Treatment of drug overuse headache using anti-CGRP or anti-CGRP-R antibodies

Abstract

The present application relates to the treatment of drug overuse headache using anti-CGRP or anti-CGRP-R antibodies, in particular, the present application provides methods for the treatment or prevention of drug overuse headache. Exemplary methods include administering an anti-CGRP antagonistic antibody to a patient in need thereof.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080007409X, application date January 8, 2020, and invention name “Treatment of drug overuse headache using anti-CGRP or anti-CGRP-R antibodies”.

[0002] Related Applications

[0003] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 840,967, filed on April 30, 2019 (Attorney Docket No. 1143257.008800); U.S. Provisional Application No. 62 / 841,585, filed on May 1, 2019 (Attorney Docket No. 1143257.008801); and U.S. Provisional Application No. 62 / 872,983, filed on July 11, 2019 (Attorney Docket No. 1143257.008802), all of which are incorporated herein by reference in their entirety.

[0004] Sequence Listing Disclosure

[0005] This application contains a sequence listing, which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. The ASCII copy created on December 11, 2019 is named "1143257o008803.txt" and is 357,503 bytes in size. Background Art Technical Field

[0006] The present invention relates to antibodies and fragments thereof (including Fab fragments) that specifically bind to human calcitonin gene-related peptide (hereinafter referred to as "CGRP"), or antibodies and fragments thereof (including Fab fragments) that specifically bind to human calcitonin gene-related peptide receptor (hereinafter referred to as "CGRP-R"), and methods for preventing or treating diseases and disorders associated with CGRP (such as medication overuse headache) by administering the antibodies or fragments thereof.

[0007] Description of Related Technology

[0008] Calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide CCGRP of 37 amino acids in length. Two forms, namely CGRP-α and CGRP-β, exist in humans and have similar activities. CGRP-α and CGRP-β differ in three amino acids in humans and are derived from different genes. CGRP is released from many tissues (such as the trigeminal nerve), which release intrameningeal neuropeptides after activation, mediating neuroinflammation characterized by vasodilation, vascular leakage and mast cell degradation. Durham, PL, New Eng. J. Med. [New England Journal of Medicine], 350 (11): 1073-75 (2004). The biological effects of CGRP are mediated by the CGRP receptor (CGRP-R), which consists of seven transmembrane components and receptor-associated membrane proteins (RAMPs). CGRP-R also requires the activity of receptor component proteins (RCPs), which are essential for the effective coupling of G proteins to adenylate cyclase and the production of cAMP. Doods, H., Curr. Op. Invest. Drugs, 2(9): 1261-68 (2001).

[0009] Migraine is a neurovascular disorder that affects approximately 10% of the adult population in the United States and is typically accompanied by severe headaches. CGRP is believed to play an important role in the development of migraines. In fact, several companies, namely Amgen, Eli Lilly, Teva, and Alder Biopharmaceuticals (recently acquired by Lundbeck A / S), have developed anti-CGRP and anti-CGRP-R antibodies for the treatment or prevention of migraines. The present assignee has previously filed patent applications related to anti-CGRP antibodies and uses thereof, including published PCT application WO / 2012 / 162243 filed on May 21, 2012, entitled “ANTI-CGRP COMPOSITIONS AND USE THEREOF”, published PCT application WO / 2012 / 162243 filed on May 21, 2012, entitled “USE OF ANTI-CGRP ANTIBODIES AND ANTIBODY FRAGMENTS TO PREVENT OR INHIBITPHOTOPHOBIA OR LIGHT AVERSION IN SUBJECTS IN NEED THEREOF, ESPECIALLY MIGRAINE SUFFERERS”, published PCT application WO / 2012 / 162257 filed on May 21, 2012, entitled “USE OF ANTI-CGRP OR PCT application WO / 2012 / 162253 entitled “ANTI-CGRP-R ANTIBODIES OR ANTIBODY FRAGMENTS TO TREAT OR PREVENT CHRONIC AND ACUTE FORMS OF DIARRHEA” and published PCT application WO / 2015 / 003122 filed on July 3, 2014 and entitled “REGULATION OF GLUCOSE METABOLISM USING ANTI-CGRP ANTIBODIES”, all of which are incorporated by reference in their entirety. Summary of the invention

[0010] The present disclosure provides methods for treating or preventing medication overuse headaches, such as headaches associated with overuse of anti-migraine medications and / or associated with overuse of triptans and / or ergots and / or analgesics, comprising administering to a patient in need thereof an effective amount of at least one anti-CGRP antibody or antibody fragment or anti-CGRP-R antibody or antibody fragment, or one or more formulations comprising the antibodies or antibody fragments as disclosed herein. The anti-CGRP antibody or antibody fragment optionally comprises any one of Ab1-Ab14 or its Fab fragment, such as Ab6 or its Fab fragment, for example, light chain CDR 1, 2 and 3 polypeptide sequences having SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and heavy chain CDR 1, 2 and 3 polypeptide sequences having SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208; or having light chain CDR 1, 2 and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, 2 and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively. The anti-CGRP antibody may comprise a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202. The anti-CGRP antibody may comprise a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212. The anti-CGRP antibody may comprise a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The anti-CGRP antibody may comprise a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567. The anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell, the recombinant cell expressing a nucleic acid sequence encoding a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202, the polypeptides being optionally linked to human light and heavy constant region polypeptides, e.g., human IgG1, IgG2, IgG3 or IgG4 constant regions, respectively, the constant regions being optionally modified to alter glycosylation or proteolysis, wherein the recombinant cell optionally comprises a yeast or mammalian cell, e.g., Pichia pastoris or a CHO cell.The anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell expressing a nucleic acid sequence encoding a light chain of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, wherein the recombinant cell optionally comprises a yeast or mammalian cell, such as a Pichia pastoris or a CHO cell, wherein the constant region thereof may optionally be modified to alter glycosylation or proteolysis or other effector functions. Any of the above anti-CGRP antibodies or antibody fragments, preferably Ab6, may optionally be included in a formulation as disclosed herein, for example, the formulation comprises histidine (L-histidine), sorbitol, polysorbate 80, for example, about 100 mg anti-CGRP antibody, about 3.1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polysorbate 80 per 1 mL volume, with a pH of about 5.8. The antibody may be administered at a dose of about 100 mg to about 300 mg, such as about 100 mg, about 300 mg, 100 mg or 300 mg. The dose may be administered in different ways, such as intravenously, such as in a saline solution such as 0.9% sodium chloride in a suitable volume such as 100 mL.

[0011] The medication overuse headache can be determined based on: (a) the occurrence of headaches 15 or more days / month in a patient with a prior headache disorder; and (b) overuse of one or more medications available for acute and / or symptomatic treatment of headache for more than 3 months.

[0012] The overuse can include use of an ergot alkaloid (e.g., ergotamine) for 10 or more days / month, use of a triptan for 10 or more days / month, use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days / month, use of one or more combination analgesics (as further described below) for 10 or more days / month, use of one or more opioids for 10 or more days / month, or use of a combination of two or more drug classes (as further described below) for 10 or more days / month.

[0013] In the methods herein, the triptan may include, but is not limited to, any one or any combination of triptans, such as sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan, among others.

[0014] The medication overuse headache can include ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple medication classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple medication classes, or medication overuse headache attributed to other medications.

[0015] The non-opioid analgesic overuse headache can include acetaminophen (acetaminophen) overuse headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, such as acetylsalicylic acid (aspirin) overuse headache or ibuprofen overuse headache, or other non-opioid analgesic overuse headache.

[0016] The ergotamine overuse headache may include headaches occurring 15 or more days / month in a patient with a pre-existing primary headache that progresses due to regular use of ergot alkaloids (e.g., ergotamine) 10 or more days / month for more than 3 months.

[0017] In the methods herein, the ergot alkaloid may comprise ergotamine, nicergoline, methysergide, or dihydroergotamine.

[0018] The triptan overuse headache may include headaches occurring 15 or more days / month in a patient who has a pre-existing primary headache that progresses due to regular use of one or more triptans 10 or more days / month for more than 3 months.

[0019] The non-opioid analgesic overuse headache can include headaches occurring 15 or more days / month in a patient who has a pre-existing primary headache and that have progressed due to regular use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), ibuprofen, another NSAID, or another non-opioid analgesic) 15 or more days / month for more than 3 months.

[0020] In the methods herein, the NSAID may comprise any NSAID or combination thereof, including but not limited to ibuprofen, naproxen, or indomethacin.

[0021] The combination-analgesic overuse headache may include headaches occurring 15 or more days / month and progressing due to regular use of one or more combination analgesics for more than 3 months on 10 or more days / month. In the context of medication overuse headache, the term combination analgesic refers to a formulation that combines two or more types of medications that have analgesic effects (e.g., acetaminophen and codeine) or an analgesic with an adjunct agent (e.g., caffeine). Commonly overused combination analgesics combine a non-opioid analgesic with at least one opioid, a barbiturate (e.g., ibutabarbital, and / or caffeine). In an exemplary embodiment, a combination analgesic overuse headache is due to acetaminophen, aspirin, and caffeine (e.g., or EXCEDRIN Other known combination analgesics include analgesics combined with at least one non-analgesic, such as vasoconstrictors (e.g., pseudoephedrine for sinus-related preparations), antihistamines (for treating allergy sufferers), and the like.

[0022] The opioid overuse headache may include headaches occurring 15 or more days / month in a patient who has a pre-existing primary headache and who has progressed due to regular use of one or more opioids 10 or more days / month for more than 3 months.

[0023] The medication overuse headache attributed to multiple medication classes rather than overuse alone can include headaches occurring 15 or more days / month in a patient with a pre-existing primary headache disorder and progressing due to regular use of any combination of ergotamine, triptans, non-opioid analgesics, and / or opioids (not overuse of any single medication or single medication class) for a total of at least 10 days / month for more than 3 months.

[0024] In the methods herein, the opioid can be any one or any combination of opioid drugs, including but not limited to oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, thebaine, oripavine, mixed opioid alkaloids such as opium alkaloids, diacetylmorphine, nicotine morphine, dipropionylmorphine, diacetyldihydromorphine, levulinylmorphine, normorphine, methylnormorphine, dibenzoylmorphine, ethylmorphine, heterocodeine, buprenorphine, etorphine, hydromorphone, oxymorphone, fentanyl, alpha methylfentanyl, alfentanil, sufentanil, remifentanil, carfentanil, hydroxymethylfentanyl, pethidine (meperidine), ketobemidone, MPPP, allylprodine, prodinatin, PEPAP, meperidine, diphenylheptazone, propoxyphene, dextropropoxyphene, dextromalamide, benzathine, pirithamide, and the like.

[0025] The medication overuse headache attributed to unspecified or unverified overuse of multiple medication classes may include headaches occurring 15 or more days / month in a patient with a preexisting primary headache disorder and progressing due to regular use of any combination of ergotamines, triptans, non-opioid analgesics, and / or opioids for at least 10 days / month for more than 3 months, where the identity, amount, and / or pattern of use or overuse of medications in these classes cannot be reliably determined.

[0026] The medication overuse headache attributed to other medications can include headaches occurring 15 or more days / month in a patient with a preexisting primary headache disorder and progressing as a result of regular use of one or more medications other than the above medications for acute or symptomatic treatment of the headache for more than 3 months, at least 10 days / month.

[0027] The amount and duration of drug use can be determined using known methods (e.g., patient or relative reported usage, diaries, medical records, drug purchase history, prescription fulfillment, biomarkers of drug use, incidence of drug toxicity, incidence of overdose, and / or other indicators of patient drug use).

[0028] The present disclosure provides a method for treating or preventing possible medication overuse headache, the method comprising administering to a patient in need thereof an effective amount of an anti-CGRP antibody or anti-CGRP antibody fragment or one or more formulations comprising the anti-CGRP antibody or anti-CGRP antibody fragment as disclosed herein. The anti-CGRP antibody optionally comprises any one of Ab1-Ab14, such as Ab6, for example, having light chain CDR 1, 2 and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and heavy chain CDR 1, 2 and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208; or having light chain CDR 1, 2 and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, 2 and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively. The anti-CGRP antibody may comprise a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202. The anti-CGRP antibody may comprise a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212. The anti-CGRP antibody may comprise a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The anti-CGRP antibody may comprise a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567. The anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell, the recombinant cell expressing a nucleic acid sequence encoding a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202, the polypeptides being optionally linked to human light and heavy constant region polypeptides, e.g., human IgG1, IgG2, IgG3 or IgG4 constant regions, respectively, the constant regions being optionally modified to alter glycosylation or proteolysis, wherein the recombinant cell optionally comprises a yeast or mammalian cell, e.g., Pichia pastoris or a CHO cell.The anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell expressing a nucleic acid sequence encoding a light chain of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, wherein the recombinant cell optionally comprises a yeast or mammalian cell, such as a Pichia pastoris or a CHO cell, wherein the constant region thereof may optionally be modified to alter glycosylation or proteolysis or other effector functions. Any of the above anti-CGRP antibodies or antibody fragments, preferably Ab6, may optionally be included in a formulation as disclosed herein, for example, the formulation comprises histidine (L-histidine), sorbitol, polysorbate 80, for example, about 100 mg anti-CGRP antibody, about 3.1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polysorbate 80 per 1 mL volume, with a pH of about 5.8. The antibody may be administered in a dose of about 100 mg to about 300 mg, such as about 100 mg, about 300 mg, 100 mg or 300 mg. The dose may be administered in different ways, such as intravenous administration, such as in a saline solution such as 0.9% sodium chloride in a suitable volume, such as 100 mL. Possible medication overuse headache refers to not fully meeting criteria (a) and (b), such as at least 80% or at least 90% of the specified headache days and / or medication use days per month and / or in a shorter period of time (e.g., at least 2 months), optionally in the absence of another ICHD-3 diagnosis.

[0029] The medication overuse headache (e.g., ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple medication classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple medication classes, or medication overuse headache attributed to other medications) can be diagnosed according to the International Classification of Headache Disorders, 3rd edition (ICHD-3). See Classification Committee of the International Headache Society (IHS), The International Classification of Headache Disorders, 3rd edition, Cephalalgia. 2018 Jan;38(1):1-211, which is hereby incorporated by reference in its entirety.

[0030] Here, the criterion of “the occurrence of headache due to overuse of one or more medications” refers to a clear link between overuse of one or more medications and headache, such as overuse of one or more medications and headache occurring at a frequency that can be inferred to be a causal relationship.

[0031] In some exemplary embodiments, the dose of the anti-CGRP antibody may be 100 mg.

[0032] In other exemplary embodiments, the dose of the anti-CGRP antibody may be 300 mg.

[0033] The method may further comprise administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0034] The method may further comprise administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0035] The patient may be a chronic migraine patient or an episodic migraine patient at risk for medication overuse headache. The patient may use acute headache medications at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days per month. The patient may use acute headache medications at least 10 days per month. Optionally, the acute medication use is determined over a baseline period of at least 28 days. The acute medication use may be reported by the patient, a caregiver or based on records. The acute medications may include use of ergot alkaloids, triptans, non-opioid analgesics, acetaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics or opioids.

[0036] Prior to said administration, the patient may exhibit from about 15 to about 30 migraine days per month, such as from about 16 to about 28 migraine days per month, such as from about 17 to about 26 migraine days per month, such as about 16 migraine days per month.

[0037] Prior to said administration, the patient may exhibit from about 15 to about 27 headache days per month, such as from about 17 to about 24 headache days per month, such as about 20 or about 21 headache days per month.

[0038] The patient may have been diagnosed with migraine at least 10 years prior to said administering, such as at least 15 years prior to said administering, such as at least 18 or at least 19 years prior to said administering.

[0039] Said patient may have been diagnosed with chronic migraine at least 5 years prior to said administration, such as at least 8 years prior to said administration, such as at least 11 or at least 12 years prior to said administration.

[0040] The patient experiences at least a 50% reduction in the number of migraine days within one month after being administered the antibody relative to a baseline number of migraine days experienced by the patient prior to said administration.

[0041] The patient experiences at least a 75% reduction in the number of migraine days within one month after being administered the antibody relative to a baseline number of migraine days experienced by the patient prior to said administration.

[0042] The patient experiences a 100% reduction in the number of migraine days within one month after being administered the antibody relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0043] The patient experiences at least a 50% reduction in the number of migraine days within 12 weeks after being administered the antibody relative to a baseline number of migraine days experienced by the patient prior to said administration.

[0044] The patient experiences at least a 75% reduction in the number of migraine days over a 12-week period following administration of the antibody relative to a baseline number of migraine days experienced by the patient prior to said administration.

[0045] The patient experiences a 100% reduction in the number of migraine days over the 12 weeks following administration of the antibody relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0046] The method can further comprise administering to the patient a second dose of the anti-CGRP antibody, eg, intravenously, about 12 weeks or about 3 months after the administering.

[0047] The administration may comprise about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-CGRP antibody.

[0048] The anti-CGRP antibody may be aglycosylated, or if only glycosylated, may contain only mannose residues.

[0049] The anti-CGRP antibody may consist of a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The anti-CGRP antibody may consist of a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0050] In some embodiments, the anti-human CGRP antibody or antibody fragment comprises a variable light chain of SEQ ID NO: 222 and / or a variable heavy chain of SEQ ID NO: 202. In some embodiments, the anti-human CGRP antibody or antibody fragment comprises a variable light chain encoded by SEQ ID NO: 232 and / or a variable heavy chain encoded by SEQ ID NO: 212.

[0051] In some embodiments, the anti-human CGRP antibody or antibody fragment comprises a light chain of SEQ ID NO: 221 and / or a heavy chain of SEQ ID NO: 201 or SEQ ID NO: 566. In some embodiments, the anti-human CGRP antibody or antibody fragment comprises a light chain encoded by SEQ ID NO: 231 and / or a heavy chain encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0052] In some embodiments, the anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell, the recombinant cell expressing a nucleic acid sequence encoding a VL polypeptide of SEQ ID NO: 222 and a VH polypeptide of SEQ ID NO: 202, the polypeptides being optionally linked to human light and heavy constant region polypeptides, e.g., human IgG1, IgG2, IgG3 or IgG4 constant regions, respectively, the constant regions being optionally modified to alter glycosylation or proteolysis, wherein the recombinant cell optionally comprises a yeast or mammalian cell, e.g., Pichia pastoris or a CHO cell.

[0053] In some embodiments, the anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell, which expresses a light chain encoding SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, wherein the recombinant cell optionally comprises a yeast or mammalian cell, such as Pichia pastoris or a CHO cell, wherein the constant region thereof may optionally be modified to alter glycosylation or proteolysis or other effector function.

[0054] In some embodiments, any of the above anti-CGRP antibodies or antibody fragments may be included in a formulation disclosed herein, for example, the formulation comprises histidine (L-histidine), sorbitol, polysorbate 80, for example, about 100 mg anti-CGRP antibody, about 3.1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polysorbate 80 per 1 mL volume, with a pH of about 5.8. The antibody or fragment can be administered by different means, for example, intravenously, for example, in a saline solution, for example, 0.9% sodium chloride, in a suitable volume, for example, 100 mL.

[0055] In some embodiments, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-CGRP antibody or antibody fragment is administered (e.g., intravenously).

[0056] In other embodiments, about 100 mg of the anti-CGRP antibody or antibody fragment is administered.

[0057] In other embodiments, about 300 mg of the anti-CGRP antibody or antibody fragment is administered (eg, intravenously).

[0058] In an exemplary embodiment, the anti-human CGRP antibody or antibody fragment is administered intravenously, for example, at a frequency of up to every 3 months or every 12 weeks, wherein the antibody dose is administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 3 months or every 12 weeks. The phrase "antibody dose is administered in a single formulation or divided into different formulations" refers to administering the amount of antibody in a relatively short period of time (e.g., within a few hours (e.g., within 1 to 8 hours), about a day, about two days, or about a week) by the same or different routes (e.g., iv, im and / or sc), administration site. In this context, the term "different formulations" refers to antibody doses administered at different times and / or at different sites and / or different routes, regardless of whether the dose is the same or different with respect to the chemical composition of the drug when each dose is administered; for example, between different doses, concentrations, excipients, carriers, pH, etc. may be the same or different.

[0059] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dose is administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 8 weeks or every 2 months.

[0060] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 12 weeks or every 3 months.

[0061] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 16 weeks or every 4 months.

[0062] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 20 weeks or every 5 months.

[0063] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dose is administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 24 weeks or every 6 months.

[0064] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dose is administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 28 weeks or every 7 months.

[0065] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 32 weeks or every 8 months.

[0066] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 36 weeks or every 9 months.

[0067] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 40 weeks or every 8 months.

[0068] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 44 weeks or every 9 months.

[0069] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 48 weeks or every 10 months.

[0070] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of approximately every 52 weeks or every 11 months.

[0071] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment doses are administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 56 weeks or every 12 months.

[0072] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dose is administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 15-18 months.

[0073] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dose is administered in a single formulation or divided into different formulations, which are administered at a frequency of approximately every 18-21 months.

[0074] In other exemplary embodiments, the dose of anti-human CGRP antibody or antibody fragment used in the above methods is administered in a single formulation or divided into different formulations, which are administered at a frequency of about every 2 years.

[0075] In other exemplary embodiments, the anti-human CGRP antibody used in the above methods is administered systemically.

[0076] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment used in the above method is administered by an administration selected from intravenous, intramuscular, intravenous, intrathecal, intracranial, topical, intranasal and oral. In a preferred embodiment, the anti-human CGRP antibody or antibody fragment used in the above method is administered intravenously.

[0077] In other exemplary embodiments, the anti-human CGRP antibody used in the above methods has an in vivo half-life of at least 10 days.

[0078] In other exemplary embodiments, the anti-human CGRP antibody has an in vivo half-life of at least 15 days.

[0079] In other exemplary embodiments, the anti-human CGRP antibody used in the above methods has an in vivo half-life of at least 20 days.

[0080] In other exemplary embodiments, the anti-human CGRP antibody used in the above methods has an in vivo half-life of at least 20-30 days.

[0081] In other exemplary embodiments, the anti-human CGRP antibody is administered at a dose of about 100 mg to about 300 mg with an in vivo half-life of at least about (284 ± 44 hours) ± 20%.

[0082] In other exemplary embodiments, the anti-human CGRP antibody used in the above methods binds to human α- and β-CGRP.

[0083] In other exemplary embodiments, the dose of anti-human CGRP antibody administered results in inhibition of vasodilation induced by topically applied capsaicin for at least 30 days following administration of the antibody.

[0084] In other exemplary embodiments, the dose of anti-human CGRP antibody administered results in inhibition of vasodilation induced by topically applied capsaicin for at least 60 days following administration of the antibody.

[0085] In other exemplary embodiments, the dose of anti-human CGRP antibody administered results in inhibition of vasodilation induced by topically applied capsaicin for at least 90 days following administration of the antibody.

[0086] In other exemplary embodiments, the dose of anti-human CGRP antibody administered results in inhibition of vasodilation induced by topically applied capsaicin for at least 120 days following administration of the antibody.

[0087] In other exemplary embodiments, the dose of anti-human CGRP antibody administered results in inhibition of vasodilation induced by topically applied capsaicin for at least 150 days following administration of the antibody.

[0088] In other exemplary embodiments, the dose of anti-human CGRP antibody administered results in inhibition of vasodilation induced by topically applied capsaicin for at least 180 days following administration of the antibody.

[0089] In other exemplary embodiments, the dose of anti-human CGRP antibody administered results in inhibition of vasodilation induced by topically applied capsaicin for more than 180 days following administration of the antibody.

[0090] In other exemplary embodiments, the anti-human CGRP antibody dose administered results in sustained pharmacodynamic (PK) activity within 5% of the maximum response (Imax) (compared to a lower antibody dose).

[0091] In other exemplary embodiments, the anti-human CGRP antibody dose administered results in sustained pharmacodynamic (PK) activity that is maintained for at least 2-3 months following antibody administration, wherein PK analysis of the anti-human CGRP antibody is derived from plasma concentrations.

[0092] In other exemplary embodiments, the dose of anti-human CGRP antibody administered is from about 100 mg to about 300 mg or more, and its administration frequency does not exceed once every 2 months.

[0093] The present invention also relates to the use of specific antibodies and fragments thereof having binding specificity to CGRP (particularly antibodies having desired epitope specificity, high affinity or avidity and / or functional properties). A preferred embodiment of the present invention relates to the use of chimeric or humanized antibodies and fragments thereof (including Fab fragments) capable of binding to CGRP and / or inhibiting biological activity mediated by binding of CGRP to CGRP receptors (CGRP-R), for example, wherein such antibodies are optionally derived from recombinant cells engineered to express them, optionally yeast or mammalian cells, further optionally Pichia pastoris and CHO cells.

[0094] In another preferred embodiment of the present invention, full-length antibodies and Fab fragments thereof that inhibit CGRP-α-, CGRP-β- and rat CGRP-driven cAMP production are contemplated. In another preferred embodiment of the present invention, full-length and Fab fragments thereof that reduce vasodilation in a recipient after administration are contemplated.

[0095] The present invention also contemplates the use of conjugates of anti-CGRP antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The present invention also contemplates the use of chimeric or humanized anti-CGRP or anti-CGRP / CGRP-R complex antibodies and binding fragments thereof. In one embodiment, the binding fragments include but are not limited to Fab, Fab', F(ab') 2 , Fv, scFv fragments, SMIP (small molecule immunopharmaceuticals), camelid antibodies, nanobodies and IgNAR. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figures 1A-1F The polypeptide sequences of the full-length heavy chains of antibodies Abl-Abl4 are provided, with the framework region (FR), complementarity determining region (CDR) and constant region sequences delimited.

[0097] Figures 2A-2D The polypeptide sequences of the full-length light chains of antibodies Abl-Abl4 are provided, with the framework region (FR), complementarity determining region (CDR) and constant region sequences delineated.

[0098] Figure 3A-3P Exemplary polynucleotide sequences encoding the full-length heavy chains of antibodies Abl-Abl4 are provided, with framework region (FR), complementarity determining region (CDR), and constant region encoding sequences delimited.

[0099] Figures 4A-4I Exemplary polynucleotide sequences encoding the full-length light chains of antibodies Abl-Abl4 are provided, with framework region (FR), complementarity determining region (CDR), and constant region encoding sequences delimited.

[0100] Figure 5 The polypeptide sequence coordinates within the full-length heavy chain polypeptide sequences of antibodies Abl-Abl4, including sequence features of the variable regions and complementarity determining regions (CDRs), are provided, along with the SEQ ID NO for each individual feature.

[0101] Figure 6 The polypeptide sequence coordinates within the full-length heavy chain polypeptide sequences of antibodies Abl-Abl4, including sequence features of the framework regions (FR) and constant regions, are provided, along with the SEQ ID NO for each individual feature.

[0102] Figure 7 Provided are polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibodies Abl-Abl4 having sequence features including variable regions and complementarity determining regions (CDRs), as well as the SEQ ID NO for each individual feature.

[0103] Figure 8The polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibodies Abl-Abl4, including sequence features of the framework regions (FR) and constant regions, are provided, along with the SEQ ID NO for each individual feature.

[0104] Fig. 9 Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding full-length heavy chain polypeptide sequences of antibodies Abl-Ab14 including sequence features of the variable regions and complementarity determining regions (CDRs) are provided, along with the SEQ ID NO for each individual feature.

[0105] Fig.10 Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding full-length heavy chain polypeptide sequences of antibodies Abl-Ab14 including sequence features of framework regions (FRs) and constant regions are provided, along with the SEQ ID NO for each individual feature.

[0106] Fig.11 Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding full-length light chain polypeptide sequences of antibodies Abl-Ab14 including sequence features of the variable regions and complementarity determining regions (CDRs) are provided, along with the SEQ ID NO for each individual feature.

[0107] Fig.12 Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding full-length light chain polypeptide sequences of antibodies Abl-Abl4 including sequence features of framework regions (FRs) and constant regions are provided, along with the SEQ ID NO for each individual feature.

[0108] Fig.13 The number of subjects treated with Ab6 (treatment group) or placebo in the human clinical trial described in Example 2 who had a 50%, 75% or 100% reduction in migraine at each monitoring point throughout the period is shown. The right column of each group corresponds to patients receiving 1000 mg of Ab6, and the left column of each group corresponds to the matched placebo control. In each response rate group, the response rate of patients receiving Ab6 was significantly higher than that of the placebo-treated control, with the p values ​​for each group indicated as 0.0155, 0.0034 and 0.0006, respectively. The administered antibody was produced in Pichia pastoris and consisted of the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201.

[0109] Fig.14 The median (±QR) % change from baseline in the number of migraine days per month for the placebo and Ab6 treated groups over 12 weeks post-treatment is shown. (p=0.0078). The upper (red) and lower (blue) lines show the results for the placebo treated control group and patients administered 1000 mg Ab6, respectively.

[0110] Fig.15 Median (±QR) % change from baseline in the number of monthly migraine attacks for placebo and Ab6 treated groups over 12 weeks post-treatment is shown. The upper (red) and lower (blue) lines show the results for the placebo treated control group and patients administered 1000 mg Ab6, respectively.

[0111] Fig.16 Median (±QR) % change from baseline in monthly migraine hours for placebo and Ab6 treated groups over 12 weeks post-treatment is shown. The upper (red) and lower (blue) lines show the results for the placebo treated control group and patients administered 1000 mg Ab6, respectively.

[0112] Fig.17 Screening of patients, allocation to treatment and control groups, and patient attrition through follow-up were summarized.

[0113] Fig.18 The HIT-6 responder analysis of the Ab6-treated and placebo-treated groups was compared at baseline, week 4, week 8, and week 12 after treatment.

[0114] Fig.19 The percentage of patients whose HIT-6 analysis indicated only "some" or "little / no" effect of headache at baseline and after Ab6 administration is shown. At baseline, most patients were "substantially" or "severely" affected by migraine. At each subsequent time point, the percentage of patients whose HIT-6 effect was only "some" or "little / no" was significantly higher in patients administered 1000 mg Ab6 (left bar in each group, blue) compared to the placebo control group (right bar in each group, red).

[0115] Fig. 20 Contains the pharmacokinetic (PK) profile of Ab6 administered intravenously at a single dose of 1000 mg.

[0116] Fig.21 The plasma-free pharmacokinetic (PK) parameters N (number of patients), mean values ​​and standard deviations (SD) of a single dose of 1000 mg of Ab6 are shown in Table 1. The parameters and units shown in the table are C max (μg / mL), AUC 0-∞ (mg*hr / mL), half-life (days), V z (L) and C L (mL / hr).

[0117] Fig. 22Shown are the changes from baseline (mean +- SEM) in the number of migraine days per month for Ab6 (1000 mg iv) relative to placebo for a single dose for the study described in Example 2.

[0118] Fig.23 Shown are the mean number of migraine days (+ / - SD) over time for the entire analysis population of the study described in Example 2. Visit intervals (where eDiaries were completed for 21-27 days) were normalized by multiplying the observed frequency by the inverse of the completion rate.

[0119] Fig.24 The distribution and change in actual number of migraine days for the Ab6 treatment group during weeks 1-4 of the study described in Example 2 are shown.

[0120] Fig.25 The distribution and change in the actual number of migraine days in the placebo group during weeks 1-4 of the study described in Example 2 are shown.

[0121] Fig.26 The distribution and change in actual number of migraine days for the Ab6 treatment group during weeks 5-8 of the study described in Example 2 are shown.

[0122] Fig. 27 The distribution and change of actual number of migraine days in the placebo group during weeks 5-8 of the study described in Example 2 are shown.

[0123] Fig.28 The distribution and change in actual number of migraine days for the Ab6 treatment group during weeks 9-12 of the study described in Example 2 are shown.

[0124] Fig.29 The distribution and change in the actual number of migraine days in the placebo group during weeks 9-12 of the study described in Example 2 are shown.

[0125] Fig.30 The 50% responder rates are shown for the Ab6 and placebo treatment groups for the study described in Example 2. Subjects with a ≥50% reduction in migraine frequency were considered 50% responders. The visit interval (where eDiary was completed for 21-27 days) was normalized by multiplying the observed frequency by the inverse of the completion rate.

[0126] Fig.31 The 75% responder rates for the Ab6 and placebo treatment groups for the study described in Example 2 are shown. Subjects with a ≥75% reduction in migraine frequency were considered 75% responders. Fig.30 The application is standardized.

[0127] Fig.32The 100% responder rates for the Ab6 and placebo treatment groups of the study described in Example 2 are shown. Subjects who achieved a 100% reduction in migraine frequency were considered 100% responders. Fig.30 The application is standardized.

[0128] Fig.33 Shown are the mean migraine severity over time for the entire analysis population of the study described in Example 2. On the scale used, the mean migraine score of 3 indicated "moderate pain".

[0129] Fig.34 The changes from baseline in the measured attributes for the placebo and treatment groups in the study described in Example 2 are summarized.

[0130] Fig.35 Shown are the percentages of patients with migraine in the 300 mg, 100 mg and placebo treatment groups on days 1, 7, 14, 21 and 28 in the clinical trial described in Example 3. The top row shows the results for the placebo, the bottom row shows the results for the 300 mg dose, and the middle row shows the results for the 100 mg dose.

[0131] Fig.36 The percentage of patients who achieved a 50% reduction in migraine days at Month 1, Months 1-3 (after first infusion), and Months 4-5 (after second infusion) in the 300 mg and 100 mg treatment groups in the clinical trial described in Example 3 are shown. In each figure, the data bars show the results for the 100 mg, 300 mg, and placebo groups from left to right. Statistical significance is as follows. ++ indicates a statistically significant difference from placebo; + indicates a statistically significant difference from placebo (unadjusted); and § indicates a statistically significant difference from placebo (post hoc).

[0132] Fig.37 Represents the percentage of patients who achieved a 75% reduction in migraine days in the 300 mg and 100 mg treatment groups at month 1, months 1-3 (after first infusion), and months 4-5 (after second infusion) in the clinical trial described in Example 3. Data order and statistical significance labels are as follows Fig.36 shown.

[0133] Fig.38 Represents the percentage of patients achieving a 100% reduction in migraine days in the 300 mg and 100 mg treatment groups at month 1, months 1-3 (after first infusion), and months 4-5 (after second infusion) in the clinical trial described in Example 3. Data order and statistical significance labels are as follows Fig.36 shown.

[0134] Fig.39The characteristics of the patients in each treatment group in the clinical trial described in Example 3 are summarized. *According to the American Academy of Neurology / American Headache Society guidelines for migrainepreventative treatment (drugs determined by clinical review of coded medical data); SD, standard deviation; BMI, body mass index.

[0135] Fig.40 .Change from baseline in mean migraine days (MMD) over 1-3 months versus placebo by baseline subgroup in human clinical trials for chronic migraine patients. In the graph, the data points are means and the lines show the 95% confidence interval (CI) of the change relative to placebo for the 100 mg (upper line) or 300 mg (lower line) treatment groups for each subgroup marked on the far left.

[0136] Fig.41 .The difference from placebo in the change from baseline in mean migraine days (MMD) over 1-3 months in a baseline subgroup of human clinical trials for patients with episodic migraine. Fig.40 The ground is marked.

[0137] Fig.42 . Change from baseline in mean migraine days (MMD) across 2 dose intervals in chronic migraine patients who used acute medications at least 1 day per month at baseline. Triangles: Placebo (n=366). Circles: 100 mg Ab6 per dose (n=356). Squares: 300 mg Ab6 per dose (n=350).

[0138] Fig.43 Mean days of acute medication use among chronic migraine patients who used acute medication at least one day per month at baseline. Triangles: Placebo (n=366). Circles: 100 mg Ab6 per dose (n=356). Squares: 300 mg Ab6 per dose (n=350).

[0139] Fig.44 Change from baseline in acute medication use in subgroups of chronic migraine patients with different baseline acute medication use days. Solid line: patients who used acute medication 10 or more days per month at baseline. Dashed line: patients who used acute medication at least 1 day per month and less than 10 days per month at baseline. Triangles: placebo. Circles: 100 mg Ab6 per dose. Squares: 300 mg Ab6 per dose.

[0140] Fig.45.Summary of acute medication use days in subgroups of chronic migraine patients with baseline acute medication use.

[0141] Fig.46 . Change from baseline in mean migraine days (MMD) across 2 dose intervals in patients with episodic migraine who used acute medications at least 1 day per month at baseline. Triangles: Placebo (n=222). Circles: 100 mg Ab6 per dose (n=221). Squares: 300 mg Ab6 per dose (n=222).

[0142] Fig.47 Mean days of acute medication use among episodic migraine patients who used acute medication at least one day per month at baseline. Triangles: Placebo (n=222). Circles: 100 mg Ab6 per dose (n=221). Squares: 300 mg Ab6 per dose (n=222).

[0143] Fig.48 .Change from baseline in acute medication use in subgroups of episodic migraine patients with different baseline acute medication use days. Solid line: patients who used acute medication 10 or more days per month at baseline. Dashed line: patients who used acute medication at least 1 day and less than 10 days per month at baseline. Triangles: placebo. Circles: 100 mg Ab6 per dose. Squares: 300 mg Ab6 per dose.

[0144] Fig.49 .Summary of acute medication use days in the subgroup of episodic migraine patients with baseline acute medication use. DETAILED DESCRIPTION

[0145] Described herein is the use of anti-CGRP antibodies for the treatment of medication overuse headache.

[0146] definition

[0147] It should be understood that the present invention is not limited to the specific methods, protocols, cell lines, animal species or genera described, and the reagents described, as they may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless the context clearly indicates otherwise, the singular forms "a", "a", and "the" as used herein include plural indicators. Thus, for example, reference to "a cell" includes a plurality of such cells, and reference to "the protein" includes reference to one or more proteins known to those skilled in the art and their equivalents, and so on. Unless otherwise expressly noted, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present invention belongs.

[0148] As used herein, the term "medication overuse headache" refers to a headache that meets the criteria set forth in ICHD-3 (Classification Committee of the International Headache Society (IHS), The International Classification of Headache Disorders, 3rd ed., Cephalalgia. 2018 Jan;38(1):1-211). The term includes subtypes of medication overuse headache as defined in ICHD-3, such as triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, etc.

[0149] As used herein, the term "chronic migraine" refers to a condition in which the patient exhibits an average of at least 15 migraine days and / or headache days per month. The term "episodic migraine" refers to a condition in which the patient exhibits an average of less than 15 headache days and / or migraine days per month.

[0150] As used herein, the term "diagnosed with chronic migraine" refers to a patient who meets the clinical criteria for chronic migraine, regardless of whether a formal diagnosis has been made for the patient.

[0151] As used herein, the term "intravenous administration" refers to a mode of administration in which a substance, such as an antibody, is introduced directly into the patient's circulation, most typically into the venous circulation. The substance can be introduced into a carrier fluid, such as an aqueous solution, such as normal saline. The substance can be administered in a single formulation or in multiple formulations, as long as the administration is completed within a short period of time (e.g., within 1 day, preferably within 12 hours, more preferably within 6 hours, and most preferably within 1-2 hours).

[0152] As used herein, the term "baseline migraine days" refers to the number of migraine days that a patient exhibits during a specified period of time, such as before treatment. For example, the baseline number of migraine days can be determined over a month or longer, such as by recording whether a migraine occurs each day.

[0153] As used herein, the term "monthly migraine days" refers to the number of days per month on which a patient experiences migraine, i.e., at any time of the day, the patient has symptoms that meet the clinical definition of migraine. Monthly migraine days can be determined by recording whether a migraine occurs each day.

[0154] As used herein, the term "monthly headache days" refers to the number of days per month on which a patient has headaches, i.e., at any time of the day, the patient has symptoms that meet the clinical definition of headaches. The monthly headache days can be determined by recording whether headaches occur each day.

[0155] Calcitonin gene-related peptide (CGRP): As used herein, CGRP encompasses not only the following Homo sapiens CGRP-α and Homo sapiens CGRP-β amino acid sequences available from American Peptides (Sunnyvale CA) and Bachem (Torrance, CA):

[0156] CGRP-α: ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH 2 (SEQ ID NO:561), wherein the terminal phenylalanine is amidated;

[0157] CGRP-β: ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF-NH 2 (SEQ ID NO: 562), wherein the terminal phenylalanine is amidated; any membrane-bound form of these CGRP amino acid sequences, as well as mutants, splice variants, isoforms, orthologs, homologs, and variants of the sequences are also encompassed.

[0158] Expression vectors: These DNA vectors contain elements that facilitate the manipulation of foreign protein expression in target host cells (e.g., yeast or mammalian cells, such as Pichia pastoris or CHO cells). Conveniently, manipulation of sequences and production of DNA for transformation are first performed in a bacterial host such as E. coli, and typically, the vector will include sequences that facilitate such manipulations, including bacterial origins of replication and appropriate bacterial selection markers. The selection marker encodes a protein necessary for the survival or growth of the transformed host cells grown in a selective medium. Host cells that are not transformed with a vector containing a selection gene will not survive in the culture medium. Typical selection genes encode proteins that (a) provide resistance to antibiotics or other toxins, (b) complement nutritional deficiencies, or (c) provide key nutrients that are not available from complex culture media. Exemplary vectors and methods for transforming yeast are described, e.g., in Burke, D., Dawson, D., & Stearns, T. (2000). Methods in yeast genetics: a Cold Spring Harbor Laboratory course manual. Plainview, NY: Cold Spring Harbor Laboratory Press.

[0159] Expression vectors for yeast or mammalian cells will generally further include yeast or mammalian specific sequences, including selective auxotrophy or drug markers for identifying transformed yeast strains or transformed mammalian cells. Drug markers can further be used to amplify the copy number of the vector in the host cell.

[0160] The target polypeptide coding sequence is effectively connected to transcription and translation regulatory sequences, which provide expression of the polypeptide in a host cell, for example, Pichia pastoris or a Chinese hamster ovary syndrome (CHO) cell. These vector components may include, but are not limited to, one or more of the following: an enhancer element, a promoter, and a transcription termination sequence. Sequences for secretion of the polypeptide may also be included, such as a signal sequence, etc. The yeast or mammalian origin of replication is optional because expression vectors are usually integrated into the host cell genome. In one embodiment of the invention, the target polypeptide is effectively connected or fused to a sequence that provides optimal secretion of the polypeptide from a yeast diploid cell.

[0161] Nucleic acid is "operably linked" when it is in a functional relationship with another nucleic acid sequence. For example, if the DNA of a signal sequence is expressed as a preprotein that participates in the secretion of a polypeptide, the DNA of the signal sequence is operably linked to the DNA of the polypeptide; if a promoter or enhancer affects the transcription of the sequence, it is operably linked to a coding sequence. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. By ligation at convenient restriction sites or alternatively by PCR / recombination methods familiar to those skilled in the art (Gateway R Technology; Invitrogen, Carlsbad, CA) to accomplish ligation. If such sites do not exist, synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.

[0162] A promoter is a non-translated sequence (usually within about 100 bp to 1000 bp) located upstream (5') of the start codon of a structural gene that controls the transcription and translation of a specific nucleic acid sequence to which it is operatively linked. These promoters are divided into several categories: inducible, constitutive, and repressible promoters (increases transcription levels in response to the absence of a repressor). Inducible promoters can initiate increased transcription levels from DNA under their control in response to certain changes in culture conditions (e.g., the presence or absence of nutrients or changes in temperature).

[0163] The promoter fragment can also be used as a site for homologous recombination and integration of the expression vector into the same site of the host genome; alternatively, a selectable marker is used as a site for homologous recombination. Examples of suitable promoters from Pichia pastoris include AOX1 and promoters (Cregg et al. (1989) Mol.Cell.Biol .[Molecular and Cell Biology] 9:1316-1323); ICL1 promoter (Menendez et al. (2003) Yeast Yeast 20(13):1097-108); glyceraldehyde-3-phosphate dehydrogenase promoter (GAP) (Waterham et al. (1997) Gene [Gene] 186(1):37-44); and FLD1 promoter (Shen et al. (1998) Gene [Gene] 216(1):93-102). The GAP promoter is a strong constitutive promoter, while the AOX and FLD1 promoters are inducible.

[0164] Other yeast promoters include ADH1, alcohol dehydrogenase II, GAL4, PHO3, PHO5, Pyk, and chimeric promoters derived therefrom. In addition, non-yeast promoters can be used in the present invention, such as mammalian, insect, plant, reptile, amphibian, viral and avian promoters. Most typically, the promoter will comprise a mammalian promoter (which may be endogenous to the gene being expressed) or will comprise a yeast or viral promoter that provides efficient transcription in a yeast system.

[0165] Examples of mammalian promoters include cytomegalovirus (CMV) derived promoters, chicken 3-actin (CBM) derived promoters, adenomatous polyposis coli (APC) derived promoters, leucine-rich repeat G protein coupled receptor 5 (LGR5) promoters, CAG promoters, β-actin promoters, elongation factor 1 (EF1) promoters, early growth response 1 (EGR-1) promoters, eukaryotic initiation factor 4A (EIF4A1) promoters, simian virus 40 (SV40) early promoters, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoters, MoMuLV promoters, avian leukosis virus promoters, Epstein-Barr virus immediate early promoters, Rous sarcoma virus promoters, and human gene promoters (such as but not limited to actin promoters, myosin promoters, hemoglobin promoters, and creatine kinase promoters), etc. A combination of two or more of the aforementioned promoters can also be used. In addition, inducible promoters can be used. The use of an inducible promoter provides a molecular switch capable of turning on the expression of a polynucleotide sequence to which it is operably linked when such expression is desired, or turning off expression when expression is not desired. Examples of inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.

[0166] The target polypeptide can not only be directly recombinantly produced, but also can be recombinantly produced as a fusion polypeptide with a heterologous polypeptide (e.g., a signal sequence or other polypeptides with a specific cleavage site at the N-terminus of a mature protein or polypeptide). Generally, the signal sequence can be a component of a vector, or can be a part of a polypeptide coding sequence inserted into a vector. Preferably, the selected heterologous signal sequence is a sequence that is recognized and processed by one of the standard approaches available in the host cell. The alpha factor prepro signal of Saccharomyces cerevisiae has been shown to effectively secrete various recombinant proteins from Pichia pastoris. Other yeast signal sequences include alpha mating factor signal sequences, invertase signal sequences, and signal sequences derived from other secreted yeast polypeptides. In addition, these signal peptide sequences can be engineered to provide enhanced secretion in a diploid yeast expression system. Secretion signals for mammals and yeast cells include mammalian signal sequences, which can be heterologous to the secreted protein, or can be the natural sequence of the secreted protein. The signal sequence includes a pre-peptide sequence, and can include a propeptide sequence in some cases. Many such signal sequences are known in the art, including those found on immunoglobulin chains, such as the K28 protoxin sequence, PHA-E, FACE, human MCP-1, human serum albumin signal sequence, human Ig heavy chain, human Ig light chain, etc. See, for example, Hashimoto et al. Protein Eng 11(2)75 (1998); and Kobayashi et al. Therapeutic Apheresis 2(4)257 (1998).

[0167] Transcription can be increased by inserting a transcriptional activation sequence into the vector. These activators are cis-acting elements of DNA, usually about 10 bp to 300 bp, which act on the promoter to increase its transcription. Transcription enhancers are relatively oriented and position-independent within introns and within the coding sequence itself relative to the 5' and 3' of the transcription unit. Enhancers can be spliced ​​into the expression vector at the 5' or 3' position of the coding sequence, but are preferably located at the 5' site of the promoter.

[0168] The expression vector used in the eukaryotic host cell can also include the sequence required for termination transcription and stabilization of mRNA. In the untranslated region of eukaryotic or viral DNA or cDNA, such sequence is usually available from 3' to the translation termination codon. These regions are included in the nucleotide fragments that are transcribed as polyadenylation fragments in the untranslated portion of the mRNA.

[0169] The construction of suitable vectors containing one or more of the above-mentioned components adopts standard connection technology or PCR / recombination method.The isolated plasmid or DNA fragment is cut, trimmed and reconnected in the desired form or by recombinant method to produce the required plasmid.In order to analyze the correct sequence in the plasmid of confirmation structure, the connection mixture is used to transform the host cell, and the transformant that succeeds by antibiotic (for example ampicillin or bleomycin) resistance selection is selected in appropriate circumstances.Prepare the plasmid from the transformant, analyze and / or order-check by restriction endonuclease digestion.

[0170] As an alternative to fragment restriction and ligation, a recombination method based on att sites and recombinases can be used to insert DNA sequences into vectors. Such methods are described, for example, by Landy (1989) Ann. Rev. Biochem [Annual Review of Biochemistry]. 58: 913-949; and are known to those skilled in the art. Such methods utilize intermolecular DNA recombination mediated by a mixture of recombination proteins encoded by λ and E. coli. Recombination occurs between specific attachment (att) sites on the interacting DNA molecules. For a description of att sites, see Weisberg and Landy (1983) Site-Specific Recombination in Phage Lambda, in Lambda II [Specific site recombination of bacteriophage λ in λII], Weisberg, ed. (Cold Spring Harbor, New York: Cold Spring Harbor Press), pp. 211-250. The DNA fragments on both sides of the recombination site are switched so that the recombined att site is a hybrid sequence consisting of sequences contributed by each parent vector. Recombination can occur between DNAs of any topological structure.

[0171] The att site can be introduced into the target sequence by: ligating the target sequence into a suitable vector; generating a PCR product containing the att B site by using specific primers; generating a cDNA library, which is cloned into a suitable vector containing the att site; and the like.

[0172] As used herein, folding refers to the three-dimensional structure of polypeptides and proteins, in which the interactions between the amino acid residues serve to stabilize the structure. Proper folding is generally the polypeptide arrangement that leads to optimal biological activity, and in the case of antibodies, can be conveniently monitored by assays of activity (e.g., antigen binding).

[0173] The expression host can be further modified by introducing sequences encoding one or more enzymes that enhance folding and disulfide bond formation, i.e., foldases, chaperones, etc. Such sequences can be constitutively or inducibly expressed in yeast host cells using vectors, markers, etc. as known in the art. Preferably, sequences including transcriptional regulatory elements sufficient to achieve the desired expression pattern are stably integrated into the yeast genome by targeted methods.

[0174] For example, eukaryotic PDI is not only an effective catalyst for protein cysteine ​​oxidation and disulfide bond isomerization, but also exhibits chaperone activity. Co-expression of PDI can promote the production of active proteins with multiple disulfide bonds. The expression of BIP (immunoglobulin heavy chain binding protein), cyclophilin, etc. is also interesting. In one embodiment of the invention, each haploid parent strain expresses different folding enzymes, for example, one strain can express BIP, and another strain can express PDI or a combination thereof.

[0175] The terms "desired protein" or "desired antibody" are used interchangeably and generally refer to a parent antibody specific for a target, i.e., a CGRP or chimeric or humanized antibody as described herein, or a binding portion thereof derived therefrom. The term "antibody" is intended to include any polypeptide chain-containing molecular structure having a specific shape suitable for and recognizing an epitope, wherein one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope. The prototype antibody molecule is an immunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc. from all sources, such as humans, rodents, rabbits, cattle, sheep, pigs, dogs, other mammals, chickens, other birds, etc., are considered "antibodies". The preferred source for producing antibodies used as the starting treatment of the present invention is rabbit. Many antibody coding sequences have been described; and others can be proposed by methods known in the art. Examples include chimeric antibodies, human antibodies and other non-human mammalian antibodies, humanized antibodies, single-chain antibodies (e.g., scFv), camelid antibodies, nanobodies, IgNAR (single-chain antibodies derived from sharks), small modular immunopharmaceuticals (SMIPs), and antibody fragments (e.g., Fab, Fab', F(ab') 2See Streltsov VA, et al., Structure of a shark IgNAR antibody variable domain and modeling of an early-developmental isotype, Protein Sci. 2005 Nov;14(11):2901-9. Epub 2005 Sep 30; Greenberg AS, et al., A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks, Nature. 1995 Mar 9;374(6518):168-73; Nuttall SD, et al., Isolation of the new antigen receptor from wobbegong sharks, and use as a scaffold for the display of protein loop. Novel antigen receptors isolated from the wopagon shark and used as scaffolds for displaying protein loop libraries, Mol Immunol. 2001 Aug;38(4):313-26; Hamers-Casterman C, et al., Naturally occurring antibodies devoid of light chains, Nature. 1993 Jun 3;363(64-28):446-8; Gill DS, et al., Biopharmaceutical drug discovery using novel protein scaffolds, Curr Opin Biotechnol. 2006 Dec;17(6):653-8. Epub 2006 Oct 19.

[0176] For example, antibodies or antigen-binding fragments can be produced by genetic engineering. In this technology, as with other methods, cells producing antibodies are sensitive to the desired antigen or immunogen. Messenger RNA isolated from cells producing antibodies is used as a template to prepare cDNA by PCR amplification. A library of vectors is produced by inserting appropriate portions of the amplified immunoglobulin cDNA into expression vectors, each vector containing a heavy chain gene and a light chain gene that retains the initial antigen specificity. A combinatorial library is constructed by combining a heavy chain gene library with a light chain gene library. This produces a clone library (similar to the Fab fragment or antigen-binding fragment of an antibody molecule) that co-expresses heavy and light chains. The vectors carrying these genes are co-transfected into host cells. When antibody gene synthesis is induced in the transfected host, the heavy and light chain proteins self-assemble to produce active antibodies, which can be detected by screening with antigens or immunogens.

[0177] The antibody coding sequence of interest includes those encoded by the native sequence, and those encoded by nucleic acids and variants thereof different from the disclosed nucleic acid sequences due to the degeneracy of the genetic code. Variant polypeptides may include amino acid (aa) substitutions, additions or deletions. Amino acid substitutions may be conservative amino acid substitutions or substitutions that eliminate non-essential amino acids, such as changing glycosylation sites, or minimizing misfolding by replacing or deleting one or more cysteine ​​residues that are not functionally necessary. Variants may be designed to retain or enhance the biological activity of specific regions (e.g., functional domains, catalytic amino acid residues, etc.) of proteins. Variants also include fragments of polypeptides disclosed herein, particularly biologically active fragments and / or fragments corresponding to functional domains. In vitro mutagenesis techniques for cloning genes are known. The present invention also includes polypeptides modified using common molecular biology techniques to improve their resistance to proteolytic degradation or optimize solubility or make them more suitable as therapeutic agents.

[0178] Chimeric antibodies can be prepared by recombinant means by combining the variable light and heavy chain regions (V L and V H ) are combined, these variable light and heavy chain regions are obtained from cells producing antibodies of one species, and the constant light and heavy chain regions are from another species. Typically, chimeric antibodies utilize rodent or rabbit variable regions and human constant regions to produce antibodies with primarily human domains. The generation of such chimeric antibodies is well known in the art and can be achieved by standard means (e.g., as described in U.S. Patent No. 5,624,659, which is incorporated herein by reference in its entirety). It is further contemplated that the human constant region of the chimeric antibody of the present invention can be selected from IgG1, IgG2, IgG3, and IgG4 constant regions.

[0179] Humanized antibodies are engineered to contain even more human-like immunoglobulin domains, and only the complementary determining regions of animal-derived antibodies are introduced. This is achieved by carefully examining the sequences of the hypervariable loops of the monoclonal antibody variable regions and adapting them to the structure of human antibody chains. Although it seems complicated, the process is clear in practice. See, for example, U.S. Patent No. 6,187,287, which is fully incorporated herein by reference.

[0180] In addition to intact immunoglobulins (or their recombinant counterparts), immunoglobulin fragments (e.g., Fab', F(ab') 2 or other fragments). "Fragments" or minimal immunoglobulins can be designed using recombinant immunoglobulin technology. For example, "Fv" immunoglobulins for use in the present invention can be produced by synthesizing fused variable light chain regions and variable heavy chain regions. Combinations of antibodies are also interesting, such as diabodies, which include two different Fv specificities. In another embodiment of the present invention, immunoglobulin fragments include SMIPs (small molecule immunopharmaceuticals), camelid antibodies, nanobodies, and IgNARs.

[0181] Immunoglobulins and fragments thereof can be modified post-translationally, for example, to add effector moieties, such as chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, chemiluminescent moieties, etc., or specific binding moieties, such as streptavidin, avidin or biotin, etc., which can be used in the methods and compositions of the invention. Examples of other effector molecules are provided below.

[0182] A polynucleotide sequence "corresponds to" a polypeptide sequence if translation of the polynucleotide sequence according to the genetic code produces a polypeptide sequence (i.e., the polynucleotide sequence "encodes" a polypeptide sequence), and one polynucleotide sequence "corresponds to" another polynucleotide sequence if the two polynucleotide sequences encode the same polypeptide sequence.

[0183] The "heterologous" region or domain of a DNA construct is an identifiable fragment of DNA in a large DNA molecule that is not found associated with the macromolecule in nature. Therefore, when a heterologous region encodes a mammalian gene, the gene is usually flanked by DNA that is not flanked by the mammalian genomic DNA in the genome of the source organism. Another example of a heterologous region is a construct that is not found in nature for the coding sequence itself (e.g., a cDNA in which the genomic coding sequence includes introns, or a synthetic sequence with codons different from the natural gene). Allelic variation or a naturally occurring mutation event will not produce a heterologous region of DNA as defined herein.

[0184] "Coding sequence" is the in-frame sequence of codons, which (with respect to genetic code) corresponds to or encodes a protein or peptide sequence. If the sequence or its complementary sequence encodes the same amino acid sequence, then the two coding sequences correspond to each other. The coding sequence associated with the appropriate regulatory sequence can be transcribed and translated into a polypeptide. Polyadenylation signals and transcription termination sequences are usually located at the 3' of the coding sequence. "Promoter sequence" is a DNA regulatory region that can bind to the RNA polymerase in the cell and initiate transcription of the downstream (3' direction) coding sequence. The promoter sequence usually includes additional sites for binding to regulatory molecules (e.g., transcription factors) that affect the transcription of the coding sequence. When RNA polymerase binds to the promoter sequence in the cell and the coding sequence is transcribed into mRNA (which is then translated into the protein encoded by the coding sequence), the coding sequence is "under the control" of the promoter sequence or "effectively connected" to the promoter.

[0185] Vector is used to introduce foreign substances (such as DNA, RNA or protein) into organisms or host cells. Typical vectors include recombinant viruses (for polynucleotides) and liposomes (for polypeptides). "DNA vector" is a replicon, such as a plasmid, a phage or a cosmid, to which another polynucleotide fragment can be attached so that the attached fragment is replicated. "Expression vector" is a DNA vector that includes a regulatory sequence that will instruct a suitable host cell to synthesize a polypeptide. This generally means a promoter that binds RNA polymerase and starts mRNA transcription, as well as a ribosome binding site and a start signal to instruct mRNA to be converted into one or more polypeptides. In the correct site and correct reading frame, the polynucleotide sequence is incorporated into the expression vector, and then the vector transforms a suitable host cell so that the polypeptide encoded by the polynucleotide sequence can be produced.

[0186] "Amplification" of a polynucleotide sequence is the in vitro production of multiple copies of a particular nucleic acid sequence. The amplified sequence is usually in the form of DNA. A variety of techniques for performing such amplification are described in a review article by Van Brunt (1990, Bio / Technol., 8(4):291-294). The polymerase chain reaction or PCR is the prototype of nucleic acid amplification, and the use of PCR herein should be considered as an example of other suitable amplification techniques.

[0187] The general structure of antibodies in vertebrates is now well understood (Edelman, GM, Ann. NY Acad. Sci. [Annual Bulletin of the New York Academic Science], 190:5 (1971)). Antibodies are composed of two identical light chain polypeptides ("light chains") of approximately 23,000 daltons and two identical heavy chains ("heavy chains") of 53,000-70,000 daltons. These four chains are connected by disulfide bonds in a "Y" configuration, with the light chain extending next to the heavy chain starting at the mouth of the "Y" configuration. The "branch" portion of the "Y" configuration is called the F ab The stem of the "Y" configuration is called F C The direction of the amino acid sequence is from the N-terminus at the top of the "Y" configuration to the C-terminus at the bottom of each chain. The N-terminus has the variable region that is specific for the antigen that caused it, and is about 100 amino acids in length, with slight variations between light and heavy chains and from antibody to antibody.

[0188] The variable region is linked in each chain to a constant region that extends the remaining length of the chain, and the constant region in a particular class of antibodies does not vary with the specificity of the antibody (i.e., the antigen that triggered it). There are five known major classes of constant regions that determine the class of immunoglobulin molecules (IgG, IgM, IgA, IgD, and IgE correspond to gamma, mu, alpha, delta, and epsilon (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions). The constant region or class determines the subsequent effector functions of the antibody, including activation of complement (Kabat, EA, Structural Concepts in Immunology and Immunochemistry, 2nd ed., pp. 413-436, Holt, Rinehart, Winston (1976)) and other cellular responses (Andrews, DW, et al., Clinical Immunobiology, pp. 1-18, WB Sanders (1980); Kohl, S., et al., Immunology, 48:187 (1983)), while the variable region determines the antigen with which it will react. Light chains are classified as either kappa or lambda. Each heavy chain can be prepared with either a kappa or lambda light chain. When the immunoglobulin is produced by a hybridoma or by a B cell, the light and heavy chains are covalently bonded to each other, and the "tail" portions of the two heavy chains are bonded to each other by covalent disulfide bonds.

[0189] The expression "variable region" or "VR" refers to the domain within each pair of light and heavy chains in an antibody that is directly involved in binding the antibody to an antigen. Each heavy chain has a variable domain (VH ), followed by multiple constant domains. Each light chain has a variable domain (V L ) and a constant domain at the other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the heavy chain variable domain.

[0190] The expression "complementarity determining region", "hypervariable region" or "CDR" refers to one or more hypervariable or complementary determining regions (CDRs) found in the variable region of the light chain or heavy chain of an antibody (see Kabat, EA et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Maryland., (1987)). These expressions include hypervariable regions as defined by Kabat et al. ("Sequences of Proteins of Immunological Interest," Kabat E., et al., U.S. Department of Health and Human Services, 1983) or hypervariable loops of the three-dimensional structure of antibodies (Chothia and Lesk, J Mol. Biol. 196 901-917 (1987)). The CDRs in each chain are closely connected by the framework regions and, together with the CDRs in the other chain, contribute to the formation of the antigen binding site. In the CDR, there are selected amino acids described as selectivity determining regions (SDRs), which represent the key contact residues used by the CDR in antibody-antigen interactions (Kashmiri, S., Methods, 36: 25-34 (2005)). In the present invention, when a specific antibody amino acid or nucleic acid residue is represented by a number, it usually refers to its position in a specific amino acid or nucleic acid sequence (i.e., a specific sequence identifier) ​​and / or numbered according to Kabat et al.

[0191] The expression "framework region" or "FR" refers to one or more framework regions within the variable regions of the light and heavy chains of antibodies (see Kabat, EA et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD, (1987)). These expressions include those amino acid sequence regions between the CDRs within the variable regions of the light and heavy chains of antibodies.

[0192] "Cmax" refers to the maximum (or peak) concentration of an antibody or other compound achieved in a test area (e.g., serum or another compartment, such as cerebrospinal fluid) after drug administration. For example, serum Cmax can be measured from serum (prepared by collecting a blood sample, causing it to clot by centrifugation or other means and separating the solid components to produce serum (blood without blood cells and coagulation factors)), and then the concentration of the analyte in the serum is detected by ELISA or other means known in the art.

[0193] Unless otherwise indicated, "AUC" refers to the area under the concentration-time curve, which is expressed in units of mg / mL*hr (or equivalently mg*hr / ml). 0-t "AUC" refers to the area under the concentration-time curve from time = 0 to the last quantifiable concentration. 0-inf ” refers to the area under the concentration-time curve extrapolated from time = 0 to infinity.

[0194] “I max "" refers to the maximal pharmacodynamic response elicited by a dose of anti-CGRP antibody (preferably 350 mg or more, more usually at least 750 mg or 1000 mg) as compared to responses elicited by lower doses of anti-CGRP antibody, such as can be measured by inhibition of vasodilation following topical application of capsaicin.

[0195] Anti-CGRP antibodies and binding fragments thereof having binding specificity for CGRP

[0196] The present invention specifically includes specific anti-CGRP antibodies and antibody fragments (including Figure 1A-12 The use of CDR, VL, VH, CL, CH polypeptide sequences identified in or consisting of the same. The polypeptides contained in the particularly preferred anti-CGRP antibody Ab6 are further described below.

[0197] Antibody Ab6

[0198] In a preferred exemplary embodiment, the invention includes a humanized antibody having binding specificity to CGRP and having a variable light chain sequence comprising the sequence listed below:

[0199] QVLTQSPSSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIYDAST LASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDCFVFGGGTKVEIKR (SEQ ID NO: 222).

[0200] The present invention also includes humanized antibodies that have binding specificity to CGRP and have a light chain sequence comprising the sequence listed below:

[0201] QVLTQSPSSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIYDASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDCFVFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:221).

[0202] The invention further includes humanized antibodies that have binding specificity to CGRP and have a variable heavy chain sequence comprising the sequence listed below:

[0203] EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGINGATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVTVSS (SEQ ID NO: 202).

[0204] The present invention also includes humanized antibodies that have binding specificity to CGRP and have a heavy chain sequence comprising the sequence listed below:

[0205] EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGINGATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ IDNO:201).

[0206] Alternatively, the heavy chain of Ab6 may lack the C-terminal lysine of SEQ ID NO: 201, i.e., a heavy chain sequence comprising the sequence listed below:

[0207] EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGVIGINGATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ IDNO:566).

[0208] The present invention also contemplates antibodies comprising the following: SEQ ID NO: 224; SEQ ID NO: 226; and one or more of the polypeptide sequences of SEQ ID NO: 228 (which correspond to the variable light chain sequence of SEQ ID NO: 222 or the complementary determining region (CDR or hypervariable region) of the light chain sequence of SEQ ID NO: 221), and / or SEQ ID NO: 204; SEQ ID NO: 206; and one or more of the polypeptide sequences of SEQ ID NO: 208 (which correspond to the variable heavy chain sequence of SEQ ID NO: 202 or the complementary determining region (CDR or hypervariable region) of the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566), or a combination of these peptide sequences. In another embodiment of the present invention, the antibody or fragment thereof of the present invention comprises or alternatively consists of a combination of one or more CDRs, variable heavy and variable light chain sequences, and heavy and light chain sequences (including all of these) listed above.

[0209] The present invention also contemplates antibody fragments having binding specificity to CGRP. In one embodiment of the present invention, the antibody fragment of the present invention comprises or alternatively consists of a polypeptide sequence of SEQ ID NO: 222 or SEQ ID NO: 221. In another embodiment of the present invention, the antibody fragment of the present invention comprises or alternatively consists of a polypeptide sequence of SEQ ID NO: 202 or SEQ ID NO: 201 or SEQ ID NO: 566.

[0210] In another embodiment of the present invention, the antibody fragment having binding specificity to CGRP comprises or alternatively consists of: one or more of the polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, which correspond to the complementarity determining region (CDR or hypervariable region) of the variable light chain sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221.

[0211] In another embodiment of the present invention, the antibody fragment having binding specificity to CGRP comprises or alternatively consists of: one or more of the polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, which correspond to the complementarity determining region (CDR or hypervariable region) of the variable heavy chain sequence of SEQ ID NO: 202 or the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566.

[0212] The present invention also contemplates antibody fragments, which include one or more antibody fragments described herein. In one embodiment of the present invention, the fragment of the antibody with binding specificity to CGRP includes one, two, three or more (including all) of the following antibody fragments, or alternatively consists of: SEQ ID NO: 222 variable light chain region; SEQ ID NO: 202 variable heavy chain region; SEQ ID NO: 222 variable light chain region complementary determining region (SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228); and SEQ ID NO: 202 variable heavy chain region complementary determining region (SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208).

[0213] In a particularly preferred embodiment of the present invention, the humanized anti-CGRP antibody is Ab6, which comprises, or alternatively consists of, SEQ ID NO: 221 and SEQ ID NO: 201 or SEQ ID NO: 566 and has at least one biological activity described herein.

[0214] In another particularly preferred embodiment of the present invention, the antibody fragment comprises or alternatively consists of a Fab (fragment antigen binding) fragment having binding specificity to CGRP. With regard to antibody Ab6, the Fab fragment includes a variable light chain sequence of SEQ ID NO: 222 and a variable heavy chain sequence of SEQ ID NO: 202. This embodiment of the present invention further contemplates additions, deletions and variants of SEQ ID NO: 222 and / or SEQ ID NO: 202 in the Fab while maintaining binding specificity to CGRP.

[0215] In another particularly preferred embodiment of the present invention, the anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell, wherein the recombinant cell expresses a nucleic acid sequence encoding a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202, wherein the polypeptides are optionally linked to human light and heavy constant region polypeptides, such as human IgG1, IgG2, IgG3 or IgG4 constant regions, respectively, and the constant regions may optionally be modified to alter glycosylation or proteolysis, wherein the recombinant cell optionally comprises a yeast or mammalian cell, such as Pichia pastoris or a CHO cell.

[0216] In another particularly preferred embodiment of the present invention, the anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell, wherein the recombinant cell expresses a light chain encoding SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, wherein the recombinant cell optionally comprises a yeast or mammalian cell, such as Pichia pastoris or a CHO cell, wherein the constant region thereof may optionally be modified to alter glycosylation or proteolysis or other effector functions.

[0217] In another particularly preferred embodiment of the present invention, any of the above-mentioned anti-CGRP antibodies or antibody fragments may be optionally included in a formulation disclosed herein, for example, the formulation comprises histidine (L-histidine), sorbitol, polysorbate 80, for example, about 100 mg anti-CGRP antibody, about 3.1 mg L-histidine, about 40.5 mg sorbitol and about 0.15 mg polysorbate 80 per 1 mL volume, with a pH of about 5.8.

[0218] In one embodiment of the invention described herein (below), Fab fragments can be produced by enzymatic digestion (e.g., papain) of Ab6. In another embodiment of the invention, anti-CGRP antibodies such as Ab6 or Fab fragments thereof can be produced by expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungi, insects or microbial systems such as yeast cells (e.g., diploid yeast, e.g., diploid Pichia pastoris) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0219] In another embodiment, the antibody fragment may exist in one or more of the following non-limiting forms: Fab, Fab', F(ab') 2 , Fv and single-chain Fv antibody formats. In a preferred embodiment, the anti-CGRP antibody described herein further comprises a kappa constant light chain sequence comprising the sequence listed below:

[0220] TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 563).

[0221] In another preferred embodiment, the anti-CGRP antibody described herein further comprises a gamma-1 constant heavy chain polypeptide sequence comprising the sequence set forth below or the same sequence lacking the carboxyl-terminal lysine residue (SEQ ID NO: 564 and SEQ ID NO: 565, respectively):

[0222] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS

[0223] GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC

[0224] DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN

[0225] WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL

[0226] PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

[0227] GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 564).

[0228] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS

[0229] GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC

[0230] DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN

[0231] WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL

[0232] PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN

[0233] GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG (SEQ ID NO: 565).

[0234] For the sake of clarity, any antibody disclosed herein is intended to include any variant of the disclosed constant region variant sequence, for example, Ab6 may include a constant region of SEQ ID NO: 564 containing a C-terminal lysine, or may include a constant region of SEQ ID NO: 565 lacking a C-terminal lysine. Thus, each disclosure herein of a heavy chain of SEQ ID NO: 201 also includes a variant lacking its C-terminal lysine residue, i.e., having a heavy chain variable region sequence of Ab6 (SEQ ID NO: 202) and a constant region sequence of SEQ ID NO: 565. For example, when expressed in a cell line such as a CHO cell, a sequence encoding an antibody comprising a C-terminal lysine in the heavy chain may produce an antibody lacking the C-terminal lysine due to proteolysis, or a mixture of heavy chains comprising or lacking the C-terminal lysine.

[0235] In another embodiment, the present invention contemplates a V comprising a compound selected from the group consisting of H Use of an isolated anti-CGRP antibody comprising a polypeptide sequence: SEQ ID NO: 2, SEQ ID NO: 42, SEQ ID NO: 82, SEQ ID NO: 122, SEQ ID NO: 162, SEQ ID NO: 202, SEQ ID NO: 242, SEQ ID NO: 282, SEQ ID NO: 322, SEQ ID NO: 362, SEQ ID NO: 402, SEQ ID NO: 442, SEQ ID NO: 482, or SEQ ID NO: 522, or a variant thereof; and further comprising a V selected from the group consisting of L Polypeptide sequence: SEQ ID NO:22, SEQ ID NO:62, SEQ ID NO:102, SEQ ID NO:142, SEQ ID NO:182, SEQ ID NO:222, SEQ ID NO:262, SEQ ID NO:302, SEQ ID NO:342, SEQ ID NO:382, SEQ ID NO:422, SEQ ID NO:462, SEQ ID NO:502, or SEQ ID NO:542, or a variant thereof, wherein the V H or V L One or more framework residues (FR residues) in the polypeptide have been replaced by another amino acid residue, resulting in an anti-CGRP antibody that specifically binds to CGRP. The present invention contemplates humanized and chimeric forms of these antibodies. Chimeric antibodies may include an Fc derived from an IgG1, IgG2, IgG3 or IgG4 constant region.

[0236] In one embodiment of the invention, prior to initiating the humanization process cited herein, the antibody or V H or V L The polypeptide is derived from or selected from one or more rabbit B cell populations.

[0237] In another embodiment of the present invention, the anti-CGRP antibodies and fragments thereof do not have binding specificity to CGRP-R. In another embodiment of the present invention, the anti-CGRP antibodies and fragments thereof inhibit the association of CGRP with CGRP-R. In another embodiment of the present invention, the anti-CGRP antibodies and fragments thereof inhibit the association of CGRP with CGRP-R and / or other proteins and / or multimers thereof, and / or antagonize their biological effects.

[0238] As described herein, antibodies and fragments thereof can be post-translationally modified to add effector moieties, e.g., chemical linkers, detectable moieties, e.g., fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties, such as, for example, streptavidin, avidin, biotin, cytotoxins, cytotoxic agents, and radioactive materials.

[0239] Antibodies or fragments thereof may also be chemically modified to provide additional advantages, such as increased polypeptide solubility, stability and circulation time (in vivo half-life) or reduced immunogenicity (see U.S. Pat. No. 4,179,337). The chemical moieties used for derivatization may be selected from water-soluble polymers, such as polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, etc. Antibodies and fragments thereof may be modified at random positions within the molecule or at predetermined positions within the molecule and may include one, two, three or more linked chemical moieties.

[0240] The polymer may be of any molecular weight and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is about 1 kDa to about 100 kDa (the term "about" indicates that in the preparation of polyethylene glycol, some molecules will weigh more than the molecular weight and some less) for ease of handling and manufacturing. Other sizes may be used, depending on the desired therapeutic properties (e.g., the duration of sustained release desired, the effect on biological activity (if any), ease of handling, the degree or lack of antigenicity, and other known effects of polyethylene glycol on therapeutic proteins or analogs). For example, the average molecular weight of the polyethylene glycol can be about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa. Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol. 56:59-72 (1996); Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999); and Caliceti et al., Bioconjug. Chem. 10:638-646 (1999), the disclosures of each of which are incorporated herein by reference.

[0241] There are many attachment methods available to those skilled in the art, see, for example, EP 0 401 384, which is incorporated herein by reference (coupling PEG to G-CSF), and also see Malik et al., Exp. Hematol. [Experimental Hematology] 20: 1028-1035 (1992) (reporting the PEGylation of GM-CSF using trityl chloride). For example, polyethylene glycol can be covalently bound through an amino acid residue via a reactive group such as a free amino group or a carboxyl group. Reactive groups are those to which activated polyethylene glycol molecules can be bound. Amino acid residues with free amino groups can include lysine residues and N-terminal amino acid residues; those with free carboxyl groups can include aspartic acid residues, glutamic acid residues, and C-terminal amino acid residues. Sulfhydryl groups can also be used as reactive groups for attaching polyethylene glycol molecules. For therapeutic purposes, attachment on amino groups, such as attachment on the N-terminus or lysine groups, is preferred.

[0242] As described above, polyethylene glycol can be linked to a protein by attachment to any one of a number of amino acid residues. For example, polyethylene glycol can be linked to a polypeptide by covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine ​​residues. Polyethylene glycol can be attached to a specific amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) or more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine, and combinations thereof) using one or more reaction chemistries.

[0243] Alternatively, the antibody or fragment thereof may have an increased in vivo half-life by being fused to albumin (including but not limited to recombinant human serum albumin or a fragment or variant thereof (see, e.g., U.S. Pat. No. 5,876,969, issued March 2, 1999, European Patent No. 0 413622, and U.S. Pat. No. 5,766,883, issued June 16, 1998, which are incorporated herein by reference in their entirety)) or other circulating blood proteins such as transferrin or ferritin. In a preferred embodiment, the polypeptide and / or antibody (including fragments or variants thereof) of the present invention is fused to a mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin, such as amino acids 1-586 of European Patent No. 0 322 094). Figures 1A-1F and Figures 2A-2D The present invention also includes polynucleotides encoding the fusion proteins of the present invention.

[0244] With respect to detectable moieties, other exemplary enzymes include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase, and luciferase. Other exemplary fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazineamine, phycoerythrin, and dansyl chloride. Other exemplary chemiluminescent moieties include, but are not limited to, luminol. Other exemplary bioluminescent materials include, but are not limited to, luciferin and aequorin. Other exemplary radioactive materials include, but are not limited to, iodine-125 ( 125 I), carbon 14( 14 C) Sulfur 35( 35 S), tritium ( 3 H) and phosphorus 32 ( 32 P).

[0245] With respect to the functional moiety, exemplary cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agents, such as nitrogen mustard, thiotepa, chlorambucil, melphalan, carmastine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclophosphamide, nitrogen mustard, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum ( II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines including daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detoxicin, carminomycin, idarubicin, epirubicin, mitoxantrone, and bisantrene; antibiotics including dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimitotics such as vinca alkaloids, vincristine, and vinblastine. Other cytotoxic agents include paclitaxel (Taxol), ricin, Pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, teniposide, colchicine, dihydroxy anthracin dione, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), interferon, and mixtures of these cytotoxic agents.

[0246] Other cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine, and bleomycin. Toxic enzymes from plants and bacteria (e.g., ricin, diphtheria, and Pseudomonas toxins) can be conjugated to humanized or chimeric antibodies or binding fragments thereof to produce cell type-specific killers (Youle, et al., Proc. Nat'l Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States] 77: 5483 (1980); Gilliland, et al., Proc. Nat'l Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States] 77: 4539 (1980); Krolick, et al., Proc. Nat'l Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States] 77: 5419 (1980)).

[0247] Other cytotoxic agents include cytotoxic ribonucleases described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the present invention also relate to radioimmunoconjugates in which a radionuclide emitting alpha or beta particles is stably coupled to an antibody or binding fragment thereof with or without a complex forming agent. Such radionuclides include beta-emitters, such as phosphorus-32 ( 32 P), Scandium-47 ( 47 Sc), copper-67( 67 Cu), Gallium-67( 67 Ga), Y-88( 88 Y), Yttrium-90 ( 90 Y), iodine-125 ( 125 I), iodine-131( 131 I), Samarium-153 ( 153 Sm), Lutetium-177( 177 Lu), rhenium-186 ( 186 Re) or rhenium-188 ( 188 Re), and α-emitters such as astatine-211 ( 211 At), lead-212( 212 Pb), Bismuth-212( 212 Bi) or -213( 213 Bi) or actinium-225( 225 Ac).

[0248] Methods for conjugating antibodies or binding fragments thereof to detectable moieties and the like are known in the art, such as those described by Hunter et al., Nature 144:945 (1962); David et al., Biochemistry 13:1014 (1974); Pain et al., J. Immunol. Meth. 40:219 (1981); and Nygren, J., Histochem. and Cytochem. 30:407 (1982).

[0249] Embodiments described herein further include variants and equivalents substantially homologous to antibodies, antibody fragments, diabodies, SMIPs, camel antibodies, nanobodies, IgNARs, polypeptides, variable regions, and CDRs described herein. These may include, for example, conservative substitution mutations (i.e., one or more amino acids are replaced by similar amino acids). For example, conservative substitutions refer to amino acids being replaced by another amino acid in the same general category, for example, an acidic amino acid is replaced by another acidic amino acid, a basic amino acid is replaced by another basic amino acid, or a neutral amino acid is replaced by another neutral amino acid. The purpose of conservative amino acid substitutions is well known in the art.

[0250] In another embodiment, the present invention contemplates polypeptide sequences having at least 90% or more sequence homology with any one or more of the polypeptide sequences of antibody fragments, variable regions, and CDRs listed herein. More preferably, the present invention contemplates polypeptide sequences having at least 95% or more sequence homology, even more preferably at least 98% or more sequence homology, and even more preferably at least 99% or more sequence homology with any one or more of the polypeptide sequences of antibody fragments, variable regions, and CDRs listed herein. Methods for determining homology between nucleic acid and amino acid sequences are well known to those of ordinary skill in the art.

[0251] In another embodiment, the present invention further contemplates the above polypeptide homologues of the antibody fragments, variable regions and CDRs described herein that further have anti-CGRP activity. Non-limiting examples of anti-CGRP activity are described herein.

[0252] The present invention also contemplates anti-CGRP antibodies comprising any polypeptide or polynucleotide sequence described herein that replaces any other polynucleotide sequence described herein. For example, but not limited to, the present invention contemplates antibodies comprising a combination of any of the variable light and variable heavy chain sequences described herein, and further contemplates antibodies generated by replacing any of the CDR sequences described herein with any of the CDR sequences described herein.

[0253] Other exemplary embodiments of the present invention

[0254] In another embodiment, the present invention contemplates a therapeutic method using one or more anti-human CGRP antibodies or antibody fragments thereof, wherein the antibody or antibody fragment thereof is an anti-human CGRP antibody selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13 or Ab14, specifically binding to the same one or more overlapping linear or conformational epitopes on the intact human CGRP polypeptide or fragment thereof and / or competing for binding to the same one or more overlapping linear or conformational epitopes. In a preferred embodiment, the anti-human CGRP antibody or fragment thereof specifically binds to the same one or more overlapping linear or conformational epitopes on the intact human CGRP polypeptide or fragment thereof and / or competes for binding to the same one or more overlapping linear or conformational epitopes as Ab3, Ab6, Ab13 or Ab14.

[0255] A preferred embodiment of the present invention relates to a therapeutic method using a chimeric antibody or humanized antibody and fragments thereof (including Fab fragments) that have binding specificity to CGRP and inhibit the biological activity mediated by the binding of CGRP to the CGRP receptor. In a particularly preferred embodiment of the present invention, the chimeric or humanized anti-CGRP antibody is selected from Ab3, Ab6, Ab13 or Ab14.

[0256] In another embodiment of the invention, the anti-human CGRP antibody used in the treatment method is an antibody that specifically binds to the same overlapping linear or conformational epitope on the intact CGRP polypeptide or a fragment thereof that is specifically bound by Ab3, Ab6, Abl3 or Ab14, as determined by epitope mapping using overlapping linear peptide fragments spanning the full length of a native human CGRP polypeptide.

[0257] The present invention also relates to therapeutic methods using anti-CGRP antibodies that bind to the same CGRP epitope as the antibodies or antibody fragments disclosed herein (including but not limited to anti-CGRP antibodies selected from Abl, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, AblO, Abl1, Ab12, Ab13 or Ab14) and / or compete with the anti-CGRP antibodies for binding to CGRP.

[0258] In another embodiment, the present invention also relates to a method of treatment using an isolated anti-CGRP antibody or antibody fragment comprising a V selected from the group consisting of H One or more CDRs comprised in the polypeptide sequence: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123 or 133, or variants thereof, and / or a V selected from the group consisting ofL One or more CDRs comprised in the polypeptide sequence: 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121 or 131, or variants thereof.

[0259] In one embodiment of the invention, the anti-human CGRP antibodies discussed in the previous two paragraphs comprise at least 2 complementarity determining regions (CDRs) in each variable light and variable heavy region that are identical to those contained in an anti-human CGRP antibody selected from Abl, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, AblO, Abl1, Ab12, Ab13 or Ab14.

[0260] In a preferred embodiment, the anti-human CGRP antibody used in the method of treatment comprises at least 2 complementary determining regions (CDRs) in each variable light and variable heavy region, which are the same as those contained in Ab3 or Ab6. In another embodiment, all CDRs of the anti-human CGRP antibodies discussed above are the same as the CDRs contained in the anti-human CGRP antibodies selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13 or Ab14. In a preferred embodiment of the present invention, all CDRs of the above-mentioned anti-human CGRP antibodies are the same as the CDRs contained in the anti-human CGRP antibodies selected from Ab3 or Ab6.

[0261] The present invention further contemplates treatment methods wherein one or more of the anti-human CGRP antibodies discussed above are aglycosylated, or if glycosylated, are only mannosylated; contain an Fc region that has been modified to alter effector function, half-life, proteolysis and / or glycosylation; are human, humanized, single chain or chimeric; and are humanized antibodies derived from a rabbit (parent) anti-human CGRP antibody. Exemplary mutations that impair glycosylation include mutations of the Asn residue at position 297 of the IgG heavy chain constant region (such as IgG1) to another amino acid, such as Ala, as described in U.S. Pat. No. 5,624,821, which is incorporated by reference in its entirety.

[0262] The present invention also contemplates one or more anti-human CGRP antibodies, wherein the framework regions (FRs) in the variable light and variable heavy regions of the antibodies are unmodified human FRs or human FRs that have been modified by substituting one or more human FR residues in the variable light or heavy chain regions with corresponding FR residues of a parent rabbit antibody, respectively, and wherein the human FRs are derived from human variable heavy and light chain antibody sequences that have been selected from a library of human germline antibody sequences relative to other human germline antibody sequences contained in the library based on their high level of homology to the corresponding rabbit variable heavy or light chain regions.

[0263] The present invention also contemplates a method for treating or preventing medication overuse headache (e.g., associated with overuse of anti-migraine medications and / or associated with overuse of triptans and / or ergots and / or analgesics), the method comprising administering a therapeutically effective amount of at least one anti-human CGRP antibody or fragment described herein to a patient exhibiting medication overuse headache or at risk of developing medication overuse headache. The present invention also contemplates that the treatment method may involve the administration of two or more anti-CGRP antibodies or fragments thereof disclosed herein. If more than one antibody is administered to a patient, multiple antibodies may be administered simultaneously, in parallel, or staggered at the time of their administration. The anti-CGRP activity of the anti-CGRP antibodies of the present invention and fragments thereof having binding specificity to CGRP may also be described by their binding strength or their affinity for CGRP. In one embodiment of the present invention, the anti-CGRP antibodies of the present invention and fragments thereof having binding specificity to CGRP are less than or equal to 5x 10 -7 M, 10 -7 M, 5x 10 -8 M, 10 -8 M, 5x 10 -9 M, 10 -9 M, 5x 10 -10 M, 10 -10 M, 5x 10 -11 M, 10 -11 M, 5x 10 -12 M, 10 -12 M, 5x 10 -13 M or 10 -13 The dissociation constant (K D ) binds to CGRP. Preferably, the anti-CGRP antibody and its fragments are less than or equal to 10 -11 M, 5x 10 -12 M or 10 -12 In another embodiment of the present invention, the anti-CGRP antibodies and fragments thereof having binding specificity to CGRP of the present invention bind to a linear or conformational CGRP epitope.

[0264] In another embodiment of the present invention, the anti-CGRP activity of the anti-CGRP antibodies and fragments thereof having binding specificity to CGRP is less than or equal to 10 -4 S -1 , 5x 10 -5 S -1 , 10 -5 S -1 , 5x 10 -6 S -1 , 10-6 S -1 , 5x 10 -7 S -1 , or 10 -7 S -1 The dissociation rate of CGRP binds to CGRP.

[0265] In another embodiment of the present invention, the anti-CGRP activity of the anti-CGRP antibodies of the present invention and fragments thereof having binding specificity to CGRP exhibits anti-CGRP activity by preventing, ameliorating or alleviating the symptoms of diseases and disorders associated with CGRP or alternatively treating diseases and disorders associated with CGRP. Non-limiting examples of diseases and disorders associated with CGRP are described herein and include headache and migraine disorders.

[0266] Polynucleotides encoding anti-CGRP antibody polypeptides

[0267] As previously mentioned, the present invention specifically includes specific anti-CGRP antibodies and antibody fragments referred to herein as Ab1-Ab14, which contain Figure 1A-12 or consisting of a CDR, VL, VH, CL and CH polypeptide of a sequence identified in. Figure 1A-12 The nucleic acid sequences encoding the aforementioned VL, VH, CL and CH polypeptides contained in Ab1-Ab14 are also included. The nucleic acid sequences encoding the CDR, VL, VH, CL and CH polypeptides of the particularly preferred anti-CGRP antibody Ab6 are further described below.

[0268] Antibody Ab6

[0269] The present invention also relates to polynucleotides encoding antibody polypeptides having binding specificity to CGRP. In one embodiment of the present invention, the polynucleotide of the present invention comprises or alternatively consists of the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 222:

[0270] CAAGTGCTGacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcAATtgcCAGGCCAGTCAGAGTGTTTATCATAACACCTACCTGGCCtggtatcagcagaaaccagggaaagttcctaagCAActgatctatGATGCATCCACTCTGGCATCT ggggtcccatctcgtttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagatgttgcaacttattactgtCTGGGCAGTTATGATTGTACTAATGGTGATTGTTTTGTTttcggcggaggaaccaaggtggaaatcaaacgt(SEQ ID NO:232).

[0271] In one embodiment of the present invention, the polynucleotide of the present invention comprises or alternatively consists of the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 221:

[0272] (SEQ ID NO:231).

[0273] In another embodiment of the present invention, the polynucleotide of the present invention comprises or alternatively consists of the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 202:

[0274] gaggtgcagctTgtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcaGTCtctggaATCGACCTCagtGGCTACTACATGAACtgggtccgtcaggctccagggaaggggctggagtgggtcGGAGTCATTGGTATTAATGGTGCC ACATACTACGCGAGCTGGGCGAAAGGCcgattcaccatctccagagacaattccaagACCACGGTGtatcttcaaatgaacagcctgagagctgaggacactgctgtgtatTTCtgtGCTAGAGGGGACATCtggggccaagggaccctcgtcaccgtcTCGAGC(SEQ ID NO:212).

[0275] In one embodiment of the present invention, the polynucleotide of the present invention comprises or alternatively consists of the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 201:

[0276] gaggtgcagctTgtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcaGTCtctggaATCGACCTCagtGGCTACTACATGAACtgggtccgtcaggctccagggaaggggctggagtgggtcGGAGTCATTGGTATTAATGGTGCCACATACTACGCGAGCTGGGCGAAAGGCcgattcaccatctccagagacaattccaagACCACGGTGtatcttcaaatgaacagcctgagagctgaggacactgctgtgtatTTCtgtGCTAGAGGGGACATCtggggccaagggaccctcgtcaccgtcTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCAcCCTCCTCCaAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACGCGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGaTCTCCCgGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAA

[0277] AGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCC

[0278] CCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAA

[0279] GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC

[0280] GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCAC

[0281] GCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCG

[0282] TGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC

[0283] ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA(SEQ IDNO:211)。

[0284]

[0285] In another embodiment of the present invention, the polynucleotide encoding an antibody fragment having binding specificity to CGRP comprises or alternatively consists of: one or more of the polynucleotide sequences of SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238 (which correspond to a polynucleotide encoding the complementarity determining region (CDR or hypervariable region) of the light chain variable sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221).

[0286] In another embodiment of the present invention, the polynucleotide encoding an antibody fragment having binding specificity to CGRP comprises or alternatively consists of: one or more of the polynucleotide sequences of SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218 (which correspond to a polynucleotide encoding the complementarity determining region (CDR or hypervariable region) of the heavy chain variable sequence of SEQ ID NO: 202 or the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566).

[0287] The present invention also contemplates polynucleotide sequences comprising one or more polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present invention, the polynucleotides encoding antibody fragments having binding specificity to CGRP include one, two, three or more (including all) of the following polynucleotides encoding antibody fragments, or alternatively consist of: a polynucleotide encoding a light chain variable sequence of SEQ ID NO: 222, SEQ ID NO: 232; a polynucleotide encoding a light chain sequence of SEQ ID NO: 221, SEQ ID NO: 231; a polynucleotide encoding a heavy chain variable sequence of SEQ ID NO: 202, SEQ ID NO: 212; a polynucleotide encoding a heavy chain sequence of SEQ ID NO: 201, SEQ ID NO: 211; a polynucleotide encoding a heavy chain sequence of SEQ ID NO: 566, SEQ ID NO: 567; a polynucleotide encoding the complementarity determining region (SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238) of the light chain variable sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221; and a polynucleotide encoding a heavy chain variable sequence of SEQ ID NO: 202 or SEQ ID NO: 201 or SEQ ID A polynucleotide of the complementarity determining region of the NO:566 heavy chain sequence (SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218).

[0288] In a preferred embodiment of the present invention, the polynucleotide of the present invention comprises a polynucleotide encoding a Fab (fragment antigen binding) fragment having binding specificity to CGRP or alternatively consists of it. Regarding antibody Ab6, the polynucleotide encoding the full-length Ab6 antibody comprises the following items or alternatively consists of it: a polynucleotide encoding the light chain sequence of SEQ ID NO: 221 SEQ ID NO: 231 and a polynucleotide encoding the heavy chain sequence of SEQ ID NO: 201 SEQ ID NO: 211 or a polynucleotide encoding the heavy chain sequence of SEQ ID NO: 566 SEQ ID NO: 567.

[0289] Another embodiment of the present invention contemplates incorporating these polynucleotides into expression vectors for expression in mammalian cells such as CHO, NSO, HEK-293 or in fungi, insects or microbial systems such as yeast cells such as yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the present invention described herein (below), Fab fragments can be produced by enzymatic digestion (e.g., papain) of Ab6 after expressing the full-length polynucleotides in a suitable host. In another embodiment of the present invention, anti-CGRP antibodies such as Ab6 or Fab fragments thereof can be produced by expressing Ab6 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungi, insects or microbial systems such as yeast cells (e.g., diploid yeast, e.g., diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0290] In one embodiment, the invention relates to an isolated polynucleotide comprising an anti-CGRP V sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 42, SEQ ID NO: 82, SEQ ID NO: 122, SEQ ID NO: 162, SEQ ID NO: 202, SEQ ID NO: 242, SEQ ID NO: 282, SEQ ID NO: 322, SEQ ID NO: 362, SEQ ID NO: 402, SEQ ID NO: 442, SEQ ID NO: 482, or SEQ ID NO: 522. H The antibody amino acid sequence or the encoding thereof (wherein at least one framework residue (FR residue) has been replaced by the rabbit anti-CGRP antibody V H The amino acid or conservative amino acid substitution at the corresponding position in the polypeptide is substituted by a polynucleotide.

[0291] In another embodiment, the invention relates to an isolated polynucleotide comprising an anti-CGRP V sequence encoding SEQ ID NO: 22, SEQ ID NO: 62, SEQ ID NO: 102, SEQ ID NO: 142, SEQ ID NO: 182, SEQ ID NO: 222, SEQ ID NO: 262, SEQ ID NO: 302, SEQ ID NO: 342, SEQ ID NO: 382, ​​SEQ ID NO: 422, SEQ ID NO: 462, SEQ ID NO: 502, or SEQ ID NO: 542. L The antibody amino acid sequence or the encoding thereof (wherein at least one framework residue (FR residue) has been replaced by the rabbit anti-CGRP antibody V L The amino acid or conservative amino acid substitution at the corresponding position in the polypeptide is substituted with a polynucleotide sequence.

[0292] In yet another embodiment, the present invention relates to one or more heterologous polynucleotides comprising a sequence encoding a polypeptide contained in the following: SEQ ID NO:22 and SEQ ID NO:2; SEQ ID NO:62 and SEQ ID NO:42; SEQ ID NO:102 and SEQ ID NO:82; SEQ ID NO:142 and SEQ ID NO:122; SEQ ID NO:182 and SEQ ID NO:162; SEQ ID NO:222 and SEQ ID NO:202; SEQ ID NO:262 and SEQ ID NO:242; SEQ ID NO:302 and SEQ ID NO:282; SEQ ID NO:342 and SEQ ID NO:322; SEQ ID NO:382 and SEQ ID NO:362; SEQ ID NO:422 and SEQ ID NO:402; SEQ ID NO:462 and SEQ ID NO:442; SEQ ID NO:502 and SEQ ID NO:482; or SEQ ID NO:542 and SEQ ID NO:522.

[0293] In another embodiment, the invention relates to an isolated polynucleotide that expresses a polypeptide comprising at least one CDR polypeptide derived from an anti-CGRP antibody, wherein the expressed polypeptide specifically binds to CGRP alone or when expressed in association with another polynucleotide sequence that expresses a polypeptide comprising at least one CDR polypeptide derived from an anti-CGRP antibody, wherein the at least one CDR is selected from the group consisting of SEQ ID NO: 22, SEQ ID NO: 2, SEQ ID NO: 62, SEQ ID NO: 42, SEQ ID NO: 102, SEQ ID NO: 82, SEQ ID NO: 142, SEQ ID NO: 122, SEQ ID NO: 182, SEQ ID NO: 162, SEQ ID NO: 222, SEQ ID NO: 202, SEQ ID NO: 262, SEQ ID NO: 242, SEQ ID NO: 302, SEQ ID NO: 282, SEQ ID NO: 342, SEQ ID NO: 322, SEQ ID NO: 382, ​​SEQ ID NO: 362, SEQ ID NO: 422, SEQ ID NO: 402, SEQ ID NO: 5 V of SEQ ID NO:462, SEQ ID NO:442, SEQ ID NO:502, SEQ ID NO:482, SEQ ID NO:542 or SEQ ID NO:522 L or V H Those contained in polypeptides.

[0294] Host cells and vectors comprising the polynucleotides are also contemplated.

[0295] The present invention also contemplates vectors comprising polynucleotide sequences encoding variable heavy and light chain polypeptide sequences as described herein and respective complementary determining regions (CDRs or hypervariable regions), and host cells comprising said vector sequences. In one embodiment of the invention, the host cell is a yeast cell. In another embodiment of the invention, the yeast host cell belongs to the genus Pichia.

[0296] Methods for producing antibodies and fragments thereof

[0297] In another embodiment, the present invention contemplates methods for producing anti-CGRP antibodies and fragments thereof. The production methods of antibodies and fragments thereof secreted from polyploid (preferably diploid or tetraploid) strains of mating competent yeast are taught in U.S. Patent Application Publication No. US2009 / 0022659 of Olson et al. and U.S. Patent No. 7,935,340 of Garcia-Martinez et al., each of which is incorporated herein by reference in its entirety. Methods for producing antibodies and fragments thereof in mammalian cells such as CHO cells are well known in the art.

[0298] Other methods of producing antibodies are also well known to those of ordinary skill in the art. For example, methods of producing chimeric antibodies are now well known in the art (see, e.g., U.S. Pat. No. 4,816,567 to Cabilly et al.; Morrison et al., PNAS USA [Proceedings of the National Academy of Sciences of the United States], 81:8651-55 (1984); Neuberger, MS et al., Nature [Nature], 314:268-270 (1985); Boulianne, GL et al., Nature [Nature], 312:643-46 (1984), the disclosure of each of which is incorporated herein by reference in its entirety.

[0299] Likewise, other methods for producing humanized antibodies are well known in the art (see, e.g., U.S. Pat. Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370 to Queen et al.; 5,225,539 and 6,548,640 to Winter; 6,054,297, 6,407,213, and 6,639,055 to Carter et al.; and 6,180,370 to Adair et al.). Jones, PT et al., Nature, 321:522-525 (1986); Reichmann, L., et al., Nature, 332:323-327 (1988); Verhoeyen, M, et al., Science, 239:1534-36 (1988), the disclosures of each of which are incorporated herein by reference in their entirety.

[0300] The term "opioid analgesics" herein refers to all natural or synthetic drugs that have morphine-like effects. Synthetic and semisynthetic opioid analgesics are derivatives of five chemical classes of compounds: phenanthrene; phenylheptylamine; phenylpiperidine; morphinanes; and benzomorphine, all of which are within the scope of the term. Exemplary opioid analgesics include codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanil, pethidine, methadone, nalbuphine, propoxyphene, and pentazocine, or a pharmaceutically acceptable salt thereof.

[0301] The term "NSAID" refers to nonsteroidal anti-inflammatory compounds. NSAIDs are classified by their ability to inhibit cyclooxygenase. Cyclooxygenase 1 and cyclooxygenase 2 are the two major isoforms of cyclooxygenase, and most standard NSAIDs are mixed inhibitors of these two isoforms. Most standard NSAIDs belong to one of the following five structural classes: (1) propionic acid derivatives, such as ibuprofen, naproxen, chlorpromazine, diclofenac, and ketoprofen; (2) acetic acid derivatives, such as tolmetin and slindac; (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid; (4) bifenac acid derivatives, such as diflunisal and flufenamic acid; and (5) oxicams, such as piroxicam, sudoxicam, and isoxicam. Another class of NSAIDs that selectively inhibit cyclooxygenase 2 has been described. Cox-2 inhibitors have been described in U.S. Pat. Nos. 5,616,601; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311, which are incorporated herein by reference in their entirety. Certain exemplary COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flusulamide (CGP-28238), meloxicam, 6-methoxy-2-naphthylacetic acid (6-MNA), rofecoxib, MK-966, nabumetone (a prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or a combination thereof.

[0302] In some embodiments, aspirin and / or acetaminophen can be used in combination with the CGRP antibodies or fragments of the invention.Aspirin is another nonsteroidal anti-inflammatory compound.

[0303] The subject to whom the pharmaceutical formulation is administered can be, for example, any human or non-human animal in need of such treatment, prevention and / or improvement, or any human or non-human animal that can benefit from inhibiting or alleviating medication overuse headache. For example, the subject can be an individual diagnosed with medication overuse headache or considered to be at risk of suffering from medication overuse headache. The present invention further includes the use of any pharmaceutical formulation disclosed herein in the preparation of a medicament for treating, preventing and / or ameliorating medication overuse headache.

[0304] Application

[0305] In one embodiment of the invention, the anti-CGRP antibodies or CGRP binding fragments thereof described herein and the combination of the antibodies or antibody fragments are administered to the subject at a concentration of about 0.1 mg / kg to 100.0 mg / kg of the subject's body weight. In a preferred embodiment of the invention, the anti-CGRP antibodies or CGRP binding fragments thereof described herein and the combination of the antibodies or antibody fragments are administered to the subject at a concentration of about 0.4 mg / kg of the subject's body weight and / or a dose of 100 mg or 300 mg. In a preferred embodiment of the invention, the anti-CGRP antibodies or CGRP binding fragments thereof described herein and the combination of the antibodies or antibody fragments are administered to the subject at the following frequency: once every twenty-six weeks or six months or less, for example, once every sixteen weeks or four months or less, once every eight weeks or two months or less, once every four weeks or monthly or less, once every two weeks or every two months or less, once a week or less, or once a day or less. Typically, administration of sequential doses may differ by plus or minus a number of days from the above schedule, for example, administration every 3 months or every 12 weeks includes administering doses by plus or minus 1, 2, 3, 4, 5, 5 or 7 days from the scheduled days.

[0306] The Fab fragment can be administered every two weeks or less, every week or less, once a day or less, multiple times a day and / or once every several hours. In one embodiment of the invention, the patient receives 0.1 mg / kg to 40 mg / kg of the Fab fragment per day, in divided doses 1 to 6 times a day or in a sustained release form effective to obtain the desired result.

[0307] It will be appreciated that the concentration of antibody or Fab administered to a given patient may be greater or less than the exemplary administration concentrations described above.

[0308] Those skilled in the art will be able to determine effective dosages and administration frequencies by routine experimentation, for example, guided by the disclosure herein and Goodman, LS, Gilman, A., Brunton, LL, Lazo, JS, & Parker, KL (2006). Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; Howland, RD, Mycek, MJ, Harvey, RA, Champe, PC, & Mycek, MJ (2006). Pharmacology. Lippincott's illustrated reviews. Philadelphia: Lippincott Williams & Wilkins; and Golan, DE (2008). Principles of pharmacology: the pathophysiologic basis of drug therapy. Philadelphia, Pennsylvania, [et al.]: Lippincott Williams & Wilkins.

[0309] In another embodiment of the present invention, the anti-CGRP antibodies or CGRP-binding fragments thereof described herein, and combinations of said antibodies or antibody fragments, are administered to a subject in a pharmaceutical formulation.

[0310] "Pharmaceutical composition" refers to a chemical or biological composition suitable for administration to a mammal. These compositions can be specifically formulated for administration by one or more of a variety of routes, including but not limited to buccal, epidermal, epidural, inhalation, intra-arterial, intracardiac, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, rectal (by enema or suppository), subcutaneous, subdermal, sublingual, transdermal and transmucosal, preferably intravenous. In addition, administration can be by injection, powder, liquid, gel, drops or other modes of administration.

[0311] A "pharmaceutical excipient" or "pharmaceutically acceptable excipient" is a carrier, typically a liquid, into which an active therapeutic agent is formulated. In one embodiment of the invention, the active therapeutic agent is a humanized antibody or one or more fragments thereof as described herein. Excipients generally do not provide any pharmacological activity to the formulation, although they may provide chemical and / or biological stability and release properties. Exemplary formulations can be found, for example, in Remington's Pharmaceutical Sciences, 19th ed., Grennaro, A., ed., 1995, which is incorporated herein by reference.

[0312] As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier may be suitable for intravenous, intraperitoneal, intramuscular or sublingual administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active compound, it is contemplated for use in the pharmaceutical compositions of the present invention. Supplementary active compounds may also be incorporated into the composition.

[0313] Pharmaceutical compositions generally must be sterile and stable under the conditions of manufacture and storage. The present invention contemplates that the pharmaceutical compositions are present in lyophilized form. The compositions can be formulated into solutions, microemulsions, liposomes or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof. The present invention also contemplates including stabilizers in the pharmaceutical compositions. For example, by maintaining the desired particle size in the case of dispersion and by using a surfactant, appropriate fluidity can be maintained.

[0314] In many cases, it is preferred to include isotonic agents, such as sugars, polyols such as mannitol, sorbitol or sodium chloride in the composition. By including agents that delay absorption in the composition, such as monostearate and gelatin, extended absorption of injectable compositions can be achieved. Moreover, basic polypeptides can be formulated into timed release formulations, such as compositions comprising slow-release polymers. The active compound can be prepared together with a carrier (such as a controlled release formulation, including implants and microencapsulated delivery systems) that protects the compound from rapid release. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic acid, polyglycolic acid copolymers (PLG). Many methods for preparing such formulations are known to those skilled in the art.

[0315] Exemplary compositions comprise, consist essentially of, or consist of an anti-CGRP antibody or fragment thereof (e.g., Ab6), an excipient (e.g., histidine), an isotonic agent (e.g., sorbitol), and a surfactant (e.g., polysorbate 80) in an aqueous solution. For example, the composition may comprise, consist essentially of, or consist of histidine (L-histidine), sorbitol, polysorbate 80, such as about 100 mg of an anti-CGRP antibody (e.g., Ab6), about 3.1 mg of L-histidine, about 40.5 mg of sorbitol, and about 0.15 mg of polysorbate 80 per 1 mL volume, with a pH of about 5.8, or about such a composition, such as within 10% of those values, within 5% of those values, within 1% of those values, within 0.5% of those values, or within 0.1% of those values, and water. For example, the pH value may be within 10% of 5.8, i.e., 5.22 to 6.38. Ab6 antibody may comprise or consist of the following: variable light and heavy chain polypeptides of SEQ ID NO: 222 and SEQ ID NO: 202, respectively, or light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 201, respectively, or light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 566, respectively. The composition may be in the form of an aqueous solution or concentrate (e.g., lyophilized) that, when reconstituted, for example, by adding water, may produce the above-described composition. Exemplary compositions are composed of the following per mL: 100 mg of light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 201, respectively, about 3.1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polysorbate 80 and water QS, or approximate the above-described composition, for example, within 10% of those numbers, within 5% of those numbers, within 1% of those numbers, within 0.5% of those numbers, or within 0.1% of those numbers. Another exemplary composition is composed of the following per mL: 100 mg of the light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 566, respectively, about 3.1 mg L-histidine, about 40.5 mg sorbitol and about 0.15 mg polysorbate 80 and water QS, or approximate said composition, for example, within 10% of those numbers, within 5% of those numbers, within 1% of those numbers, within 0.5% of those numbers or within 0.1% of those numbers. The composition can be suitable for intravenous or subcutaneous administration, preferably intravenous administration. For example, the composition can be suitable for mixing with an intravenous solution (e.g., 0.9% sodium chloride) in an amount of about 100 mg to about 300 mg of antibody added to 100 mL of intravenous solution.Preferably, the composition is storage stable for at least 1, 3, 6, 12, 18 or 24 months, for example, showing no more than 5% or no more than 10% aggregate formation of the antibody or fragment after storage at room temperature or at 4°C for a specified period of time, or in an accelerated aging test simulating the storage period.

[0316] For each of the described embodiments, the compounds can be administered in a variety of dosage forms. Any biologically acceptable dosage form known to those of ordinary skill in the art and combinations thereof are contemplated. Examples of such dosage forms include, but are not limited to, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, powders, granules, particles, microparticles, dispersible particles, cachets, inhalants, aerosol inhalants, patches, particle inhalants, implants, long-acting implants, injections (including subcutaneous, intramuscular, intravenous and intradermal, preferably intravenous), infusions and combinations thereof.

[0317] The above description of various illustrative embodiments of the present invention is not intended to be exhaustive or to limit the present invention to the disclosed precise form. Although specific embodiments and embodiments of the present invention are described herein for illustrative purposes, various equivalent modifications may be made within the scope of the present invention as will be appreciated by those skilled in the relevant art. In addition to the above-described embodiments, the teachings provided herein by the present invention may be applied to other purposes.

[0318] Based on the above detailed description, these and other changes can be made to the present invention. Generally, in the appended claims, the terms used should not be interpreted as limiting the present invention to the specific embodiments disclosed in the specification and claims. Therefore, the present invention is not limited by the disclosure, but the scope of the present invention will be determined entirely by the appended claims.

[0319] The invention may be practiced otherwise than as particularly described in the foregoing description and examples. Many modifications and variations of the invention are possible in light of the above teachings and are therefore within the scope of the appended claims.

[0320] Certain CGRP antibody polynucleotides and polypeptides are disclosed in the sequence listing accompanying the present patent application document, and the disclosure of the sequence listing is incorporated herein by reference in its entirety.

[0321] The entire disclosure of each document (including patents, patent applications, journal articles, abstracts, manuals, books, or other publications) cited in the Background, Detailed Description, and Examples is incorporated herein by reference in its entirety.

[0322] The following examples are presented to provide a complete disclosure and description of how to make and use the present invention to those of ordinary skill in the art, and are not intended to limit the scope of the invention. Efforts have been made to ensure accuracy with respect to the numerals used (e.g., amount, temperature, concentration, etc.), but some experimental errors and deviations should be allowed. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric pressure or near atmospheric pressure.

[0323] Other exemplary embodiments

[0324] Other exemplary embodiments of the present invention are provided as follows:

[0325] S1. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment in the preparation of a medicament for treating or preventing medication overuse headache.

[0326] S2. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment in the preparation of a medicament for treating or preventing possible medication overuse headache.

[0327] S3. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises any one of Ab1-Ab14 or a fragment thereof.

[0328] S4. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises Ab6 or a fragment thereof.

[0329] S5. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises light chain complementary determining region (CDR) 1, 2 and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively.

[0330] S6. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively.

[0331] S7. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0332] S8. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0333] S9. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0334] S10. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0335] S11. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222.

[0336] S12. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232.

[0337] S13. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202.

[0338] S14. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0339] S15. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202.

[0340] S16. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0341] S17. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221.

[0342] S18. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231.

[0343] S19. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0344] S20. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0345] S21. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0346] S22. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0347] S23. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in Pichia pastoris or obtained by expressing in Pichia pastoris.

[0348] S24. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells or obtained by expression in CHO cells.

[0349] S25. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody is administered in an amount between about 100 mg and about 300 mg, or about 100 mg, or about 300 mg.

[0350] S26. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody is administered in an amount of 100 mg.

[0351] S27. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, further comprising administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0352] S28. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S1-S26, further comprising administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0353] S29. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient is a chronic migraine patient or an episodic migraine or cluster headache patient at risk of developing medication overuse headache.

[0354] S30. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S29, wherein the patient uses acute headache medication at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0355] S31. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S29, wherein the patient uses acute headache medication at least 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0356] S32. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S30-S31, wherein the acute medication comprises the use of ergot alkaloids, triptans, non-opioid analgesics, acetaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics, or opioids.

[0357] S33. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the medication overuse headache comprises (a) the patient experiences headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for acute and / or symptomatic headache treatment for more than 3 months.

[0358] S34. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein prior to said administration, said patient exhibits about 15 to about 22 migraine days per month.

[0359] S35. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein prior to said administration, said patient exhibits about 15 to about 27 headache days per month.

[0360] S36. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein prior to said administration, said patient exhibits about 17 to about 24 headache days per month.

[0361] S37. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein prior to said administration, the patient exhibits about 15 to about 19 migraine days per month, or about 20 or about 21 headache days per month, or about 16 migraine days per month.

[0362] S38. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient was diagnosed with migraine at least 10 years prior to the administration.

[0363] S39. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient was diagnosed with migraine at least 15 years prior to the administration.

[0364] S40. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient was diagnosed with migraine at least 18 years or at least 19 years before the administration.

[0365] S41. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient's migraine days within one month after being administered the antibody are reduced by at least 50% relative to the baseline number of migraine days experienced by the patient before the administration.

[0366] S42. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient's migraine days within one month after being administered the antibody are reduced by at least 75% relative to the baseline number of migraine days experienced by the patient before the administration.

[0367] S43. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient has a 100% reduction in migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to the administration.

[0368] S44. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient has at least 50% fewer migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0369] S45. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient has at least 75% fewer migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0370] S46. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient has a 100% reduction in migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to the administration.

[0371] S47. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, further comprising administering a second dose of the anti-CGRP antibody to the patient about 12 weeks or about 3 months after the administration.

[0372] S48. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the administration comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg of the anti-CGRP antibody.

[0373] S49. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody or antibody fragment is aglycosylated, or if only glycosylated, contains only mannose residues.

[0374] S50. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody consists of a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0375] S51. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody consists of a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0376] S52. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the medication overuse headache comprises (a) the patient experiences headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for acute and / or symptomatic headache treatment for more than 3 months.

[0377] S53. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the drug overuse includes the use of ergotamine for 10 days or more per month, the use of triptan for 10 days or more per month, the use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 days or more per month, the use of one or more combinations of The invention relates to a combination of analgesics (as further described below) for 10 or more days / month, one or more opioids for 10 or more days / month, or a combination of two or more drug classes (as further described below) for 10 or more days / month, wherein the triptan use optionally includes the use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or wherein the opioid use optionally includes the use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone.

[0378] S54. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the medication overuse headache comprises ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other drugs, wherein the triptan use optionally includes the use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan, and / or wherein the opioid use optionally includes the use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine and hydrocodone.

[0379] S55. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the non-opioid analgesic overuse headache includes acetaminophen (acetaminophen) overuse headache, non-steroidal anti-inflammatory drug (NSAID) overuse headache, such as acetylsalicylic acid (aspirin) overuse headache, or other non-opioid analgesic overuse headache.

[0380] S56. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the ergotamine overuse headache comprises 15 or more days / month of headache and ergotamine use for 10 or more days / month for more than 3 months.

[0381] S57. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the triptan overuse headache comprises headaches occurring 15 or more days / month and use of one or more triptans for 10 or more days / month for more than 3 months, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan.

[0382] S58. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the non-opioid analgesic overuse headache comprises headache occurring 15 or more days / month and the use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days / month for more than 3 months.

[0383] S59. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the combination analgesic overuse headache comprises headache occurring 15 or more days / month and the use of one or more combination analgesics for 10 or more days / month for more than 3 months, wherein the combination analgesic comprises two or more classes of drugs, each having an analgesic effect (e.g., acetaminophen and codeine) or as an adjuvant (e.g., caffeine), optionally, wherein the combination-analgesic combination non-opioid analgesic comprises the use of at least one opioid (e.g., tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof), a barbiturate (e.g., ibutabarbital and / or caffeine).

[0384] S60. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the opioid overuse headache comprises 15 or more days / month of headache and use of one or more opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for 10 or more days / month for more than 3 months.

[0385] S61. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the medication overuse headache attributable to multiple drug classes rather than overuse alone includes headaches occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for a total of at least 10 days / month for more than 3 months.

[0386] S62. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes includes headaches occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for at least 10 days / month for more than 3 months, wherein the identity, amount and / or pattern of use or overuse of these classes of drugs cannot be reliably determined.

[0387] S63. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the medication overuse headache attributed to other medications includes headaches occurring 15 or more days / month and the use of one or more medications other than the above-mentioned medications for acute or symptomatic treatment of headaches for at least 10 days / month for more than 3 months.

[0388] S64. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the patient has a pre-existing primary headache before developing the medication overuse headache.

[0389] S65. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein headache days and / or medication use days are determined by: patient or relative reports, diaries, medical records, medication purchase history, prescription fulfillment, biomarkers of medication use, incidence of drug toxicity, incidence of overdose, and / or other indicators of patient medication use.

[0390] S66. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the medication overuse headache is diagnosed according to the International Classification of Headache Disorders, Third Edition, wherein the medication overuse headache optionally includes ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other drugs.

[0391] S67. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of the preceding embodiments, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is contained in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80 and water.

[0392] S68. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or an amount of each ingredient within 10% of the stated values, and having a pH of 5.8 or within + / - 10% of the stated values.

[0393] S69. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 5% of the stated value, and / or having a pH of 5.8 or within + / - 5% of the stated value.

[0394] S70. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 1% of the stated values, and / or having a pH of 5.8 or within 1% of the stated values.

[0395] S71. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 0.5% of the stated value, and / or having a pH of 5.8 or within 0.5% of the stated value.

[0396] S72. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 0.1% of the stated values, and / or having a pH of 5.8 or within 0.1% of the stated values.

[0397] S73. A pharmaceutical composition comprising or consisting of: an anti-CGRP antibody or an anti-CGRP antibody fragment in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80 and water.

[0398] S74. A pharmaceutical composition as described in embodiment S73, wherein the formulation comprises or consists of the following: per 1 mL volume of aqueous solution, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or an amount of each ingredient within 10% of the stated values, and having a pH of 5.8 or within + / - 10% of the stated values.

[0399] S75. A pharmaceutical composition as described in embodiment S73, wherein the formulation comprises or consists of the following: 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80 per 1 mL volume of aqueous solution, or having an amount of each ingredient within + / - 5% of the stated values, and / or having a pH of 5.8 or within 5% of the stated values.

[0400] S76. A pharmaceutical composition as described in embodiment S73, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 1% of the stated values, and / or having a pH of 5.8 or within 1% of the stated values.

[0401] S77. A pharmaceutical composition as described in embodiment S73, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 0.5% of the stated values, and / or having a pH of 5.8 or within 0.5% of the stated values.

[0402] S78. A pharmaceutical composition as described in embodiment S73, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 0.1% of the stated values, and / or having a pH of 5.8 or within 0.1% of the stated values.

[0403] S79. A pharmaceutical composition as described in any of embodiments S73-S79, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2, and CDR 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and heavy chain CDR 1, CDR 2, and CDR3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0404] S80. A pharmaceutical composition as described in any one of embodiments S73-S79, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0405] S81. A pharmaceutical composition as described in any one of embodiments S73-S79, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202.

[0406] S82. A pharmaceutical composition as described in any one of embodiments S73-S79, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0407] S83. A pharmaceutical composition as described in any one of embodiments S73-S79, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0408] S84. A pharmaceutical composition as described in any one of embodiments S73-S79, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0409] S85. A pharmaceutical composition as described in any one of embodiments S73-S84, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in Pichia pastoris or obtained by expressing in Pichia pastoris.

[0410] S86. A pharmaceutical composition as described in any one of embodiments S73-S84, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO or obtained by expression in CHO.

[0411] S87. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment and / or at least one anti-CGRP-R antibody or anti-CGRP-R antibody fragment in the preparation of a medicament for treating or preventing migraine, further comprising the use of at least one additional drug for the acute and / or symptomatic treatment of headache, wherein the drug is selected from the group consisting of ergot alkaloids, triptans, non-opioid analgesics, acetaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics, or opioids.

[0412] S88. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87, wherein the combined administration of (i) and (ii) reduces the symptoms, severity and / or onset of medication overuse headache in the patient.

[0413] S89. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87 or S88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises an ergot alkaloid.

[0414] S90. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S89, wherein the ergot alkaloid is selected from ergotamine, nicergoline, methysergide, dihydroergotamine and combinations of the foregoing.

[0415] S91. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87 or S88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises a triptan.

[0416] S92. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S91, wherein the triptan is selected from sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, and combinations of the foregoing.

[0417] S93. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87 or S88, wherein the medication for the acute and / or symptomatic treatment of headache comprises a non-opioid analgesic.

[0418] S94. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S93, wherein the non-opioid analgesic comprises acetaminophen (paracetamol) or aspirin.

[0419] S95. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87 or S88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises an NSAID.

[0420] S96. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S95, wherein the NSAID is selected from salicylates, propionic acid derivatives, enolic acid derivatives, anthranilic acid derivatives (fenamates), selective COX-2 inhibitors (coxibs), sulfonanilides and combinations of the foregoing.

[0421] S97. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S95, wherein the NSAID is selected from salicylates, such as aspirin (acetylsalicylic acid), diflunisal (Dolobid), salicylic acid and its salts, and disalcid (Disalcid); propionic acid derivatives, such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and loxoprofen; acetic acid derivatives, such as indomethacin, tolmetin, sulindac, etodolac, Ketorolac, diclofenac, aceclofenac and nabumetone; enolic acid (oxicam) derivatives, such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam and phenylbutazone (Bute); anthranilic acid derivatives (fenamates), such as mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid; selective COX-2 inhibitors (coxibs), such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib and firocoxib; sulfonanilides, such as nimesulide; clonixin, levofloxacin, H-harpagine or Devil's Claw and combinations of the foregoing.

[0422] S98. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87 or S88, wherein the medication for the acute and / or symptomatic treatment of headache comprises a non-opioid analgesic.

[0423] S99. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87 or S88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises a combination analgesic.

[0424] S100. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S99, wherein the combination analgesic comprises a combination of a non-opioid analgesic and at least one opioid or barbiturate, such as ibutabarbital and / or caffeine; or a combination of acetaminophen, aspirin and caffeine, such as or EXCEDRIN Or a combination analgesic comprising an analgesic in combination with at least one non-analgesic, such as a vasoconstrictor, such as pseudoephedrine, or with an antihistamine.

[0425] S101. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S87 or S88, wherein the drug for the acute and / or symptomatic treatment of headache comprises an opioid.

[0426] S102. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S101, wherein the opioid is selected from oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, thebaine, oripavine, mixed opioid alkaloids such as opium, diacetylmorphine, nicotine morphine, dipropionylmorphine, diacetyldihydromorphine, levulinylmorphine, normorphine, morphine, methylnormorphine, dibenzoylmorphine, ethylmorphine, heterocodeine, buprenorphine, etorphine, hydromorphone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanil, sufentanil, remifentanil, carfentanil, hydroxymethylfentanyl, pethidine (meperidine), ketobemidone, MPPP, allylprodine, prodinatin, PEPAP, meperidine, diphenylhexylamine, propoxyphene, dextropropoxyphene, dextromalamide, benziramide, pirithamide, and combinations of the foregoing.

[0427] S103. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S102, wherein the anti-CGRP antibody comprises any one of Ab1-Ab14 or a fragment thereof.

[0428] S104. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S103, wherein the anti-CGRP antibody comprises Ab6 or a fragment thereof.

[0429] S105. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S104, wherein the anti-CGRP antibody comprises light chain complementary determining region (CDR) 1, 2 and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively.

[0430] S106. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S105, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively.

[0431] S107. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S106, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0432] S108. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S107, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0433] S109. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S108, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2, and CDR 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and heavy chain CDR 1, CDR 2, and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0434] S110. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87 to S109, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0435] S111. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S110, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222.

[0436] S112. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S111, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232.

[0437] S113. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S112, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202.

[0438] S114. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S113, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO:212.

[0439] S115. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S114, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202.

[0440] S116. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S115, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0441] S117. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S116, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221.

[0442] S118. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S117, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231.

[0443] S119. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S118, wherein the anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0444] S120. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S119, wherein the anti-CGRP antibody comprises a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0445] S121. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S120, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0446] S122. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S121, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0447] S123. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S122, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in Pichia pastoris or obtained by expression in Pichia pastoris.

[0448] S124. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S123, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells or obtained by expression in CHO cells.

[0449] S125. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S124, wherein the anti-CGRP antibody is administered in an amount between about 100 mg and about 300 mg, or about 100 mg, or about 300 mg.

[0450] S126. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S125, wherein the anti-CGRP antibody is administered in an amount of 100 mg.

[0451] S127. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S126, further comprising administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0452] S128. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S127, further comprising administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0453] S129. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S128, wherein the patient is a chronic migraine patient or an episodic migraine or cluster headache patient at risk of developing medication overuse headache.

[0454] S130. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S129, wherein the patient uses acute headache medication at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0455] S131. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S130, wherein the patient uses acute headache medication at least 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0456] S132. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S131, wherein the medication overuse headache comprises (a) the patient experiences headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for acute and / or symptomatic headache treatment for more than 3 months.

[0457] S133. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S132, wherein prior to said administration, said patient exhibits about 15 to about 22 migraine days per month.

[0458] S134. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S133, wherein prior to said administration, said patient exhibits about 15 to about 27 headache days per month.

[0459] S135. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S134, wherein prior to said administration, said patient exhibits about 17 to about 24 headache days per month.

[0460] S136. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87 to S135, wherein prior to said administration, the patient exhibits about 15 to about 19 migraine days per month, or about 20 or about 21 headache days per month, or about 16 migraine days per month.

[0461] S137. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S136, wherein the patient was diagnosed with migraine at least 10 years prior to the administration.

[0462] S138. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87 to S137, wherein the patient was diagnosed with migraine at least 15 years prior to the administration.

[0463] S139. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S138, wherein the patient was diagnosed with migraine at least 18 years or at least 19 years prior to the administration.

[0464] S140. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S139, wherein the patient has at least 50% fewer migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0465] S141. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S140, wherein the patient has at least 75% fewer migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0466] S142. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S141, wherein the patient has a 100% reduction in migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0467] S143. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S142, wherein the patient has at least 50% fewer migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0468] S144. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S143, wherein the patient has at least 75% fewer migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0469] S145. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S144, wherein the patient has a 100% reduction in migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to the administration.

[0470] S146. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S145, further comprising administering a second dose of the anti-CGRP antibody to the patient about 12 weeks or about 3 months after the administration.

[0471] S147. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S146, wherein the administration comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg of the anti-CGRP antibody.

[0472] S148. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87 to S147, wherein the anti-CGRP antibody or antibody fragment is aglycosylated, or if only glycosylated, contains only mannose residues.

[0473] S149. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S148, wherein the anti-CGRP antibody consists of a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0474] S150. Use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S149, wherein the anti-CGRP antibody consists of a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0475] S151. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S150, wherein the medication overuse headache comprises (a) the patient experiences headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for more than 3 months.

[0476] S152. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S151, wherein the drug overuse includes the use of ergotamine for 10 days or more per month, the use of triptan for 10 days or more per month, the use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 days or more per month, the use of one or more multiple combination analgesics (as further described below) for 10 or more days / month, use of one or more opioids for 10 or more days / month, or use of a combination of two or more drug classes (as further described below) for 10 or more days / month, wherein the triptan use optionally includes use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or wherein the opioid use optionally includes use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone.

[0477] S153. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87 to S152, wherein the medication overuse headache comprises ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other drugs, wherein the triptan use optionally includes the use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan, and / or wherein the opioid use optionally includes the use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine and hydrocodone.

[0478] S154. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S153, wherein the non-opioid analgesic overuse headache includes acetaminophen (acetaminophen) overuse headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, such as acetylsalicylic acid (aspirin) overuse headache, or other non-opioid analgesic overuse headache.

[0479] S155. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S154, wherein the ergotamine overuse headache comprises 15 or more days / month of headache and ergotamine is used for 10 or more days / month for more than 3 months.

[0480] S156. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87 to S155, wherein the triptan overuse headache comprises headache occurring on 15 or more days / month and use of one or more triptans for 10 or more days / month for more than 3 months, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan.

[0481] S157. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S156, wherein the non-opioid analgesic overuse headache comprises headache occurring 15 or more days / month and using one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days / month for more than 3 months.

[0482] S158. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S157, wherein the combination analgesic overuse headache comprises headache occurring 15 or more days / month and using one or more combination analgesics for 10 or more days / month for more than 3 months, wherein the combination analgesic comprises two or more classes of drugs, each having an analgesic effect (e.g., acetaminophen and codeine) or as an adjuvant (e.g., caffeine), optionally, wherein the combination-analgesic combination non-opioid analgesic comprises at least one opioid (e.g., tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof), a barbiturate (e.g., ibutabarbital and / or caffeine).

[0483] S159. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S158, wherein the opioid overuse headache comprises 15 or more days / month of headache and use of one or more opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for 10 or more days / month for more than 3 months.

[0484] S160. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S159, wherein the medication overuse headache attributable to multiple drug classes rather than overuse alone comprises headaches occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for a total of at least 10 days / month for more than 3 months.

[0485] S161. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S160, wherein the medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes includes headaches occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for at least 10 days / month for more than 3 months, wherein the identity, amount and / or pattern of use or overuse of these classes of drugs cannot be reliably determined.

[0486] S162. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S161, wherein the medication overuse headache attributed to other medications includes headaches occurring 15 or more days / month and the use of one or more medications other than the above-mentioned medications for acute or symptomatic treatment of headaches for at least 10 days / month for more than 3 months.

[0487] S163. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S162, wherein the patient has a pre-existing primary headache before developing the medication overuse headache.

[0488] S164. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S163, wherein headache days and / or medication use days are determined by: patient or relative reports, diaries, medical records, medication purchase history, prescription fulfillment, biomarkers of medication use, incidence of drug toxicity, incidence of overdose, and / or other indicators of patient medication use.

[0489] S165. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any of embodiments S87-S164, wherein the medication overuse headache is diagnosed according to the International Classification of Headache Disorders, Third Edition, wherein the medication overuse headache optionally includes ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other drugs.

[0490] S166. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in any one of embodiments S87-S165, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is contained in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80 and water.

[0491] S167. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S166, wherein the formulation comprises or consists of the following items: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or an amount of each ingredient within 10% of the stated value, and having a pH of 5.8 or within + / - 10% of the stated value.

[0492] S168. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S166, wherein the formulation comprises or consists of the following items: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 5% of the stated value, and / or having a pH of 5.8 or within + / - 5% of the stated value.

[0493] S169. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S166, wherein the formulation comprises or consists of the following items: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 1% of the stated value, and / or having a pH of 5.8 or within 1% of the stated value.

[0494] S170. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S166, wherein the formulation comprises or consists of the following items: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 0.5% of the stated value, and / or having a pH of 5.8 or within 0.5% of the stated value.

[0495] S171. The use of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment as described in embodiment S166, wherein the formulation comprises or consists of the following items: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within + / - 0.1% of the stated value, and / or having a pH of 5.8 or within 0.1% of the stated value.

[0496] Further exemplary embodiments

[0497] Further exemplary embodiments of the present invention are provided as follows:

[0498] E1. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use in treating or preventing medication overuse headache.

[0499] E2. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use in treating or preventing possible medication overuse headache.

[0500] E3. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody comprises any one of Ab1-Ab14 or a fragment thereof.

[0501] E4. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody comprises Ab6 or a fragment thereof.

[0502] E5. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises light chain complementary determining region (CDR) 1, 2 and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively.

[0503] E6. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively.

[0504] E7. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0505] E8. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0506] E9. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises the light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and the heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0507] E10. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0508] E11. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222.

[0509] E12. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232.

[0510] E13. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202.

[0511] E14. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0512] E15. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202.

[0513] E16. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0514] E17. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221.

[0515] E18. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231.

[0516] E19. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0517] E20. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0518] E21. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0519] E22. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0520] E23. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in Pichia pastoris or obtained by expression in Pichia pastoris.

[0521] E24. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells or obtained by expression in CHO cells.

[0522] E25. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody is administered in an amount between about 100 mg and about 300 mg, or about 100 mg, or about 300 mg.

[0523] E26. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody is administered in an amount of 100 mg.

[0524] E27. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, further comprising administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0525] E28. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E1-E26, further comprising administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0526] E29. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the patient is a chronic migraine patient or an episodic migraine or cluster headache patient at risk of developing medication overuse headache.

[0527] E30. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to embodiment E29, wherein the patient uses acute headache medication at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0528] E31. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E29, wherein the patient uses acute headache medication at least 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0529] E32. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E30-E31, wherein the acute medication comprises the use of ergot alkaloids, triptans, non-opioid analgesics, acetaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics, or opioids.

[0530] E33. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the medication overuse headache comprises (a) the patient experiences headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for acute and / or symptomatic headache treatment for more than 3 months.

[0531] E34. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein prior to said administration, said patient exhibits about 15 to about 22 migraine days per month.

[0532] E35. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein prior to said administration, said patient exhibits about 15 to about 27 headache days per month.

[0533] E36. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein prior to said administration, said patient exhibits about 17 to about 24 headache days per month.

[0534] E37. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein prior to said administration, said patient exhibits about 15 to about 19 migraine days per month, or about 20 or about 21 headache days per month, or about 16 migraine days per month.

[0535] E38. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein said patient was diagnosed with migraine at least 10 years prior to said administration.

[0536] E39. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein said patient was diagnosed with migraine at least 15 years prior to said administration.

[0537] E40. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein said patient was diagnosed with migraine at least 18 years or at least 19 years before said administration.

[0538] E41. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the patient has at least 50% fewer migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0539] E42. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the patient has at least 75% fewer migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient before said administration.

[0540] E43. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the patient has a 100% reduction in migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient before said administration.

[0541] E44. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the patient has at least 50% fewer migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0542] E45. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the patient has at least 75% fewer migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient before said administration.

[0543] E46. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the patient has a 100% reduction in migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient before said administration.

[0544] E47. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, further comprising administering a second dose of the anti-CGRP antibody to the patient about 12 weeks or about 3 months after the administration.

[0545] E48. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the administration comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg of the anti-CGRP antibody.

[0546] E49. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the anti-CGRP antibody or antibody fragment is aglycosylated, or if only glycosylated comprises only mannose residues.

[0547] E50. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody consists of a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0548] E51. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody consists of a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0549] E52. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the medication overuse headache comprises (a) the patient experiences headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for acute and / or symptomatic headache treatment for more than 3 months.

[0550] E53. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the drug overuse comprises use of ergotamine for 10 or more days / month, use of triptan for 10 or more days / month, use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days / month, use of one or more combinations of analgesics (as further described below) for 10 or more days / month, use of one or more opioids for 10 or more days / month, or use of a combination of two or more drug classes (as further described below) for 10 or more days / month, wherein the triptan use optionally includes use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or wherein the opioid use optionally includes use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone.

[0551] E54. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the medication overuse headache comprises ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other drugs, wherein the triptan use optionally comprises the use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan, and / or wherein the opioid use optionally comprises the use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine and hydrocodone.

[0552] E55. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the non-opioid analgesic overuse headache comprises acetaminophen (acetaminophen) overuse headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, such as acetylsalicylic acid (aspirin) overuse headache, or other non-opioid analgesic overuse headache.

[0553] E56. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the ergotamine overuse headache comprises 15 or more days / month of headache and ergotamine is used for 10 or more days / month for more than 3 months.

[0554] E57. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the triptan overuse headache comprises headaches occurring 15 or more days / month and use of one or more triptans for 10 or more days / month for more than 3 months, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan.

[0555] E58. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the non-opioid analgesic overuse headache comprises headaches occurring 15 or more days per month and use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days per month for more than 3 months.

[0556] E59. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the combination analgesic overuse headache comprises headache occurring 15 or more days / month and use of one or more combination analgesics for 10 or more days / month for more than 3 months, wherein the combination analgesic comprises two or more classes of drugs, each having an analgesic effect (e.g., acetaminophen and codeine) or as an adjuvant (e.g., caffeine), optionally, wherein the combination-analgesic combination non-opioid analgesic comprises at least one opioid (e.g., tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof), a barbiturate (e.g., ibutabarbital and / or caffeine).

[0557] E60. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the opioid overuse headache comprises 15 or more days / month of headache and use of one or more opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for 10 or more days / month for more than 3 months.

[0558] E61. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the medication overuse headache attributable to multiple drug classes rather than overuse alone comprises headache occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for a total of at least 10 days / month for more than 3 months.

[0559] E62. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the medication overuse headache attributable to unspecified or unverified overuse of multiple drug classes comprises headache occurring on 15 or more days / month and use of any combination of ergotamine, triptans (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for at least 10 days / month for more than 3 months, wherein the identity, amount and / or pattern of use or overuse of these classes of drugs cannot be reliably determined.

[0560] E63. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the medication overuse headache attributed to other medications comprises headache occurring 15 or more days / month and use of one or more medications other than the above-mentioned medications for acute or symptomatic treatment of headache for at least 10 days / month for more than 3 months.

[0561] E64. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any of the preceding embodiments, wherein the patient had a pre-existing primary headache before developing the medication overuse headache.

[0562] E65. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein headache days and / or medication use days are determined by: patient or relative reports, diaries, medical records, medication purchase history, prescription fulfillment, biomarkers of medication use, incidence of drug toxicity, incidence of overdose and / or other indicators of patient medication use.

[0563] E66. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the medication overuse headache is diagnosed according to the International Classification of Headache Disorders, Third Edition, wherein the medication overuse headache optionally includes ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other drugs.

[0564] E67. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any of the preceding embodiments, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is contained in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80 and water.

[0565] E68. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within 10% of the stated values, and has a pH of 5.8 or within + / - 10% of the stated values.

[0566] E69. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 5% of the stated values, and / or has a pH of 5.8 or within + / - 5% of the stated values.

[0567] E70. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 1% of the stated values, and / or has a pH of 5.8 or within 1% of the stated values.

[0568] E71. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 0.5% of the stated values, and / or has a pH of 5.8 or within 0.5% of the stated values.

[0569] E72. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E67, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 0.1% of the stated values, and / or has a pH of 5.8 or within 0.1% of the stated values.

[0570] E73. A pharmaceutical composition comprising or consisting of: an anti-CGRP antibody or an anti-CGRP antibody fragment in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80 and water.

[0571] E74. A pharmaceutical composition as described in embodiment E73, wherein the formulation comprises or consists of the following: per 1 mL volume of aqueous solution, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within 10% of the stated values, and having a pH of 5.8 or within + / - 10% of the stated values.

[0572] E75. A pharmaceutical composition as described in embodiment E73, wherein the formulation comprises or consists of the following: per 1 mL volume of aqueous solution, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 5% of the stated values, and / or has a pH of 5.8 or within 5% of the stated values.

[0573] E76. A pharmaceutical composition as described in embodiment E73, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 1% of the stated values, and / or has a pH of 5.8 or within 1% of the stated values.

[0574] E77. A pharmaceutical composition as described in embodiment E73, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 0.5% of the stated values, and / or has a pH of 5.8 or within 0.5% of the stated values.

[0575] E78. A pharmaceutical composition as described in embodiment E73, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 0.1% of the stated values, and / or has a pH of 5.8 or within 0.1% of the stated values.

[0576] E79. A pharmaceutical composition as described in any one of embodiments E73-E79, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2, and CDR 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and heavy chain CDR 1, CDR 2, and CDR3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0577] E80. A pharmaceutical composition as described in any one of embodiments E73-E79, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0578] E81. A pharmaceutical composition as described in any one of embodiments E73-E79, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202.

[0579] E82. A pharmaceutical composition as described in any one of embodiments E73-E79, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0580] E83. A pharmaceutical composition as described in any one of embodiments E73-E79, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0581] E84. A pharmaceutical composition as described in any one of embodiments E73-E79, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0582] E85. A pharmaceutical composition as described in any one of embodiments E73-E84, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in Pichia pastoris or obtained by expressing in Pichia pastoris.

[0583] E86. A pharmaceutical composition as described in any one of embodiments E73-E84, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO or obtained by expression in CHO.

[0584] E87. At least one anti-CGRP antibody or anti-CGRP antibody fragment and / or at least one anti-CGRP-R antibody or anti-CGRP-R antibody fragment for treating or preventing migraine, further comprising using at least one drug for the acute and / or symptomatic treatment of headache to treat or prevent migraine, wherein the drug is selected from the group consisting of ergot alkaloids, triptans, non-opioid analgesics, acetaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics, or opioids.

[0585] E88. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E87, wherein the combined administration of (i) and (ii) reduces the symptoms, severity and / or onset of medication overuse headache in the patient.

[0586] E89. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E87 or E88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises an ergot alkaloid.

[0587] E90. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E89, wherein the ergot alkaloid is selected from ergotamine, nicergoline, methysergide, dihydroergotamine and combinations of the foregoing.

[0588] E91. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E87 or E88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises a triptan.

[0589] E92. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E91, wherein the triptan is selected from sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, and combinations thereof.

[0590] E93. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E87 or E88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises a non-opioid analgesic.

[0591] E94. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E93, wherein the non-opioid analgesic comprises acetaminophen (paracetamol) or aspirin.

[0592] E95. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E87 or E88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises an NSAID.

[0593] E96. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E95, wherein the NSAID is selected from salicylates, propionic acid derivatives, enolic acid derivatives, anthranilic acid derivatives (fenamates), selective COX-2 inhibitors (coxibs), sulfonanilides and combinations of the foregoing.

[0594] E97. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E95, wherein the NSAID is selected from salicylates, such as aspirin (acetylsalicylic acid), diflunisal (Dolobid), salicylic acid and its salts, and salsalate (Disalcid); propionic acid derivatives, such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin and loxoprofen; acetic acid derivatives, such as indomethacin, tolmetin, sulindac, etoprin, succinate, phenoxyethanol, succinate, phenoxyethanol, succinate-containing products; todolac, ketorolac, diclofenac, aceclofenac and nabumetone; enolic acid (oxicam) derivatives, such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam and phenylbutazone (Bute); anthranilic acid derivatives (fenamates), such as mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid; selective COX-2 inhibitors (coxibs), such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib and firocoxib; sulfonanilides, such as nimesulide; clonixin, levofloxacin, H-harpagine or hookworm and combinations of the foregoing.

[0595] E98. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E87 or E88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises a non-opioid analgesic.

[0596] E99. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E87 or E88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises a combination analgesic.

[0597] E100. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E99, wherein the combination analgesic comprises a combination of a non-opioid analgesic and at least one opioid or barbiturate, such as ibutabarbital and / or caffeine; or a combination comprising acetaminophen, aspirin and caffeine, such as or EXCEDRIN Or a combination analgesic comprising an analgesic in combination with at least one non-analgesic, such as a vasoconstrictor, such as pseudoephedrine, or with an antihistamine.

[0598] E101. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to embodiment E87 or E88, wherein the medicament for the acute and / or symptomatic treatment of headache comprises an opioid.

[0599] E102. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E101, wherein the opioid is selected from oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, thebaine, oripavine, mixed opioid alkaloids such as opium, diacetylmorphine, nicotinic morphine, dipropionylmorphine, diacetyldihydromorphine, levulinylmorphine, normorphine , methylnormorphine, dibenzoylmorphine, ethylmorphine, heterocodeine, buprenorphine, etorphine, hydromorphone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanil, sufentanil, remifentanil, carfentanil, hydroxymethylfentanyl, pethidine (meperidine), ketobemidone, MPPP, allylprodine, prodinatin, PEPAP, meperidine, diphenylhexamine, propoxyphene, dextropropoxyphene, dextromalamide, benzathine, pirithramide, and combinations of the foregoing.

[0600] E103. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87-E102, wherein the anti-CGRP antibody comprises any one of Ab1-Ab14 or a fragment thereof.

[0601] E104. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E103, wherein the anti-CGRP antibody comprises Ab6 or a fragment thereof.

[0602] E105. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E104, wherein the anti-CGRP antibody comprises light chain complementary determining region (CDR) 1, 2 and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively.

[0603] E106. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E105, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively.

[0604] E107. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E106, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0605] E108. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E107, wherein the anti-CGRP antibody comprises heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0606] E109. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E108, wherein the anti-CGRP antibody comprises the light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and the heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0607] E110. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E109, wherein the anti-CGRP antibody comprises light chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively, and heavy chain CDR 1, CDR 2, and CDR 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0608] E111. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E110, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222.

[0609] E112. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E111, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232.

[0610] E113. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E112, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202.

[0611] E114. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E113, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0612] E115. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E114, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202.

[0613] E116. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E115, wherein the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232 and a variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0614] E117. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E116, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221.

[0615] E118. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E117, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231.

[0616] E119. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E118, wherein the anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0617] E120. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E119, wherein the anti-CGRP antibody comprises a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0618] E121. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E120, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0619] E122. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E121, wherein the anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0620] E123. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E122, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in Pichia pastoris or obtained by expression in Pichia pastoris.

[0621] E124. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E123, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells or obtained by expression in CHO cells.

[0622] E125. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E124, wherein the anti-CGRP antibody is administered in an amount between about 100 mg and about 300 mg, or about 100 mg, or about 300 mg.

[0623] E126. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E125, wherein the anti-CGRP antibody is administered in an amount of 100 mg.

[0624] E127. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E126, further comprising administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0625] E128. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E127, further comprising administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks.

[0626] E129. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E128, wherein the patient is a chronic migraine patient or an episodic migraine or cluster headache patient at risk of developing medication overuse headache.

[0627] E130. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E129, wherein the patient uses acute headache medication at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0628] E131. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E130, wherein the patient uses acute headache medication at least 10 days per month, wherein optionally, the acute medication use is determined during a baseline period of at least 28 days.

[0629] E132. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E131, wherein the medication overuse headache comprises (a) the patient experiencing headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for acute and / or symptomatic headache treatment for more than 3 months.

[0630] E133. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E132, wherein prior to said administration, said patient exhibits about 15 to about 22 migraine days per month.

[0631] E134. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E133, wherein prior to said administration, said patient exhibits about 15 to about 27 headache days per month.

[0632] E135. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E134, wherein prior to said administration, said patient exhibits about 17 to about 24 headache days per month.

[0633] E136. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E135, wherein prior to said administration, said patient exhibits about 15 to about 19 migraine days per month, or about 20 or about 21 headache days per month, or about 16 migraine days per month.

[0634] E137. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E136, wherein said patient was diagnosed with migraine at least 10 years prior to said administering.

[0635] E138. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E137, wherein said patient was diagnosed with migraine at least 15 years prior to said administering.

[0636] E139. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E138, wherein the patient was diagnosed with migraine at least 18 years or at least 19 years before said administration.

[0637] E140. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E139, wherein the patient has at least 50% fewer migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0638] E141. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E140, wherein the patient has at least 75% fewer migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0639] E142. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E141, wherein the patient has a 100% reduction in migraine days within one month after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0640] E143. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E142, wherein the patient has at least 50% reduction in migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient before said administration.

[0641] E144. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E143, wherein the patient has at least 75% less migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient before said administration.

[0642] E145. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E144, wherein the patient has a 100% reduction in migraine days within 12 weeks after being administered the antibody, relative to the baseline number of migraine days experienced by the patient prior to said administration.

[0643] E146. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E145, further comprising administering a second dose of the anti-CGRP antibody to the patient about 12 weeks or about 3 months after said administration.

[0644] E147. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E146, wherein the administration comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg of the anti-CGRP antibody.

[0645] E148. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E147, wherein the anti-CGRP antibody or antibody fragment is aglycosylated, or if only glycosylated comprises only mannose residues.

[0646] E149. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E148, wherein the anti-CGRP antibody consists of a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0647] E150. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87-E149, wherein the anti-CGRP antibody consists of a light chain polypeptide encoded by SEQ ID NO: 231 and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0648] E151. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E150, wherein the medication overuse headache comprises (a) the patient experiences headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overuses one or more medications for more than 3 months.

[0649] E152. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E151, wherein the drug overuse comprises use of ergotamine for 10 or more days / month, use of triptan for 10 or more days / month, use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days / month, use of one or more multiple combination analgesics (as further described below) for 10 or more days / month, use of one or more opioids for 10 or more days / month, or use of a combination of two or more drug classes (as further described below) for 10 or more days / month, wherein the triptan use optionally includes use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or wherein the opioid use optionally includes use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone.

[0650] E153. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E152, wherein the medication overuse headache comprises ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other medications, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan, and / or wherein the opioid use optionally comprises use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine and hydrocodone.

[0651] E154. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E153, wherein the non-opioid analgesic overuse headache comprises acetaminophen (acetaminophen) overuse headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, such as acetylsalicylic acid (aspirin) overuse headache, or other non-opioid analgesic overuse headache.

[0652] E155. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E154, wherein the ergotamine overuse headache comprises 15 or more days / month of headache and ergotamine is used for 10 or more days / month for more than 3 months.

[0653] E156. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E155, wherein the triptan overuse headache comprises headaches occurring 15 or more days / month and use of one or more triptans for 10 or more days / month for more than 3 months, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan.

[0654] E157. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E156, wherein the non-opioid analgesic overuse headache comprises headache occurring 15 or more days / month and use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days / month for more than 3 months.

[0655] E158. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E157, wherein the combination analgesic overuse headache comprises headache occurring 15 or more days / month and use of one or more combination analgesics for 10 or more days / month for more than 3 months, wherein the combination analgesic comprises two or more classes of drugs, each having an analgesic effect (e.g., acetaminophen and codeine) or as an adjuvant (e.g., caffeine), optionally, wherein the combination-analgesic combination non-opioid analgesic comprises at least one opioid (e.g., tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof), a barbiturate (e.g., ibutabarbital and / or caffeine).

[0656] E159. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E158, wherein the opioid overuse headache comprises 15 or more days / month of headache and use of one or more opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for 10 or more days / month for more than 3 months.

[0657] E160. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E159, wherein the medication overuse headache attributable to multiple drug classes rather than overuse alone comprises headache occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for a total of at least 10 days / month for more than 3 months.

[0658] E161. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E160, wherein the medication overuse headache attributable to unspecified or unverified overuse of multiple drug classes comprises headache occurring on 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for at least 10 days / month for more than 3 months, wherein the identity, amount and / or pattern of use or overuse of these classes of drugs cannot be reliably determined.

[0659] E162. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E161, wherein the medication overuse headache attributed to other medications comprises headache occurring 15 or more days / month and use of one or more medications other than the above-mentioned medications for acute or symptomatic treatment of headache for at least 10 days / month for more than 3 months.

[0660] E163. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use according to any one of embodiments E87 to E162, wherein the patient had a pre-existing primary headache prior to developing the medication overuse headache.

[0661] E164. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E163, wherein headache days and / or medication use days are determined by: patient or relative report, diary, medical record, medication purchase history, prescription fulfillment, biomarkers of medication use, incidence of drug toxicity, incidence of overdose and / or other indicators of patient medication use.

[0662] E165. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E164, wherein the medication overuse headache is diagnosed according to the International Classification of Headache Disorders, Third Edition, wherein the medication overuse headache optionally includes ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other drugs.

[0663] E166. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in any one of embodiments E87 to E165, wherein the anti-CGRP antibody or anti-CGRP antibody fragment is contained in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80 and water.

[0664] E167. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E166, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or having an amount of each ingredient within 10% of the stated values, and having a pH of 5.8 or within + / - 10% of the stated values.

[0665] E168. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E166, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 5% of the stated values, and / or has a pH of 5.8 or within + / - 5% of the stated values.

[0666] E169. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E166, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 1% of the stated values, and / or has a pH of 5.8 or within 1% of the stated values.

[0667] E170. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E166, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 0.5% of the stated values, and / or has a pH of 5.8 or within 0.5% of the stated values.

[0668] E171. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment for use as described in embodiment E166, wherein the formulation comprises or consists of the following: per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-histidine, 40.5 mg sorbitol and 0.15 mg polysorbate 80, or has an amount of each ingredient within + / - 0.1% of the stated values, and / or has a pH of 5.8 or within 0.1% of the stated values.

[0669] Example

[0670] The following examples are provided to illustrate the invention but should not be construed as limiting the scope of the claims in any way.

[0671] Example 1

[0672] Preparation of antibodies binding to CGRP

[0673] have Figure 1A-12 The preparation of exemplary anti-CGRP antibodies Ab1-Ab14 of sequences in is disclosed in co-owned PCT application WO / 2012 / 162243 (published on November 29, 2012), the contents of which are incorporated herein by reference. The present application exemplifies the synthesis of these antibodies in Pichia pastoris cells. The applicant further contemplates the synthesis of anti-CGRP antibodies Ab1-Ab14 and particularly Ab6 in CHO cells.

[0674] Example 2

[0675] Human clinical studies to evaluate the safety and efficacy of anti-CGRP antibodies according to the present invention

[0676] Clinical treatment plan

[0677] The ability of a humanized anti-CGRP IgG1 antibody identified herein as Ab6 to inhibit, reduce or prevent the number, duration and / or intensity of migraine attacks was evaluated in human subjects. The Ab6 antibody comprises V sequences of SEQ ID NO: 222 and SEQ ID NO: 221, respectively. L and light chain polypeptides, and comprising V and L polypeptides of SEQ ID NO: 202 and SEQ ID NO: 201, respectively. H The antibody comprises an IgG1 constant region comprising a mutation in the heavy chain constant region (the asparagine residue at position 297 is substituted with an alanine residue, which substantially eliminates glycosylation and cleavage activity (see U.S. Pat. No. 5,624,821).

[0678] Specifically, the clinical efficacy of Ab6 antibody was tested in a placebo-controlled double-blind randomized study. All individuals in the study were selected according to specific criteria. In particular, all patients diagnosed with migraine aged ≤50 years (ICHD-II, 2004 Section 1) and with a history of migraine ≥12 months, with ≥5 and ≤14 migraine days in every 28 days within 3 months before screening.

[0679] In addition, all subjects in the study used acute migraine medications ≤14 days per 28 days within the 3 months prior to screening and completed an eDiary for 28 days prior to randomization, and used triptans ≤10 days per 28 days during these days.

[0680] Table 1 summarizes the demographic characteristics of the study population.

[0681]

[0682]

[0683] All individuals were required to record their migraines daily throughout the study using an electronic diary (e-diary). In the e-diary, study participants were asked to record the number of migraine days / month, number of migraine attacks / month, number of migraine hours / month, migraine severity, and any use of abortive medications (such as triptans).

[0684] Additionally, study participants were asked to record their migraines using an electronic diary for 28 days prior to treatment with the antibody or placebo to establish a monthly baseline of migraine days / hours / attacks. Also, this familiarized study participants with the use of an electronic diary.

[0685] After a 28-day run-in, the subjects in the study were divided into two groups, each consisting of 80 subjects ( Fig.17 In the first group, the antibody treatment group (n=80), each subject in the group was administered a single 1000 mg dose of Ab6 intravenously. In the second group (n=80), the placebo group, each subject was given an intravenous injection of only an aqueous solution containing the antibody carrier.

[0686] Individuals in the treatment and placebo groups were evaluated over the 24 weeks following administration. Initially, a 12-week interim analysis was performed. After the 12-week interim analysis, a refined analysis was performed. This refined analysis may include, for example, adding or removing patient data according to the study protocol, for example, updating data that has not been fully loaded from the e-diary. This refinement resulted in slight changes, but did not change the overall conclusions.

[0687] The efficacy of the antibody compared to placebo was assessed in part based on data recorded in electronic diary entries. For example, the analysis included comparing the subjects' recorded migraine days / month, migraine attacks / month, and migraine hours / month between the treatment group and the placebo group. The percentage of responders (i.e., subjects with a 50%, 75%, and 100% reduction in migraine days) in each group was also compared between the two groups.

[0688] In addition, the responses of Ab6- and placebo-treated subjects in both groups to the MSQ and HIT-6 questionnaires will be assessed and compared. The MSQ is a commonly used disease-specific instrument for assessing the impact of migraine on health-related quality of life (HRQL). The MSQ contains a 16-item migraine-specific quality of life questionnaire (version 1.0) developed by Glaxo Wellcome Inc. It is assumed that the MSQ can measure 3 parameters: (i) role function-limitation; (ii) role function-preventive; and (iii) emotional function.

[0689] The HIT-6 or Functional Impact (also called the Headache Impact Test or HIT-6) is similarly a well-known tool for assessing the intensity of migraines. This test uses six questions to describe the impact of headaches and their treatment on an individual's functional health and well-being.

[0690] Likewise, the pharmacokinetic (PK) properties and immunogenicity of the CGRP antibody will be evaluated in Ab6 antibody-treated subjects.

[0691] Clinical results and analysis

[0692] The results of this human clinical trial and analyses through Week 12 in treated subjects are summarized in Table 2 below.

[0693] Table 2. Responder analysis on migraine day

[0694]

[0695] In addition, clinical study results were compared based on the number of responders in the treatment and placebo groups. Fig.13 As shown in the Figure, the number of subjects in the treatment group and the placebo group who achieved a 50%, 75% or 100% reduction in the number of migraine days per month during the period was compared. As shown, 60% of the subjects in the Ab6 treatment group achieved at least a 50% reduction in headache days, 31% of the subjects in the Ab6 treatment group achieved at least a 75% reduction in headache days, and 15% of the subjects in the Ab6 treatment group achieved a 100% reduction in headache days.

[0696] In comparison, 33% of the placebo-treated subjects had at least a 50% reduction in headache days, 9% of the placebo-treated subjects had at least a 75% reduction in headache days, and 0% of the placebo-treated subjects (none) had a 100% reduction in headache days.

[0697] These results clearly show that the Ab6 treatment group had a greater reduction in migraine days. But the difference between these numbers would have been much more pronounced with a significant placebo effect. (An elevated placebo effect is not surprising, as it is typically high for migraine and other neurological drugs).

[0698] In addition, the percentage change from baseline in the number of migraine days per month was compared between the placebo group and the Ab6-treated group. Fig.14 As shown in the table, the median (±QR) % change in the number of migraine days per month from baseline within 12 weeks after treatment was compared between the placebo and Ab6 treatment groups. These statistically significant results (p=0.0078) clearly show that the Ab6 treatment group had a greater reduction in the number of headache days per month from baseline than the placebo treatment group.

[0699] In addition, the percentage change from baseline in the number of monthly migraine attacks was compared between the placebo group and the Ab6-treated group. Fig.15 As shown in, the median (±QR) % change in the number of monthly migraine attacks from baseline over the 12 weeks after treatment was compared between the placebo and Ab6 treatment groups. These results show that the Ab6 treatment group had a significantly greater reduction in the number of monthly migraine attacks from baseline compared to the placebo treatment group.

[0700] In addition, the percentage change from baseline in monthly migraine hours was compared between the placebo and Ab6 treatment groups. Fig.16 As shown in the Figure 2, the median (±QR) % change in monthly migraine hours from baseline over the 12 weeks after treatment was compared between the placebo and Ab6 treatment groups. These results clearly show that the Ab6 treatment group had a greater reduction in monthly migraine hours from baseline than the placebo treatment group.

[0701] Additionally, the HIT-6 results were compared between the two groups. As mentioned previously, this questionnaire has found recognized usage in assessing migraine status in patients with frequent / chronic migraine. Fig.18 The HIT-6 responder analysis of the Ab6-treated group and the placebo group was compared at baseline, week 4, week 8, and week 12. The results at each time point showed that the Ab6-treated group had a statistically significant improvement in HIT-6 scores compared to the placebo group, i.e., 54.4% in the Ab6-treated group vs. 30% in the placebo group at week 4 (p=0.0023), 51.3% in the Ab6-treated group vs. 38.0% in the placebo group at week 8 (p=0.1094), and 61.1% in the Ab6-treated group vs. 33.3% in the placebo group at week 12 (p=0.0007). Fig.19 The percentages of patients in the placebo and Ab6 treatment groups with some or low / no HIG-6 scores over time are shown (statistically significant).

[0702] in addition, Fig. 20 Contains the pharmacokinetic (PK) profile of Ab6 administered intravenously at a single dose of 1000 mg (mg / mL) over 24 weeks after Ab6 administration.

[0703] Fig.21 The plasma-free pharmacokinetic (PK) parameters N (number of patients), mean values ​​and standard deviations (SD) of a single dose of 1000 mg of Ab6 are shown in Table 1. The parameters and units shown in the table are C max (μg / mL), AUC 0-∞ (mg*hr / mL), half-life (days), V z (L) and C L (mL / hr).

[0704] Patient data were further analyzed at weeks 12 to 24. The treatment group continued to show a reduction in migraine days compared to the control group, however, the magnitude of the difference decreased over time. In addition, the control group showed fewer migraine days per month than at baseline. This is thought to be due, at least in part, to "diary fatigue," in which patients may not report a migraine on the day it actually occurred, avoiding the time and effort of answering additional questions about migraine because they gave a positive answer to the question of whether they had a migraine on a given day.

[0705] Further analysis of the findings showed that Figure 22-33 These results included analysis of the change from baseline in the number of migraine days per month for Ab6 (1000 mg iv) compared to placebo (mean + / - SEM) ( Fig. 22 ), mean number of migraine days over time for the entire analysis group (+ / -SD) ( Fig.23 In addition, the actual distribution and change of migraine days in the Ab6 treatment group during weeks 1-4 are shown ( Fig.24 ), distribution and change of actual number of migraine days in the placebo group during weeks 1-4 ( Fig.25 ), the actual distribution and changes of migraine days in the A...

Claims

1. Use of an anti-CGRP antibody or an anti-CGRP antibody fragment in the preparation of a medicament for treating or preventing medication overuse headache, wherein the anti-CGRP antibody comprises the light chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively, and the heavy chain CDR 1, CDR 2 and CDR 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

2. The use of claim 1, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO:

202.

3. The use of claim 1 or 2, wherein the anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO:

566.

4. The use of any one of claims 1-3, wherein the dose of the anti-CGRP antibody is between about 100 mg and about 300 mg, or is about 100 mg, or is about 300 mg.

5. The use of any one of claims 1-4, wherein the patient is a chronic migraine patient or an episodic migraine or cluster headache patient at risk for developing medication overuse headache.

6. The use of any one of claims 1-5, wherein the medication overuse headache comprises (a) the patient experiencing headaches 15 or more days / month, wherein the patient has a pre-existing headache disorder; and (b) the patient overusing one or more medications for acute and / or symptomatic headache treatment for more than 3 months.

7. The use of any one of claims 1-6, wherein the drug overuse comprises use of ergotamine for 10 or more days / month, use of a triptan for 10 or more days / month, use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days / month, use of one or more combination analgesics (as further described below) for 10 or more days / month, use of one or more opioids for 10 or more days / month, or use of a combination of two or more drug classes (as further described below) for 10 or more days / month, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or wherein the opioid use optionally comprises use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone.

8. The use of any one of claims 1-7, wherein the medication overuse headache comprises ergotamine overuse headache, triptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, medication overuse headache attributed to multiple drug classes rather than overuse alone, medication overuse headache attributed to unspecified or unverified overuse of multiple drug classes, or medication overuse headache attributed to other medications, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or wherein the opioid use optionally comprises use of one or more of oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone.

9. The use of claim 8, wherein the non-opioid analgesic overuse headache comprises acetaminophen (acetaminophen) overuse headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, such as acetylsalicylic acid (aspirin) overuse headache, or other non-opioid analgesic overuse headache.

10. The use of claim 8 or 9, wherein the triptan overuse headache comprises headaches occurring 15 or more days / month and use of one or more triptans for 10 or more days / month for more than 3 months, wherein the triptan use optionally comprises use of one or more of sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and frovatriptan.

11. The use of any one of claims 8-10, wherein the non-opioid analgesic overuse headache comprises headaches occurring 15 or more days per month and use of one or more non-opioid analgesics (e.g., acetaminophen (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic) for 15 or more days per month for more than 3 months.

12. The use of any one of claims 8-11, wherein the combination analgesic overuse headache comprises headaches occurring 15 or more days / month and use of one or more combination analgesics for 10 or more days / month for more than 3 months, wherein the combination analgesic comprises two or more classes of drugs, each having an analgesic effect (e.g., acetaminophen and codeine) or as an adjunct (e.g., caffeine), optionally wherein the combination-analgesic combination non-opioid analgesic comprises at least one opioid (e.g., tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof), a barbiturate (e.g., ibutabarbital and / or caffeine).

13. The use of any one of claims 8-12, wherein the opioid overuse headache comprises headaches occurring 15 or more days / month and use of one or more opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for 10 or more days / month for more than 3 months.

14. The use of any one of claims 8-13, wherein the medication overuse headache attributable to multiple drug classes rather than overuse alone comprises headaches occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics, and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for a total of at least 10 days / month for more than 3 months.

15. The use of any one of claims 8-14, wherein the medication overuse headache attributable to unspecified or unverified overuse of multiple drug classes comprises headaches occurring 15 or more days / month and use of any combination of ergotamine, triptan (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, or any combination thereof), non-opioid analgesics, and / or opioids (e.g., oxycodone, tramadol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof) for at least 10 days / month for more than 3 months, wherein the identity, amount, and / or pattern of use or overuse of these classes of drugs cannot be reliably determined.

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