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`the
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`International application number: PCT /IB2006/003 l 8 l
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`World Intellectual Property Organization (WIPO) - Geneva, Switzerland
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`'!!Qi AIDD, '{1Q) '>'i.!!Al!MJ:'IIHrES~\ )!HiEl SiE1Ni!l~ Sm@, (!10MIEl~
`UNITED STATES DEPARTMENT OF COMMERCE
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`Jorg
`ZELLER
`San Francisco, California
`Kristian T.
`POULSEN
`San Francisco, California
`Yasmine N.
`ABDICHE
`Sunnvvale, California
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`pa-1025351
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`PROVISIONAL APPLICATION COVER SHEET
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`First Named Inventor I Jorg ZELLER
`I Docket Number
`514713003000
`INVENTOR(S)/APPLICANT(S)
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`Given Name llll"S! and middle Hf anvl\
`Jaume
`Sierra Leigh
`Amon
`
`Famllv or Surname
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`PONS
`JONES
`ROSENTHAL
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`Residence
`(Cttv and either State or Forelon Countrvl
`San Carlos, California
`Redwood City, California
`Woodside, California
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`Application Data Sheet
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`Germany
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`Jorg
`ZELLER
`San Francisco
`CA
`us
`157 Saturn Street #3
`San Francisco
`CA
`94114
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`pa-1025350
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`T.
`POULSEN
`San Francisco
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`2080 Third Street #7
`San Francisco
`CA
`94107
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`Inventor
`United Kingdom
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`Yasmina
`N.
`ABDICHE
`Sunnyvale
`CA
`us
`442 Madera Avenue
`Apartment 1 o
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`Inventor
`Spain
`Full Capacity
`Jaume
`PONS
`San Carlos
`CA
`us
`3311 La Mesa Drive #3
`San Carlos
`CA
`94070
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`Inventor
`us
`Full Capacity
`Sierra
`Leigh
`JONES
`Redwood City
`CA
`us
`67 Columbia Avenue
`Redwood City
`CA
`94063
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`pa-1025350
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`ROSENTHAL
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`

`

`ANTAGONIST ANTIBODIES DIRECTED AGAINST CALCITONIN GENE-RELATED
`PEPTIDE AND METHODS USING SAME
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`Not applicable.
`
`[0001)
`
`STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
`[0002]
`Not applicable.
`
`FIELD OF THE INVENTION
`[0003]
`The present invention relates to the use of anti-CORP antagonist antibodies for the
`prevention, amelioration, or treatment of CORP related headaches (e.g., migraine).
`
`BACKGROUND OF THE INVENTION
`[0004)
`CORP (calcitonin gene-related peptide) is a 37 amino acid neuropeptide, which belongs
`to a family of peptides that includes calcitonin, adrenomedullin and amylin. In humans, two forms
`of CORP ( a-CORP and J3-CORP) exist and have similar activities. They vary by three amino acids
`and exhibit differential distribution. At least two CORP receptor subtypes may also account for
`differential activities. CORP is a neurotransmitter in the central nervous system, and has been
`shown to be a potent vasodilator in the periphery, where CORP-containing neurons are closely
`associated with blood vessels. CORP-mediated vasodilatation is also associated with neurogenic
`inflammation, as part of a cascade of events that results in extravasation of plasma and vasodilation
`of the microvasculature and is present in migraine.
`[0005)
`CORP is a potent vasodilator that has been implicated in the pathology of all forms of
`vascular headache, including migraines (with or without aura) and cluster headache. Durham, N
`Engl. J Med. 350:1073-1075, 2004. The serum levels of CORP in the external jugular vein are
`elevated in patients during migraine headache. Ooadsby et al., Ann. Neurol. 28: 183-7, 1990.
`Intravenous administration of human a-CORP induced headache and migraine in patients suffering
`from migraine without aura, suggesting that CORP has a causative role in migraine. Lassen et al.,
`Cephalalgia 22:54-61, 2002.
`
`1
`
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`

`

`[0006]
`Possible CORP 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 at the
`CORP receptor (e.g., dipeptide derivative BIBN4096BS (Boerhringer Ingelheim); CORP(8-37)), or
`interact with one or more of receptor-associated proteins, such as, receptor activity membrane
`protein (RAMP) or receptor component protein (RCP), both of which affect binding of CORP to its
`receptors. Brain, S. et al., Trends in Pharmacological Sciences 23:51-53, 2002. Alpha-2
`adrenoceptor subtypes and adenosine Al receptors also control (inhibit) CORP release and
`trigeminal activation (Ooadsby et al., Brain 125:1392-401, 2002). The adenosine Al receptor
`agonist OR79236 (metrafadil), which has been shown to inhibit neurogenic vasodilation and
`trigeminal nociception in humans, may also have anti-migraine activity (Arulmani et al.,
`Cephalalgia 25:1082-1090, 2005; Giffin et al., Cephalalgia 23:287-292, 2003.)
`[0007]
`Confounding this theory is the observation that treatment with compounds that
`exclusively inhibit neurogenic inflammation (e.g., tachykinin NKI receptor antagonists) or
`trigeminal activation (e.g., 5HTm receptor agonists) have been shown to be relatively ineffective as
`acute treatments for migraine, leading some investigators to question whether inhibiting release of
`CORP is the primary mechanism of action of effective anti-migraine treatments. Arulmani et al.,
`Eur. J. Pharmacol. 500:315-330, 2004.
`[0008) 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 accompanied
`by an aura. The headache pain may be severe and may also be unilateral in certain patients.
`[0009] 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 is recommended
`for those patients having more than 3-4 attacks of migraine per month. Ooadsby et al. New Engl. J.
`Med. 34(>(4): 257-275, 2002.
`[0010]
`The variety ofpharmacologic interventions that have been used to treat migraine and the
`variability in responses among patients are a testament to the diverse nature of this disorder. Thus,
`such relatively non-selective drugs as ergot alkaloids (e.g., ergotamine, dihydroergotamine,
`
`2
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`

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`methysergide ), which exhibit serotonergic, as well as adrenergic, noradrenergic and dopaminergic
`activity, have been used for over eighty years to treat migraine. Other treatments include opiates
`(e.g., oxycodone) and P-adrenergic antagonists (e.g., propranolol). Some patients, usually those
`with milder symptoms, are able to control their symptoms with non-prescription remedies such as
`one or more non-steroidal anti-inflammatory agents (NSAIDs), such as a combination of aspirin,
`acetaminophen and caffeine (e.g., Excedrin® Migraine).
`[0011) More recently, 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 SHT-IB/1D and/or SHT-la receptor agonists, such as
`sumatriptan, in some patients has led researchers to propose a serotonergic etiology of the disorder.
`Unfortunately, while soine patients respond well to this treatment, others are relatively resistant to
`its effects.
`[0012)
`It has been postulated that a dysfunction of an ion channel in the aminergic brainstem
`nuclei underlies the disorder, however, the precise pathophysiology of migraine is not yet well
`understood. One fo~ of migraine, familial hemiplagic migraine, has been shown to associated
`with missense mutations in the al subunit of the voltage-gated P/Q-type calcium channel, and it is
`thought likely that other ion-channel mutations will also be found in other populations of patients.
`While dilation of blood vessels is associated with and exacerbates the pain symptoms of migraine,
`such neurovascular events are now thought to be a result of, rather than causative of, the condition. ,
`Overall, dysfunction of brainstem pathways modulating sensory input is considered to be a unifying
`feature of migraine. Goadsby, P.J. et al., New Engl. J. Med 346(4): 257-275, 2002.
`[0013)
`Throughout this application various publications (including patents and patent
`applications) are referenced. The disclosures of these publications in their entireties are hereby
`incorporated by reference.
`
`BRIEF SUMMARY OF THE INVENTION
`[0014)
`The invention disclosed herein concerns anti-CGRP antagonist antibodies and methods
`of using anti-CGRP antagonist antibodies for treating or preventing headaches, such as migraine
`with or without aura, hemiplegic migraine, cluster headaches, migrainous neuralgia, chronic
`
`3
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`

`

`headaches, tension headaches, and headaches resulting from other medical conditions (such as
`infection or increased pressure in the skull due to a tumor).
`[0015)
`In one aspect, the present invention provides a method for treating or preventing
`headache (e.g., migraine and cluster headache) in an individual comprising administering to the
`individual an effective amount of an anti-CGRP antagonist antibody.
`[0016)
`In another aspect, the invention provides a method for ameliorating, controlling,
`reducing incidence of, or delaying the development or progression of headache (e.g., migraine and
`cluster headache) in an individual comprising administering to the individual an effective amount of
`an anti-CGRP antagonist antibody.
`[0017]
`In some embodiments, the anti-CGRP antagonist antibody recognizes a human CGRP.
`In some embodiments, the anti-CORP antagonist antibody binds to both human a-CGRP and ~(cid:173)
`CGRP. In some embodiments, the anti-CG RP antagonist antibody binds human and rat CORP. In
`some embodiments, the anti-CGRP antagonist antibody binds the C-terminal fragment having
`amino acids 25-37 of CGRP. In some embodiments, the anti-CGRP antagonist antibody binds a C(cid:173)
`terminal epitope within amino acids 25-37 ofCGRP.
`[0018)
`In some embodiments, the anti-CGRP antagonist antibody is a monoclonal antibody. In
`some embodiments, the anti-CORP antagonist antibody is humanized. In some embodiments, the
`antibody is human. In some embodiments, the anti-CORP antagonist antibody is antibody G 1 (as
`described herein). In some embodiments, the anti-CGRP antagonist antibody comprises one or more
`CDR(s) (such as one, two, three, four, five, or, in some embodiments, all six CDRs) of antibody GI
`or variants of G 1 shown in Table 6. In still other embodiments, the anti-CGRP antagonist antibody
`comprises the amino acid sequence of the heavy chain variable region shown in Figure 5 (SEQ ID
`N0:1) and the amino acid sequence of the light chain variable region shown in Figure 5 (SEQ ID N0:2).
`[0019]
`In some embodiments, the antibody comprises a modified constant region, such as a
`constant region that is immunologically inert (including partially immunologically inert), e.g., does
`not trigger complement mediated lysis, does not stimulate antibody-dependent cell mediated
`cytotoxicity (ADCC), does not activate microglia, or having reduced one or more of these activities.
`In some embodiments, the constant region is modified as described in Eur. J. Immunol. (1999)
`29:2613-2624; PCT Application No. PCT/GB99/01441; and/or UK Patent Application No.
`9809951.8. In other embodiments, the antibody comprises a human heavy chain IgG2a constant
`
`4
`
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`

`

`region comprising the following mutations: A330P33 l to S330S331 (amino acid numbering with
`reference to the wildtype IgG2a sequence). Eur. J. Immunol. (1999) 29:2613-2624. In some
`embodiments, the heavy chain constant region of the antibody is a human heavy chain IgG I with
`any of the following mutations: 1) A327A330P331 to O327S330S331; 2) E233L234L235G236 to
`P233V234A235 with 0236 deleted; 3) E233L234L235 to P233V234A235; 4)
`E233L234L235G236A327 A330P33 l to P233V234A235G327S330S33 l with 0236 deleted; 5)
`E233L234L235A327 A330P33 l to P233V234A235G327S330S33 l; and 6) N297 to A297 or any
`other amino acid except N. In some embodiments, the heavy chain constant region of the antibody
`is a human heavy chain IgG4 with any of the following mutations: E233F234L235G236 to
`P233V234A235 with 0236 deleted; E233F234L235 to P233V234A235; and S2281235 to
`P228E235. In still other embodiments, the constant region is aglycosylated for N-linked
`glycosylation. In some embodiments, the constant region is aglycosylated for N-linked
`glycosylation by mutating the oligosaccharide attachment residue (such as Asn297) and/or flanking
`residues that are part of the N-glycosylation recognition sequence in the constant region. In some
`embodiments, the constant region is aglycosylated for N-linked glycosylation. The constant region
`may be aglycosylated for N-linked glycosylation enzymatically or by expression in a glycosylation
`deficient host cell.
`[0020]
`The binding affinity (Ko) of an anti-CORP antagonist antibody to CORP (such as human
`a-CORP) can be about 0.02 to about 200 nM. In some embodiments, the binding affinity is any of
`about 200 nM, about 100 nM, about 50 nM, about 10 nM, about 1 nM, about 500 pM, about 100
`pM, about 60 pM, about 50 pM, about 20 pM, about 15 pM, about IO pM, about 5 pM, or about 2
`pM. In some embodiments, the binding affinity is less than any of about 250 nM, about 200 nM,
`about I 00 nM, about 50 nM, about IO nM, about 1 nM, about 500 pM, about I 00 pM, or about 50
`pM.
`[0021)
`The anti-CORP antagonist antibody may be administered prior to, during and/or after
`headache. In some embodiments, the anti-CORP antagonist antibody is administered prior to the
`attack of headache ( e.g., migraine and cluster headache). Administration of an anti-CORP
`antagonist antibody can be by any means known in the art, including: orally, intravenously,
`subcutaneously, intraarterially, intramuscularly, intracardially, intraspinally, intrathoracically,
`
`5
`
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`

`

`intraperitoneally, intraventricularly, sublingually, transdermally, and/or via inhalation.
`Administration may be systemic, e.g. intravenously, or localized.
`[0022]
`In some embodiments, the anti-CORP antagonist antibody may be administered in
`conjunction with an another agent, such as another agent for treating headache.
`[0023]
`In another aspect, the invention provides use of an anti-CORP antagonist antibody for
`the manufacture of a medicament for use in any of the methods described herein, for example, for
`treating or preventing headache.
`[0024]
`In another aspect, the invention provides a pharmaceutical composition for preventing or
`treating headache ( e.g., migraine and cluster headache) comprising an effective amount of an anti(cid:173)
`CORP antagonist antibody, in combination with one or more pharmaceut~cally acceptable
`excipients.
`[0025]
`In another aspect, the invention provides a kit for use in any of the methods described
`herein. In some embodiments, the kit comprises a container, a composition comprising an anti(cid:173)
`CORP antagonist antibody described herein, in combination with a pharmaceutically acceptable
`carrier, and instructions for using the composition in any of the methods described herein.
`(0026]
`The present invention also provides anti-CORP antagonist antibodies and polypeptides
`derived from antibody G l or its variants shown in Table 6. Accordingly, in one aspect, the
`invention is an antibody G 1 (interchangeably termed "G l ") that is produced by expression vectors
`having ATCC Accession Nos. PTA-6866 and PTA-6867. The amino acid sequences of the heavy
`chain and light chain variable regions of GI are shown in Figure 5. The complementarity
`determining region (CDR) portions of antibody G 1 (including Chothia and Kabat CDRs) are also
`shown in Figure 5. It is understood that reference to any part of or entire region of G 1 encompasses
`sequences produced by the expression vectors having ATCC Accession Nos. PTA-6866 and PTA-
`6867, and/or the sequences depicted in Figure 5. The invention also provides antibody variants of
`GI with amino acid sequences depicted in Table 6.
`[0027]
`In another aspect, the invention is an antibody comprising a fragment or a region of the
`antibody GI or its variants shown in Table 6. In one embodiment, the fragment is a light chain of
`the antibody G 1. In another embodiment, the fragment is a heavy chain of the antibody GI. In yet
`another embodiment, the fragment contains one or more variable regions from a light chain and/or a
`heavy chain of the antibody G 1. In yet another embodiment, the fragment contains one or more
`
`6
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`Copy provided by USPTO from the IFW Image Database on 10/06/2006
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`

`

`variable regions from a light chain and/or a heavy chain shown in Figure 5. In yet another
`embodiment, the fragment contains one or more CDRs from a light chain and/or a heavy chain of
`the antibody G 1.
`[0028]
`In another aspect, the invention provides polypeptides (which may or may not be an
`antibody) comprising any one or more of the following: a) one or more CDR(s) of antibody GI or
`its variants shown in Table 6; b) CDR H3 from the heavy chain of antibody GI or its variants shown
`in Table 6; c) CDR L3 from the light chain of antibody G 1 or its variants shown in Table 6; d) three
`CDRs from the light chain of antibody GI or its variants shown in Table 6; e) three CDRs from the
`heavy chain of antibody G 1 or its variants shown in Table 6; t) three CDRs from the light chain and
`three CDRs from the heavy chain of antibody G 1 or its variants shown in Table 6. The invention
`further provides polypeptides (which may or may not be an antibody) comprising any one or more
`of the following: a) one or more (one, two, three, four, five, or six) CDR(s) derived from antibody
`G 1 or its variants shown in Table 6; b) a CDR derived from CDR H3 from the heavy chain of
`antibody G 1; and/or c) a CDR derived from CDR L3 from the light chain of antibody G 1. In some
`embodiments, the CDR is a CDR shown in Figure 5. In some embodiments, the one or more CDRs
`derived from antibody GI or its variants shown in Table 6 are at least about 85%, at least about
`86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about
`91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about
`96%, at least about 97%, at least about 98%, or at least about 99% identical to at least one, at least
`two, at least three, at least four, at least five, or at least six CD Rs of G 1 or its variants.
`[0029]
`In some embodiments, the CDR is a Kabat CDR. In other embodiments, the CDR is a
`Chothia CDR. In other embodiments, the CDR is a combination of a Kabat and a Chothia CDR
`(also termed "combined CDR" or "extended CDR"). In other words, for any given embodiment
`containing more than one CDR, the CDRs may be any of Kabat, Chothia, and/or combined.
`[0030]
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid
`sequence of KASKXaaVXaaTYVS, wherein Xaa at position 5 is R, W, G, L, or N; and wherein
`Xaa at position 7 is T, A, D, G, R, S, W, or V. In some embodiments, the amino acid sequence of
`KASKXaa VXaaTYVS is CDRl of an antibody light chain.
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid
`[0031)
`sequence ofXaaXaaSNRYXaa, wherein Xaa at position 1 is G or A; wherein Xaa at position 2 is A
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`or H; and wherein Xaa at position 7 is L, T, I, or S. In some embodiments, the amino acid
`sequence ofXaaXaaSNRYXaa is CDR2 of an antibody light chain.
`[0032)
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid
`sequence ofEIRSXaaSDXaaXaaATXaaYAXaaA VKG, wherein Xaa at position 5 is E, R, K, Q, or
`N; wherein Xaa at position 8 is A, G, N, E, H, S, L, R, C, F, Y, V, D, or P; wherein Xaa at position
`9 is S, G, T, Y, C, E, L, A, P, I, N, R, V, D, or M; wherein Xaa at position 12 is Hor F; wherein
`Xaa at position 15 is E or D. In some embodiments, the amino acid sequence of
`EIRSXaaSDXaaXaaA TXaa Y AXaaA VKG is CDR2 of an antibody heavy chain.
`[0033)
`In some embodiments, the polypeptide (such as an antibody) comprises the amino acid
`sequence of SEQ ID NO: 1, wherein amino acid residue at position 99 of SEQ ID NO: 1 is L or is
`substituted by A, N, S, T, V, or R; and wherein amino acid residues at position 100 of SEQ ID NO: 1
`is A or is substituted by L, R, S, V, Y, C, G, T, K, or P.
`[0034)
`In some embodiments, the antibody of the invention is a human antibody. In other
`embodiments, the antibody of the invention is a humanized antibody. In some embodiments, the
`antibody is monoclonal. In some embodiments, the antibody (or polypeptide) is isolated. In some
`embodiments, the antibody ( or polypeptide) is substantially pure.
`[0035)
`The heavy chain constant region of the antibodies may be from any types of constant
`region, such as IgG, IgM, IgD, IgA, and IgE; and any isotypes, such as IgGl, IgG2, IgG3, and
`IgG4.
`[0036)
`herein.
`[0037)
`In another aspect, the invention provides a polynucleotide (which may be isolated)
`comprising a polynucleotide encoding a fragment or a region of the antibody G 1 or its variants
`shown in Table 6. In one embodiment, the fragment is a light chain of the antibody G 1. In another
`embodiment, the fragment is a heavy chain of the antibody G 1. In yet another embodiment, the
`fragment contains one or more variable regions from a light chain and/or a heavy chain of the
`antibody G 1. In yet another embodiment, the fragment contains one or more (i.e., one, two, three,
`four, five, or six) complementarity determining regions (CDRs) from a light chain and/or a heavy
`chain of the antibody G 1.
`
`In some embodiments, the antibody comprises a modified constant region as described
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`(0038)
`In another aspect, the invention is a polynucleotide (which may be isolated) comprising a
`polynucleotide that encodes for antibody G 1 or its variants shown in Table 6. In some
`embodiments, the polynucleotide comprises either or both of the polynucleotides shown in SEQ ID
`NO:9 and SEQ ID NO: 10.
`[0039]
`In another aspect, the invention provides polynucleotides encoding any of the antibodies
`(including antibody fragments) or polypeptides described herein.
`(0040]
`In another aspect, the invention provides vectors (including expression and cloning
`vectors) and host cells comprising any of the polynucleotide disclosed herein. In some
`embodiments, the vector is pDb.CGRP.hFcGI having ATCC No. PTA-6867. In other
`embodiments, the vector is pEb.CGRP.hKGI having ATCC No. PTA-6866.
`[0041)
`In another aspect, the invention is a host cell comprising a polynucleotide encoding any
`of the antibodies described herein.
`[0042]
`In another aspect, the invention is a complex of CGRP bound by any of the antibodies or
`polypeptides described herein. In some embodiments, the antibody is antibody G 1 or its variants
`shown in Table 6.
`[0043]
`In another aspect, the invention is a pharmaceutical composition comprising an effective
`amount of any of the polypeptides (including antibodies, such as an antibody comprising one or
`more CDRs of antibody Gl) or polynucleotides described herein, and a pharmaceutically acceptable
`excipient.
`[0044]
`In another aspect, the invention is a method of generating antibody G 1 comprising
`culturing a host cell or progeny thereof under conditions that allow production of antibody G 1,
`wherein the host cell comprises an expression vector that encodes for antibody G 1; and, in some
`embodiments, purifying the antibody G 1. In some embodiments, the expression vector cpmprises
`one or both of the polynucleotide sequences shown in SEQ ID NO:9 and SEQ ID NO: 10.
`[0045]
`In another aspect, the invention provides methods of generating any of the antibodies or
`polypeptides described herein by expressing one or more polynucleotides encoding the antibody
`(which may be separately expressed as a single light or heavy chain, or both a light and a heavy
`chain are expressed from one vector) or the polypeptide in a suitable cell, generally followed by
`recovering and/or isolating the antibody or polypeptides of interest.
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`[0046)
`The anti-CGRP antagonist antibody and poly