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`Patent Cooperation Treaty (PCT)
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`the
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`International application number: PCT/US2006/062272
`
`International filing date:
`
`19 December 2006 (19.12.2006)
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`Document type:
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`Document details:
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`Country/Office: US
`Number:
`60/753,044
`Filing date:
`22 December 2005 (22.12.2005)
`
`Date of receipt at the International Bureau:
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`13 February 2007 (13.02.2007)
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`Priority document submitted or transmitted to the International Bureau in
`compliance with Rule 17.l(a) or (b)
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`World Intellectual Property Organization (WIPO) - Geneva, Switzerland
`Organisation Mondiale de la Propriete Intellectuelle (OMPI) - Geneve, Suisse
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`l J Nff'F.:[) SL\TE:S l)U'AIH'M:ENT OF <:OMM.ERCE
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`LAST NAME
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`Gehlert
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`Shanafelt
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`Robert
`I ndianapolis IN. 46256
`R.
`Indianapolis IN. 46202
`Donald
`M.
`Kalpana
`Zionsville, IN. 46077
`Armen
`B.
`Carmel, IN. 46032
`TITLE OF THE INVENTION (280 characters max)
`TREATMENT OF MIGRAINE WITH ANTI-CGRP ANTIBODIES
`
`'
`Q ~
`o....a,- ~
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`;~
`
`,..
`
`P-17257
`
`1
`
`TREATMENT OF MIGRAINE WITH ANTI-CGRP ANTIBODIES
`
`FIELD OF THE INVENTION
`
`The present invention is in the field of medicine. More specifically, the invention
`
`relates to antibodies to CGRP and the use of such antibodies for therapy and prophylaxis of
`migraines.
`
`BACKGROUND OF THE INVENTION
`
`Calcitonin gene related peptide (CGRP) is a 37 amino acid neuropeptide secreted by
`
`the nerves of the central and peripheral nervous sy'stems. CGRP exists as highly homologous
`a and 13 isoforms in both human and rat although each is encoded by a distinct gene. The a
`
`and ~ isoforms of the CGRP peptides differ by three amino acids in humans and one amino
`
`acid in rats.. The amino acid sequences of CGRP peptides are well conserved among species
`
`and are considered members of a family of peptides that includes amylin, calcitonin, and
`adrenomedullin.
`
`CGRP is widely distributed in sensory nerves, both in the peripheral and central
`
`nervous syst~m and displays a large number of different biological activities. When released
`
`from trigeminal and other nerve fibers, CGRP is thought to mediate its biological responses
`
`by binding to specific cell surface receptors.
`
`CGRP receptors have bee_n identified and pharmacologic_ally evaluated in several
`
`tissues and cells, including brain, cardiovascular, endothelial and smooth muscle. Multiple
`
`CGRP receptors have been characterized based on distinct phannacological properties.
`
`"Express Mail" mailing label n·umlier =Er-V-=3=9=-31,3_..28=3""5'------------
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`Datc of Deposit
`I hereby certify that this paper or fee is being deposited with the United States Postal Service "Express Mail Post Office to
`Addressee" service under 37 C.F.R. 1.10 on the date indicated above and is addressed to the Commissioner for Patents. P.O.
`Box I 450, Alexandria, VA 22313-1450.
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`Printed Nnmc
`
`·
`
`

`

`P-17257
`
`,,
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`2
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`These receptors are divided into at least two subtypes, denoted as CGRP, and CGRP2 ·
`(Phannacol. Rev 54:233-246, 2002).
`·
`
`·Recently, Arulmozhi and collegues have reported various'"theories on migraines
`
`(Vascular Pharmacology 43; 176-187, 2005). One of the theories proposes that the currently
`
`· unknown triggers of migraine stirnulate-trigeminal nerves and ganglia that innervate cephalic
`
`tissue, giving rise to release of neuropeptide messenger molecules-from axons on the
`
`vasculature. Release of these neuropeptides then activates a series of events, a consequence
`· of which is migraine pain. In addition, release of these neuropeptides changes vascular
`permeability resulttng in subsequent leakage of plasma proteins in tissues innervated by ·
`
`stimulated trigeminal fibers. This leakage results in neurogenic inflammation which leads to
`migraines.
`.
`
`Qf these ~europ<?p~id~s. CGRP has been reported to play" a role in migraines as CGRP
`
`is releas~d. upqp stimulation of sensory nerves and has potent vasodilatory activity. (Vascular
`Pharmacology 43; 176-187, 2005). Further, the release ofCGRP increases vascular
`
`permeability and subsequent pl~~a protein leakage (plasma protein extravasation) in tissues
`
`innervated by trig~miJ;lal nerve fibers upon stimulation of these fibers. (Vascular
`
`Pharmacology 43; 176-187, 2005). In addition, studies have reported that infusion ofCGRP
`
`in patients who suffer from migraines has resulted in migraine:..like symptoms. (Cephalagia
`22(1): 54-61, ~ooi) .
`Historically, small molecuJe agonists of serotonin 5- HT18/rn receptors have been
`used as treatments for migraines. These so-called triptans are potent.vasoconstrictors and
`
`have been shown to inhibit plasma protein extravasation due to stimulation of trigeminal · ·
`
`nerve fibers in ~ experimental animal migraine model. In addition, doses of a triptan that
`decreased plasma protein extravasation also anenuated CGRP levels in the same
`experimental animal model. (Br. J. Phannacology 99; 202-206, 1990; Neuropharmacology
`30(11): I 193-1200, 1991)
`
`Although triptans have been found to be efficacious, many patients who respond_fo·
`
`triptan treatment suffer from recurrent headaches within several hours after treatment.
`
`Further, since triptans are potent vasoconstrictors, they are contraindicated in certain patient
`
`

`

`P-17257
`
`,,
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`3
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`populations, such as populations of patients suffering from hypertension or suffering from
`
`ischemic heart disease. There is therefore a need for therapeutic compounds to prevent
`
`and/or treat migraiJ:ies ':Vithout unwanted side effects such as cardiovascular-related effects.
`
`The compowids used in the methods of treatment encompassed by the present
`
`invention solve problems associated with cardiovascular and other unwanted side:.effects by
`
`specifically binding CGRP itself rather than binding CGRP receptoi's ·1ocated throughout the
`
`body. Furthermore, the anti-CGRP antibodies of the present invention preferentially bind
`CGRP over. otper homologous proteins, including those of the calcitonin protein family · ·
`
`. which further minimizes potential side effects. While there is some research focused on
`
`developing CGRP receptor antagonists, this is the first report of compounds that block
`
`receptor activation by binding to a specific region on the CGRP peptide itself.
`
`SUMMARY OF THE INVENTION
`The present invention relates to a method of treating migraines comprising
`
`administering to a subject in need thereof, an effective amount of an anti-CGRP antibody that
`binds to and inhibits the ability of CGRP to bind to the CGRP receptor. The invention ·
`
`. . · ... :
`
`,
`
`further provides for a method of preventing migraines comprising administering to a subject
`who has suffered at least one migraine previously, preferably a human, an effective amount
`of an anti-CGRP antibody that binds to and inhibits the ability of CGRP to bind to the CGRP
`receptor. In another embodiment, anti-CGRP antibodies are administered for reducing pain(cid:173)
`due to migraines.
`
`The.invention also embo~ies an anti-CGRP antibody that binds to and inhibits the
`
`ability of CGRP to bind to the CGRP receptor for use in the manufacture of a medicament ·
`
`for administration to a subject, preferably a human, for the treatment of migraines.
`
`The invention further embodies a method of inhibiting binding of CGRP to a C9RP
`
`receptor in a patient suffering from migraine, comprising administration of an anti-CGRP
`
`antibody. In another embodiment, an anti-CGRP antibody of the invention is used in a
`
`method of inhibiting CGRP receptor activation in a patient suffering from migraine
`comprising administering an anti-CGRP antibody.
`
`

`

`P-17257
`
`,,
`
`4
`
`In one embodiment, the anti-CGRP antibodies of the invention specifically bind
`CGRP ~i.t.4 an EC50 of less than about 2.33 x 10-9 M, or less than about 2.09 x 10-9 M, or less
`than about 1.24 x 10·9 Mor less than about 1.07 x 10·9 M.
`In another pr~ferred embodiment, the anti-CGRP antibodies of the invention have
`Ko's to CGRP of less than about-2.99 x 10·9 M, or less than about 2.21 x 10·9 M, or less than
`1.50 X 10·10 M.
`
`In an embodiment, the anti-CGRP antibodies of the invention will-inhibit.or-prevent
`
`activation of the CGRP receptor. For example, in an in vitro assay, the anti-CGRP antibodies
`will preferably have an ICso of less than about 1.45 x 10·8 M, or less than about 5.49 x 10·9 M. -
`.. In another embodiment of the invention, an article of manufacture containing
`
`materials useful for the treatment of the disorders described above is provided. The article of
`
`manufacture comprises a container and a label. Suitable containers include, for example,
`
`bottles, vials, syringes, and test tubes. The containers may be formed from a _variety of
`
`materials such as glass or plastic. The container holds a composition, preferably sterile,
`
`which is effective for treating the condition and may have a sterile access port (for example ·
`
`the container may be an intravenous solution bag or a vial having a stopper pierceable by a
`'
`hypodermic injection needle). The active agent in the composition is the anti-CGRP
`
`· . ·
`
`antibody. The label on, or associated with, the container indicates that the composition is·
`used for.treating the condition of choice. The article of manufacture may further comprise a ·
`
`second container comprising a pharmaceutically-acceptable buffer, such a,; phosphate(cid:173)
`buffered saline, Ringer's solution and dextrose solution. It may further include other
`
`materials desirable from a commercial and user standpoint, including other buffers, diluents, ·
`filters, needles, syringes, and package inserts with instructions for use. .
`
`In another embodiment, the invention provides a pharmaceutical composition .
`
`comprising an anti-CGRP monoclonal antibody of the invention. The pharmaceutical
`composition of the invention may further comprise a pharmaceutically acceptable carrier. In
`
`said pharmaceutical composition, the anti-CGRP monoclonal antibody of the invention is the
`
`active ingredient. Preferably the pharmaceutical composition comprises a homogeneous or
`
`substantially homogeneous population of an anti-CGRP monoclonal antibody of the
`
`

`

`P-17257
`
`. .,
`
`5
`
`invention. The composition for therapeutic use is sterile and may be lyophilized, optionally
`
`supplied with an appropriate diluent.
`
`SUMMARY OF THE FIGURES
`FIG. 1 shows the amino acid sequence of human a calcitonin gene related· peptide
`(aCG~).
`FIG. 2 shows the amino acid sequence of human 13 <:=alcit~nin -gene related P.~ptide
`(l3CGRP).
`
`..
`
`FIG. 3 show the DNA sequence of the human calcitonin gene
`
`FIG. 4 shows an ali.gnment of the amino acid sequence of calcitonin gene family
`
`peptides of human and rat species.
`
`FIG. 5 show_~ the amino acid sequence of CDRs of the LCVR o( various antibodj~~ 9f
`the -invention.
`
`FIG. 6 shows the amino acid sequence Qf CDRs of the HCVR of various antibodies of
`the invention.
`
`FIG. 7 shows the alignment of the amino acid sequence of LCVRs of various
`.
`..
`-·
`.
`.
`.
`.
`antibodies or'the invention. The CDR domains are underlined iil ll?:e fn:st ant~body sequence.
`FIG. 8 shows the alignment of the amino acid sequence of ~CV~s of various
`
`.,.
`
`antibodies of the invention. The CDR domains are underlined in the first antibody sequence.
`
`FIG. 9 shows the murine IgG l heavy chain constant chain (SEQ ID 40) and the
`.
`.
`.
`-
`murine kappa light chain constant chain (SEQ ID 41_)
`
`DETAILED DESCRIPTION
`
`.
`.
`The invention presents anti-CGRP antibod_ies useful for the preventipn and treatment
`of migraines.
`
`Definitions
`
`

`

`P-17257
`
`,t
`
`6
`
`As used herein, the tenn "CGRP" refers to the human a and 13 isoforms of calcitonin
`gene-related peptide, collectively. "a.CGRP refers to the a isoform (SEQ ID NO: I) that is
`en~oded by the calcitonin gene and results from alternative splicing of the calcitonin g~ne
`
`(SEQ ID NO: 3). f3CGRP refers to the 13 isofonn (SEQ ID NO: 2) of calcitonin gene-related
`peptide.
`
`The term "migraine" as used herein refers to "migraines without aura" (formerly
`
`"common migraine") and "migraines with aura" (formerly "classical migraines") accor~ing
`
`to the Headache Classification Committee of the International Headache Society
`
`(International Headache Society, 2004). For example, "migraines withc;mt aura", typically
`
`may be characterized as having a pulsating quality, a moderate or severe intensity, are
`.
`.
`aggravated by routine physical activity, are unilaterally located aµd are associated_ with
`
`nausea ·and with pl\otophobia and phonophobia. "Migraines with aura" may ine:lude
`
`disturbances in vision, disturbances in other senses, unilateral weakness, and in some
`
`inst~ces difficulty with speech.
`
`The term "antibody," in reference to an anti-CGRP antibody of the invention (or
`
`simply, "antibody of the invention"), as used herein, refers to a monoclonal antibody. A
`
`"monoclonal antibody'~ refers to an antibody that is deriyed from a single _copy or clone,
`
`including e.g., any eukaryotic, prokaryotic, or phage clone, and not the method by which jt is _
`produced. In addition, a "monoclonal antibody" as used herein refers to a hu~anized
`.
`.
`antibody or a fully human antibody, unless otherwise indicated herein. Preferably a
`
`monoclonal antibody of the invention exists in a homogene_ous or substantially homogeneous
`
`populat~on. A "monoclonal antibody" can be an intact antibody (comprising a complete or
`
`full length Fe region), a substantially intact antibody, or a portion or fragment of an antibody(cid:173)
`
`comprising an _antigen-binding portion, e.g., a Fab fragment, Fab' fragment or F(ab')2
`
`fragment of a humanized or human antibody. "Monoclonal antibodies" of the invention can
`be produced using e.g., hybridoma techniques well known in the art, as well as recombinant
`
`technologies, phage display technologies, synthetic technologies or combinations of such
`
`technologies or other technologies readily known in the art.
`
`

`

`P-17257
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`7
`
`A full-length antibody as it exists naturally is an immwioglobulin molecule
`
`_coroP.rised of four peptide chains, two heavy (H) chains (about 50-70 kDa when full length)
`
`and two light (L) chains (about 25 kDa when full length) interconnected by disulfide bonds.
`
`The amino terminal portion of each chain includes ·a variable region of about 100-11 0 or
`
`more amino acids primarily responsible for antigen recognition. The carboxy-terminal
`portion of each chain defines a constant region primarily responsible for effector function.
`Light c~~ii:is are classified as kappa or -lambda and characterized by a pai:ticular
`
`constant region as lqlown in the art. Heavy chains are classified as gamma, mu, alpha, delta,
`
`or epsilon, and define the antiboqy's isotype as IgG, IgM, lgA, IgD, and IgE, respectively
`
`and seye!al _of these may be further divided into subclasses (sub-isotypes) e.g., IgG1, IgG2,
`IgG3, IgG4, IgA1, and lgA2. Each heavy chain type is characterized by a part-icular_constant
`region know11 in the art. The.subunit structures and three-dimensional configurations of
`
`different .classes of anti:t,oqies ~e well known in the art. Each heavy chain is comprised of
`an N-terminal heavy chain variable region (herein_ "HCVR") and a heavy chain constant
`
`region. The.heavy cl!ain cons~t region is comprised of three domains (CHI, CH2, and
`CH3) for IgG, l_gD, and lgA; and 4 domains (CHI, CH2, CH3, and CH4) for lgM and IgE.
`
`Each light chain is comprised of a light chain variable region (herein "LCVR") and a light
`.
`.
`.
`... ,
`chain constant region, CL. The HCVR and LCVR regions can be further subdivided into
`
`regiqns of hy~rv~ability, tt:rmed complementarity determining regions (CDRs),
`
`interspersed with regions that .are more conserved, termed framework regions (FR). Each
`
`HCVR and LCVR is composed of three CD Rs and four FRs, arranged from amino-terminus ..
`
`to carboxy-terminus in the following order: FRI, CDRl, FR2, CDR2, FR3, CDR3, FR4 . .
`
`Herein the 3 CDRs of the heavy chain are referred to as " CDRHl , CDRH2, and CDRH3"
`
`and the 3 CDRs of the light chain are referred to as "CDRLl , CDRL2 and CDRL3." The
`
`CD Rs contain most of the residues which form specific interactions with the antigen. CDR3
`
`is typic~ly ~e greatest source of molecular diversity within the antibody-binding site.
`
`Assignment of amino acids to each domain is in accordance with well-known convention~
`
`[e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of
`
`: ..
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`

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`P-17257
`
`8
`
`Health, Bethesda, Md. (1991)]. The functional ability of an antibody to bind a particular
`
`antigen is largely influenced by the six CDRs.
`
`The variable regions of each light/heavy chain pair form the antigen-binding ·sites·of ·
`
`the antibody. Thus; ~ intact IgG antibody has two binding sites. Except in bifunctional or
`
`bispecific antibodies, the two binding sites are the same. As used herein, the "antigen(cid:173)
`
`binding portion" ~~ '.'antigen-binding region" or "antigen-binding fragment" refers
`
`interchangeably to that portion of an antibody molecule, within the variable region, which
`
`contains the amino acid residues that interact with an antigen·and confer·on the antibody its
`
`specifi~ity and affinity for the antigen. This antibody portion includes the framework amino
`
`acid residues necessary to maintain the proper conformation of the antigen-binding residues.
`
`Preferably, the CDRs of the.antigen-binding region of the antibodies of the invention will be
`of murine origin or. substantially of murine origin with certain amino acids residues altered· to ·
`improve a particular ac,tivity. Preferably, the framework regions of antibodies of the
`
`inven\ion are of human origin or substantially of human origin (or have at least 95%, 97% or
`
`99%, sequence identity with a particular human germ-line framework). In other
`
`embodiments, the antigen-binding.region, or the CDRs of the antigen-binding region, can·be
`
`synthetic and/or derived from other non-human species including, but not limited to, rabbit, ·
`
`rat or hamster. In other embodiments, the antigen-binding region can be entirely of human · ·
`
`origin or substantially of human origin with certain amino acids residues altered to improve a
`particular activity, e.g., affinity or specificity.
`
`Furthermore, a "monoclonal antibody" as used herein can be a single chain-Fv
`fragment that may be produced by joining the DNA encoding the LCVR and HCVR with a .
`linker sequenc~. (See, Pluckthun, The Phann<icology of Monoclonal Antibodies, vol. 113,
`Rosenburg and Moore eds., Springer-Verlag, New York, pp 269-315, 1994). It is
`
`understood that reg~dless of whether fragments or portions are specified, the term
`"antibody" as used herein includes such fragments or portions as well as single chain forms.
`As long as the protein retains the ability to specifically or preferentially bind its intended
`target Ci-'!·, epitope or antigen), it is included within the term "antibody."
`
`

`

`P-17257
`
`.,,
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`9
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`The term "humanized antibody" as; ·used herein refers to an antibody comprising
`
`portions of antibodies of different origin, wherein at least one portion is of human origin. For
`
`example, the humanized antibody can comprise portions derived from an antibody of ··
`
`nonhuman origin with the requisite specificity, such as a mouse, and from an antibody of .
`
`human origin, joined together chemically by conventional technfques (e.g., synthetic) or··
`
`prepared as a contiguous polypeptide using genetic engineering techniques: In addition, a
`
`"humanized antibody" has CDRs that originate from a non-human antibody (preferably a
`
`mouse monoclonal antibody) while framework ·and constant region, to the extent it is present;·
`
`(or a signifi~ant or substantial portion_thereof, .i.e., at least about 90%, 92%, 94%, 95%, 96%; ··
`
`97%, 98% or 99%f are encoded by nucleic acid sequence information that occurs in the
`
`human germline immunoglobulin region (see, e.g., the International ImMunoGeneTics
`Database)
`A "popµlation of monoc!onal antibodies," refers to a homogeneous or substantially
`homogeneous antibody population (i.e., at least about 90%; 91 %, 92%, 93%, 94%; 95%, ·
`
`·
`
`96%, more preferably at least about 97% or 98% or most preferably at least 99% of the·
`
`aI1tibodies-in the population would compete in an ELISA assay for the same antigen ·or
`
`epitope). Antibodies may or .may not be glycosylated and still fall within the bounds of the
`invention. Monoclonal antibodies may be homogeneous if they·have identical amino acid
`
`sequence although they may differ in a post-translational modification, e.g., glycosylation
`pattern.
`
`The term "specifically binds" as u·sed herein refers to·the situation in which one
`
`member of a specific binding pai_r does not significantly bind to molecules other than its
`
`specific binding partner(s) as measured by a technique available in the art, e.g., competition
`ELISA or BIACORE assay. The term is also applicable where e.g., an antigen-binding
`
`domain of an antibody of the invention is specific for a particular epitope that is carried by a
`· number of related proteins, in which case the specific antibody carrying the antigen-bin~ing
`
`domain will be able to specifically bind to the various·related proteins carrying the epitope.
`
`If the related proteins do not carry the particular epitope, the antigen-binding domain, will
`
`

`

`P-17257
`
`10
`
`not bind to the proteins. Accordingly a monoclonal antibody of the present invention
`
`specifically binds to CGRP and not to other members of the calcitonin family of proteins.
`
`The term "preferentially binds" as used herein refers to the•situation in which an
`
`antibody binds a specific antigen at _least about 20% greater than it binds a different antigen
`
`.as measured by a technique available in the art, e.g., competition ELISA or Ko measuremeht ·
`
`with BIACORE assay. Similarly, an antibody may preferentially bind one epitop~ within rut
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`antigt;:~ over a different epitope within the same antigen. ·
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`The t~rm "epitope" ~efers to that portion of a mol~cule e:apable of being recognized
`
`by and ~,ound by an antibody at one or more of~e-~tibody's antigen-binding regions.-.
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`Epitopes often consist of a chemic~l)'. active surface groupin~ of ~olecules. such as ~ino
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`acids or sugar side chains and have specific three-dimensional structural characteristics as
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`well as specific charge characteristics. An "inhibiting epitope" and/or "ne4tralizing epitope" ..
`is an epitope, which when in the context of the intact molecule (in this case, CGRP) and
`
`when bound by antibody specific to the epitope, results ip. loss ~r diip.inution of a biological
`-
`activity of the molecule or organism containing the molecule, in viyo 9,r in vitro.
`.
`.
`
`.
`
`.
`
`.
`
`,
`
`The term· "antigenic epitope," as used her~in, is defined as a portion of a polypeptide
`to which an antibody can specifically hind ~ determi~ed:by -~y m~thod ~~it known in tile .
`art·, for example, by conventional° immunoassays. Antigenic epit6pes ~eed not necessarily be .
`
`immunogenic, but may be immunogenic. An "immunogenic epitope," as used herein, is
`....
`defined as a portion of a polypeptide that elicits an antibody response in an animal, as
`determined by any method known in the art. (See, e.g., Geysen et· al., Proc. Na.ti. Acad. Sci.
`..
`.
`USA 81:3998-4002 (1983)). For example, an epitope may be determined using tlie ·
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`techniques as. outlined in Example I or Example 2 discuss~d below. Briefly, in an ELISA or
`
`a BIACORE assay as outlined in Example lor Example 2, peptide fragments of differing size
`.
`.
`.
`and sequence are synthesized and the antibodies of interest are tested for their ability to bind
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`to the specific fragments.
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`P-17257
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`11
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`The phrases "biological property" or "bioactivity," "activity" or "biologic:=al activity,"
`
`in reference to an antibody of the present invention, are used interchangeably herein and
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`includ~, but are not limited to, epitope/antigen affinity and specificity, ability to neutralize or
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`antagonize an activity of CGRP in vivo or.-in vitro,- ICso in a cAMP assay or other in vitro . · ·
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`activity ass~y; the-in vivo stability of the antibody and the imrnunogenic properties of the · · ·· · ·.
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`antibody. Other identifiable biological properties of an·antibody include, for example, cross(cid:173)
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`reactivity, (i.e., with non-human homologs of the targeted_ peptide, or with other proteins or
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`tissues, generally), and ability to preserve high expression levels of protein in mammalian
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`cells. The aforementioned properties or characteristics can be observed or measured or
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`assessed using art-recognized techniques including, but not limited to, ELISA, competitive
`ELISA; BIACORE analysis, in vitro and in vivo neutralization assays without limit, receptor
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`binding, and immunohistochernistry with tissue sections from different sources incl1:1ding
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`human, primate, or any other sow:ce as the need may be.
`
`The term "inhibit" or "neutralize" as used herein with respect to an activity of an
`
`antibody of the invention means the ability to substantially antagonize, prohibit, prevent,
`restrain, slow, disrupt, eliminate, stop, reduce or reverse the biological effects of CGRP
`binding lo the CGRP receptor.
`
`The term "isolated" when used in relation to a protein (e.g., an antibody) refers to
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`protein that is identified and separated from at least one cont~nant with which it is
`
`ordinarily associated in.its natural source. Preferably, an "isolated antibody" is an antibody
`
`that ~s substantially free of other antibodies having different antigenic specificities (e.g.,
`
`phannaceutical compositions of the invention comprise an isolated antibody that specifically
`
`binds CGRP and is substantially free of antibodies that specifically bind antigens other than
`CGRP).
`
`The terms "Kabat numbering" and "Kabat labeling" ~e used interchangeably herein.
`
`These terms, which are recognized in the art, refer to a system of numbering amino acid_ ..
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`residues which are more variable (i.e., hypervariable) than other amino acid residues in the
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`heavy and light chain variable regions of an antibody (Kabat, et al., Ann. NY Acaa. Sci.
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`190:382-93 (1971); Kabat, et al., Sequences of Proteins of Immunological Interest, Fifth
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`P-17257
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`12
`
`Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242
`
`(1991)).
`
`The terms "individual," "subject," and "patient," used interchangeably herein, refer to
`
`a subject, preferably-human, suffering from a migr~e or susceptible to -migraines that would ·
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`benefit from a decreased level or.decreased bioactivity of CGRP .
`
`. As used herein, the terms "treatment", "treating", and the like, refer to obtaining a
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`desired pharrnacologic and/or physiologic effect. The effect may be prophylactic in tenris of
`
`completely or partially preventing a migraine or symptom Lhereof and/or may be therapeutic
`in terms of a partial or complete cure for migraines and/or adverse affect attributable to ·
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`migraines. "Treatment"~ as used.herein, includes administration of an antibody of the present
`
`invention for treatment of migraines in a subject, particularly in a human, and includes: (a)
`preventing the migraine from occurring in a subject which may be predisposed to migraines;·
`(b) inhibiting migraines, i.e., arresting its development; and (c) relieving migraines, i.e.,
`
`alleviating symptQms or complications thereof. Dosage regimens may be adjusted to provide
`
`the optimum desired response (e.g .• a therapeutic or prophylactic response). For example, a
`single .bolus-may be administered, several divided doses may be administered over time or
`
`the dose may be proportionally reduced or increased as indicated-by the exigencies of the
`therapeutic situation.
`
`Furlher-as used herein, a "therapeutically effective amount" refers to an amount
`
`effective, at dosages and for periods of time necessary to treat migraines, and/or to reduce
`
`pain due to migraines. A therapeutically effective amount of the antibody may vary .
`according to factors such as the disease state, age, sex, and weight of the individual, and the
`
`ability of the antibody or antibody portion to elicit a desired response in the individual. · A ·
`therapeutically effective amount is also one in which any toxic or detrimental effect of the
`
`antibody, are outweighed by the therapeutically beneficial effects.
`
`A "prophylactically effective amount" refers to an amount effective; at dosages and
`
`for periods of time necessary, to achieve the desired prophylactic result. Typically, a
`
`prophylactic dose is.used in subjects prior to the onset of'~ migraine and/or prior to the· onset
`
`of symptoms of migraines such as to prevent or inhibit the occurrence of a migraine.
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`P-17257
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`13
`
`A "therapeutically-effective" or "prophylactically-effective" amount is at least the
`
`minimal dose, but less than a toxic dose, of an active agent which is necessary to impart
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`therapeutic-benefit to a subject. Stated another way, a therapeutically-effective amount of an ..
`
`antibody o( the invention is an amount which in a_ subject, treats conditions wherein the
`
`presence of CGRP causes or contributes to undesirable pathological effects or the decrease in
`CGRP levels results in a beneficial therapeutic effect in a subject, _preferably a human,
`
`. in~lud~g,_ but.not limited to, redu_ction in pain due to migraines; prevention of migraines and
`treatment of migraines.
`
`· Antibody Characterization
`
`An antibody of the present invention will be char~cterized by its ability to s