Anti-cgrp compositions and use thereof

Abstract

The present invention is directed to antibodies and fragments thereof having binding specificity for CGRP. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the VH, VL and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-CGRP antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-CGRP antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-CGRP antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with CGRP.

1 . An anti-human CGRP antibody or antibody fragment which specifically binds to human CGRP, said antibody or antibody fragment comprising the same CDRs as an anti-CGRP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab, Ab9, Ab10, Ab11, Ab12, Ab13 or Ab14, optionally Ab6. 
     
     
         2 . (canceled) 
     
     
         3 . The antibody fragment of  claim 1 , wherein said fragment is selected from a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, or a monovalent antibody fragment. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . The antibody or antibody fragment of  claim 1 , comprising a variable light chain comprising the CDR 1 sequence of SEQ ID NO:55, the CDR 2 sequence of SEQ ID NO:56, and the CDR 3 sequence of SEQ ID NO:57, and/or a variable heavy chain comprising the CDR 1 sequence of SEQ ID NO:58, the CDR 2 sequence of SEQ ID NO:59, and the CDR 3 sequence of SEQ ID NO:60. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The anti-human CGRP antibody or antibody fragment of  claim 7  which:
 (i) comprises a variable light polypeptide possessing at least 80% sequence identity to SEQ ID NO: 51 and a variable heavy chain polypeptide possessing at least 80% sequence identity to SEQ ID NO: 53; 
 (ii) comprises a variable light polypeptide possessing at least 90% sequence identity to SEQ ID NO: 51 and a variable heavy chain polypeptide possessing at least 90% sequence identity to SEQ ID NO: 53; 
 (iii) comprises a variable light polypeptide possessing at least 95% sequence identity to SEQ ID NO: 51 and a variable heavy chain polypeptide possessing at least 95% sequence identity to SEQ ID NO: 53; 
 (iv) comprises a variable light polypeptide possessing at least 96% sequence identity to SEQ ID NO: 51 and a variable heavy chain polypeptide possessing at least 96% sequence identity to SEQ ID NO: 53; 
 (v) comprises a variable light polypeptide possessing at least 97% sequence identity to SEQ ID NO: 51 and a variable heavy chain polypeptide possessing at least 97% sequence identity to SEQ ID NO: 53; 
 (vi) comprises a variable light polypeptide possessing at least 98% sequence identity to SEQ ID NO: 51 and a variable heavy chain polypeptide possessing at least 98% sequence identity to SEQ ID NO: 53; 
 (vii) comprises a variable light polypeptide possessing at least 99% sequence identity to SEQ ID NO: 51 and a variable heavy chain polypeptide possessing at least 99% sequence identity to SEQ ID NO: 53; 
 (viii) comprises a variable light identical to SEQ ID NO: 51 and a variable heavy chain polypeptide identical to SEQ ID NO: 53; 
 (ix) comprises a human Fc region; 
 (x) comprises a human Fc region selected from an IgG1, IgG2, IgG3 and IgG4, further optionally IgG1, which optionally is modified to alter at least one of effector function, half-life, proteolysis, and/or glycosylation; 
 (xi) is aglycosylated or if glycosylated only contains only mannose residues; 
 (xii) is not N-glycosylated; 
 (xiii) it contains an Fc region, optionally a human IgG1 Fc region that has been modified to alter one or more of effector function, half-life, proteolysis, and/or glycosylation; 
 (xiv) it is a humanized, single chain or chimeric antibody; 
 (xv) it specifically binds to CGRP expressing human cells and/or to circulating soluble CGRP molecules in vivo; 
 (xvi) it specifically binds to CGRP expressed on or by human cells in a patient with a disease associated with cells that bind CGRP; 
 (xvii) it specifically binds to CGRP expressed on or by human cells in a patient with a disease associated with cells that bind CGRP selected from migraine (with or without aura), a condition with CGRP-associated pain, weight loss, cancer or tumors, overactive bladder, urinary incontinence, pruritis, psoriasis, ulcer, a cardiac condition, angiogenesis associated with cancer or tumor growth, angiogenesis associated with cancer or tumor survival, migraines, chronic migraines, frequent episodic migraines, menstrual migraines, hemiplagic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flushes, chronic paroxysomal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches (such as for example associated with sinusitis), allergy-induced headaches or migraines, pain, TMJ, temporomandibular jaw disorders, inflammatory pain, visceral pain, post-operative incision pain, complex regional pain syndrome, cancer pain, primary or metastatic bone cancer pain, fracture pain, osteoporotic fracture pain, pain resulting from burn, osteoporosis, gout joint pain, pain associated with sickle cell crises, and other nociceptic pain, as well as hepatocellular carcinoma, breast cancer, liver cirrhosis, neurogenic pain, neuropathic pain, nociceptic pain, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain, fibromyalgia, menstrual pain, ovarialgia, reflex sympathetic dystrophy, neurogenic pain, osteoarthritis or rheumatoid arthritis pain, lower back pain, diabetic neuropathy, sciatica, or visceral pain associated with gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ileitis, ulcerative colitis, renal colic, dysmenorrhea, cystitis, menstrual period, labor, menopause, prostatitis, or pancreatitis. 
 (xviii) it specifically binds to CGRP expressed on or by human cells in a patient with a disease associated with cells that bind CGRP selected from pain, visceral pain, TMJ, temporomandibular jaw disorders, headache, overactive bladder, urinary incontinence or migraine; 
 (xix) it specifically binds to CGRP expressed on or by human cells in a patient with a disease associated with cells that bind CGRP, wherein the disease is migraine; 
 (xx) it specifically binds to CGRP expressed on or by human cells in a patient with a disease associated with cells that bind CGRP, wherein the disease is migraine with or without aura; 
 (xxi) it specifically binds to CGRP expressed on or by human cells in a patient with a disease associated with cells that bind CGRP, wherein the disease is wherein the disease is one of the following types of migraines: chronic migraine, frequent episodic migraines, or menstrual migraines; 
 (xxii) it specifically binds to CGRP expressed on or by human cells in a patient with a disease associated with cells that bind CGRP, wherein the disease is wherein the disease is cluster headache; 
 (xxiii) it is directly or indirectly attached to a detectable label or therapeutic agent; 
 (xxiv) said antibody or antibody fragment binds to CGRP with an off-rate (K off ) of less than or equal to 10 −4  S −1 , 5×10 −5  S −1 , 10 −5  S −1 , 5×10 −6  S −1 , 10 −6  S −1 , 5×10 −7  S −1 , or 10 −7  S −1 . 
 (xxv) said antibody or antibody fragment inhibits the production of a complex of CGRP with CGRP-R and/or multimers thereof, and the production of CGRP with CGRP-R and one or more additional proteins in a complex; 
 (xxvi) said antibody or antibody fragment is selected from a Fab fragment, a Fab′ fragment, or a F(ab′)2 fragment; 
 (xxvii) said antibody or antibody fragment further comprises an effector moiety, optionally a detectable moiety or a functional moiety, further optionally wherein said detectable moiety is a fluorescent dye, an enzyme, a substrate, a bioluminescent material, a radioactive material, or a chemiluminescent material and/or optionally said functional moiety is streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, or a radioactive material; 
 (xxviii) said antibody or antibody fragment comprises a light chain polypeptide having the amino acid sequence of SEQ ID NO: 52 and a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 54; or 
 (xxix) any combination of the foregoing. 
 
     
     
         11 - 22 . (canceled) 
     
     
         23 . A nucleic acid sequence or nucleic acid sequences which result in the expression of an anti-human CGRP antibody or antibody fragment according to  claim 1  or a vector containing said nucleic acid sequence or nucleic acid sequences. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . A cultured or recombinant cell which expresses an antibody or antibody fragment according to  claim 1 , optionally Ab6, wherein said cell is optionally selected from a mammalian, yeast, bacterial, fungal, or insect cell, further optionally a  Pichia pastoris  or CHO cell. 
     
     
         28 - 31 . (canceled) 
     
     
         32 . A method of treatment comprising administering to a patient with a disease or condition treatable by the administration of a CGRP antagonist a therapeutically effective amount of at least one anti-human CGRP antibody or fragment according to  claim 1 . 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 32  wherein:
 (i) the disease is selected from migraine (with or without aura), weight loss, cancer or tumors, angiogenesis associated with cancer or tumor growth, angiogenesis associated with cancer or tumor survival, migraine, chronic migraine, frequent episodic migraines, or menstrual migraines hemiplagic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flushes, chronic paroxysomal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches, allergy-induced headaches or migraines, pain, inflammatory pain, post-operative incision pain, complex regional pain syndrome, cancer pain, primary or metastatic bone cancer pain, fracture pain, osteoporotic fracture pain, pain resulting from burn, osteoporosis, gout joint pain, pain associated with sickle cell crises, and other nociceptic pain, as well as hepatocellular carcinoma, breast cancer, liver cirrhosis, neurogenic pain, neuropathic pain, nociceptic pain, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain, fibromyalgia, menstrual pain, ovarialgia, reflex sympathetic dystrophy, neurogenic pain, osteoarthritis or rheumatoid arthritis pain, lower back pain, diabetic neuropathy, sciatica, or visceral pain associated with gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ileitis, ulcerative colitis, renal colic, dysmenorrhea, cystitis, menstrual period, labor, menopause, prostatitis, or pancreatitis; 
 (ii) the condition comprises overactive bladder; urinary incontinence; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; post-surgical pain, trauma related pain, diabetes; non-insulin dependent diabetes mellitus and other inflammatory autoimmune disorders, vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases including pruritis, neurogenic cutaneous redness, skin rosaceousness and erythema; inflammatory bowel disease, irritable bowel syndrome, cystitis; and dysmennorhea; 
 (iii) the disease or condition is pain, overactive bladder, urinary incontinence, headache or migraine; 
 (iv) the treatment further includes the administration of another therapeutic agent or regimen selected from anti-histamines, anti-inflammatory agents, analgesics or antibiotics; 
 (v) the treatment further includes the administration of an analgesic, optionally an NSAID, an opioid analgesic, an antibody or antibody fragment or another analgesic biologic; 
 (vi) the treatment further includes the administration of an opioid and the method is optionally used to reduce or prevent tolerance to the opioid; 
 (vii) the treatment further includes the administration of an opioid, wherein the opioid is morphine or a morphine derivative; 
 (viii) the treatment further includes the administration of a NGF antibody or antibody fragment; or 
 (ix) any combination of the foregoing. 
 
     
     
         35 - 41 . (canceled) 
     
     
         42 . A method of in vivo imaging which detects the presence of cells which express CGRP comprising administering a diagnostically effective amount of at least one anti-human CGRP antibody or antibody fragment according to  claim 1 , optionally Ab6 or a fragment thereof comprising the same CDRs as Ab6. 
     
     
         43 - 64 . (canceled) 
     
     
         65 . A method of ameliorating or reducing symptoms of a disease or disorder treatable by the administration of a CGRP antagonist comprising administering to an individual in need thereof a therapeutically effective amount of a CGRP antibody or antibody fragment according to  claim 10 . 
     
     
         66 . The method of  claim 65 , wherein
 (i) the disease is associated with increased CGRP;   (ii) said disease or disorder is selected from migraine (with or without aura), weight loss, cancer or tumors, angiogenesis associated with cancer or tumor growth, angiogenesis associated with cancer or tumor survival, hemiplagic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flushes, chronic paroxysomal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches (such as for example associated with sinusitis), allergy-induced headaches or migraines, pain, inflammatory pain, post-operative incision pain, complex regional pain syndrome, cancer pain, primary or metastatic bone cancer pain, fracture pain, osteoporotic fracture pain, pain resulting from burn, osteoporosis, gout joint pain, pain associated with sickle cell crises, and other nociceptic pain, as well as hepatocellular carcinoma, breast cancer, liver cirrhosis, neurogenic pain, neuropathic pain, nociceptic pain, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain, fibromyalgia, menstrual pain, ovarialgia, reflex sympathetic dystrophy, neurogenic pain, osteoarthritis or rheumatoid arthritis pain, lower back pain, diabetic neuropathy, sciatica, or visceral pain associated with gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ileitis, ulcerative colitis, renal colic, dysmenorrhea, cystitis, menstrual period, labor, menopause, prostatitis, or pancreatitis;   (iii) the condition comprises overactive bladder, pain; TMJ, temporomandibular jaw disorders, chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; post-surgical pain, trauma related pain, diabetes; non-insulin dependent diabetes mellitus and other inflammatory autoimmune disorders, vascular disorders; inflammation; arthritis; sarcoidosis, bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases including pruritis, neurogenic cutaneous redness, skin rosaceousness and erythema; inflammatory bowel disease, irritable bowel syndrome, cystitis; and dysmennorhea;   (iv) the disease or condition is pain, overactive bladder, headache, or migraine;   (v) the treatment is for treating a condition associated with pain and the treatment includes the administration of another therapeutic agent; optionally wherein the other therapeutic agent is selected from a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, an antiemetic and a cytotoxin;   (vi) the treatment is for treating a condition associated with pain and the treatment includes the administration of another therapeutic agent which comprises an analgesic, optionally an NSAID, an opioid analgesic, an antibody or a non-antibody biologic, further optionally a NGF antibody or antibody fragment or an NSAID which comprises a cyclooxygenase 1 and/or cyclooxygenase 2 inhibitor or an NSAID selected from (1) propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives including tolmetin and slindac; (3) fenamic acid derivatives including mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives including diflunisal and flufenisal; and (5) oxicams including piroxim, sudoxicam, and isoxicam;   (vii) the treatment is for treating a condition associated with pain and the treatment includes the administration of another therapeutic agent which comprises an analgesic, which is a phenanthrene; phenylheptylamine; phenylpiperidine; morphinans; or benzomorphan compound.   (viii) the treatment is for treating a condition associated with pain and the treatment includes the administration of another therapeutic agent which comprises an opioid analgesic selected from codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine or pharmaceutically acceptable salts thereof;   (ix) the treatment is for treating a condition associated with pain and the treatment includes the combined administration of the opioid analgesic and the CGRP antibody or antibody fragment increase the analgesic effect elicited thereby and/or alleviates tolerance to the analgesic, wherein optionally the opioid analgesic is morphine or a morphine derivative or pharmaceutically acceptable salt thereof; or   (x) any combination of the foregoing.   
     
     
         67 - 81 . (canceled) 
     
     
         82 . A method of making the antibody or antibody fragment of  claim 1 , optionally Ab6 or an antibody or antibody fragment comprising the same CDRs as Ab6, in a polyploid yeast culture, optionally a  Pichia pastoris  yeast culture, that stably expresses and secretes into the culture medium said antibody, comprising:
 (i) introducing at least one expression vector containing one or more heterologous polynucleotides encoding said antibody operably linked to a promoter and a signal sequence into a haploid yeast cell;   (ii) producing by mating or spheroplast fusion a polyploidal yeast from said first and/or second haploid yeast cell;   (iii) selecting polyploidal yeast cells that stably express said antibody; and   (iv) producing stable polyploidal yeast cultures from said polyploidal yeast cells that stably express said antibody into the culture medium.   
     
     
         83 - 85 . (canceled) 
     
     
         86 . An isolated polynucleotide comprising a polynucleotide encoding an anti-CGRP V H  antibody amino acid sequence selected from SEQ ID NO: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123 or 133, or encoding a variant thereof comprising the same CDRs which exhibits at least 90% sequence identity therewith and/or one comprising a polynucleotide encoding an anti-CGRP V L  amino acid sequence selected from SEQ ID NO: 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121 or 131, or a polynucleotide encoding a variant thereof comprising the same CDRs which exhibits at least 90% sequence identity therewith or a vector comprising said isolated polynucleotide. 
     
     
         87 - 94 . (canceled) 
     
     
         95 . A host cell, optionally a CHO cell or  Pichia pastoris  cell, comprising the polynucleotide or a vector containing according to claim  93 . 
     
     
         96 - 142 . (canceled) 
     
     
         143 . A pharmaceutical or diagnostic composition containing at least one anti-CGRP antibody or antibody fragment according to  claim 1 , optionally Ab6 or an anti-CGRP antibody or fragment comprising the same CDRs as Ab6, and a pharmaceutically acceptable carrier, wherein said composition optionally comprises at least one stabilizer and/or optionally is lyophilized. 
     
     
         144 - 145 . (canceled) 
     
     
         146 . The pharmaceutical or diagnostic composition of  claim 143 , which comprises one or more anti-CGRP antibodies according to  claim 10 . 
     
     
         147 - 149 . (canceled) 
     
     
         150 . A method of treating a disease or condition or at least one symptom associated therewith treatable or preventable by the administration of a CGRP antagonist comprising administering a therapeutically effective amount of a pharmaceutical composition according to  claim 143 . 
     
     
         151 . The method of  claim 150 , wherein:
 (i) the disease is selected from migraine (with or without aura), weight loss, cancer or tumors, angiogenesis associated with cancer or tumor growth, angiogenesis associated with cancer or tumor survival, hemiplagic migraines, cluster headaches, migrainous neuralgia, chronic headaches, tension headaches, general headaches, hot flushes, chronic paroxysomal hemicrania, secondary headaches due to an underlying structural problem in the head or neck, cranial neuralgia, sinus headaches, allergy-induced headaches or migraines, pain, inflammatory pain, post-operative incision pain, complex regional pain syndrome, cancer pain, primary or metastatic bone cancer pain, fracture pain, osteoporotic fracture pain, pain resulting from burn, osteoporosis, gout joint pain, pain associated with sickle cell crises, and other nociceptic pain, as well as hepatocellular carcinoma, breast cancer, liver cirrhosis, neurogenic pain, neuropathic pain, nociceptic pain, trigeminal neuralgia, post-herpetic neuralgia, phantom limb pain, fibromyalgia, menstrual pain, ovarialgia, reflex sympathetic dystrophy, neurogenic pain, osteoarthritis or rheumatoid arthritis pain, lower back pain, diabetic neuropathy, sciatica, or visceral pain associated with gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ileitis, ulcerative colitis, renal colic, dysmenorrhea, cystitis, menstrual period, labor, menopause, prostatitis, or pancreatitis;   (ii) the disease is pain, a pain associated disorder, overactive bladder, headache, or migraine;   (iii) the condition comprises overactive bladder, pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; post-surgical pain, trauma related pain, diabetes; non-insulin dependent diabetes mellitus and other inflammatory autoimmune disorders, vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases including pruritis, neurogenic cutaneous redness, skin rosaceousness and erythema; inflammatory bowel disease, irritable bowel syndrome, cystitis; and dysmennorhea;   (iv) the condition or disorder is migraine, overactive bladder, a pain associated disease or condition, or opioid analgesic tolerance;   (v) the CGRP antibody or antibody fragment containing composition is administered in a therapeutic regimen for treatment of a specific disease or condition associated with pain that includes the administration of another therapeutic agent, optionally selected from a chemotherapeutic, an analgesic, an anti-inflammatory, an immunosuppressant, a cytokine, an antiproliferative, an antiemetic and a cytotoxin;   (vi) the CGRP antibody or antibody fragment containing composition is administered in a therapeutic regimen for treatment of a specific disease or condition associated with pain that includes the administration of another therapeutic agent, wherein the other therapeutic agent is an analgesic, wherein the other analgesic optionally is an NSAID, an opioid analgesic, an antibody or a non-antibody biologic, optionally a NGF antibody or antibody fragment and/or optionally an NSAID which optionally comprises a cyclooxygenase 1 and/or cyclooxygenase 2 inhibitor or optionally comprises an NSAID is selected from (1) propionic acid derivatives including ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives including tolmetin and slindac; (3) fenamic acid derivatives including mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives including diflunisal and flufenisal; and (5) oxicams including piroxim, sudoxicam, and isoxicam; or optionally the other analgesic is a phenanthrene; phenylheptylamine; phenylpiperidine; morphinans; or benzomorphan compound or optionally the other analgesic is an opioid analgesic selected from codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine or pharmaceutically acceptable salts thereof;   (vii) the CGRP antibody or antibody fragment containing composition is administered in a therapeutic regimen for treatment of a specific disease or condition associated with pain that comprises the combined administration of the opioid analgesic and the CGRP antibody or antibody fragment containing composition in order to increase the analgesic effect elicited thereby and/or alleviates tolerance to the opioid analgesic, wherein optionally the opioid analgesic is morphine or a morphine derivative or pharmaceutically acceptable salt thereof; or   (viii) any combination of the foregoing.   
     
     
         152 - 176 . (canceled) 
     
     
         177 . A method of treating pain, comprising administering an effective amount of an anti-CGRP antibody or fragment thereof which inhibits the association of CGRP with CGRP-R, wherein said anti-CGRP antibody or fragment thereof is one according to  claim 1  and wherein optionally the pain is associated with trauma to the musculoskeletal system, burn, or pre- or post-operative surgery, or is visceral pain associated with gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ileitis, ulcerative colitis, renal colic, dysmenorrhea, cystitis, menstrual period, labor, menopause, prostatitis, psoriasis, IBD, or pancreatitis. 
     
     
         178 - 182 . (canceled) 
     
     
         183 . A method of treating or preventing migraine or a a non-migraine headache, comprising administering an effective amount of an anti-CGRP antibody or fragment thereof which inhibits the association of CGRP with CGRP-R wherein said anti-CGRP antibody or fragment thereof is one according to  claim 1 . 
     
     
         184 - 211 . (canceled)