ser Ile Leu Tyr Pr o Phe I l e Val Val Pr o Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Gl n Ser Lys Ar g Thr 130 135 140

    Gl u Gl y I l e Val 145 <210> 218 <211> 148 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 218

    Met Ala Arg Ala Leu Cys Arg Leu Pro Arg Arg Gy Leu Trp Leu Leu Page 170

    2018203471 16 May 2018

    A14 72PC T 1 5 10 15 Leu Al a Hi s Hi s Leu Phe Met Thr Thr Al a Cys Gl n Gl u Al a As n Tyr 20 25 30 Gl y Al a Leu Leu Ar g Gl u Leu Cys Leu Thr Ar g Phe Lys Gl u As p Met 35 40 45 Gl u Thr I l e Gl y Lys Thr Leu Tr p Cys As p Tr p Gl y Ar g Thr Ile Ar g 50 55 60 Ser Tyr Ar g Gl u Leu Al a As p Cys Thr Tr p Hi s Met Al a Gl u Lys Leu 65 70 75 80 Gl y Cys Phe Tr p Pr o As n Al a Gl u Val As p Ar g Phe Phe Leu Al a Val 85 90 95 Hi s Gl y Ar g Tyr Phe Ar g Ser Cys Pr o I l e Ser Gl y Ar g Al a Val Ar g 100 105 110 As p Pr o Pr o Gl y Ser Ile Leu Tyr Pr o Phe I l e Val Val Pr o Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Gl n Ser Lys Ar g Thr

    130 135 140

    Gl u Gl y I l e Val 145 <210> 219 <211> 148 <212> PRT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ypept i de <400> 219

    Met Ala Arg Ala Leu Cys Arg Leu Pro Arg Arg Gly Leu Trp Leu Leu 1 5 10 15

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    Leu Al a Hi s Hi s 20 Leu Phe Met Thr Thr 25 Al a Cys Gl n Gl u Al a 30 As n Tyr Gl y Al a Leu Leu Ar g Gl u Leu Cys Leu Thr Gl n Phe Gl n Val As p Met 35 40 45 Gl u Al a Val Gl y Gl u Thr Leu Tr p Cys As p Tr p Gl y Ar g Thr Ile Ar g 50 55 60 Ser Tyr Gl y Gl u Leu Thr Hi s Cys Thr Lys Leu Val Al a As n Lys Leu 65 70 75 80 Gl y Cys Phe Tr p Pr o As n Al a Gl u Val As p Ar g Phe Phe Leu Al a Val 85 90 95 Hi s Gl y Ar g Tyr Phe Ar g Ser Cys Pr o I l e Ser Gl y Ar g Al a Val Ar g 100 105 110 As p Pr o Pr o Gl y Ser Ile Leu Tyr Pr o Phe I l e Val Val Pr o Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Al a Leu Val Val Tr p Gl n Ser Lys Ar g Thr 130 135 140 Gl u Gl y I l e Val

    145 <210> 220 <211> 464 <212> PRT

    <213> Rat t us sp. <400> 220 Met Met As p Lys Lys Cys Thr Leu Cys Phe Leu Ph e Leu Leu Leu Leu 1 5 10 15 As n Met Al a Leu Ile Al a Al a Gl u Ser Gl u Gl u Gl ^y Al a As n Gl n Thr 20 25 30 As p Leu Gl y Val Thr Ar g As n Lys I l e Met Thr Al a Gl n Tyr Gl u Cys 35 40 45

    Page 172

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    Ty r Gl n 50 Lys I l e Met A1472PCT Gl n As p 55 Pr o I l e Gl n Gl n Gl y 60 Gl u Gl y Leu Ty r Cy s 65 As n Ar g Thr Tr p As p 70 Gl y Tr p Leu Cy s Tr p 75 As n As p Val Al a Al a 80 Gl y Thr Gl u Ser Met 85 Gl n Ty r Cy s Pr o As p Ty r 90 Phe Gl n As p Phe 95 As p Pr o Ser Gl u Lys Val 100 Thr Lys Ile Cy s 105 As p Gl n As p Gl y As n 110 Tr p Phe Ar g Hi s Pr o 115 Asp Ser As n Ar g Thr 120 Tr p Thr As n Ty r Thr 125 Leu Cy s As n As n Ser 130 Thr Hi s Gl u Lys Val 135 Lys Thr Al a Leu As n 140 Leu Phe Ty r Leu Thr 145 I l e I l e Gl y Hi s Gl y 150 Leu Ser I l e Al a Ser 155 Leu Ile Ile Ser Leu 160 I l e I l e Phe Phe Ty r 165 Phe Lys Ser Leu Ser Cys 170 Gl n Ar g Ile Thr 175 Leu Hi s Lys As n Leu Phe 180 Phe Ser Phe Val 185 Cy s As n Ser Ile Val 190 Thr Ile I l e Hi s Leu 195 Thr Al a Val Al a As n 200 As n Gl n Al a Leu Val 205 Al a Thr As n Pr o Val 210 Ser Cys Lys Val Ser 215 Gl n Phe I l e Hi s Leu 220 Ty r Leu Met Gl y Cy s 225 As n Ty r Phe Tr p Met 230 Leu Cy s Gl u Gl y I l e 235 Ty r Leu Hi s Thr Leu 240 I l e Val Val Al a Val 245 Phe Al a Gl u Lys Gl n Hi s 250 Leu Met Tr p Ty r 255 Ty r Phe Leu Gl y Tr p Gl y 260 Phe Pr o Leu Leu 265 Pr o Al a Cy s Ile Hi s 270 Al a Ile

    Page 173

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    Al a Ar g Ser 275 Leu Tyr Tyr As n As p 280 As n Cys Tr p Ile Ser 285 Ser As p Thr Hi s Leu Leu Tyr Ile Ile Hi s Gl y Pr o I l e Cys Al a Al a Leu Leu Val 290 295 300 As n Leu Phe Phe Leu Leu As n Ile Val Ar g Val Leu Ile Thr Lys Leu 305 310 315 320 Lys Val Thr Hi s Gl n Al a Gl u Ser As n Leu Tyr Met Lys Al a Val Ar g 325 330 335 Al a Thr Leu Ile Leu Val Pr o Leu Leu Gl y I l e Gl u Phe Val Leu Phe 340 345 350 Pr o Tr p Ar g Pr o Gl u Gl y Lys Val Al a Gl u Gl u Val Tyr As p Tyr Val 355 360 365 Met Hi s I l e Leu Met Hi s Tyr Gl n Gl y Leu Leu Val Ser Thr Ile Phe 370 375 380 Cys Phe Phe As n Gl y Gl u Val Gl n Al a I l e Leu Ar g Ar g As n Tr p As n 385 390 395 400 Gl n Tyr Lys Ile Gl n Phe Gl y As n Gl y Phe Ser Hi s Ser As p Al a Leu 405 410 415 Ar g Ser Al a Ser Tyr Thr Val Ser Thr I l e Ser As p Val Gl n Gl y Tyr 420 425 430 Ser Hi s As p Cys Pr o Thr Gl u Hi s Leu As n Gl y Lys Ser Ile Gl n As p 435 440 445 I l e Gl u As n Val Al a Leu Lys Pr o Gl u Lys Met Tyr As p Leu Val Met 450 455 460

    <210> 221 <211> 461 <212> PRT <213> Macaca f asci cul ar i s

    Page 174

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    <400> 221 Leu Tyr Phe Leu 10 Val Leu Leu Pr o Phe 15 Phe Met 1 Gl u Lys Lys Cys 5 Thr Met I l e Phe Val 20 Thr Al a Gl u Leu Gl u 25 Gl u Ser Pr o Gl u As p 30 Ser Ile Gl n Leu Gl y 35 Val Thr Ar g As n Lys 40 I l e Met Thr Al a Gl n 45 Tyr Gl u Cys Tyr Gl n 50 Lys Ile Met Gl n As p 55 Pr o I l e Gl n Gl n Al a 60 Gl u Gl y Val Tyr Cys 65 As n Ar g Thr Tr p As p 70 Gl y Tr p Leu Cys Tr p 75 As n As n Val Al a Al a 80 Gl y Thr Gl u Ser Met 85 Gl n Leu Cys Pr o As p 90 Tyr Phe Gl n As p Phe 95 As p Pr o Ser Gl u Lys 100 Val Thr Lys Ile Cys 105 As p Gl n As p Gl y As n 110 Tr p Phe Ar g Hi s Pr o 115 Al a Ser As n Ar g Thr 120 Tr p Thr As n Tyr Thr 125 Gl n Cys As n Val As n 130 Thr Hi s Gl u Lys Val 135 Lys Thr Al a Leu As n 140 Leu Phe Tyr Leu Thr 145 I l e I l e Gl y Hi s Gl y 150 Leu Ser I l e Al a Ser 155 Leu Leu Ile Ser Leu 160 Gl y I l e Phe Phe Tyr 165 Phe Lys Ser Leu Ser 170 Cys Gl n Ar g Ile Thr 175 Leu Hi s Lys As n Leu 180 Phe Phe Ser Phe Val 185 Cys As n Ser Val Val 190 Thr Ile I l e Hi s Leu 195 Thr Al a Val Al a As n 200 As n Gl n Al a Leu Val 205 Al a Thr As n

    Page 175

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    Pr o Val 210 Ser Cys A1472PCT Lys Val Ser 215 Gl n Phe I l e Hi s Leu 220 Tyr Leu Met Gl y Cys As n Tyr Phe Tr p Met Leu Cys Gl u Gl y I l e Tyr Leu Hi s Thr Leu 225 230 235 240 I l e Val Val Al a Val Phe Al a Gl u Lys Gl n Hi s Leu Met Tr p Tyr Tyr 245 250 255 Phe Leu Gl y Tr p Gl y Phe Pr o Leu I l e Pr o Al a Cys Ile Hi s Al a Ile 260 265 270 Al a Ar g Ser Leu Tyr Tyr As n As p As n Cys Tr p Ile Ser Ser As p Thr 275 280 285 Hi s Leu Leu Tyr Ile Ile Hi s Gl y Pr o I l e Cys Al a Al a Leu Leu Val 290 295 300 As n Leu Phe Phe Leu Leu As n Ile Val Ar g Val Leu Ile Thr Lys Leu 305 310 315 320 Lys Val Thr Hi s Gl n Al a Gl u Ser As n Leu Tyr Met Lys Al a Val Ar g 325 330 335 Al a Thr Leu Ile Leu Val Pr o Leu Leu Gl y I l e Gl u Phe Val Leu Ile 340 345 350 Pr o Tr p Ar g Pr o Gl u Gl y Lys Ile Al a Gl u Gl u Val Tyr As p Tyr Ile 355 360 365 Met Hi s I l e Leu Met Hi s Phe Gl n Gl y Leu Leu Val Ser Thr Ile Phe 370 375 380 Cys Phe Phe As n Gl y Gl u Val Gl n Al a I l e Leu Ar g Ar g As n Tr p As n 385 390 395 400 Gl n Tyr Lys Ile Gl n Phe Gl y As n Ser Phe Ser As n Ser Gl u Al a Leu 405 410 415 Ar g Ser Al a Ser Tyr Thr Val Ser Thr I l e Ser As p Gl y Pr o Gl y Tyr 420 425 430

    Page 176

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    Ser Hi s As p 435 Cy s Pr o Ser Gl u Hi s 440 Leu As n Gl y Lys Ser 445 Ile Hi s As p I l e Gl u As n Val Val Leu Lys Pr o Gl u As n Leu Ty r As n 450 455 460 <210> 222 <211> 461 <212> PRT <213> Macaca mul at t a <400> 222 Met Gl u Lys Lys Cy s Thr Leu Ty r Phe Leu Val Leu Leu Pr o Phe Phe 1 5 10 15 Met I l e Phe Val Thr Al a Gl u Leu Gl u Gl u Ser Pr o Gl u As p Ser Ile 20 25 30 Gl n Leu Gl y Val Thr Ar g As n Lys I l e Met Thr Al a Gl n Ty r Gl u Cy s 35 40 45 Ty r Gl n Lys Ile Met Gl n As p Pr o I l e Gl n Gl n Al a Gl u Gl y Val Ty r 50 55 60 Cy s As n Ar g Thr Tr p As p Gl y Tr p Leu Cy s Tr p As n As n Val Al a Al a 65 70 75 80 Gl y Thr Gl u Ser Met Gl n Leu Cy s Pr o As p Ty r Phe Gl n As p Phe As p 85 90 95 Pr o Ser Gl u Lys Val Thr Lys Ile Cy s As p Gl n As p Gl y As n Tr p Phe 100 105 110 Ar g Hi s Pr o Al a Ser As n Ar g Thr Tr p Thr As n Ty r Thr Gl n Cy s As n 115 120 125 Val As n Thr Hi s Gl u Lys Val Lys Thr Al a Leu As n Leu Phe Ty r Leu 130 135 140 Thr I l e I l e Gl y Hi s Gl y Leu Ser I l e Al a Ser Leu Leu Ile Ser Leu 145 150 155 160

    Page 177

    A1472PCT

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    Gl y I l e Phe Phe Tyr 165 Phe Lys Ser Leu Ser 170 Cys Gl n Ar g Ile Thr 175 Leu Hi s Lys As n Leu Phe Phe Ser Phe Val Cys As n Ser Val Val Thr Ile 180 185 190 I l e Hi s Leu Thr Al a Val Al a As n As n Gl n Al a Leu Val Al a Thr As n 195 200 205 Pr o Val Ser Cys Lys Val Ser Gl n Phe I l e Hi s Leu Tyr Leu Met Gl y 210 215 220 Cys As n Tyr Phe Tr p Met Leu Cys Gl u Gl y I l e Tyr Leu Hi s Thr Leu 225 230 235 240 I l e Val Val Al a Val Phe Al a Gl u Lys Gl n Hi s Leu Met Tr p Tyr Tyr 245 250 255 Phe Leu Gl y Tr p Gl y Phe Pr o Leu I l e Pr o Al a Cys Ile Hi s Al a Ile 260 265 270 Al a Ar g Ser Leu Tyr Tyr As n As p As n Cys Tr p Ile Ser Ser As p Thr 275 280 285 Hi s Leu Leu Tyr Ile Ile Hi s Gl y Pr o I l e Cys Al a Al a Leu Leu Val 290 295 300 As n Leu Phe Phe Leu Leu As n Ile Val Ar g Val Leu Ile Thr Lys Leu 305 310 315 320 Lys Val Thr Hi s Gl n Al a Gl u Ser As n Leu Tyr Met Lys Al a Val Ar g 325 330 335 Al a Thr Leu Ile Leu Val Pr o Leu Leu Gl y I l e Gl u Phe Val Leu Ile 340 345 350 Pr o Tr p Ar g Pr o Gl u Gl y Lys Ile Al a Gl u Gl u Val Tyr As p Tyr Ile 355 360 365

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    Met Hi s 370 I l e Leu Met Hi s Phe 375 Gl n Gl y Leu Leu Val 380 Ser Thr Ile Phe Cy s Phe Phe As n Gl y Gl u Val Gl n Al a I l e Leu Ar g Ar g As n Tr p As n 385 390 395 400 Gl n Ty r Lys Ile Gl n Phe Gl y As n Ser Phe Ser As n Ser Gl u Al a Leu 405 410 415 Ar g Ser Al a Ser Ty r Thr Val Ser Thr I l e Ser As p Gl y Pr o Gl y Ty r 420 425 430 Ser Hi s As p Cy s Pr o Ser Gl u Hi s Leu As n Gl y Lys Ser Ile Hi s As p 435 440 445 I l e Gl u As n Val Val Leu Lys Pr o Gl u As n Leu Ty r As n 450 455 460 <210> 223 <211> 460 <212> PRT <213> Art i fi ci al Sequenc e

    <220>

    <221> sour ce

    <223> / not e Descr i pt i on of Ar t i f i ci al Sequence: Sy nt het i c pol ypept i de <400> 223 Met Gl u Lys Lys Cy s Thr Leu Ty r Phe Leu Val Leu Leu Pr o Phe Phe 1 5 10 15 Met I l e Leu Val Thr Al a Gl u Ser Gl u Gl u Gl y Al a As n Gl n Thr As p 20 25 30 Leu Gl y Val Thr Ar g As n Lys Ile Met Thr Al a Gl n Ty r Gl u Cy s Ty r 35 40 45 Gl n Lys I l e Met Gl n As p Pr o Ile Gl n Gl n Al a Gl u Gl y Val Ty r Cy s 50 55 60 As n Ar g Thr Tr p As p Gl y Tr p Leu Cy s Tr p As n As p Val Al a Al a Gl y 65 70 75 80

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    Thr Gl u Ser Met Gl n 85 Leu Cy s Pr o As p Ty r 90 Phe Gl n As p Phe As p 95 Pr o Ser Gl u Lys Val 100 Thr Lys Ile Cy s As p 105 Gl n As p Gl y As n Tr p 110 Phe Ar g Hi s Pr o Al a 115 Ser As n Ar g Thr Tr p 120 Thr As n Ty r Thr Gl n 125 Cy s As n Val As n Thr 130 Hi s Gl u Lys Val Lys 135 Thr Al a Leu As n Leu 140 Phe Ty r Leu Thr I l e 145 I l e Gl y Hi s Gl y Leu 150 Ser Ile Al a Ser Leu 155 Leu Ile Ser Leu Gl y 160 I l e Phe Phe Ty r Phe 165 Lys Ser Leu Ser Cy s 170 Gl n Ar g Ile Thr Leu 175 Hi s Lys As n Leu Phe 180 Phe Ser Phe Val Cy s 185 As n Ser Val Val Thr 190 Ile Ile Hi s Leu Thr 195 Al a Val Al a As n As n 200 Gl n Al a Leu Val Al a 205 Thr As n Pr o Val Ser 210 Cy s Lys Val Ser Gl n 215 Phe I l e Hi s Leu Ty r 220 Leu Met Gl y Cy s As n 225 Ty r Phe Tr p Met Leu 230 Cy s Gl u Gl y I l e Ty r 235 Leu Hi s Thr Leu Ile 240 Val Val Al a Val Phe 245 Al a Gl u Lys Gl n Hi s 250 Leu Met Tr p Ty r Ty r 255 Phe Leu Gl y Tr p Gl y 260 Phe Pr o Leu Ile Pr o 265 Al a Cy s Ile Hi s Al a 270 Ile Al a Ar g Ser Leu 275 Ty r Ty r As n As p As n 280 Cy s Tr p I l e Ser Ser 285 As p Thr Hi s Leu Leu Ty r Ile Ile Hi s Gl y Pr o I l e Cy s Al a Al a Leu Leu Val As n

    Page 180

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    A1472PCT

    290 295 300

    Leu 305 Phe Phe Leu Leu As n 310 Ile Val Ar g Val Leu 315 Ile Thr Lys Leu Lys 320 Val Thr Hi s Gl n Al a Gl u Ser As n Leu Ty r Met Lys Al a Val Ar g Al a 325 330 335 Thr Leu I l e Leu Val Pr o Leu Leu Gl y I l e Gl u Phe Val Leu Ile Pr o 340 345 350 Tr p Ar g Pr o Gl u Gl y Lys Ile Al a Gl u Gl u Val Ty r As p Ty r Ile Met 355 360 365 Hi s I l e Leu Met Hi s Phe Gl n Gl y Leu Leu Val Ser Thr Ile Phe Cy s 370 375 380 Phe Phe As n Gl y Gl u Val Gl n Al a I l e Leu Ar g Ar g As n Tr p As n Gl n 385 390 395 400 Ty r Lys I l e Gl n Phe Gl y As n Ser Phe Ser As n Ser Gl u Al a Leu Ar g 405 410 415 Ser Al a Ser Ty r Thr Val Ser Thr I l e Ser As p Gl y Pr o Gl y Ty r Ser 420 425 430 Hi s As p Cy s Pr o Ser Gl u Hi s Leu As n Gl y Lys Ser Ile Hi s As p Ile 435 440 445 Gl u As n Val Leu Leu Lys Pr o Gl u As n Leu Ty r As n

    450 455 460 <210> 224 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 224

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    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g aggccccagg acagaaggt c 120 accat ct cct gct ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagct cccag gaacagcccc caaact cct c at t t at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt cag ccaccct ggg cat caccgga 300 ct ccagact g gggacgaggc cgat t at t ac t gcggaacat gggat agccg cct gagt gct 360 gt ggt t t t cg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714

    <210> 225 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 225 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gct gac t cagccaccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at ct t t agga gt aat cagcg gccct caggg 240 gt ccct gacc gat t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt ggg 300 ct ccggt ccg aggat gaggc t gat t at t ac t gt gcagcat gggat gacag cct gagt ggt 360 tgggt gt t cg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540

    Page 182

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    2018203471 16 May 2018 gt caaggcgg agcagct acc gt cacgcat g

    gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714

    <210> 226 <211> 708 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 226

    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gaca t ccagat gac ccagt ct cca t cct ccct gt ct gcat ct gt aggagacaga 120 gt caccat ca ct t gccgggc aagt cagggc at t agaaat g at t t aggct g gt 11 cagcag 180 aaaccaggga aagcccct aa gcgcct gat c t at gct gcat ccagt t t gca aagt ggggt c 240 ccat caaggt t cagcggcag t ggat ct ggg acagaat t ca ct ct cacaat cagcagcct g 300 cagcct gaag at t t agcaac t t at t act gt ct acagt at a at at t t accc gtggacgttc 360 ggccaaggga ccaaggt gga aat caaacgt acggt ggct g caccat ct gt ct t cat ct t c 420 ccgccat ct g at gagcagt t gaaat ct gga act gcct ct g ttgt gtgcct gct gaat aac 480 11 ct at ccca gagaggccaa agt acagt gg aaggt ggat a acgccct cca at cgggt aac 540 t cccaggaga gt gt cacaga gcaggacagc aaggacagca cct acagcct cagcagcacc 600 ct gacgct ga gcaaagcaga ct acgagaaa cacaaagt ct acgcct gcga agt cacccat 660 cagggcct ga gct cgcccgt cacaaagagc t t caacaggg gagagt gt 708

    <210> 227 <211> 708 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 227

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    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt t ct t ct gagct gac t caggaccct act gt gt ct g t ggcct t ggg acagacagt c 120 aaaat cacat gccaaggaga cagcct caga agt t t t t at g caagct ggt a ccagcagaag 180 ccaggacagg cccct gt act t gt ct t ct at ggt aaaaaca accggccct c agggat ccca 240 gaccgat t ct ct ggct ccag ct caggaaac acagct t cct t gaccat cac t ggggct cag 300 gcggaagat g aggct gact a t t at t gt aat t cccgggaca gcagt gt t t a ccat ct ggt a 360 ct cggcggag ggaccaagct gaccgt cct a ggt cagccca aggccaaccc cact gt cact 420 ct gt t cccgc cct cct ct ga ggagct ccaa gccaacaagg ccacact agt gt gt ct gat c 480 agt gact t ct acccgggagc t gt gacagt g gcct ggaagg cagat ggcag ccccgt caag 540 gcgggagt gg agaccaccaa accct ccaaa cagagcaaca acaagt acgc ggccagcagc 600 t acct gagcc t gacgcccga gcagt ggaag t cccacagaa gct acagct g ccaggt cacg 660 cat gaaggga gcaccgt gga gaagacagt g gcccct acag aat gt t ca 708

    <210> 228 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 228 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gat a 11 at act ggc ccagact cca ct t t ct ct gt ccgt cacccc t ggacagccg 120 gcct ccat ct cct gcaagt c t agt cagagc ct cct gcaca gt gct ggaaa gacct at t t g 180 t at t ggt acc t gcagaagcc aggccagcct ccacagct cc t gat ct at ga agt 11 ccaac 240 cggt t ct ct g gagt gccaga t aggt t cagt ggcagcgggt cagggacaga 111 cacact g 300 aaaat cagcc gggt ggaggc tgaggat gt t gggat t t at t act gcat gca aagt t t t ccg 360 ct t ccgct ca cttt cggcgg agggaccaag gt ggagat ca aacgt acggt ggct gcacca 420 t ct gt ct t ca t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 t gcct gct ga at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aacgcc 540

    Page 184

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    ct ccaat cgg gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600 agcct cagca gcaccct gac gct gagcaaa gcagact acg agaaacacaa agt ct acgcc 660 t gcgaagt ca cccat caggg cct gagct cg cccgt cacaa agagct t caa caggggagag 720 t gt 723

    <210> 229 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 229

    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g cggccccagg acagaaggt c 120 accat ct cct gct ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagct cccag gaacagcccc caaact cct c at t t at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt caa ccaccct ggg cat caccgga 300 ct ccagact g gggacgaggc cgat t at t ac t gcggaacat gggat agccg cct gagt gct 360 gt ggt t t t cg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714

    <210> 230 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

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    <400> 230 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gat a t t gt gat gac t cagt ct cca ct ct ccct gc ccgt cacccc t ggagagccg 120 gcct ccat ct cct gcaggt c t agt cagagc ct cct gcat a gt t t t gggt a caact at t t g 180 gat t ggt acc t gcagaagcc agggcagt ct ccacagct cc t gat ct at t t gggt t ct aat 240 cgggcct ccg gggt ccct ga caggt t cagt ggcagt ggat caggcacaga 1111 acact g 300 aaaat cagca gagt ggaggc tgaggat gtt ggggt t t at t act gcat gca agct ct acaa 360 act ccat t ca ct t t cggccc t gggaccaaa gt ggat at ca aacgt acggt ggct gcacca 420 t ct gt ct t ca t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 t gcct gct ga at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aacgcc 540 ct ccaat cgg gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600 agcct cagca gcaccct gac gct gagcaaa gcagact acg agaaacacaa agt ct acgcc 660 t gcgaagt ca cccat caggg cct gagct cg cccgt cacaa agagct t caa caggggagag 720

    t gt 723 <210> 231 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 231 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gat a 11 at t ct gac ccagact cca ct t t ct ct gt ccgt cacccc t ggacagccg 120 gcct ccat ct cct gcaagt c t agt cagagc ct cct gcaca gt gat ggaaa gacct at t t g 180 t at t ggt acc t gcagaagcc cggccagcct ccacagct cc t gat ct at ga agt 11 ccaac 240 cggt t ct ct g gagagccaga t aggt t cagt ggcagcgggt cagggacaga 111 cacact g 300 aaaat cagcc gggt ggaggc tgaggat gtt gggact t at t at t gcat gca aagt t t t ccg 360 ct t ccgct ca cttt cggcgg agggaccaag gt ggagat ca aacgt acggt ggct gcacca 420

    Page 186

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    t ct gt ct t ca t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 t gcct gct ga at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aacgcc 540 ct ccaat cgg gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600 agcct cagca gcaccct gac gct gagcaaa gcagact acg agaaacacaa agt ct acgcc 660 t gcgaagt ca cccat caggg cct gagct cg cccgt cacaa agagct t caa caggggagag 720

    tgt 723 <210> 232 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 232 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g cggccccagg acagaaggt c 120 accat ct cct gct ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagt t cccag gaacagcccc caaact cct c at t t at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt cag ccaccct ggg cat caccgga 300 ct ccagact g gggacgaggc cgat t at t ac t gcggaacat gggat agccg cct gagt gct 360 gt ggt t t t cg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714

    <210> 233 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

    Page 187

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    A1472PCT <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 233 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gct gac t cagt caccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at cct t agga at aat cagcg gccct caggg 240 gt ccct gacc gat t ct ct gg ct ccaagt ct ggcacct cag cct ccct gac cat cagt ggg 300 ct ccggt ccg aggat gaggc t gact at t at t gt gcagcat gggat gacag cct gagt ggt 360 tgggt gt t cg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714 <210> 234 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 234 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gct gac t cagccaccc t cagcgt ct g ggacccccgg gcagagggt c 120 accat ct ct t gt t ct ggaag cagt t ccaat at cggaagt a at act gt gaa ct ggt accag 180 cagct cccag gaacggcccc caaact cct c at ct at act a at aat cagcg gccct caggg 240 gt ccct gacc gat t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt gga 300 ct ccagt ct g aggat gaggc t gat 1111 ac t gt gcagcgc gggat gagag cct gaat ggt 360

    Page 188

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    gt ggt at t cg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714

    <210> 235 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 235 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gct gac t cagccaccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at ct t t agga at aat cagcg gccct caggg 240 gt ccct gacc gct t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt ggg 300 ct ccggt ccg aggat gaggc t gat t at t ac t gt gcagcat gggat gacag cct gagt ggt 360 tgggt gttcg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714

    <210> 236 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

    Page 189

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    A1472PCT <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 236 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gct gac t cagccaccc t cagcgt ct g ggacccccgg gcagagagt c 120 accat ct ct t gt t ct ggaag cagct ccaac at cggcagt a at t at gt at a ct ggt accag 180 cagct cccag gagcggcccc caaact cct c at ct t t agga at aat cagcg gccct caggg 240 gt ccct gacc gct t ct ct gg ct ccaagt ct ggcacct cag cct ccct ggc cat cagt ggg 300 ct ccggt ccg aggat gaggc t gat t at t ac t gt gcagcat gggat gacag cct gagt ggt 360 tgggt gttcg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714 <210> 237 <211> 723 <212> DNA <213> Ar t i f i ci al Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 237 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gat a 11 acact gac ccagact cca ct t t ct ct gt ccgt ct cccc t ggacagccg 120 gcct ccat ct cct gcaagt c t agt cagagc ct cct gcaca gt gat ggaag gaact at ct g 180 t at t ggt acc t gcagaagcc aggccagcct ccacagct cc t gat ct at ga agt gt ccaac 240 cggt t ct ct g gact gccaga t aggt t cagt ggcagcgggt cagggacaga 111 cacact g 300 aaaat cagcc gggt ggaggc tgaggat gtt gggat t t at t act gcat gca aagt t t t ccg 360

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    ct t ccgct ca cttt cggcgg agggaccaag gt ggagat ca aacgt acggt ggct gcacca 420 t ct gt ct t ca t ct t cccgcc at ct gat gag cagt t gaaat ct ggaact gc ct ct gt t gt g 480 t gcct gct ga at aact t ct a t cccagagag gccaaagt ac agt ggaaggt ggat aacgcc 540 ct ccaat cgg gt aact ccca ggagagt gt c acagagcagg acagcaagga cagcacct ac 600 agcct cagca gcaccct gac gct gagcaaa gcagact acg agaaacacaa agt ct acgcc 660 t gcgaagt ca cccat caggg cct gagct cg cccgt cacaa agagct t caa caggggagag 720

    t gt 723 <210> 238 <211> 714 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 238 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagt ct gt gt t gac gcagccgccc t cagt gt ct g cggccccagg acagaaggt c 120 accat ct cct gct ct ggaag cagct ccaac at t gggaat a at t at gt at c ct ggt accag 180 cagct cccag gaacagcccc caaact cct c at t t at gaca at aat aagcg accct caggg 240 at t cct gacc gat t ct ct gg ct ccaagt ct ggcacgt cag ccaccct ggg cat caccgga 300 ct ccagact g gggacgaggc cgat t at t ac t gcggaacat gggat agccg cct gagt gct 360 gt ggt t t t cg gcggagggac caagct gacc gt cct aggt c agcccaaggc caaccccact 420 gt cact ct gt t cccgccct c ct ct gaggag ct ccaagcca acaaggccac act agt gt gt 480 ct gat cagt g act t ct accc gggagct gt g acagt ggcct ggaaggcaga t ggcagcccc 540 gt caaggcgg gagt ggagac caccaaaccc t ccaaacaga gcaacaacaa gt acgcggcc 600 agcagct acc t gagcct gac gcccgagcag t ggaagt ccc acagaagct a cagct gccag 660 gt cacgcat g aagggagcac cgt ggagaag acagt ggccc ct acagaat g t t ca 714

    <210> 239 <211> 708 <212> DNA

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    A1472PCT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 239

    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gaca t ccagat gac ccagt ct cca t cct ccct gt ct gcat ct gt aggagacaga 120 gt caccat ca ct t gccgggc aagt cagggc at t agaaagg at t t aggct g gt at cagcag 180 aaaccaggga aagcccct aa gcgcct gat c t at ggagcat ccagt t t gca aagt ggggt c 240 ccat caaggt t cagcggcag t ggat ct ggg acagaat t ca ct ct cacaat cagcagcct g 300 cagcct gaag at t t t gcaac t t at t act gt ct acagt at a at agt t t ccc gtggacgttc 360 ggccaaggga ccaaggt gga aat caaacgt acggt ggct g caccat ct gt ct t cat ct t c 420 ccgccat ct g at gagcagt t gaaat ct gga act gcct ct g ttgt gtgcct gct gaat aac 480 11 ct at ccca gagaggccaa agt acagt gg aaggt ggat a acgccct cca at cgggt aac 540 t cccaggaga gt gt cacaga gcaggacagc aaggacagca cct acagcct cagcagcacc 600 ct gacgct ga gcaaagcaga ct acgagaaa cacaaagt ct acgcct gcga agt cacccat 660 cagggcct ga gct cgcccgt cacaaagagc t t caacaggg gagagt gt 708 <210> 240 <211> 705 <212> DNA <213> Artificial Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 240 at ggaaaccc cagct cagct t ct ct t cct c ct gct act ct ggct cccaga t accaccgga 60 gaaat t gt gt t gacgcagt c t ccaggcacc ct gt ct t t gt ct ccagggga aagagccacc 120 ct ct cct gca gggccagt ca gagt gt t agc agcggct act t aacct ggt a ccagcagaaa 180 cct ggccagg ct cccaggct cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 240 gacaggt t ca gt ggcagt gg gt ct gggaca gact t cact c t caccat cag cagact ggag 300

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    cct gaagat t t t gcagt gt a 11 act gt cag cagt at ggt a act cact gt g caggt t t ggc 360 caggggacca agct ggagat caaacgt acg gt ggct gcac cat ct gt ct t cat ct t cccg 420 ccat ct gat g agcagt t gaa at ct ggaact gcct ct gt t g t gt gcct gct gaat aact t c 480 t at cccagag aggccaaagt acagt ggaag gt ggat aacg ccct ccaat c gggt aact cc 540 caggagagt g t cacagagca ggacagcaag gacagcacct acagcct cag cagcaccct g 600 acgct gagca aagcagact a cgagaaacac aaagt ct acg cct gcgaagt cacccat cag 660 ggcct gagct cgcccgt cac aaagagct t c aacaggggag agt gt 705

    <210> 241 <211> 705 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 241 at ggaaaccc cagct cagct t ct ct t cct c ct gct act ct ggct cccaga t accaccgga 60 gaaat t gt gt t gacgcagt c t ccaggcacc ct gt ct t t gt ct ccagggga aagagccacc 120 ct ct cct gca gggccagt ca gagt gt t agc agcggct act t aacct ggt a ccagcagaaa 180 cct ggccagg ct cccagact cct cat ct at ggt gcat cca gcagggccac t ggcat ccca 240 gacaggt t ca gt ggcagt gg gt ct gggacg gact t cact c t caccat cag cagact ggag 300 cct gaagat t t t gcagt gt a 11 act gt cag cagt at ggt a act cact gag caggt t t ggc 360 caggggacca agct ggagat caaacgt acg gt ggct gcac cat ct gt ct t cat ct t cccg 420 ccat ct gat g agcagt t gaa at ct ggaact gcct ct gt t g t gt gcct gct gaat aact t c 480 t at cccagag aggccaaagt acagt ggaag gt ggat aacg ccct ccaat c gggt aact cc 540 caggagagt g t cacagagca ggacagcaag gacagcacct acagcct cag cagcaccct g 600 acgct gagca aagcagact a cgagaaacac aaagt ct acg cct gcgaagt cacccat cag 660 ggcct gagct cgcccgt cac aaagagct t c aacaggggag agt gt 705

    <210> 242 <211> 1434 <212> DNA

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    A1472PCT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 242 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt ggaat ct ggg ggaggcgt gg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc t t cagt agct t t ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at at cat t t gat gg aagt at t aag 240 t at t ct gt ag act ccgt gaa gggccgatt c accat ct cca gagacaat t c aaagaacacg 300 ct gt t t ct gc aaat gaacag cct gcgagcc gaggacacgg ct gt gt at t a ct gt gcgaga 360 gat cggct ca at t act at ga t agt agt ggt t at t at cact acaaat act a cggt at ggcc 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat cggt c 480 t t ccccct gg cgccct gct c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt cga gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c acgt gcgt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt acgt g gacggcgt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg ttccgt gtgg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaacgg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat cg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaaggct t ct accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat gct ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat gct c cgt gat gcat 1380

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    A1472PCT gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg taaa 1434 <210> 243 <211> 1437 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 243 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gagg t gcagct ggt ggagt ct ggg ggaggct t gg t aaagcct gg ggggt ccct t 120 agact ct cct gt gcagcct c t ggat t cact t t cagt aacg cct ggat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagt gggt t ggccgt at t a aaagcacaac t gat ggt ggg 240 acaacagact acgct gcacc cgt gaaaggc agat t cacca t ct caagaga t gat t caaaa 300 aacacgct gt at ct gcaaat gaacagcct g aaaaccgagg acacagccgt gt at t act gt 360 accacagat c ggaccggat a t agcat cagc tggt ct agtt act act act a ct acggt at g 420 gacgt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat cg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct gggct gc 540 ct ggt caagg act act t ccc cgaaccggt g acggt gt cgt ggaact cagg cgct ct gacc 600 agcggcgt gc acacct t ccc agct gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t cggc acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagcgca aat gt t gt gt cgagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t cc t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt gcg t ggt ggt gga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc acgt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act ggct gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200

    Page 195

    2018203471 16 May 2018 gt caaaggct aacaact aca aagct caccg cat gaggct c t ct accccag agaccacacc t ggacaagag t gcacaacca cgacat cgcc t cccat gct g caggt ggcag ct acacgcag

    A1472PCT gt ggagt ggg gact ccgacg caggggaacg aagagcct ct agagcaat gg gct cct t ct t t ct t ct cat g ccct gt ct cc gcagccggag cct ct acagc ct ccgt gat g gggt aaa <210> 244 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 244

    1260

    1320

    1380

    1437

    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gagg t gcagct at t ggagt ct ggg ggaggct t gg t acagcct gg ggagt ccct g 120 agact ct cct gt gcagcct c t gggt t cacc t t t agcagct at gccat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagt gggt c t cagct at t a gt ggt agt gg t ggt cgcaca 240 t act acgcag act ccgt gaa gggccggtt c accat ct cca gagacaat t c caagaacacg 300 ct gt at ct gc aaat gaat ag cct gagagcc gaggacacgg ccgt at at t a ct gt gcgaaa 360 gat caaaggg aggt agggcc gt at agcagt ggct ggt acg act act act a cggt at ggac 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat cggt c 480 t t ccccct gg cgccct gct c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt cga gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c acgt gcgt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt acgt g gacggcgt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg ttccgt gtgg t cagcgt cct caccgt t gt g 1020

    Page 196

    A1472PCT

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    caccaggact ggct gaacgg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat cg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaaggct t ct accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat gct ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat gct c cgt gat gcat 1380 gaggct ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

    <210> 245 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 245 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagtt ggt gcagt ct ggg gct gaggt ga agaagcct gg ggcct cagt g 120 aaggt ct cct gcaaggct t c t ggat acacc 11 caccggct act at at gca ct gggt gcga 180 caggcccct g gacaagggct t gagt ggat g ggat ggat ca accct aacag t ggt ggcaca 240 aact at gcac agaagt t t ca gggcagggt c accat gacca gggacacgt c cat cagcaca 300 gcct acat gg agct gagcag gct gagat ct gacgacacgg ccgt gt at t t ct gt gcgaga 360 gat caaat ga gt at t at t at gctt cgggga gt t t t t cccc ct t act at t a cggt at ggac 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat cggt c 480 11 ccccct gg cgccct gct c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt cga gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840

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    accct cat ga t ct cccggac ccct gaggt c acgt gcgt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt acgt g gacggcgt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg ttccgt gtgg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaacgg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat cg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaaggct t ct accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat gct ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat gct c cgt gat gcat 1380 gaggct ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

    <210> 246 <211> 1431 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 246 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt ggagt ct ggg ggaggcgt gg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc t t cagt agct at ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at 11 cat at gat gg aagt cat gaa 240 t cct at gcag act ccgt gaa gggccgatt c accat ct cca gagacat t t c caagaacacg 300 ct gt at ct gc aaat gaacag cct gagagct gaggacacgg ct gt gt at t t ct gt gcgaga 360 gagaggaaac gggt t acgat gt ct acct t a t at t act act t ct act acgg t at ggacgt c 420 t ggggccaag ggaccacggt caccgt ct ct agt gcct cca ccaagggccc at cggt ct t c 480 cccct ggcgc cct gct ccag gagcacct cc gagagcacag cggccct ggg ct gcct ggt c 540 aaggact act t ccccgaacc ggt gacggt g t cgt ggaact caggcgct ct gaccagcggc 600 gt gcacacct t cccagct gt cct acagt cc t caggact ct act ccct cag cagcgt ggt g 660

    Page 198

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    accgt gccct ccagcaact t cggcacccag acct acacct gcaacgt aga t cacaagccc 720 agcaacacca aggt ggacaa gacagt t gag cgcaaat gt t gt gt cgagt g cccaccgt gc 780 ccagcaccac ct gt ggcagg accgt cagt c t t cct ct t cc ccccaaaacc caaggacacc 840 ct cat gat ct cccggacccc t gaggt cacg tgcgtggtgg t ggacgt gag ccacgaagac 900 cccgaggt cc agt t caact g gt acgt ggac ggcgtggagg t gcat aat gc caagacaaag 960 ccacgggagg agcagt t caa cagcacgt t c cgt gt ggt ca gcgt cct cac cgt t gt gcac 1020 caggact ggc t gaacggcaa ggagt acaag t gcaaggt ct ccaacaaagg cct cccagcc 1080 cccat cgaga aaaccat ct c caaaaccaaa gggcagcccc gagaaccaca ggt gt acacc 1140 ct gcccccat cccgggagga gat gaccaag aaccaggt ca gcct gacct g cct ggt caaa 1200 ggct t ct acc ccagcgacat cgccgt ggag t gggagagca at gggcagcc ggagaacaac 1260 t acaagacca cacct cccat gct ggact cc gacggct cct t ct t cct ct a cagcaagct c 1320 accgt ggaca agagcaggt g gcagcagggg aacgt ct t ct cat gct ccgt gat gcat gag 1380 gct ct gcaca accact acac gcagaagagc ct ct ccct gt ct ccgggt aa a 1431

    <210> 247 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 247 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt ggaat ct ggg ggaggcgt gg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc t t cagt agct t t ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at at cat t t gat gg aagt at t aag 240 t at t ct gt ag act ccgt gaa gggccgatt c accat ct cca gagacaat t c aaagaacacg 300 ct gt t t ct gc aaat gaacag cct gcgagcc gaggacacgg ct gt gt at t a ct gt gcgaga 360 gat cggct ca at t act at ga t agt agt ggt t at t at cact acaaat act a cggt at ggcc 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat cggt c 480

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    t t ccccct gg cgccct gct c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt cga gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c acgt gcgt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt acgt g gacggcgt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg t t ccgt gt gg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaacgg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat cg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaaggct t ct accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat gct ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat gct c cgt gat gcat 1380 gaggct ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434 <210> 248 <211> 1407 <212> DNA <213> Artificial Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Artificial Sequence: Synthetic <400> 248 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gagg t gcagct ggt ggagt ct ggg ggaggct t gg t aaagccagg gcggt ccct g 120 agact ct cct gt acagct t c t ggat t cacc tttggtgatt at gct at gag ct ggt t ccgc 180 caggct ccag ggaaggggct ggagt ggat a ggt t t cat t a gaagcagagc ttatggtggg 240 acaccagaat acgccgcgt c t gt gaaaggc agat t cacca t ct caagaga t gat t ccaaa 300

    Page 200

    A1472PCT

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    accat cgcct at ct gcaaat gaacagcct g aaaaccgagg acacagccgt gt at t t ct gt 360 gct agaggac ggggt at t gc agct cgt t gg gact act ggg gccagggaac cct ggt cacc 420 gt ct ct agt g cct ccaccaa gggcccat cg gt ct t ccccc t ggcgccct g ct ccaggagc 480 acct ccgaga gcacagcggc cct gggct gc ct ggt caagg act act t ccc cgaaccggt g 540 acggt gt cgt ggaact cagg cgct ct gacc agcggcgt gc acacct t ccc agct gt cct a 600 cagt cct cag gact ct act c cct cagcagc gt ggt gaccg t gccct ccag caact t cggc 660 acccagacct acacct gcaa cgt agat cac aagcccagca acaccaaggt ggacaagaca 720 gt t gagcgca aat gt t gt gt cgagt gccca ccgt gcccag caccacct gt ggcaggaccg 780 t cagt ct t cc t ct t cccccc aaaacccaag gacaccct ca t gat ct cccg gacccct gag 840 gt cacgt gcg tggtggtgga cgt gagccac gaagaccccg aggt ccagt t caact ggt ac 900 gt ggacggcg t ggaggt gca t aat gccaag acaaagccac gggaggagca gt t caacagc 960 acgt t ccgt g t ggt cagcgt cct caccgt t gt gcaccagg act ggct gaa cggcaaggag 1020 t acaagt gca aggt ct ccaa caaaggcct c ccagccccca t cgagaaaac cat ct ccaaa 1080 accaaagggc agccccgaga accacaggt g t acaccct gc ccccat cccg ggaggagat g 1140 accaagaacc aggt cagcct gacct gcct g gt caaaggct t ct accccag cgacat cgcc 1200 gt ggagt ggg agagcaat gg gcagccggag aacaact aca agaccacacc t cccat gct g 1260 gact ccgacg gct cct t ct t cct ct acagc aagct caccg t ggacaagag caggt ggcag 1320 caggggaacg t ct t ct cat g ct ccgt gat g cat gaggct c t gcacaacca ct acacgcag 1380 aagagcct ct ccct gt ct cc gggt aaa 1407

    <210> 249 <211> 1431 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 249 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgctgtcagg tgcagctggt ggagt ct ggg ggaggcgt gg tccagcctgg gaggt ccct g 120

    Page 201

    A1472PCT

    2018203471 16 May 2018

    agact ct cct gt gcagcct c t ggat t cacc t t cagt agct at ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at 11 cat at gat gg aagt cat gaa 240 t cct at gcag act ccgt gaa gggccgatt c accat ct cca gagacat t t c caagaacacg 300 ct gt at ct gc aaat gaacag cct gagagct gaggacacgg ct gt gt at t t ct gt gcgaga 360 gagaggaaac gggt t acgat gt ct acct t a t at t act act t ct act acgg t at ggacgt c 420 t ggggccaag ggaccacggt caccgt ct ct agt gcct cca ccaagggccc at cggt ct t c 480 cccct ggcgc cct gct ccag gagcacct cc gagagcacag cggccct ggg ct gcct ggt c 540 aaggact act t ccccgaacc ggt gacggt g t cgt ggaact caggcgct ct gaccagcggc 600 gt gcacacct t cccagct gt cct acagt cc t caggact ct act ccct cag cagcgt ggt g 660 accgt gccct ccagcaact t cggcacccag acct acacct gcaacgt aga t cacaagccc 720 agcaacacca aggt ggacaa gacagt t gag cgcaaat gt t gt gt cgagt g cccaccgt gc 780 ccagcaccac ct gt ggcagg accgt cagt c 11 cct ct t cc ccccaaaacc caaggacacc 840 ct cat gat ct cccggacccc t gaggt cacg tgcgtggtgg t ggacgt gag ccacgaagac 900 cccgaggt cc agt t caact g gt acgt ggac ggcgtggagg t gcat aat gc caagacaaag 960 ccacgggagg agcagt t caa cagcacgt t c cgt gt ggt ca gcgt cct cac cgt t gt gcac 1020 caggact ggc t gaacggcaa ggagt acaag t gcaaggt ct ccaacaaagg cct cccagcc 1080 cccat cgaga aaaccat ct c caaaaccaaa gggcagcccc gagaaccaca ggt gt acacc 1140 ct gcccccat cccgggagga gat gaccaag aaccaggt ca gcct gacct g cct ggt caaa 1200 ggct t ct acc ccagcgacat cgccgt ggag t gggagagca at gggcagcc ggagaacaac 1260 t acaagacca cacct cccat gct ggact cc gacggct cct t ct t cct ct a cagcaagct c 1320 accgt ggaca agagcaggt g gcagcagggg aacgt ct t ct cat gct ccgt gat gcat gag 1380 gct ct gcaca accact acac gcagaagagc ct ct ccct gt ct ccgggt aa a 1431

    <210> 250 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    Page 202

    A1472PCT

    2018203471 16 May 2018 <400> 250

    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt ggaat ct ggg ggaggcgt gg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc t t cagt agct t t ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at at cat t t gat gg aagt at t aag 240 t at t ct gt ag act ccgt gaa gggccgatt c accat ct cca gagacaat t c aaagaacacg 300 ct gt t t ct gc aaat gaacag cct gcgagcc gaggacacgg ct gt gt at t a ct gt gcgaga 360 gat cggct ca at t act at ga t agt agt ggt t at t at cact acaaat act a cggt at ggcc 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat cggt c 480 t t ccccct gg cgccct gct c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt cga gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c acgt gcgt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt acgt g gacggcgt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg ttccgt gtgg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaacgg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat cg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaaggct t ct accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat gct ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat gct c cgt gat gcat 1380 gaggct ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434

    <210> 251 <211> 1437 <212> DNA

    Page 203

    2018203471 16 May 2018

    A1472PCT <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 251 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gagg t gcagct ggt ggagt ct ggg ggaggct t gg t aaagcct gg ggggt ccct t 120 agact ct cct gt gcagcct c t ggat t cact t t cagt aacg cct ggat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagt gggt t ggccgt at t a aaagcaaaac t gat ggt ggg 240 acaacagact acact gcacc cgt gaaaggc agat t cacca t ct caagaga t gat t caaaa 300 aacacgct gt at ct gcaaat gaat agcct g aaagccgagg acacagccgt gt at t act gt 360 accacagat c ggaccgggt a t agcat cagc tggt ct agtt act act act a ct acggt at g 420 gacgt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat cg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct gggct gc 540 ct ggt caagg act act t ccc cgaaccggt g acggt gt cgt ggaact cagg cgct ct gacc 600 agcggcgt gc acacct t ccc agct gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t cggc acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagcgca aat gt t gt gt cgagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t cc t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt gcg t ggt ggt gga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc acgt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act ggct gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat cgcc gt ggagt ggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat gct g gact ccgacg gct cct t ct t cct ct acagc 1320 aagct caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380

    Page 204

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    A1472PCT catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaa 1437 <210> 252 <211> 1425 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de

    <400> 252 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt gcagt ct ggg gct gaggt ga agaagcct gg ggcct cagt g 120 aaggt ct cct gcaaggct t c t ggat acacc 11 caccgact act at at gt a ct gggt gcga 180 caggcccct g gacaagggct t gagt ggat g ggat ggat ca gccct aat ag t ggt ggcaca 240 aact at gccc agaagt t t ca gggcagggt c accat gacca gggacacgt c t at cagcaca 300 gcct acat gg agct gagt ag gct gagat ct gacgacacgg ccgt gt at t a ct gt gt gaga 360 ggaggat at a gt ggct acgc t gggct ct ac t cccact act acggt at gga cgt ct ggggc 420 caagggacca cggt caccgt ct ct agt gcc t ccaccaagg gcccat cggt ct t ccccct g 480 gcgccct gct ccaggagcac ct ccgagagc acagcggccc t gggct gcct ggt caaggac 540 t act t ccccg aaccggt gac ggt gt cgt gg aact caggcg ct ct gaccag cggcgt gcac 600 acct t cccag ct gt cct aca gt cct cagga ct ct act ccc t cagcagcgt ggt gaccgt g 660 ccct ccagca act t cggcac ccagacct ac acct gcaacg t agat cacaa gcccagcaac 720 accaaggt gg acaagacagt t gagcgcaaa tgttgt gt cg agt gcccacc gt gcccagca 780 ccacct gt gg caggaccgt c agt ct t cct c t t ccccccaa aacccaagga caccct cat g 840 at ct cccgga cccct gaggt cacgt gcgt g gt ggt ggacg t gagccacga agaccccgag 900 gt ccagt t ca act ggt acgt ggacggcgt g gaggt gcat a at gccaagac aaagccacgg 960 gaggagcagt t caacagcac gttccgt gtg gt cagcgt cc t caccgt t gt gcaccaggac 1020 t ggct gaacg gcaaggagt a caagt gcaag gt ct ccaaca aaggcct ccc agcccccat c 1080 gagaaaacca t ct ccaaaac caaagggcag ccccgagaac cacaggt gt a caccct gccc 1140 ccat cccggg aggagat gac caagaaccag gt cagcct ga cct gcct ggt caaaggct t c 1200

    Page 205

    A1472PCT

    2018203471 16 May 2018 t accccagcg accacacct c gacaagagca cacaaccact acat cgccgt ccat gct gga ggt ggcagca acacgcagaa ggagt gggag ct ccgacggc ggggaacgt c gagcct ct cc agcaat gggc t cct t ct t cc t t ct cat gct ct gt ct ccgg agccggagaa t ct acagcaa ccgt gat gca gt aaa caact acaag gct caccgt g t gaggct ct g <210> 253 <211> 1437 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 253

    1260

    1320

    1380

    1425

    at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gagg t acagct ggt ggagt ct ggg ggaggct t gg t aaagcct gg ggggt ccct c 120 agact ct cct gt gcagcct c t ggat t cact t t cggt aacg cct ggat gag ct gggt ccgc 180 caggct ccag ggaaggggct ggagt gggt t ggccgt at t a aaagcaaaac t gat ggt ggg 240 acaacagact acgct gcacc cgt gaaaggc agat t cacca t ct caagaga t gat t caaaa 300 aacacgct gt at ct gcaaat gaacagcct g aaaaccgagg acacagccgt gt at t t ct gt 360 accacagat c ggaccgggt a t agcat cagc tggt ct agtt act act act a ct acggt at g 420 gacgt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat cg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct gggct gc 540 ct ggt caagg act act t ccc cgaaccggt g acggt gt cgt ggaact cagg cgct ct gacc 600 agcggcgt gc acacct t ccc agct gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t cggc acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagcgca aat gt t gt gt cgagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t cc t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt gcg t ggt ggt gga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc acgt t ccgt g t ggt cagcgt cct caccgt t 1020

    Page 206

    A1472PCT

    2018203471 16 May 2018 gt gcaccagg ccagccccca t acaccct gc gt caaaggct aacaact aca aagct caccg cat gaggct c act ggct gaa t cgagaaaac ccccat cccg t ct accccag agaccacacc t ggacaagag t gcacaacca cggcaaggag cat ct ccaaa ggaggagat g cgacat cgcc t cccat gct g caggt ggcag ct acacgcag t acaagt gca accaaagggc accaagaacc gt ggagt ggg gact ccgacg caggggaacg aagagcct ct aggt ct ccaa agccccgaga aggt cagcct agagcaat gg gct cct t ct t t ct t ct cat g ccct gt ct cc caaaggcct c accacaggt g gacct gcct g gcagccggag cct ct acagc ct ccgt gat g gggt aaa

    1080

    1140

    1200

    1260

    1320

    1380

    1437 <210> 254 <211> 1437 <212> DNA <213> Artificial Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 254 at ggacat ga cgct gt gagg agact ct cct caggct ccag acaacagact aacacgct gt accacagat c gacgt ct ggg gt ct t ccccc ct ggt caagg agcggcgt gc gt ggt gaccg aagcccagca ccgt gcccag gggt gcccgc t acagct ggt gt gcagcct c ggaaggggct acgct gcacc at ct gcaaat ggaccgggt a gccaagggac t ggcgccct g act act t ccc acacct t ccc t gccct ccag acaccaaggt caccacct gt t cagct cct g ggagt ct ggg t ggat t cact ggagt gggt t cgt gaaaggc gaacagcct g t agcat cagc cacggt cacc ct ccaggagc cgaaccggt g agct gt cct a caact t cggc ggacaagaca ggcaggaccg gggct cct gc ggaggct t gg t t cggt aacg ggccgt at t a agat t cacca aaaaccgagg tggt ct agtt gt ct ct agt g acct ccgaga acggt gt cgt cagt cct cag acccagacct gt t gagcgca t cagt ct t cc t gct gt ggct t aaagcct gg cct ggat gag aaagcaaaac t ct caagaga acacagccgt act act act a cct ccaccaa gcacagcggc ggaact cagg gact ct act c acacct gcaa aat gt t gt gt t ct t cccccc gagaggt gcg ggggt ccct t ct gggt ccgc t gat ggt ggg t gat t caaaa gt at t act gt ct acggt at g gggcccat cg cct gggct gc cgct ct gacc cct cagcagc cgt agat cac cgagt gccca aaaacccaag

    120

    180

    240

    300

    360

    420

    480

    540

    600

    660

    720

    780

    840

    Page 207

    A1472PCT

    2018203471 16 May 2018

    gacaccct ca t gat ct cccg gacccct gag gt cacgt gcg tggt ggt gga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc acgt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act ggct gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat cgcc gt ggagt ggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat gct g gact ccgacg gct cct t ct t cct ct acagc 1320 aagct caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380 cat gaggct c t gcacaacca ct acacgcag aagagcct ct ccct gt ct cc gggt aaa 1437

    <210> 255 <211> 1431 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 255 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt ggagt ct ggg ggaggcgt gg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc t t cagt agct at ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at 11 cat at gat gg aagt cat gaa 240 t cct at gcag act ccgt gaa gggccgatt c accat ct cca gagacat t t c caagaacacg 300 ct gt at ct gc aaat gaacag cct gagagct gaggacacgg ct gt gt at t t ct gt gcgaga 360 gagaggaaac gggt t acgat gt ct acct t a t at t act act t ct act acgg t at ggacgt c 420 t ggggccaag ggaccacggt caccgt ct ct agt gcct cca ccaagggccc at cggt ct t c 480 cccct ggcgc cct gct ccag gagcacct cc gagagcacag cggccct ggg ct gcct ggt c 540 aaggact act t ccccgaacc ggt gacggt g t cgt ggaact caggcgct ct gaccagcggc 600 gt gcacacct t cccagct gt cct acagt cc t caggact ct act ccct cag cagcgt ggt g 660

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    accgt gccct ccagcaact t cggcacccag acct acacct gcaacgt aga t cacaagccc 720 agcaacacca aggt ggacaa gacagt t gag cgcaaat gt t gt gt cgagt g cccaccgt gc 780 ccagcaccac ct gt ggcagg accgt cagt c t t cct ct t cc ccccaaaacc caaggacacc 840 ct cat gat ct cccggacccc t gaggt cacg tgcgtggtgg t ggacgt gag ccacgaagac 900 cccgaggt cc agt t caact g gt acgt ggac ggcgtggagg t gcat aat gc caagacaaag 960 ccacgggagg agcagt t caa cagcacgt t c cgt gt ggt ca gcgt cct cac cgt t gt gcac 1020 caggact ggc t gaacggcaa ggagt acaag t gcaaggt ct ccaacaaagg cct cccagcc 1080 cccat cgaga aaaccat ct c caaaaccaaa gggcagcccc gagaaccaca ggt gt acacc 1140 ct gcccccat cccgggagga gat gaccaag aaccaggt ca gcct gacct g cct ggt caaa 1200 ggct t ct acc ccagcgacat cgccgt ggag t gggagagca at gggcagcc ggagaacaac 1260 t acaagacca cacct cccat gct ggact cc gacggct cct t ct t cct ct a cagcaagct c 1320 accgt ggaca agagcaggt g gcagcagggg aacgt ct t ct cat gct ccgt gat gcat gag 1380 gct ct gcaca accact acac gcagaagagc ct ct ccct gt ct ccgggt aa a 1431

    <210> 256 <211> 1434 <212> DNA <213> Ar t i f i ci al Sequence

    <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 256 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt ggaat ct ggg ggaggcgt gg t ccagcct gg gaggt ccct g 120 agact ct cct gt gcagcct c t ggat t cacc t t cagt agct t t ggcat gca t tgggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at at cat t t gat gg aagt at t aag 240 t act ct gt ag act ccgt gaa gggccgatt c accat ct cca gagacaat t c aaagaacacg 300 ct gt t t ct gc aaat gaacag cct gcgagcc gaggacacgg ct gt gt at t a ct gt gcgaga 360 gat cggct ca at t act at ga t agt agt ggt t at t at cact acaaat act a cggt ct ggcc 420 gt ct ggggcc aagggaccac ggt caccgt c t ct agt gcct ccaccaaggg cccat cggt c 480

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    t t ccccct gg cgccct gct c caggagcacc t ccgagagca cagcggccct gggct gcct g 540 gt caaggact act t ccccga accggt gacg gt gt cgt gga act caggcgc t ct gaccagc 600 ggcgt gcaca cct t cccagc t gt cct acag t cct caggac t ct act ccct cagcagcgt g 660 gt gaccgt gc cct ccagcaa ct t cggcacc cagacct aca cct gcaacgt agat cacaag 720 cccagcaaca ccaaggt gga caagacagt t gagcgcaaat gt t gt gt cga gt gcccaccg 780 t gcccagcac cacct gt ggc aggaccgt ca gt ct t cct ct t ccccccaaa acccaaggac 840 accct cat ga t ct cccggac ccct gaggt c acgt gcgt gg t ggt ggacgt gagccacgaa 900 gaccccgagg t ccagt t caa ct ggt acgt g gacggcgt gg aggt gcat aa t gccaagaca 960 aagccacggg aggagcagt t caacagcacg ttccgt gtgg t cagcgt cct caccgt t gt g 1020 caccaggact ggct gaacgg caaggagt ac aagt gcaagg t ct ccaacaa aggcct ccca 1080 gcccccat cg agaaaaccat ct ccaaaacc aaagggcagc cccgagaacc acaggt gt ac 1140 accct gcccc cat cccggga ggagat gacc aagaaccagg t cagcct gac ct gcct ggt c 1200 aaaggct t ct accccagcga cat cgccgt g gagt gggaga gcaat gggca gccggagaac 1260 aact acaaga ccacacct cc cat gct ggac t ccgacggct cct t ct t cct ct acagcaag 1320 ct caccgt gg acaagagcag gt ggcagcag gggaacgt ct t ct cat gct c cgt gat gcat 1380 gaggct ct gc acaaccact a cacgcagaag agcct ct ccc t gt ct ccggg t aaa 1434 <210> 257 <211> 1437 <212> DNA <213> Artificial Sequence <220> <221> sour ce <223> / not e= Descr i pt i pol ynucl eot i de on of Ar t i f i c i al Sequenc e: Sy nt het i c <400> 257 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt gagg t gcagct ggt ggagt ct ggg ggaggcct gg t caagcct gg ggggt ccct g 120 agact ct cct gt gcagcct c t ggat acacc t t cagt acct at agcat gaa ct gggt ccgc 180 caggct ccag ggaaggggct ggagt gggt c t cat ccat t a gt agt agt ag t agt t acaga 240 t at t acgcag act cagt gaa gggccgatt c accat ct cca gagacaacgc caagaact ca 300

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    ct gt at ct gc aaat gagt ag cct gagagcc gaggacacgg ct gt gt at t a ct gt gcgaga 360 gaaggggt gt ct ggcagt t c gccgt at agc at cagct ggt acgact act a t t acggt at g 420 gacgt ct ggg gccaagggac cacggt cacc gt ct ct agt g cct ccaccaa gggcccat cg 480 gt ct t ccccc t ggcgccct g ct ccaggagc acct ccgaga gcacagcggc cct gggct gc 540 ct ggt caagg act act t ccc cgaaccggt g acggt gt cgt ggaact cagg cgct ct gacc 600 agcggcgt gc acacct t ccc agct gt cct a cagt cct cag gact ct act c cct cagcagc 660 gt ggt gaccg t gccct ccag caact t cggc acccagacct acacct gcaa cgt agat cac 720 aagcccagca acaccaaggt ggacaagaca gt t gagcgca aat gt t gt gt cgagt gccca 780 ccgt gcccag caccacct gt ggcaggaccg t cagt ct t cc t ct t cccccc aaaacccaag 840 gacaccct ca t gat ct cccg gacccct gag gt cacgt gcg tggtggtgga cgt gagccac 900 gaagaccccg aggt ccagt t caact ggt ac gt ggacggcg t ggaggt gca t aat gccaag 960 acaaagccac gggaggagca gt t caacagc acgt t ccgt g t ggt cagcgt cct caccgt t 1020 gt gcaccagg act ggct gaa cggcaaggag t acaagt gca aggt ct ccaa caaaggcct c 1080 ccagccccca t cgagaaaac cat ct ccaaa accaaagggc agccccgaga accacaggt g 1140 t acaccct gc ccccat cccg ggaggagat g accaagaacc aggt cagcct gacct gcct g 1200 gt caaaggct t ct accccag cgacat cgcc gt ggagt ggg agagcaat gg gcagccggag 1260 aacaact aca agaccacacc t cccat gct g gact ccgacg gct cct t ct t cct ct acagc 1320 aagct caccg t ggacaagag caggt ggcag caggggaacg t ct t ct cat g ct ccgt gat g 1380 cat gaggct c t gcacaacca ct acacgcag aagagcct ct ccct gt ct cc gggt aaa 1437

    <210> 258 <211> 1422 <212> DNA <213> Ar t i f i ci al Sequence <220>

    <221> sour ce <223> / not e= Descr i pt i on of Artificial Sequence: Synthetic pol ynucl eot i de <400> 258 at ggacat ga gggt gcccgc t cagct cct g gggct cct gc t gct gt ggct gagaggt gcg 60 cgct gt cagg t gcagct ggt ggagt ct ggg ggaggcgt gg tccagcctgg gaggt ccct g 120

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    agact ct cct gt gcagcgt c t ggat t cacc 11 cagt agct at ggcat gca ct gggt ccgc 180 caggct ccag gcaaggggct ggagt gggt g gcagt t at at ggt at gat gg aagt aat aaa 240 t act at gcag act ccgt gaa gggccgatt c at cat ct cca gagat aaat c caagaacacg 300 ct gt at ct gc aaat gaacag cct gagagcc gaggacacgg ct gt gt at t a ct gt gcgaga 360 gcggggggt a t agcagcagc t ggcct ct ac t act act acg gt at ggacgt ct ggggccaa 420 gggaccacgg t caccgt ct c t agt gcct cc accaagggcc cat cggt ct t ccccct ggcg 480 ccct gct cca ggagcacct c cgagagcaca gcggccct gg gct gcct ggt caaggact ac 540 t t ccccgaac cggt gacggt gt cgt ggaac t caggcgct c t gaccagcgg cgt gcacacc 600 t t cccagct g t cct acagt c ct caggact c t act ccct ca gcagcgt ggt gaccgt gccc 660 t ccagcaact t cggcaccca gacct acacc t gcaacgt ag at cacaagcc cagcaacacc 720 aaggt ggaca agacagt t ga gcgcaaat gt t gt gt cgagt gcccaccgt g cccagcacca 780 cct gt ggcag gaccgt cagt ct t cct ct t c cccccaaaac ccaaggacac cct cat gat c 840 t cccggaccc ct gaggt cac gtgcgtggtg gt ggacgt ga gccacgaaga ccccgaggt c 900 cagt t caact ggt acgt gga cggcgt ggag gt gcat aat g ccaagacaaa gccacgggag 960 gagcagt t ca acagcacgt t ccgt gt ggt c agcgt cct ca ccgt t gt gca ccaggact gg 1020 ct gaacggca aggagt acaa gt gcaaggt c t ccaacaaag gcct cccagc ccccat cgag 1080 aaaaccat ct ccaaaaccaa agggcagccc cgagaaccac aggt gt acac cct gccccca 1140 t cccgggagg agat gaccaa gaaccaggt c agcct gacct gcct ggt caa aggct t ct ac 1200 cccagcgaca t cgccgt gga gt gggagagc aat gggcagc cggagaacaa ct acaagacc 1260 acacct ccca t gct ggact c cgacggct cc 11 ct t cct ct acagcaagct caccgt ggac 1320 aagagcaggt ggcagcaggg gaacgt ct t c t cat gct ccg t gat gcat ga ggct ct gcac 1380 aaccact aca cgcagaagag cct ct ccct g t ct ccgggt a aa 1422 <210> 259 <211> 981 <212> DNA <213> Homo sapi ens <400> 259 gct agcacca agggcccat c ggt ct t cccc ct ggcgccct gct ccaggag cacct ccgag 60 agcacagcgg ccct gggct g cct ggt caag gactacttcc ccgaaccggt Page 212 gacggt gt cg 120

    A1472PCT

    2018203471 16 May 2018

    t ggaact cag gcgct ct gac cagcggcgt g cacacct t cc cagct gt cct acagt cct ca 180 ggact ct act ccct cagcag cgt ggt gacc gt gccct cca gcaact t cgg cacccagacc 240 t acacct gca acgt agat ca caagcccagc aacaccaagg t ggacaagac agttgagcgc 300 aaat gt t gt g t cgagt gccc accgt gccca gcaccacct g t ggcaggacc gt cagt ct t c 360 ct ct t ccccc caaaacccaa ggacaccct c at gat ct ccc ggacccct ga ggt cacgt gc 420 gt ggt ggt gg acgt gagcca cgaagacccc gaggt ccagt t caact ggt a cgt ggacggc 480 gt ggaggt gc at aat gccaa gacaaagcca cgggaggagc agt t caacag cacgt t ccgt 540 gt ggt cagcg t cct caccgt t gt gcaccag gact ggct ga acggcaagga gt acaagt gc 600 aaggt ct cca acaaaggcct cccagccccc at cgagaaaa ccat ct ccaa aaccaaaggg 660 cagccccgag aaccacaggt gt acaccct g cccccat ccc gggaggagat gaccaagaac 720 caggt cagcc t gacct gcct ggt caaaggc t t ct acccca gcgacat cgc cgt ggagt gg 780 gagagcaat g ggcagccgga gaacaact ac aagaccacac ct cccat gct ggact ccgac 840 ggct cct t ct t cct ct acag caagct cacc gt ggacaaga gcaggt ggca gcaggggaac 900 gt ct t ct cat gct ccgt gat gcat gaggct ct gcacaacc act acacgca gaagagcct c 960 t ccct gt ct c cgggt aaat g a 981 <210> 260 <211> 324 <212> DNA <213> Homo sapi ens <400> 260 cgt acggt gg ct gcaccat c t gt ct t cat c t t cccgccat ct gat gagca gt t gaaat ct 60 ggaact gcct ct gt t gt gt g cct gct gaat aact t ct at c ccagagaggc caaagt acag 120 t ggaaggt gg at aacgccct ccaat cgggt aact cccagg agagt gt cac agagcaggac 180 agcaaggaca gcacct acag cct cagcagc accct gacgc t gagcaaagc agact acgag 240 aaacacaaag t ct acgcct g cgaagt cacc cat cagggcc t gagct cgcc cgt cacaaag 300 agct t caaca ggggagagt g tt ag 324

    <210> 261 <211> 321 <212> DNA

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    A1472PCT

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    <213> Homo sapi ens <400> 261 ggt cagccca aggccaaccc cact gt cact ct gt t cccgc cct cct ct ga ggagct ccaa 60 gccaacaagg ccacact agt gt gt ct gat c agt gact t ct acccgggagc t gt gacagt g 120 gcct ggaagg cagat ggcag ccccgt caag gcgggagt gg agaccaccaa accct ccaaa 180 cagagcaaca acaagt acgc ggccagcagc t acct gagcc t gacgcccga gcagt ggaag 240 t cccacagaa gct acagct g ccaggt cacg cat gaaggga gcaccgt gga gaagacagt g 300 gcccct acag aat gt t cat a ^g 321

    Page 214