Treatment of medication overuse headache using Anti-CGRP or Anti-CGRP-r antibodies

Abstract

To provide methods for treatment or prevention of medication overuse headache.SOLUTION: The present invention provides a method comprising administering to a patient in need thereof an effective amount of at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or anti-CGRP-R antibody fragment.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application is a continuation of U.S. Provisional Patent Application No. 62 / 840,967, filed April 30, 2019. No. (Attorney Reference No. 1143257.008800); filed on May 1, 2019 No. 62 / 841,585 (Attorney Docket No. 1143257.0088) No. 01); and U.S. Provisional Patent Application No. 62 / 872,98, filed July 11, 2019. Claiming priority to No. 3 (Attorney Reference Number 1143257.008802) No. 6,399,633, all of which are incorporated herein by reference in their entireties.

[0002] Disclosure of sequence listing This application contains a sequence listing submitted in ASCII format via EFS-Web. , which is incorporated herein by reference in its entirety. It was created on December 11th, named "1143257o008803.txt", and has 35 It is 7,503 bytes in size.

[0003] Background Fields The present invention relates to a method for the production of a compound that specifically binds to human calcitonin gene-related peptide (hereinafter, "CGRP"). Antibodies and fragments thereof (including Fab fragments) that bind to human calcitonin gene-related peptides Antibodies and fragments thereof (Fa The administration of the antibody or a fragment thereof, which contains the antibody α-aminobutyric acid ... The present invention relates to methods for preventing or treating diseases and disorders associated with CGRP. [Background technology]

[0004] Calcitonin gene-related peptide (CGRP) is a 37 amino acid long multifunctional neuropeptide. Two forms of CGRP, CGRP-α and CGRP-β, are produced by the CGRP-α and CGRP-β are present in three receptors in humans and have similar activity. CGRP is produced in many tissues, including the trigeminal nerve. When released and activated, neuropeptides are released in the meninges, causing vasodilation, vascular leakage, and obesity. Mediates neurogenic inflammation characterized by cell destruction. Durham, PL, New E ng.J.Med.,350(11):1073-75(2004). Biology of CGRP The therapeutic effect of CGRP is mediated by the CGRP receptor (CGRP-R), which consists of seven transmembrane domains. CGRP-R is mediated by binding to the receptor for receptor-associated membrane proteins (RAMPs). The receptor component T is essential for efficient coupling to the adenovirus-associated adenylyl cyclase and production of cAMP. Doods, H., Curr. Op. In vest.Drugs,2(9):1261-68(2001).

[0005] Migraine is a neurovascular disorder that affects approximately 10% of the adult population in the United States and is typically characterized by severe headaches. CGRP is thought to play a prominent role in the pathogenesis of migraines. In fact, several companies, namely Amgen, Eli Lilly, Teva and Al der Biopharmaceuticals (Lundbeck A / S) Recently obtained, the present invention provides an anti-CGRP antibody and an anti-CGRP antibody for use in the treatment or prevention of migraine. The assignee has developed an RP-R antibody, "ANTI-CGRP COMPOSITION S AND USE THEREOF” was filed on May 21, 2012. PCT Application International Publication No. 2012 / 162243 Brochure, "USE OF ANT I-CGRP ANTIBODIES AND ANTIBODY FRAGMENTS TO PREVENT OR INHIBIT PHOTOPHOBIA OR LI GHT AVERSION IN SUBJECTS IN NEED THEREOF ,ESPECIALLY MIGRAINE SUFFERERS" PCT Application WO 2012 / 162257 filed on May 21, 2012 "USE OF ANTI-CGRP OR ANTI-CGRP-R ANTIB ODIES OR ANTIBODY FRAGMENTS TO TREAT OR PREVENT CHRONIC AND ACUTE FORMS OF DIARR PCT application WO 2012 / 05 / 21 entitled "HEA" / 162253 pamphlet and "REGULATION OF GLUCOSE Titled "METABOLISM USING ANTI-CGRP ANTIBODIES" PCT application WO 2015 / 003122, filed July 3, 2014 No. 5,333,363, all of which are incorporated by reference in their entireties. The company has previously filed patent applications relating to GRP antibodies and their uses. Summary of the Invention

[0006] The present disclosure relates to, for example, overuse of anti-migraine medications and / or triptans and / or ergots. and / or a method for treating or preventing medication-overuse headache associated with analgesic drug abuse, comprising and administering to a patient suffering from the disease an effective amount of at least one anti-CGRP antibody or antibody fragment or anti-CGRP antibody or RP-R antibody or antibody fragment or said antibody or antibody fragment disclosed herein. The method further comprises administering to the patient one or more formulations comprising the anti-CGRP antibody or antibody fragment thereof. The fragments may, for example, comprise the light chain CDRs of SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:228, respectively. 1, 2, and 3 polypeptide sequences and SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO: 208 heavy chain CDR 1, 2, and 3 polypeptide sequences; or 34; SEQ ID NO:236; and light chain CDRs 1, 2, and 3 polypeptide sequences, respectively, SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218. Ab1 to have a heavy chain CDR 1, 2, and 3 polypeptide sequence encoded by Optionally, Ab14 or any one of its Fab fragments, e.g., Ab6 or its Fab fragment. The anti-CGRP antibody optionally comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: The anti-CGRP antibody may comprise a variable heavy chain polypeptide of SEQ ID NO: 232. and a variable light chain polypeptide encoded by SEQ ID NO:212. The anti-CGRP antibody may comprise a light chain polypeptide of SEQ ID NO: 221 and and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The antibody comprises a light chain polypeptide encoded by SEQ ID NO:231 and a light chain polypeptide encoded by SEQ ID NO:211 or The anti-CGRP antibody may comprise a heavy chain polypeptide encoded by sequence number 567. The variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202 are The antibody may include an antibody expression product isolated from a recombinant cell expressing a nucleic acid sequence encoding the antibody. These polypeptides optionally include human light and heavy chain constant region polypeptides, e.g., Each of these constant regions is linked to a human IgG1, IgG2, IgG3, or IgG4 constant region. The region may optionally be modified to alter glycosylation or proteolysis. The recombinant cell is optionally a yeast or mammalian cell, e.g., Pichia pastoris. The anti-CGRP antibody includes Pichia pastoris or CHO cells. 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. It can include the antibody expression product isolated from a recombinant cell expressing the encoding nucleic acid sequence. The recombinant cell may be a yeast or a mammalian cell, such as Pichia pastoris (Pichia pastoris). hia pastoris or CHO cells, the constant region of which is Optionally modified to alter silylations or proteolysis or other effector functions. Any of the above-mentioned anti-CGRP antibodies or antibody fragments, preferably Ab6, can be used in any Optionally, for example, histidine (L-histidine), sorbitol, polysorbate 80, e.g., about 100 mg of anti-CGRP antibody per mL volume, about 3 0.1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg poly sorbate 80. The amount is about 100 mg to about 300 mg, for example, about 100 mg, about 300 mg, 100 mg or 300 mg. The dosage can be administered by different means, for example, intravenously, For example, a suitable volume (e.g., 100 mL) of saline solution such as 0.9% sodium chloride It may also be administered in water.

[0007] The medication overuse headache may be determined based on fulfilling the following criteria: (b) headache occurring 15 or more days per month in patients with an existing headache disorder; and Excessive use of one or more drugs taken for sexual and / or symptomatic treatment for more than 3 months .

[0008] The excessive use is defined as the use of ergot alkaloids (e.g., ergotamine) for 10 days or more per month. use of triptans on ≥10 days / month; use of one or more non-opioids on ≥15 days / month Painkillers (e.g. paracetamol (acetaminophen), acetylsalicylic acid (aspirin) use of antidepressants (analgesics, other NSAIDs, or other non-opioid painkillers) for ≥10 days / month Use of one or more combination analgesics (described further below), including one or more on 10 days / month or more Use of any of the above opioids or two or more drug classes (described further below) on ≥10 days / month The present invention may include the use of a combination of

[0009] In the methods herein, the triptans include, inter alia, sumatriptan, zolmitri triptan, naratriptan, rizatriptan, eletriptan, almotriptan, and triptans, such as lobatriptan, any one or any combination thereof. Not limited to.

[0010] The drug overuse headaches are ergotamine overuse headaches, triptan overuse headaches, non-ophthalmic opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache , medication overuse headache resulting from multiple drug classes that are not individually overused, multiple medications Medication overuse headache due to unspecified or untested overuse of a drug class; or May include medication overuse headaches caused by other medications.

[0011] Non-opioid analgesic overuse headache is caused by excessive use of paracetamol (acetaminophen). use headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, e.g. acetylsalicylic acid Aspirin overuse headache or ibuprofen overuse headache, or another non-opioid These may include idiopathic analgesic overuse headache.

[0012] The ergotamine overuse headache occurred 15 days / month in patients with pre-existing primary headache ergot alkaloids such as ergotamine, occurring for ≥10 days / month for ≥3 months These may include headaches that develop as a result of regular use of

[0013] In the methods herein, the ergot alkaloids are ergotamine, nicergoline, methicillin, It may also include ergotamine, ruthenium, or dihydroergotamine.

[0014] The triptan overuse headache was observed 15 days or more per month in patients with pre-existing primary headache. occurs as a result of regular use of one or more triptans for 10 days / month or more over a 3-month period. These symptoms may include headaches as a result.

[0015] Non-opioid analgesic overuse headache occurred in 15 to 20 patients with pre-existing primary headache. ≥ 1 non-opioid analgesic on ≥ 15 days / month over ≥ 3 months (Paracetamol (acetaminophen), acetylsalicylic acid (aspirin), ibuprape as a result of regular use of antidepressants (such as bronchodilators, another NSAID, or another non-opioid pain reliever) These may include headaches that occur after a period of stress.

[0016] In the methods herein, the NSAID is ibuprofen, naproxen, or indole. May include any NSAID or combination thereof, including but not limited to methacin .

[0017] The combination analgesic overuse headache was ≥1 headache occurring ≥10 days / month for ≥3 months. Headaches occurring 15 days or more per month as a result of regular use of a combination of painkillers In the context of medication overuse headache, the term combination analgesics may include Two or more classes of drugs with the same effect (e.g. paracetamol and codeine), or A combination painkiller combined with a drug that acts as an adjuvant (e.g., caffeine) A commonly overused combination of analgesics is a combination of a non-opioid analgesic and and one opioid, barbiturate, e.g. butalbital and / or caffeine. In an exemplary embodiment, the combination analgesic overuse headache is Phen, aspirin, and caffeine, such as EXCEDRIN® or EX CEDRIN MIGRAINE® combination. The combined analgesic agent may contain at least one non-analgesic agent, e.g., a pseudomycin for sinus-related preparations. Vasoconstrictors such as doephedrine, antihistamines used to treat allergy sufferers This includes painkillers combined with antidepressants, etc.

[0018] The opioid overuse headache was observed in patients with pre-existing primary headaches on 15 or more days per month. Occurring above 10 days / month for 3 months or more, as a result of regular use of 1 or more opioids These symptoms may include headaches as a result.

[0019] Medication overuse headaches caused by multiple drug classes that are not individually overused are considered to be Occurring ≥15 days / month in patients with primary headache and associated with only a single drug or drug class Ergotamine for a total of at least 10 days / month over a 3-month period without excessive use; Regular intake of any combination of triptans, non-opioid analgesics and / or opioids Symptoms may include headaches that develop as a result of taking it.

[0020] In the methods herein, the opioid may be, among others, oxycodone, tramadol, butyrate, or benzodiazepine. Lufanol, morphine, codeine, hydrocodone, thebaine, oripavine, mixed opium Alkaloids, such as papaveretum, diacetylmorphine, nicomorphine, dipropanoic acid Diacetylhydromorphine, Acetylpropionylmorphine, Desomorphine , methyldesorphine, dibenzoylmorphine, ethylmorphine, heterocodeine, bupoxycycline Renorphine, etorphine, hydromorphone, oxymorphone, fentanyl, alpha Methylfentanyl, alfentanil, sufentanil, remifentanil, carfe phenantanil, omefentanil, pethidine (meperidine), ketobemidone, MPPP, Rilprozine, Prozine, PEPAP, Promedol, Diphenylpropylamine, Pro Poxyphene, dextropropoxyphene, dextromoramide, bezitramide, pyrimidine Any one or any combination of opioid drugs, including but not limited to tramide It could be.

[0021] The medication overuse headache resulting from unspecific or untested overuse of multiple drug classes is Occurring ≥15 days / month in patients with pre-existing primary headache and associated with a single drug or drug class ergotamine for at least 10 days / month for at least 3 months, without excessive use of ergotamine alone Regular intake of any combination of triptans, non-opioid analgesics and / or opioids The identity, amount, and / or class of these drugs may include headaches that occur as a result of taking Patterns of use or overuse have not been reliably established.

[0022] Medication overuse headache due to other medications is considered to be a common symptom in patients with pre-existing primary headaches. Occurring ≥15 days / month and for at least 3 months for the acute or symptomatic treatment of headache As a result of regular ingestion of one or more drugs other than those listed above, taken for at least 10 days / month These symptoms may include a persistent headache.

[0023] The amount and duration of drug use were determined based on patient or relative reported use, diaries, and medical records. Medical records, drug purchase history, prescription fulfillment, biomarkers of drug use, and drug toxicity Known methods, such as incidence, incidence of drug overdose, and / or other indicators of patient drug use. can be determined using

[0024] The present disclosure provides a method for treating or preventing headaches due to potential medication overuse, the method comprising: an effective amount of an anti-CGRP antibody or an anti-CGRP antibody fragment disclosed herein, or an anti-C Administered to a patient in need of one or more preparations containing a GRP-R antibody or an anti-CGRP antibody fragment The anti-CGRP antibody may, for example, be one of SEQ ID NO: 224; 6; and the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 228 and SEQ ID NO: 2 04; SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptides of SEQ ID NO:208. or SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:238, respectively. and light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:214, respectively; SEQ ID NO:216; and heavy chain CDRs 1, 2, and 3 encoded by SEQ ID NO:218 Optionally, any one of Ab1 to Ab14, e.g., Ab6, having a polypeptide sequence The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: 2 The anti-CGRP antibody may comprise a variable heavy chain polypeptide of SEQ ID NO: 232. and a variable light chain polypeptide encoded by SEQ ID NO:212. The anti-CGRP antibody may comprise a light chain polypeptide of SEQ ID NO: 221 and The anti-CGRP antibody may comprise a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. a light chain polypeptide encoded by SEQ ID NO: 231 and a light chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: The anti-CGRP antibody may comprise a heavy chain polypeptide encoded by sequence ID No. 567. The variable light chain polypeptide of SEQ ID NO:222 and the variable heavy chain polypeptide of SEQ ID NO:202 are encoded by The antibody may include an antibody expression product isolated from a recombinant cell expressing a nucleic acid sequence encoding the antibody. These polypeptides can optionally include human light and heavy chain constant region polypeptides, e.g., human IgG1, IgG2, IgG3 or IgG4 constant regions, The common region may optionally be modified to alter glycosylation or proteolysis. Preferably, the recombinant cell is optionally a yeast or mammalian cell, such as Pichia pastoris. The anti-CGRP antibody is a Pichia pastoris or CHO cell. 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. and the antibody expression product isolated from a recombinant cell expressing a nucleic acid sequence encoding the antibody. The recombinant cell may be a yeast or a mammalian cell, such as Pichia pastoris. Optionally, the constant region comprises a glycosylated lysate, a CHO cell, or a lysosome. Optionally modified to alter cleavage or proteolysis or other effector function. Any of the above-mentioned anti-CGRP antibodies or antibody fragments, preferably Ab6, can be used in any Alternatively, for example, histidine (L-histidine), sorbitol, which has a pH of about 5.8 , polysorbate 80, e.g., about 100 mg of anti-CGRP antibody per mL volume, about 3. 1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polyisoprene. The antibody may be included in the formulations disclosed herein, including Lubet 80. is about 100 mg to about 300 mg, for example, about 100 mg, about 300 mg, 100 mg, or 300 mg. The dosage may be administered by different means, e.g., intravenously, e.g. For example, a suitable volume (e.g., 100 mL) of saline solution such as 0.9% sodium chloride Potential medication overuse headache is when criteria (a) and (b) are met. Incomplete fulfillment of the criteria, e.g., specified number of headache days per month and / or have at least 80% and / or at least 90% of the days of drug use; and / or Optionally, if there is no other ICHD-3 diagnosis, a shorter period of time, such as at least 2 months, may be considered. It refers to something that has not been fulfilled in many ways.

[0025] Drug overuse headache (ergotamine overuse headache, triptan overuse headache, non-opioid headache) opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, Medication overuse headache due to multiple drug classes that are not individually overused, multiple drugs Medication overuse headache due to class-unspecified or untested overuse, or other Medication overuse headaches due to certain drugs (e.g., medication overuse headaches) are classified as International Class The third edition of the International Conference on Headache Disorders (ICHD- 3) can be diagnosed according to the Headache Classification Com. mittee of the International Headache Soc iety(IHS),The International Classificati on of Headache Disorder,3rd edition,Ceph alalgia. 2018 Jan;38(1):1-211 (the entire disclosure is hereby incorporated by reference). (incorporated herein).

[0026] Here, the criterion for headache occurring as a "result" of drug overuse is A clear association between, for example, drug overuse and headaches, such that a causal relationship can be inferred , refers to the presence at the specified frequency above.

[0027] In some exemplary embodiments, the dose of the anti-CGRP antibody is 100 mg. This is also fine.

[0028] In another exemplary embodiment, the dose of the anti-CGRP antibody may be 300 mg. stomach.

[0029] The method further comprises administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks. may include:

[0030] The method further comprises administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks. may include:

[0031] The patient is a chronic migraine sufferer or an episodic migraine sufferer at risk of developing medication-overuse headache. The patient may be a patient who has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or The patient may use acute headache medication at least 10 days per month. Optionally, the acute drug use is determined during a baseline period of at least 28 days. The acute drug use is determined by the patient, a healthcare professional, or based on records. The acute medications may be reported as ergot alkaloids, triptans, non-opioid analgesics, etc. Medication, acetaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics, or may involve the use of opioids.

[0032] Prior to said administration, the patient should have about 15 to about 30 migraine days per month, e.g., about 16 to about 20 migraine days per month. About 28 days of migraine headaches per month, e.g., about 17 to about 26 days of migraine headaches per month, e.g., about 1 The number of 6 migraine days may be shown.

[0033] Prior to said administration, the patient is receiving about 15 to about 27 headache days per month, e.g., about 17 to about 27 headache days per month. There may be about 24 headache days, for example about 20 or about 21 headache days per month.

[0034] The patient may have had a history of at least 10 years, for example at least 15 years, prior to the administration. For example, a patient who has been diagnosed with migraine at least 18 years or at least 19 years prior to said administration. It's fine.

[0035] The patient may have had a history of rheumatoid arthritis at least 5 years prior to the administration, e.g., at least 8 years prior to the administration, e.g. For example, a patient who has been diagnosed with chronic migraine at least 11 years or at least 12 years prior to said administration. It's fine.

[0036] The patient is administered a migraine headache treatment to determine whether the patient has a baseline number of migraine days compared to the baseline number of migraine days experienced by the patient prior to the administration. and having at least a 50% reduction in the number of migraine days in the month following administration of the antibody. Good too.

[0037] The patient is administered a migraine headache treatment, the migraine headache treatment being compared to a baseline number of migraine days experienced by the patient prior to the administration. and having at least a 75% reduction in the number of migraine days in the month following administration of the antibody. Good too.

[0038] The patient is administered a migraine headache treatment to determine whether the patient has a baseline number of migraine days compared to the baseline number of migraine days experienced by the patient prior to the administration. In one embodiment, the patient may have a 100% reduction in the number of migraine days in the month following administration of the antibody.

[0039] The patient is administered a migraine headache treatment to determine whether the patient has a baseline number of migraine days compared to the baseline number of migraine days experienced by the patient prior to the administration. and at least a 50% reduction in the number of migraine days over the 12 week period following administration of the first dose. It may have.

[0040] The patient is administered a migraine headache treatment to determine whether the patient has a baseline number of migraine days compared to the baseline number of migraine days experienced by the patient prior to the administration. and having at least a 75% reduction in the number of migraine days 12 weeks after administration of the antibody. Good too.

[0041] The patient is administered a migraine headache treatment to determine whether the patient has a baseline number of migraine days compared to the baseline number of migraine days experienced by the patient prior to the administration. and may have a 100% reduction in number of migraine days 12 weeks after administering the antibody.

[0042] The method further includes administering the anti-CGRP antibody within about 12 weeks or about 3 months after said administration. to said patient, for example intravenously.

[0043] The administration may be at about 100 mg, at about 125 mg, at about 150 mg, at about 175 mg, at about 200 mg, g, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-CGRP antibody. may include.

[0044] The anti-CGRP antibody may be aglycosylated or glycosylated. In some cases, the mannose residues may be present alone.

[0045] The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 201 or The anti-CGRP antibody may consist of a heavy chain polypeptide of SEQ ID NO: 231. and a light chain polypeptide encoded by SEQ ID NO:211 or SEQ ID NO:567. The polypeptide may consist of a heavy chain polypeptide that is encoded by the

[0046] In some embodiments, the anti-human CGRP antibody or antibody fragment has the sequence of SEQ ID NO: 222. In some embodiments, the antibody comprises a variable light chain and / or a variable heavy chain of SEQ ID NO: 202. The human CGRP antibody or antibody fragment may comprise a variable light chain encoded by SEQ ID NO:232 and / or or the variable heavy chain encoded by SEQ ID NO:212.

[0047] In some embodiments, the anti-human CGRP antibody or antibody fragment has the sequence of SEQ ID NO: 221. In some embodiments, the antibody comprises a light chain and / or a heavy chain of SEQ ID NO: 201 or SEQ ID NO: 566. The anti-human CGRP antibody or antibody fragment has 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.

[0048] In some embodiments, the anti-CGRP antibody comprises the V L Polypeptides and V of SEQ ID NO:202 H From recombinant cells expressing a nucleic acid sequence encoding the polypeptide. The isolated antibody expression products may include polypeptides, which may optionally be human light chains. Chain and heavy chain constant region polypeptides, such as human IgG1, IgG2, IgG3 or Ig G4 constant region, which may optionally be glycosylated or tandemly modified. The recombinant cell may be optionally modified to alter protein degradation. or mammalian cells, such as Pichia pastoris or CHO cells.

[0049] In some embodiments, the anti-CGRP antibody has a light chain of SEQ ID NO: 221 and a light chain of SEQ ID NO: A recombinant cell expressing a nucleic acid sequence encoding the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The recombinant cell may comprise an antibody expression product isolated from a yeast or mammalian cell. Animal cells, such as Pichia pastoris or CHO The constant region may optionally be modified to modify glycosylation or proteolysis or other phenotypes. The vector can be optionally modified to alter vector function.

[0050] In some embodiments, any of the aforementioned anti-CGRP antibodies or antibody fragments is administered intracellularly, e.g., Histidine (L-histidine), sorbitol, polysorbate, which has a pH of about 5.8 80, for example, about 100 mg of anti-CGRP antibody and about 3.1 mg of L-his stidine, about 40.5 mg sorbitol, and about 0.15 mg polysorbate 80 The antibodies or fragments may be administered by different means. For example, a suitable volume (e.g., 100 mL) of 0.9% sodium chloride may be administered intravenously. It may be administered in saline, such as thorium.

[0051] 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 above. The anti-CGRP antibody or antibody fragment is administered, for example, intravenously.

[0052] In another embodiment, about 100 mg of the anti-CGRP antibody or antibody fragment is administered.

[0053] In another embodiment, about 300 mg of the anti-CGRP antibody or antibody fragment is administered intravenously, e.g., intravenously. It is administered intravenously.

[0054] In an exemplary embodiment, the anti-human CGRP antibody or antibody fragment is administered at most every 3 months or at most once a day. The antibody dose may be administered in a single formulation, for example, intravenously, at a frequency of every two weeks. or split into different formulations, which are administered approximately every 3 months or every 12 weeks. The expression "the total systemic dose may be administered in a single formulation or divided into different formulations" means By the same or different routes of administration (e.g., vi, im and / or sc) A relatively short period of time, e.g., a few hours, e.g., 1 to 8 hours, within about 1 day, within about 2 days In this context, "different" refers to administration of the recited amount of antibody within one or about one week of administration. The term "dose formulation" refers to a combination of doses that are identical in terms of the chemical composition of the pharmaceutical formulation in which each dose is administered. Whether the changes are the same or different, they may occur at different times and / or at different sites and / or through different routes. For example, concentrations, excipients, carriers, pH, etc. may vary depending on the route of administration. The doses may be the same or may vary.

[0055] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. It is administered in a single dose or split into different formulations, which can be administered approximately every 8 weeks or every 2 months. It is given.

[0056] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 12 weeks or every 3 months. is administered.

[0057] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 16 weeks or every 4 months. is administered.

[0058] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 20 weeks or every 5 months. is administered.

[0059] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 24 weeks or every 6 months. is administered.

[0060] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 28 weeks or every 7 months. is administered.

[0061] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 32 weeks or every 8 months. is administered.

[0062] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 36 weeks or every 9 months. is administered.

[0063] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 40 weeks or every 8 months. is administered.

[0064] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 44 weeks or every 9 months. is administered.

[0065] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 48 weeks or every 10 months. It is administered at .

[0066] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 52 weeks or every 11 months. It is administered at .

[0067] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or split into different formulations, which may be administered approximately every 56 weeks or every 12 months. It is administered at .

[0068] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. It is administered in one dose or split into different formulations, which is administered approximately every 15 to 18 months. will be done.

[0069] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. It is administered in one dose or split into different formulations, which is administered approximately every 18 to 21 months. will be done.

[0070] In another exemplary embodiment, the dose or amount of an anti-human CGRP antibody used in the aforementioned methods is The body fragments may be administered in a single formulation or split into different formulations, which may be done approximately every 2 years. It is administered at a frequency.

[0071] In another exemplary embodiment, the anti-human CGRP antibody used in the above method is administered systemically. will be done.

[0072] In another exemplary embodiment, the anti-human CGRP antibody or antibody fragment used in the aforementioned method is is selected from intravenous, intramuscular, intravenous, intrathecal, intracranial, topical, intranasal, and oral. In a preferred embodiment, the anti-human IgG antibody used in the above method is administered according to the mode of administration. The CGRP antibody or antibody fragment is administered intravenously.

[0073] In another exemplary embodiment, the anti-human CGRP antibody used in the aforementioned method comprises at least also has an in vivo half-life of 10 days.

[0074] In other exemplary embodiments, the anti-human CGRP antibody has an in vivo half-life of at least 15 days. It has a period.

[0075] In another exemplary embodiment, the anti-human CGRP antibody used in the aforementioned method comprises at least also has an in vivo half-life of 20 days.

[0076] In another exemplary embodiment, the anti-human CGRP antibody used in the aforementioned method comprises at least It also has an in vivo half-life of 20 to 30 days.

[0077] In another exemplary embodiment, the anti-human CGRP antibody is administered at a dose of about 100 mg to about 300 mg. and has an in vivo half-life of at least about (284±44 hours)±20%. do.

[0078] In another exemplary embodiment, the anti-human CGRP antibody used in the aforementioned method is a human α- and binds to β-CGRP.

[0079] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than or equal to 100 mg / kg of antibody. Inhibition of vasodilation induced by topically applied capsaicin at least 30 days after administration bring about.

[0080] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than or equal to 100 mg / kg of antibody. Inhibition of vasodilation induced by topically applied capsaicin at least 60 days after administration bring about.

[0081] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than or equal to 100 mg / kg of antibody. Inhibition of vasodilation induced by topically applied capsaicin at least 90 days after administration bring about.

[0082] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than or equal to 100 mg / kg of antibody. Inhibition of vasodilation induced by topically applied capsaicin after at least 120 days. results.

[0083] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than or equal to 100 mg / kg of antibody. Inhibition of vasodilation induced by topically applied capsaicin after at least 150 days. results.

[0084] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than or equal to 100 mg / kg of antibody. Inhibition of vasodilation induced by topically applied capsaicin after at least 180 days. results.

[0085] In another exemplary embodiment, the administered anti-human CGRP antibody dose is administered within 1 hour of antibody administration. Inhibition of vasodilation induced by topically applied capsaicin after more than 80 days results.

[0086] In another exemplary embodiment, the administered anti-human CGRP antibody dose is Provide sustained pharmacodynamic (PK) activity within 5% of the maximum response (Imax) (relative to the dose) Glass.

[0087] In another exemplary embodiment, the administered dose of anti-human CGRP antibody is administered at least once a day after administration of the antibody. The anti-human C PK analysis of GRP antibodies is derived from plasma concentrations.

[0088] In another exemplary embodiment, the administered anti-human CGRP antibody dose is about 100 mg to about 100 mg. About 300 mg or more, which is administered no more frequently than every two months.

[0089] The present invention further relates to specific antibodies and fragments thereof that have binding specificity for CGRP, in particular Use of antibodies with desired epitope specificity, high affinity or avidity and / or functional properties. A preferred embodiment of the present invention relates to a method for treating CGRP-related disorders, comprising administering to a subject a therapeutically effective amount of Biological activities mediated by binding of CGRP to the CGRP receptor ("CGRP-R") Use of chimeric or humanized antibodies and their fragments (including Fab fragments) capable of inhibiting For example, such antibodies can be used in combination with recombinant vectors, optionally in combination with recombinant constructs engineered to express the same. Recombinant cells, optionally yeast or mammalian cells, and optionally Pichia pastoris (Pi chia pastoris and CHO cells.

[0090] In another preferred embodiment of the present invention, the CGRP-α-, CGRP-β-, and Also contemplated are full length antibodies and Fab fragments thereof that inhibit rat CGRP-driven production. In a further preferred embodiment, the compound of the present invention reduces vasodilation in a recipient after administration. Full length and Fab fragments thereof are contemplated.

[0091] The present invention also provides an anti-CGR antibody conjugated to one or more functional or detectable moieties. The present invention also contemplates the use of conjugates of the P antibodies and binding fragments thereof. The present invention relates to the use of humanized anti-CGRP or anti-CGRP / CGRP-R complex antibodies and binding fragments thereof. In one embodiment, the binding fragments include Fab, Fab', F(ab')2, Fv, s cFv fragments, SMIPs (small molecule immunopharmaceuticals), camelbodies, nano These include, but are not limited to, antibodies, antibodies against human IgNAR ... and antibodies against human IgNAR. [Brief description of the drawings]

[0092] [Figure 1-1] 1A-1F provide the polypeptide sequences of the full-length heavy chains of antibodies Ab1-Ab14, delineated by framework regions (FR), complementarity determining regions (CDR), and constant region sequences. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 2-1] 2A-2D provide the polypeptide sequences of the full-length light chains of antibodies Ab1-Ab14, delineated by framework regions (FR), complementarity determining regions (CDR), and constant region sequences. [Figure 2-2] Same as above. [Figure 3-1] 3A-3P provide representative polynucleotide sequences encoding the full-length heavy chains of antibodies Ab1-Ab14, delimited by framework regions (FR), complementarity determining regions (CDR), and constant region coding sequences. [Figure 3-2] Same as above. [Figure 3-3] Same as above. [Diagram 3-4] Same as above. [Figure 3-5] Same as above. [Diagram 3-6] Same as above. [Diagram 3-7] Same as above. [Diagram 3-8] Same as above. [Figure 4-1] 4A-4I provide representative polynucleotide sequences encoding the full-length light chains of antibodies Ab1-Ab14, delimited by framework regions (FR), complementarity determining regions (CDR), and constant region coding sequences. [Figure 4-2] Same as above. [Figure 4-3] Same as above. [Figure 4-4] Same as above. [Figure 4-5] Same as above. [Diagram 5]Provided are polypeptide sequence coordinates within the full-length heavy chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features, including variable regions and complementarity determining regions (CDRs), as well as the SEQ ID NO for each of the individual features. [Figure 6] Provided are the polypeptide sequence coordinates within the full-length heavy chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features, including framework regions (FR) and constant regions, as well as the SEQ ID NO for each of the individual features. [Figure 7] Provided are polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features, including variable regions and complementarity determining regions (CDRs), as well as the SEQ ID NO for each of the individual features. [Figure 8] Polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features, including framework regions (FR) and constant regions, as well as the SEQ ID NO of each of the individual features are provided. [Figure 9] Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding the full-length heavy chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features including variable regions and complementarity determining regions (CDRs) are provided, as well as the SEQ ID NO for each of the individual features. [Figure 10] Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding the full-length heavy chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features including framework regions (FR) and constant regions, as well as the SEQ ID NO of each of the individual features, are provided. [Figure 11] Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding the full-length light chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features including variable regions and complementarity determining regions (CDRs) are provided, as well as the SEQ ID NO for each of the individual features. [Figure 12] Polynucleotide sequence coordinates within exemplary polynucleotide sequences encoding the full-length light chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features including framework regions (FR) and constant regions, as well as the SEQ ID NO of each of the individual features, are provided. [Figure 13]The number of subjects in the human clinical trial described in Example 2 treated with either Ab6 (treatment group) or placebo group who showed a 50%, 75% or 100% reduction in migraine headaches at each monitoring point throughout the period is shown. The graph on the right side of each group corresponds to patients who received 1000 mg of Ab6, and the graph on the left side of each group corresponds to the corresponding placebo control. In each response rate group, patients who received Ab6 had a significantly greater response rate than the placebo-treated control, with p values ​​of 0.0155, 0.0034, and 0.0006 in each group, as shown. The administered antibody was produced in P. pastoris and consisted of a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201. [Figure 14] Figure 1 shows the median (±QR) % change from baseline in number of migraine days per month in the placebo and Ab6-treated groups over 12 weeks of treatment (p=0.0078). The upper (red) and lower (blue) lines show the results for placebo-treated controls and patients receiving 1000 mg Ab6, respectively. [Figure 15] Figure 1 shows the median (±QR) % change from baseline in the number of migraine episodes per month in the placebo and Ab6-treated groups over the 12-week post-treatment period. The upper (red) and lower (blue) lines show the results for placebo-treated controls and patients receiving 1000 mg Ab6, respectively. [Figure 16] Figure 1 shows the median (±QR) % change from baseline in number of migraine hours per month in the placebo and Ab6-treated groups over the 12-week post-treatment period. The upper (red) and lower (blue) lines show the results for placebo-treated controls and patients receiving 1000 mg Ab6, respectively. [Figure 17] Patient screening, allocation to treatment and control groups, and patient loss throughout the follow-up period will be summarized. [Figure 18] HIT-6 responder analyses for the Ab6 treatment group and placebo group at baseline, 4 weeks post-treatment, 8 weeks post-treatment, and 12 weeks post-treatment will be compared. [Figure 19]Shown are the percentage of patients whose HIT-6 analysis indicated that their headaches were only "somewhat" or "little / nothing" affected at baseline and after Ab6 administration. At baseline, most patients had a "substantial" or "severe" effect from their migraines. At each subsequent time point, a significantly greater percentage of patients who received 1000 mg Ab6 had only "somewhat" or "little / nothing" HIT-6 effect (left bars for each group, blue) compared with placebo controls (right bars for each group, red). [Figure 20] Pharmacokinetic (PK) profiles for Ab6 administered intravenously at a single dose of 1000 mg are included. [Figure 21] Plasma free pharmacokinetic (PK) parameters for a single 1000 mg intravenous dose of Ab6. N (number of patients), mean, standard deviation (SD). Parameters and units shown in the table are Cmax (μg / mL), AUC0-∞ (mg*hr / mL), half-life (days), Vz (L) and CL (mL / hr). [Figure 22] 1 shows the change from baseline (mean±SEM) in number of migraine days per month as a single dose for Ab6 (1000 mg iv) vs. placebo for the study described in Example 2. [Diagram 23] Hourly mean number of migraine days (+ / -SD) are shown for the entire analysis population for the study described in Example 2. Normalization was applied to the visit interval and 21-27 day e-diaries were completed by multiplying the observed frequency by the inverse of the completion rate. [Figure 24] 1 shows the distribution of actual migraine days and change for the Ab6 treatment group between weeks 1 and 4 for the study described in Example 2. [Diagram 25] 1 shows the distribution of actual migraine days and change for the placebo group between weeks 1 and 4 for the study described in Example 2. [Figure 26] 1 shows the distribution of actual migraine days and change for the Ab6 treatment group between weeks 5 and 8 for the study described in Example 2. [Figure 27]1 shows the distribution of actual migraine days and change for the placebo group between weeks 5 and 8 for the study described in Example 2. [Figure 28] 1 shows the distribution of actual migraine days and change for the Ab6 treatment group between weeks 9 and 12 for the study described in Example 2. [Figure 29] 1 shows the distribution of actual migraine days and change for the placebo group between weeks 9 and 12 for the study described in Example 2. [Diagram 30] Figure 1 shows the 50% responder rates for Ab6 and placebo treatment groups for the study described in Example 2. Subjects who experienced a 50% or greater reduction in migraine frequency were considered 50% responders. Normalization was applied to the visit interval, and 21-27 day e-diaries were completed by multiplying the observed frequency by the inverse of the completion rate. [Diagram 31] Figure 3 shows the 75% responder rates for Ab6 and placebo treatment groups for the study described in Example 2. Subjects who experienced a 75% or greater reduction in migraine frequency were considered 75% responders. Normalization was applied as described in Figure 30. [Diagram 32] Figure 3 shows the 100% responder rates for Ab6 and placebo treatment groups for the study described in Example 2. Subjects with a 100% reduction in migraine frequency are considered 100% responders. Normalization was applied as described in Figure 30. [Diagram 33] Figure 1 shows the time-averaged migraine severity for the entire analysis population for the study described in Example 2. In the scale used, a mean migraine score of 3 represents a "moderate headache." [Diagram 34] 1 summarizes the changes from baseline in measured attributes for the placebo and treatment groups in the study described in Example 2. [Diagram 35] 1 shows the percentage of patients with migraine headaches 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 line shows the placebo results, the bottom line shows the 300 mg dose results, and the middle line shows the 100 mg dose results. [Diagram 36]Figure 1 shows the percentage of patients in the 300 mg and 100 mg treatment groups achieving a 50% reduction in migraine days at month 1, over months 1-3 (after the first infusion), and over months 4-5 (after the second infusion) in the clinical trial described in Example 3. In each graph, data bars from left to right show results for the 100 mg, 300 mg, and placebo groups. Statistical significance is as indicated. ++ indicates statistically significant difference from placebo; + indicates statistically significant difference from placebo (unadjusted); § indicates statistically significant difference from placebo (post-hoc). [Figure 37] The percentage of patients in the 300 mg and 100 mg treatment groups achieving a 75% reduction in migraine days at Month 1, over Months 1-3 (after the first infusion), and over Months 4-5 (after the second infusion) are shown. Data ordering and statistical significance labels are as shown in Figure 36. [Figure 38] The percentage of patients in the 300 mg and 100 mg treatment groups achieving a 100% reduction in migraine days at Month 1, over Months 1-3 (after the first infusion), and over Months 4-5 (after the second infusion) are shown. Data ordering and statistical significance labels are as shown in Figure 36. [Figure 39] The characteristics of patients in each treatment group in the clinical trial described in Example 3 are summarized below. *According to the American Academy of Neurology / American Headache Society guidelines for migraine preventive treatment (agents identified by clinical review of coded medical data); SD, standard deviation; BMI, body mass index. [Diagram 40] Difference from placebo in change from baseline in mean number of migraine days (MMD) over months 1-3 by baseline subgroup in human clinical trials of patients with chronic migraine. In the graph, data points refer to means and lines indicate 95% confidence intervals (CI) of the change from placebo for the 100 mg (upper line) or 300 mg (lower line) treatment groups for each subgroup indicated on the far left. [Diagram 41]Difference versus placebo in change from baseline in mean number of migraine days (MMD) over months 1-3 by baseline subgroup in human clinical trials of episodic migraine patients. The graph is displayed as in Figure 40. [Diagram 42] Change from baseline in mean number of migraine days (MMD) across two dose intervals in patients with chronic migraine who had at least 1 day of acute medication use per month at baseline. Triangles: placebo (n=366). Circles: 100 mg Ab6 / dose (n=356). Squares: 300 mg Ab6 / dose (n=350). [Diagram 43] Mean number of days of acute medication use among patients with chronic migraine who had at least 1 day of acute medication use per month at baseline. Triangles: placebo (n=366). Circles: 100 mg Ab6 / dose (n=356). Squares: 300 mg Ab6 / dose (n=350). [Diagram 44] Change from baseline in acute medication use by subgroups of chronic migraine patients with different baseline days of acute medication use. Solid line: patients with ≥10 days of acute medication use per month at baseline. Dashed line: patients with at least 1 day and <10 days of acute medication use per month at baseline. Triangles: placebo. Circles: 100 mg Ab6 / dose. Squares: 300 mg Ab6 / dose. [Diagram 45] Overview of acute medication days by subgroup of chronic migraineurs with baseline acute medication use. [Figure 46] Change from baseline in mean number of migraine days (MMD) across two dose intervals in patients with episodic migraine who had at least 1 day of acute medication use per month at baseline. Triangles: placebo (n=222). Circles: 100 mg Ab6 / dose (n=221). Squares: 300 mg Ab6 / dose (n=222). [Figure 47] Mean number of days of acute medication use among patients with episodic migraine who had at least 1 day of acute medication use per month at baseline. Triangles: placebo (n=222). Circles: 100 mg Ab6 / dose (n=221). Squares: 300 mg Ab6 / dose (n=222). [Figure 48]Change from baseline in acute medication use by subgroups of chronic migraine patients with different baseline days of episodic medication use. Solid line: patients with ≥10 days of acute medication use per month at baseline. Dashed line: patients with at least 1 day and <10 days of acute medication use per month at baseline. Triangles: placebo. Circles: 100 mg Ab6 / dose. Squares: 300 mg Ab6 / dose. [Figure 49] Overview of acute medication days by subgroup of episodic migraine patients with baseline acute medication use. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0093] Detailed Description Described herein is the use of anti-CGRP antibodies for the treatment of medication overuse headache.

[0094] definition The present invention relates to the specific methodology, protocols, cell lines, animal species or genera, and reagents described. It should be understood that the present invention is not limited to drugs, as these may vary. The terminology used in the document is for the purpose of describing particular embodiments only and is to be construed as limiting the scope of the appended claims. It is understood that no limitation to the scope of the present invention is intended, which is limited only by the claims. As used herein, the singular forms "a," "and," and "the" are , includes plural referents unless the context clearly indicates otherwise. Thus, For example, a reference to "a cell" includes a plurality of such cells, and a reference to "a protein" includes a plurality of such cells. The term "protein" includes one or more proteins and equivalents known to those of skill in the art. All technical and scientific terms used herein are those of the present invention unless expressly stated to the contrary. It has the same meaning as commonly understood by a person skilled in the art to which the invention belongs.

[0095] As used herein, the term "medication overuse headache" refers to the headache syndrome described in ICHD-3 (Heada che Classification Committee of the Inte rnational Headache Society(IHS), The Inte National Classification of Headache Dis order,3rd edition,Cephalalgia.2018 Jan;3 8(1):1-211). As defined by ICHD-3, for example, triptan overuse headache, non-opioid headache Subtypes of medication overuse headache, such as analgesic overuse headache, opioid overuse headache, etc. include.

[0096] As used herein, the term "chronic migraine" refers to a condition in which a patient experiences, on average, at least one migraine headache per month. The term "episodic migraine" refers to a condition in which the patient experiences at least 15 migraines and / or headache days. It refers to a condition in which a person experiences, on average, fewer than 15 headache and / or migraine days per month.

[0097] As used herein, the term "diagnosed with chronic migraine" refers to a formal diagnosis of the patient. It means that a patient meets the criteria for chronic migraine, regardless of whether or not a diagnosis is made.

[0098] As used herein, the term "administered intravenously" refers to the administration of a substance, such as an antibody, to the patient. This refers to a mode of administration in which a substance is introduced directly into the circulation of a patient, most typically into the venous circulation. The agent may be introduced in a carrier fluid, such as a solution, for example normal saline. As long as it is completed within a certain time (e.g., within one day, preferably within 12 hours, more preferably 6 hours, most preferably 1-2 hours), in a single formulation or in multiple formulations. Good too.

[0099] As used herein, the term "baseline number of migraine days" refers to the number of migraine days during a particular period of time. For example, the baseline number of migraine days is the number of migraine days reported by the patient before treatment. The number of headaches was calculated by recording whether or not a migraine occurred on each day, for example, over a period of one month or more. can be determined.

[0100] As used herein, the term "number of headache days per month" refers to the number of days per month in which a patient has migraines. That is, the number of times per month that a patient has symptoms that meet the clinical definition of migraine at any time during that day. The number of days with migraine headaches per month is calculated by recording whether or not a migraine headache occurred on each day. can be determined by:

[0101] As used herein, the term "headache days per month" refers to the number of days per month during which a patient has headaches. The number of days per month on which patients had symptoms that met the clinical definition of headache at any time on those days. The number of headache days per month was determined by recording whether or not a headache occurred on each day. It can be done.

[0102] Calcitonin gene-related peptide (CGRP): As used herein, CGRP is a wholly owned subsidiary of American Peptides (Sunnyvale, CA) and Bache The following Homo sapiens strains are available from Yahoo! News & Trends (Torrance, CA): iens)CGRP-α and Homo sapiensCGRP-β It does not just include amino acid sequences: CGRP-α:ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVG SKAF-NH2 (SEQ ID NO:561), where the terminal phenylalanine is amidated There are; CGRP-β:ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVG SKAF-NH2 (SEQ ID NO:562), in which the terminal phenylalanine is amidated However, any membrane-bound form of these CGRP amino acid sequences, as well as mutants of these sequences, (mutiens), splice variants, isoforms, orthologues, homologues and mutations The same goes for the body.

[0103] Expression Vectors: These DNA vectors are capable of expressing the target host cell, e.g., yeast or mammalian cells. Within cells, such as Pichia pastoris or CHO cells Conveniently, the vector contains elements that facilitate manipulation for expression of foreign proteins in the host. Manipulation of sequences for transformation and production of DNA can be carried out in bacterial hosts, such as E. coli. ) and the vector usually contains a bacterial origin of replication and an appropriate bacterial selection marker. A selectable marker will contain sequences to facilitate such manipulation, including the It encodes a protein necessary for the survival or growth of a transformed host cell grown in culture medium. Host cells not transformed with the vector containing the selection gene will not survive in the culture medium. Typical selection genes include (a) those that confer resistance to antibiotics or other toxins. (b) to complement an auxotrophic deficiency, or (c) to provide important nutrients not available from complex media. Exemplary vectors for yeast transformation and The method is described, for example, in Burke, D., Dawson, D., & Stearns, T. ( 2000).Methods in yeast genetics:a Cold S pring Harbor Laboratory course manual.Pl ainview,NY:Cold Spring Harbor Laborato It is published in the ry Press.

[0104] Expression vectors for use in yeast or mammalian cells are generally derived from transformed yeast strains or Enzymes containing selectable auxotrophic or drug markers for identifying transformed mammalian cells The drug marker may further comprise a vector specific sequence in the host cell. It can be used to amplify the copy number of a vector.

[0105] The coding sequence for the polypeptide of interest is expressed in a host cell, e.g., Pichia pastoris Transcription and transcriptional regulation providing expression of the polypeptide in CHO cells and translational regulatory sequences. These vector components include one or more of the following: These may include, but are not limited to: enhancer elements, promoters, and transcription terminators. Sequences for secretion of the polypeptide, such as a signal sequence, may also be included. Since vectors often integrate into the host cell genome, a yeast or mammalian origin of replication is In one embodiment of the invention, the polypeptide of interest is isolated from a yeast diploid cell. The polypeptide is operably linked or fused to a sequence which provides for optimized secretion of the polypeptide.

[0106] A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, The signal sequence DNA is expressed as a preprotein involved in the secretion of the polypeptide. is operably linked to the DNA of the polypeptide; A gene is operably linked to a coding sequence if it affects the transcription of the sequence. "Operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous This means that the sequence is in the reading frame. However, enhancers are The nucleic acid need not be contiguous, but may be joined by ligation at convenient restriction sites or by other techniques well known to those skilled in the art. The PCR / recombination method (Gateway® Technology; Inv This is accomplished through the use of a 3D printer (available at http: / / www.biodegrad.com / ). If such sites do not exist, synthetic oligonucleotide adaptors or linkers may be used, as conventional It is used in accordance with the practice of

[0107] Promoters control the transcription and translation of specific nucleic acid sequences to which they are operably linked. It is located upstream (5') of the start codon of a structural gene (usually about 100-100 These promoters are classified into several classes: These include: inducible, constitutive, and repressible promoters (transcriptional in response to the absence of a repressor) Inducible promoters increase the expression level of a gene in response to some change in culture conditions, e.g., nutrient The expression of nucleotides from DNA under the control of the presence or absence of nutrients or changes in temperature. It can initiate increased levels of transcription.

[0108] The promoter fragment also facilitates homologous recombination and integration of the expression vector into the same site in the host genome. Alternatively, the selectable marker may serve as a site for homologous recombination. Examples of suitable promoters from Pichia include AOX 1 and the promoter (Cregg et al. (1989) Mol. Cell. Biol. l.9:1316-1323); ICL1 promoter (Menendez et al. .(2003)Yeast 20(13):1097-108);Glyceraldehyde- 3-phosphate dehydrogenase promoter (GAP) (Waterham et al. (1997) Gene 186(1):37-44); and the FLD1 promoter (S Hen et al. (1998) Gene 216(1):93-102) The GAP promoter is a strong constitutive promoter and is involved in the regulation of AOX and FLD1 promoters. The motor is inductive.

[0109] Other yeast promoters include ADH1, alcohol dehydrogenase II, and GAL 4, PHO3, PHO5, Pyk, and chimeric promoters derived therefrom. In addition, non-yeast promoters, such as mammalian, insect, plant, reptile, amphibian, viral, Both human and avian promoters may be used in the present invention. The promoter may be a mammalian promoter (which may be endogenous to the expressed gene). ), or a yeast or viral promoter that provides efficient transcription in a yeast system. This will include

[0110] Examples of mammalian promoters include, among others, promoters from cytomegalovirus (CMV). Motor, chicken 3-actin (CBM) derived promoter, adenomatous polyposis coli Promoter derived from adenomatous polyposis coli (APC) leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) promoter -, CAG promoter, β-actin promoter, elongation factor-1 (EF1) promoter -, early growth response 1 (EGR-1) promoter, eukaryotic initiation factor 4A (EIF4A1 ) promoter, simian virus 40 (SV40) early promoter, mouse mammary tumor virus MMTV, human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter , MoMuLV promoter, avian leukosis virus promoter, Epstein-Barr Virus immediate early promoter, Rous sarcoma virus promoter, and actin promoter promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter These include, but are not limited to, human gene promoters such as the promoter described above. A combination of two or more of the above promoters may be used. If such expression is desired through the use of an inducible promoter, It either turns on expression of an operably linked polynucleotide sequence or inhibits expression when expression is undesirable. Inducible promoters provide a molecular switch that can turn off expression when the promoter is not activated. Examples of promoters include metallothionine promoters, glucocorticoid promoters, and progestin promoters. These include, but are not limited to, the tetracycline promoter and the tetracycline promoter. do not have.

[0111] The polypeptide of interest may be a heterologous polypeptide (e.g., a mature protein or polypeptide). A fusion polypeptide with a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the polypeptide In general, the signal sequence may be a component of the vector. or may be part of a polypeptide coding sequence inserted into a vector. The heterologous signal sequence preferably is recognized through one of the standard pathways available in the host cell. The yeast S. cerevisiae α-factor promoter is The Repro signal is a signal that expresses various recombinant proteins from P. pastoris. Other yeast signal sequences have been shown to be effective in secreting proteins. The enzyme signal sequence, the invertase signal sequence, and sequences derived from other secreted yeast polypeptides In addition, these signal peptide sequences are also useful in diploid yeast expression. The system can be engineered to provide enhanced secretion in mammalian and yeast cells. The secretion signal used can be heterologous to the protein to be secreted, or Mammalian signal sequences are included, which may be the native sequence of the protein to be secreted. The sequence includes a pre-peptide sequence, and in some instances may include a propeptide sequence. signal sequences found on immunoglobulin chains, such as the K28 preprotoxin sequence; PHA-E, FACE, human MCP-1, human serum albumin signal sequence, human Ig heavy Many such signal sequences are known in the art, including human Ig light chain, human Ig light chain, and the like. For example, Hashimoto et.al. Protein Eng 11(2)75 (1998); and Kobayashi et. al. Therapeutic Aph See Eresis 2(4)257(1998).

[0112] Transcription can be increased by inserting a transcriptional activator sequence into the vector. These activators are cis-acting elements of DNA, usually about 10-300 bp in length. Transcriptional enhancers are transcription factors that act on promoters to increase their transcription. It is relatively orientation and position independent, and can be found 5' and 3' to the transcription unit, within introns, and Enhancers are found within the coding sequence itself. The promoter can be spliced ​​into the expression vector at a site 5' from the promoter, but preferably at a site Located in.

[0113] Expression vectors used in eukaryotic host cells contain the necessary transcription factors for terminating transcription and stabilizing the mRNA. Such sequences may include any suitable sequence found in eukaryotic or viral DNA or cDNA. are generally available 3' to the translation termination codon in the untranslated region of A region is a set of nucleotides that are transcribed as polyadenylated fragments into the untranslated portion of the mRNA. Includes fragments.

[0114] Construction of a suitable vector containing one or more of the components listed above can be carried out using standard ligation procedures. Use PCR / recombinant techniques. Isolated plasmids or DNA fragments are can be digested, tailored, and religated in the desired form to produce the required plasmid, or or produced via recombinant methods. Confirm correct sequence in constructed plasmid. The ligation mixture is used to transform host cells and the appropriate In some cases, successful transformation was confirmed by antibiotic resistance (e.g., ampicillin or zeocin). Select the transformants. Prepare plasmids from the transformants and use restriction endonuclease digestion to isolate the transformants. Further analysis and / or sequencing.

[0115] Recombination based on att sites and recombinase as an alternative to fragment restriction and ligation Methods can be used to insert a DNA sequence into a vector. Such methods include, for example, See, for example, Landy (1989) Ann. Rev. Biochem. 58:913-949. Such methods are described by and known to those skilled in the art. Intermolecular DNA recombination mediated by a mixture of recombination proteins encoded by oli Recombination occurs between specific binding (att) sites on interacting DNA molecules. For a description of the att site, see Weisberg and Landy (198 3)Site-Specific Recombination in Phage L ambda,in Lambda II,Weisberg,ed.(Cold Spr. ing Harbor, NY:Cold Spring Harbor Press), See pp. 211-250. The DNA segments flanking the recombination sites are exchanged. Thus, after recombination, the att site consists of sequences contributed by each parent vector. Recombination can occur between DNA of any topology.

[0116] Att sites allow for the ligation of sequences of interest into appropriate vectors; use of specific primers 2. Generate a PCR product containing an attB site by: The sequence of interest can be identified by, for example, generating a cDNA library in which the sequence is cloned into a can be introduced into

[0117] Folding, as used herein, refers to the three-dimensional structure of polypeptides and proteins. where interactions between amino acid residues act to stabilize the structure. Folding is typically the configuration of a polypeptide that results in optimal biological activity and is In the case of antibodies, this is conveniently monitored by assays for activity (e.g., antigen binding). obtain.

[0118] The expression host may contain one or more enzymes that enhance folding and disulfide bond formation, i.e., phosphatase inhibitors. It can be further modified by the introduction of sequences encoding enzymes, chaperonins, etc. Such sequences can be introduced into yeast host cells using vectors, markers, etc., known in the art. The gene can be constitutively or inducibly expressed in the target cell. Preferably, the gene is transfected in a manner sufficient for the desired expression pattern. Sequences containing transcriptional regulatory elements were stably integrated into the yeast genome by targeted methodology. can be.

[0119] For example, eukaryotic PDI regulates protein cysteine ​​oxidation and disulfide bond isomerization. PDI is not only an efficient catalyst but also exhibits chaperone activity. It can promote the production of active proteins with disulfide bonds. Also of interest is the expression of cyclophilin, cyclophilin, etc. In this mode, each of the monoploid parent strains expresses a different folding enzyme, e.g., one strain expresses BIP. Some strains may express PDI, while other strains may express PDI or a combination thereof.

[0120] The terms "protein of interest" or "antibody of interest" are used interchangeably and generally refer to a target A specific parent antibody, i.e., a CGRP or chimeric or humanized antibody as described herein. The term "antibody" refers to an antibody that binds to and recognizes an epitope. It is intended to include any polypeptide chain-containing molecular structure having a specific shape that is recognized by the Here, one or more non-covalent interactions stabilize the complex between the molecular structure and the epitope. The prototypic antibody molecule is an immunoglobulin and is available from all sources, including human, rodent, and mouse. All the data from herons, cows, sheep, pigs, dogs, other mammals, chickens, other birds, etc. The types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc., are called "antibodies." It is believed that the preferred sources for producing antibodies useful as starting materials according to the present invention are The source is rabbit. A number of antibody coding sequences have been described; others are available in the art. Antibodies can be produced by well-known methods, examples of which include chimeric antibodies, human antibodies and other non-human antibodies. Mammalian antibodies, humanized antibodies, single chain antibodies (e.g., scFvs), camelid antibodies, nanobodies, IgNAR (shark-derived single-chain antibody), small modular immunopharmaceuticals (SMIPs), and Fa These include antibody fragments such as bs, Fab', and F(ab')2. Streltsov VA ,et al.,Structure of a shark IgNAR antib ody variable domain and modeling of an e early-developmental isotype,Protein Sci.2 005 Nov;14(11):2901-9.Epub 2005 Sep 30;G reenberg AS, et al., A new antigen receptor r gene family that undergoes rearrangeme nt and extensive somatic diversification in sharks,Nature.1995 Mar 9;374(6518):1 68-73;Nuttall SD,et al.,Isolation of the new antigen receptor from wobbegong sha rks,and use as a scaffold for the displa y of protein loop libraries, Mol Immunol. 2001 Aug;38(4):313-26;Hamers-Casterman C ,et al.,Naturally occurring antibodies d evoid of light chains,Nature.1993 Jun 3; 363(6428):446-8;Gill DS,et al.,Biopharma ceutical drug discovery using novel prot ein scaffolds,Curr Opin Biotechnol.2006 Dec;17(6):653-8.Epub 2006 Oct 19.

[0121] For example, antibodies or antigen-binding fragments can be produced by genetic engineering. As with other methods, antibody-producing cells are sensitized to the desired antigen or immunogen. Messenger RNA isolated from somatic cells was used as a template for PCR amplification. cDNA is generated using one heavy chain gene and one light chain gene that retain the original antigen specificity. The library of vectors, each containing a gene, was then cloned into the appropriate amplified immunoglobulin cDNA. Combinatorial libraries are created by inserting suitable fragments into expression vectors. The gene library was constructed by combining a heavy chain gene library with a light chain gene library. This is constructed from heavy and light chains (similar to the Fab fragment or antigen-binding fragment of an antibody molecule). The resulting library of clones co-expressing the genes is transformed into a vector carrying the genes. Co-transfect the cells. Antibody gene synthesis in the transfected host. When induced, the heavy and light chain proteins self-assemble and stimulate stimulation with an antigen or immunogen. The antibody produces active antibodies which can be detected by screening.

[0122] Antibody coding sequences of interest include those encoded by natural sequences, as well as those encoded by the genetic code. Due to degeneracy, nucleic acids that are not identical in sequence to the disclosed nucleic acids and variants thereof, as well as Variant polypeptides may include amino acid (aa) substitutions, additions, or deletions. Amino acid substitutions can be made to eliminate non-essential amino acids, for example to modify glycosylation sites. or by substitution or deletion of one or more cysteine ​​residues that are not required for function. The amino acid substitutions may be conservative amino acid substitutions to minimize misfolding due to the presence of the mutant. The enhancement of specific regions of a protein (e.g., functional domains, catalytic amino acid residues, etc.) Mutants may be designed to retain or have the desired biological activity. Fragments of the polypeptides disclosed herein, particularly biologically active fragments and / or functional domains, are also contemplated. Techniques for in vitro mutagenesis of cloned genes are known. To improve their resistance to proteolysis or to optimize solubility properties, or to make them more suitable as therapeutic agents, using conventional molecular biology techniques. Polypeptides modified in this manner are also encompassed by the present invention.

[0123] Chimeric antibodies are antibodies that combine variable light and heavy chain regions (VCH) derived from antibody-producing cells of one species. L and V H) with constant light and heavy chain regions from another species, Typically, chimeric antibodies are produced by recombinant human antibodies that have predominantly human domains. To generate such antibodies, rodent or rabbit variable regions and human constant regions are used. Production of antibodies is well known in the art and can be accomplished by standard means. (See, e.g., U.S. Pat. No. 5,624,659, the entirety of which is incorporated herein by reference. In addition, the human constant regions of the chimeric antibodies of the present invention include It is contemplated that the constant regions may be selected from IgG1, IgG2, IgG3, and IgG4 constant regions. do.

[0124] Humanized antibodies are antibodies that have been engineered to contain more human-like immunoglobulin domains and are Only the complementarity determining regions of the derived antibody are incorporated. This is This was achieved by carefully examining the sequences of the variable loops and adapting them to the structure of human antibody chains. Although superficially complex, this process is actually simple. See U.S. Pat. No. 6,187,287, which is incorporated herein by reference. .

[0125] In addition to whole immunoglobulins (or their recombinant counterparts), they contain epitope binding sites. Immunoglobulin fragments (e.g., Fab', F(ab')2, or other fragments) can be synthesized. "Fragments", or minimal immunoglobulins, are designed using recombinant immunoglobulin technology. For example, an "Fv" immunoglobulin for use in the present invention may be Alternatively, antibodies may be produced by synthesizing fused variable light and heavy chain regions. Combinations of Fv specificities, such as diabodies comprising two different Fv specificities, are also of interest. In another embodiment, SMIPs (small molecule immunopharmaceuticals), camelid antibodies, nanobodies, and I The gNAR is encompassed by an immunoglobulin fragment.

[0126] Immunoglobulins and fragments thereof can be linked to effector moieties, such as chemical linkers, fluorescent Detectable moieties such as dyes, enzymes, toxins, substrates, bioluminescent substances, radioactive substances, and chemiluminescent moieties It may be post-translationally modified to add a moiety, or may be modified with streptavidin, avidin, or Specific binding moieties, such as ribozyme, ribozyme, or biotin, may be used in the methods and compositions of the invention. Examples of effector molecules are provided below.

[0127] A polynucleotide sequence is a sequence that is translated according to the genetic code into a polypeptide. A polynucleotide sequence "corresponds" to a polypeptide sequence (i.e., a polynucleotide sequence , "encodes" a polypeptide sequence), and two sequences encode the same polypeptide sequence. One polynucleotide sequence "corresponds to" another polynucleotide sequence if

[0128] A "heterologous" region or domain of a DNA construct is one that is found in association with a larger naturally occurring molecule. It is an identifiable segment of DNA within a larger DNA molecule that cannot be identified. When the heterologous region encodes a mammalian gene, the gene is usually located in the genome of the source organism. It will be flanked by DNA that does not flank the mammalian genomic DNA. The coding sequence itself is a construct not found in nature (e.g., the genomic coding sequence is an introductory (cDNA containing codons different from the natural gene, or synthetic sequences with codons different from the natural gene). or naturally occurring mutational events resulting in a heterologous region of DNA as defined herein. No.

[0129] "Coding sequence" means a sequence (in terms of the genetic code) that corresponds to a protein or peptide sequence. Two coding sequences are in-frame sequences of codons that are identical in sequence or their complementary sequences. The coding sequences correspond to each other when they code for amino acid sequences. can be transcribed and translated into a polypeptide. Polyadenylation signal and transcription termination sequence A "promoter sequence" is a sequence that is normally located 3' to the coding sequence. It can bind RNA polymerase and initiate transcription of the downstream (3' direction) coding sequence. A promoter sequence is a DNA regulatory region that typically influences the transcription of a coding sequence. The coding sequence contains additional sites for the binding of regulatory molecules (e.g., transcription factors). A polymerase binds to the promoter sequence in the cell and transcribes the coding sequence into mRNA "Under the control of" a promoter sequence or "operably linked to" a promoter, The mRNA is then translated into the protein encoded by the coding sequence.

[0130] A vector is a vector that delivers foreign material, such as DNA, RNA, or proteins, into an organism or host cell. Typical vectors include recombinant viruses (for polynucleotides ) and liposomes (for polypeptides). "DNA vector" includes plasmids, Replicons, such as phages, cosmids, etc., that contain separate polynucleotide segments can be linked together to bring about the replication of the linked segments. A DNA vector containing a regulatory sequence that directs polypeptide synthesis by a suitable host cell. This is usually because the promoter binds to RNA polymerase and initiates transcription of mRNA. and ribosome binding sites and initiation signals direct the translation of the mRNA into a polypeptide. Insertion into an expression vector at the appropriate site and in the correct reading frame. The incorporation of the polynucleotide sequence and subsequent transformation of a suitable host cell with the vector can be carried out by This allows for the production of the polypeptide encoded by the polynucleotide sequence.

[0131] "Amplification" of a polynucleotide sequence is the in vitro production of multiple copies of a particular nucleic acid sequence. The amplified sequences are usually in the form of DNA. The various techniques are described by Van Brunt (1990, Bio / Technol., 8(4): The polymerase chain reaction, or PCR, is PCR is a prototype of nucleic acid amplification, and its use herein is exemplary of other suitable amplification techniques. should be considered as indicative.

[0132] The general structure of antibodies in vertebrates is now well understood (Edelman, GM, Ann. NY Acad. Sci., 190:5 (1971). The antibody Two identical light polypeptide chains ("light chains") of molecular weight approximately 23,000 daltons and It consists of two identical heavy chains ("heavy chains") with molecular masses of 53,000-70,000. The four chains are: The light chains are linked by disulfide bonds in a "Y" configuration. It wraps around the heavy chain starting at the mouth. The "branch" part of the "Y" configuration is F ab It is called the area, The stem of the "Y" configuration is F C The amino acid sequence is oriented in a "Y" position. The N-terminus of each chain extends from the N-terminus at the top of the conformational arrangement to the C-terminus at the bottom of the chain. The light chain has a variable region having specificity for a given antigen, is about 100 amino acids in length, and There is slight variation between heavy chains and from antibody to antibody.

[0133] The variable regions are linked in each chain to a constant region which extends the remaining length of the chain and gives the antibody its specific characteristics. The class of certain antibodies does not vary with the specificity of the antibody (ie, the antigen that elicits it). There are five known major classes of constant regions that determine the class of immunoglobulin molecule ( γ, μ, α, δ, and ε (gamma, mu, alpha, delta, or epsilon) heavy chain definitions The constant region or class is complement activation (Kabat, EA, Structural Concepts in Immunology and Immunochemistry,2nd Ed ., p.413-436, Holt, Rinehart, Winston (1976)) , and other cellular responses (Andrews, DW, et al., Clinical I mmunobiology,pp 1-18,WBSanders(1980);K ohl, S., et al., Immunology, 48:187 (1983)). The variable region determines the subsequent effector functions of the antibody, including the binding of the antibody to the antigen; Light chains are classified as either κ (kappa) or λ (lambda). The antibodies can be prepared with either kappa or lambda light chains. The immunoglobulins are produced by either hybridomas or B cells. When the heavy chains are bound together by covalent disulfide bonds, the "tail" portions of the two heavy chains are bound to each other by covalent disulfide bonds. do.

[0134] The term "variable region" or "VR" refers to the region of an antibody that is directly involved in binding the antibody to an antigen. Refers to the domains within each pair of light and heavy chains. Each heavy chain contains a variable domain (V H ) This is followed by a number of constant domains. Each light chain has a variable domain (V L ) and others the constant domain of the light chain is aligned with the first constant domain of the heavy chain , the light chain variable domain is aligned with the variable domain of the heavy chain.

[0135] The term "complementarity determining region," "hypervariable region," or "CDR" refers to the light or Refers to one or more of the hypervariable or complementarity determining regions (CDRs) found in the variable region of the heavy chain (K abat,EAet al.,Sequences of Proteins of Immunological Interest,National Institute tes of Health, Bethesda, Md., (1987) These expressions were reported by Kabat et al. teins of Immunological Interest,” Kabat E., et al., US Dept. of Health and Human Se The hypervariable region, or the three-dimensional structure of an antibody, as defined by (Rorvices, 1983). Hypervariable loops in (Chothia and Lesk, J Mol. Biol. 1 96 901-917 (1987)). The CDRs of each chain are bounded by framework regions. They are held in close proximity by the CDRs from the other chain and contribute to the formation of the antigen-binding site. Within the DRs are shown important contact residues used by the CDRs in antibody-antigen interactions. There are selective amino acids that have been described as selectivity determining regions (SDRs) (Kashm In the present invention, When a particular antibody amino acid or nucleic acid residue is referred to by a number, this generally refers to the particular amino acid. the amino acid or its position within the nucleic acid sequence (i.e., the specific sequence identifier), and / or the Refers to its position by numbering.

[0136] The term "framework region" or "FR" refers to a region within the variable region of an antibody light or heavy chain. (Kabat, EA et al., Sequencing) ences of Proteins of Immunological Inter est,National Institutes of Health,Bethes (See, e.g., da, Md., (1987)). These terms refer to the possible positions of the light and heavy chains of an antibody. It includes the amino acid sequence region intervening between the CDRs in the variable region.

[0137] "Cmax" is the maximum concentration of an antibody or other compound in a test area (e.g., blood) after a drug is administered. It refers to the maximum (or peak) concentration achieved in the serum or another compartment, such as the cerebrospinal fluid. For example, serum Cmax can be measured from serum, e.g., by collecting a blood sample and measuring The blood is allowed to clot, and the solid components are separated by centrifugation or other means to obtain serum (blood cells and clotting factors). The antibody is prepared by producing a ELISA or other method known in the art. The concentration of the analyte in the serum is detected by other means known in the art.

[0138] "AUC" is mg / mL x hr (or equivalently mg x hr / ml AUC is the area under the concentration-time curve expressed in units of 0-t " is the time from time=0 to AUC refers to the area under the concentration-time curve until a quantifiable concentration is reached after 0-inf " is time = Area under the concentration-time curve extrapolated from 0 to infinity.

[0139] "I max " compared with responses induced by lower anti-CGRP antibody doses. The CGRP antibody dosage is preferably at least 350 mg, more typically at least 750 or The maximum pharmacodynamic response induced by a dose of 1000 mg is shown in Fig. 1. The response may be detected by inhibition of vasodilation following topical application of capsaicin.

[0140] Anti-CGRP antibodies and their binding fragments having binding specificity for CGRP The present invention relates to specific anti-CGRP antibodies, herein designated Ab1 to Ab14, and These specifically include the use of CDR, VL, VH, CDRs, and CDR fragments identified in Figures 1A-12. Particularly preferred anti-CGRP antibodies include, but are not limited to, the L and CH polypeptide sequences. The polypeptides included in b6 are described further below.

[0141] Antibody Ab6 In a preferred exemplary embodiment, the present invention provides an antibody having binding specificity for CGRP, Humanized antibodies having a variable light chain sequence comprising the sequence set forth below: [ka]

[0142] The present invention also relates to a light chain having binding specificity for CGRP and comprising the sequence set forth below. The humanized antibody has the sequence: [ka]

[0143] The present invention also relates to a variant polypeptide having binding specificity for CGRP and comprising the sequence set forth below. The humanized antibody has the heavy chain sequence: [ka]

[0144] The present invention also relates to a heavy chain having binding specificity for CGRP and comprising the sequence set forth below. The humanized antibody has the sequence: [ka]

[0145] Alternatively, the heavy chain of Ab6 may lack the C-terminal lysine of SEQ ID NO:201, i.e., The sequences include those set forth below: [ka]

[0146] The present invention further relates to the variable light chain sequence of SEQ ID NO: 222 or the complement of the light chain sequence of SEQ ID NO: 221. SEQ ID NO:224, corresponding to the sex determining regions (CDRs, or hypervariable regions); SEQ ID NO:226; and one or more of the polypeptide sequences of SEQ ID NO: 228 and / or the possible sequences of SEQ ID NO: 202. The complementarity determining regions (CDRs) of the variant heavy chain sequence or the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566 , or hypervariable regions), SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:208 or a combination of these polypeptide sequences. In another embodiment of the invention, the antibody or fragment thereof of the invention comprises one or more of the CDRs. The variable heavy and variable light chain sequences, as well as the heavy and light chain sequences described above (their entirety) The term "compound" includes or consists of a combination of the following:

[0147] The present invention also contemplates fragments of antibodies that have binding specificity for CGRP. In one embodiment, the antibody fragment of the invention comprises the polypeptide of SEQ ID NO:222 or SEQ ID NO:221. In another embodiment of the invention, the antibody fragment of the invention comprises or consists of the sequence comprising or including the polypeptide sequence of SEQ ID NO: 202 or SEQ ID NO: 201 or SEQ ID NO: 566; It consists of:

[0148] In a further embodiment of the invention, a fragment of an antibody that has binding specificity for CGRP has the sequence The complementarity determining regions (CDRs) of the variable light chain sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221 or hypervariable regions) of SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:228 It comprises or consists of one or more of the polypeptide sequences.

[0149] In a further embodiment of the invention, a fragment of an antibody that has binding specificity for CGRP has the sequence 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 SEQ ID NO:204; SEQ ID NO:206, which correspond to the complementarity determining regions (CDRs, or hypervariable regions) and comprising or consisting of one or more of the polypeptide sequences of SEQ ID NO:208.

[0150] The present invention also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the invention, the fragment of the antibody having binding specificity for CGRP is SEQ ID NO: 22, including all, including one, two, three or more of the body fragments. 2; the variable heavy chain region of SEQ ID NO: 202; the variable light chain region of SEQ ID NO: 222 Complementarity determining regions (SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:228); and SEQ ID NO: The complementarity determining regions of the variable heavy chain region of SEQ ID NO:202 (SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:207) No. 208).

[0151] In a particularly preferred embodiment of the invention, the humanized anti-CGRP antibody has the sequence SEQ ID NO: 221 and SEQ ID NO: 222. 201 or SEQ ID NO: 566, The Ab6 has at least one of the following inhibitory activities:

[0152] In a further particularly preferred embodiment of the invention, the antibody fragment has binding specificity for CGRP. In relation to the antibody Ab6, it comprises or consists of a Fab (fragment antigen-binding) fragment having the following structure: The Fab fragment comprises the variable light chain region of SEQ ID NO: 222 and the variable heavy chain region of SEQ ID NO: 202. This embodiment of the invention further comprises the steps of: Additions, deletions, and variants of SEQ ID NO: 222 and / or SEQ ID NO: 202 in Fab are intended. Figure.

[0153] In another particularly preferred embodiment of the invention, the anti-CGRP antibody has the amino acid sequence of SEQ ID NO: 222. The nucleic acid sequences encoding the variable light chain polypeptide and the variable heavy chain polypeptide of SEQ ID NO: 202 are These polypeptides may include antibody expression products isolated from recombinant cells expressing the polypeptides. Optionally, human light and heavy chain constant region polypeptides, e.g., human IgG1, Ig IgG2, IgG3 or IgG4 constant regions, each of which is optionally linked to , glycosylation or proteolysis, Optionally, the cell is a yeast or mammalian cell, such as Pichia pastoris. pastoris) or CHO cells.

[0154] In another particularly preferred embodiment of the invention, the anti-CGRP antibody has the amino acid sequence of SEQ ID NO: 221. The present invention relates to a method for producing a nucleic acid sequence encoding a polypeptide of the heavy chain of SEQ ID NO: 201 or SEQ ID NO: 566. The antibody can include an antibody expression product isolated from a recombinant cell expressing the enzyme, the recombinant cell being Mother or mammalian cells, such as Pichia pastoris s) or CHO cells, the constant region of which may be glycosylated or protein-modified. The peptides can be optionally modified to alter their affinity or other effector functions.

[0155] In another particularly preferred embodiment of the invention, any of the aforementioned anti-CGRP antibodies or antibody fragments is For example, histidine (L-histidine), sorbitol, which has a pH of about 5.8 , polysorbate 80, e.g., about 100 mg of anti-CGRP antibody per mL volume, about 3. 1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polyisoprene. It may also be included in the formulations disclosed herein, including Lubet 80.

[0156] In one embodiment of the present invention described herein (below), the Fab fragment is an enzyme of Ab6. In another embodiment of the present invention, anti-CG can be produced by selective digestion (e.g., with papain). The RP antibody, e.g., Ab6 or a Fab fragment thereof, can be cultured in mammalian cells, e.g., CHO, NSO or The vectors may be derived from HEK 293 cells, fungal, insect, or microbial systems, such as yeast cells (e.g., diploid yeast , for example, via expression in diploid Pichia and other yeast strains. Suitable Pichia species include Pichia pastoris. storis), but are not limited to

[0157] In another embodiment, the antibody fragment may exist in one or more of the following non-limiting forms: In a preferred embodiment, the antibody is The anti-CGRP antibodies described herein further comprise a kappa constant light chain sequence comprising the sequence set forth below. Contains columns: [ka]

[0158] In another preferred embodiment, the anti-CGRP antibodies described herein further comprise one or more of the following: or a carboxy-terminal lysine residue. 564 and 565, respectively, containing the same sequences lacking: [ka] [ka]

[0159] For clarity, any antibody disclosed herein may be selected from the group consisting of the disclosed constant region variant sequences. For example, Ab6 is intended to include any variant of SEQ ID NO: 564, or may comprise the constant region of SEQ ID NO: 565 lacking the C-terminal lysine. Thus, all disclosure herein of the heavy chain of SEQ ID NO:201 includes the C-terminal lysine residue The heavy chain variable region sequence of Ab6 (SEQ ID NO: 202) lacks the nucleotide sequence of SEQ ID NO: 565. For example, an antibody that contains a C-terminal lysine in the heavy chain may be cloned. The loading sequence, when expressed in a cell line, e.g., CHO cells, is resistant to proteolysis. For this purpose, an antibody lacking said C-terminal lysine or a mixture of heavy chains containing or lacking said C-terminal lysine is provided. A compound can be produced.

[0160] In another embodiment, the present invention provides: SEQ ID NO:2, SEQ ID NO:42, SEQ ID NO:82, SEQ ID NO:1 22, SEQ ID NO:162, SEQ ID NO:202, SEQ ID NO:242, SEQ ID NO:282, SEQ ID NO:3 22, SEQ ID NO: 362, SEQ ID NO: 402, SEQ ID NO: 442, SEQ ID NO: 482, or SEQ ID NO: No. 522, or a variant thereof. H and further comprising: 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. Selected V L The present invention contemplates the use of an isolated anti-CGRP antibody comprising a polypeptide sequence, V H Or V L One or more of the framework residues (FR residues) in a polypeptide may be The amino acid residues are replaced to generate anti-CGRP antibodies that specifically bind to CGRP. The invention contemplates humanized and chimeric forms of these antibodies. Chimeric antibodies include IgG1, I The Fc may be derived from a gG2, IgG3, or IgG4 constant region.

[0161] In one embodiment of the present invention, an antibody or V H Or V L Polypeptides are referred to herein. Prior to initiation of the humanization process, the humanized B cells may be derived from or derived from one or more rabbit B cell populations. Be selected.

[0162] In another embodiment of the invention, the anti-CGRP antibodies and fragments thereof bind to CGRP-R. In a further embodiment of the invention, the anti-CGRP antibodies and fragments thereof have no binding specificity. In another embodiment of the present invention, an anti-CGRP antibody inhibits the association of GRP with CGRP-R. and fragments thereof, which are intended to be used in the treatment of CGRP and CGRP-R and / or additional proteins and / or multiple The present invention relates to a method for treating cancer, the method comprising: inhibiting the association with the dimer and / or antagonizing its biological effect.

[0163] As described herein, antibodies and fragments thereof can be post-translationally modified to incorporate chemical linkers. effector moieties such as fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and a detectable moiety, such as a chemiluminescent moiety, or, for example, streptavidin, avidin, Functional moieties such as biotin, cytotoxins, cytotoxic materials, and radioactive materials may be added.

[0164] The antibody or fragment thereof may also be used to determine the solubility, stability and circulation time (in vivo half-life) of the polypeptide. They may be chemically modified to provide additional advantages, such as increased affinity, increased potency, or decreased immunogenicity. (See U.S. Pat. No. 4,179,337.) Chemical Derivatization The part is polyethylene glycol, ethylene glycol / propylene glycol copolymer Water-soluble polymers such as cellulose, carboxymethylcellulose, dextran, and polyvinyl alcohol Antibodies and fragments thereof may be selected from random positions within the molecule or from may be modified at predetermined positions and may contain one, two, three or more linking chemical moieties.

[0165] The polymer may be of any molecular weight and may be branched or unbranched. In the case of polyethylene glycol, the preferred molecular weight is 1.0 to 1.5, for ease of handling and manufacturing. The molecular weight is about 1 kDa to about 100 kDa (the term "about" refers to the molecular weight of the polyethylene glycol). In this study, some molecules were heavier and some were lighter than the molecular weight stated. The desired therapeutic profile (e.g., the desired duration of sustained release, the desired biological activity, the efficacy (if any) of the therapeutic protein in treating a disease, ease of handling, degree or lack of antigenicity, and Other sizes may be used depending on other known effects of polyethylene glycol on proteins or analogs. For example, polyethylene glycol can be used at about 200, 500, 10 00, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 50 00, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 90 00, 9500, 10,000, 10,500, 11,000, 11,500, 12,0 00, 12,500, 13,000, 13,500, 14,000, 14,500, 15 ,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,00 0, 30,000, 35,000, 40,000, 50,000, 55,000, 60, 000, 65,000, 70,000, 75,000, 80,000, 85,000, 9 The copolymer may have an average molecular weight of 0,000, 95,000, or 100,000 kDa. Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; rpurgo et al.,Appl.Biochem.Biotechnol.56 :59-72(1996);Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999); and Calice ti et al.,Bioconjug.Chem.10:638-646(1999 ), the disclosures of each of which are incorporated herein by reference.

[0166] There are numerous conjugation methods available to one of skill in the art. See European Patent No. 0 401 384, which discloses the addition of PEG to G-CSF. Concatenation). Malik et al.,Exp.Hematol.20:1028-103 5(1992)(reporting pegylation of GM-CSF u Also see Polyethylene glycol. The carboxyl groups are covalently linked to amino acid residues via reactive groups such as free amino or carboxyl groups. A reactive group is one to which an activated polyethylene glycol molecule can be attached. Amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residue; The amino acid residues having a carboxyl group are aspartic acid residues, glutamic acid residues and C The terminal amino acid residues may also contain sulfhydryl groups to attach polyethylene glycol molecules. For therapeutic purposes, preferred is an amino group. for example at the N-terminus or at a lysine group.

[0167] As alluded to above, polyethylene glycol can be any of a number of amino acid residues. For example, polyethylene glycol can be attached to a protein via a linkage to lysine. via covalent bonds to amino acid, histidine, aspartic acid, glutamic acid, or cysteine ​​residues Polyethylene glycol can be linked to a polypeptide using one or more reaction chemistries. The amino acid residues of the nucleotides are selected from the group consisting of lysine, histidine, aspartic acid, and glutamic acid. , or cysteine), or to two or more types of amino acid residues (e.g., lysine, histidine, Glutamic acid, cysteine, aspartic acid, glutamic acid, cysteine, and combinations thereof) Good too.

[0168] Alternatively, the antibody or fragment thereof may be bound to albumin (recombinant human serum albumin or a fragment thereof or or variants thereof (e.g., those herein incorporated by reference in their entirety). No. 5,876,969, issued March 2, 1999, which is incorporated herein by reference. The specification, European Patent No. 0 413 622, and the application published on June 16, 1998 See U.S. Pat. No. 5,766,883) or other circulating blood proteins. , e.g., via fusion with transferrin or ferritin, In a preferred embodiment, the polypeptide and / or antibody of the present invention (fragment thereof) can be used. The mature form of human serum albumin (i.e., the fragments or variants thereof) is the mature form of human serum albumin (i.e., the fragments or variants thereof) are incorporated herein by reference in their entirety. As shown in Figures 1 and 2 of European Patent No. 0 322 094, which is incorporated herein by reference. The fusion protein of the present invention is fused to amino acids 1 to 585 of human serum albumin. Polynucleotides encoding the proteins are also encompassed by the present invention.

[0169] Further exemplary enzymes for the detectable moiety include horseradish peroxidase. , acetylcholinesterase, alkaline phosphatase, β-galactosidase and Further exemplary fluorescent materials include, but are not limited to, luciferase. , rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone , dichlorotriazinylamine, phycoerythrin and dansyl chloride. Further exemplary chemiluminescent moieties include, but are not limited to, luminol. Further exemplary bioluminescent materials include, but are not limited to, luciferin and enzyme. Further exemplary radioactive materials include, but are not limited to, quorine. Iodine 125( 125 I), Carbon-14 ( 14 C), sulfur 35( 35 S), tritium ( 3 H) and phosphorus 32 ( 32 P), but are not limited to these.

[0170] With respect to functional moieties, exemplary cytotoxic agents include methotrexate, aminopterid. 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil deca rubazine; alkylating agents such as mechlorethamine, thioepa, chloramate Bucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (C CNU), 1-methylnitrosourea, cyclothosphamid mide), mechlorethamine, busulfan, dibromomannitol, streptozotocin Cisplatin, mitomycin C, cis-dichlorodiamineplatinum(II) (DDP) and and carboplatin (Paraplatin); anthracyclines include daunorubicin (formerly daunorubicin unonomycin), doxorubicin (adriamycin), detorubicin, carminomycin Antibiotics including idarubicin, idarubicin, epirubicin, mitoxantrone and bisantrene; Dactinomycin (actinomycin D), bleomycin, calicheamicin, mitochondrial and antimitotic agents, such as bile acid inhibitors, These include, but are not limited to, anca alkaloids, vincristine and vinblastine. Other cytotoxic agents include paclitaxel (Taxol), ricin, pseudomonas Eggplant exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, em cin, etoposide, tenoposide, colchicine, dihydroxyanthracinedione, 1-de Hydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, Propranolol, puromycin, procarbazine, hydroxyurea, asparaginase azeta, corticosteroids, mitotane (O,P'-(DDD)), interferon, and mixtures of these cytotoxic agents.

[0171] Further cytotoxic agents include chemotherapeutic agents, such as carboplatin, cisplatin, paclitaxel, cisplatin, gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, Itomycin C, actinomycin D, cyclophosphamide, vincristine and bleomycin Toxic enzymes from plants and bacteria, such as lysine, Diphtheria toxin and Pseudomonas toxin were humanized and or chimeric antibodies, or binding fragments thereof, to generate cell type specific killing reagents. (Youle, et al., Proc. Nat'l Acad. Sci. US A 77:5483(1980);Gilliland,et al.,Proc.Na t'l Acad.Sci.USA 77:4539(1980);Krolick,e t al.,Proc.Nat'l Acad.Sci.USA 77:5419(19 80)).

[0172] Other cytotoxic agents include those disclosed by Goldenberg in U.S. Pat. No. 6,653,104. The present invention also includes cytotoxic ribonucleases as described in the specification. Additionally, radionuclides that emit alpha or beta particles may be used with or without a complexing agent. Regardless, the present invention relates to a radioimmunoconjugate that is stably bound to an antibody or a binding fragment thereof. Radionuclides such as 32 P), Scandium -47( 47 Sc), Copper-67( 67 Cu), Gallium-67( 67 Ga), Yttrium Mu-88( 88 Y), Yttrium-90 ( 90 Y), iodine-125( 125 I), Yo Uranium-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 P b), Bismuth-212( 212 Bi) or -213( 213 Bi) or Actinium- 225( 225 Ac) is included.

[0173] See, for example, Hunter et al., Nature 144:945 (1962); vid et al,Biochemistry 13:1014(1974);Pai n et al, J. Immunol. Meth. 40:219 (1981); and Ny gren, J., Histochem.and Cytochem.30:407(19 82) by coupling an antibody or a binding fragment thereof to a detectable moiety or the like. Methods for conjugating are known in the art.

[0174] The embodiments described herein include the antibodies, antibody fragments, diabody fragments, and Antibodies, SMIPs, camelid antibodies, nanobodies, IgNAR, polypeptides, variable regions and CD Further included are variants and equivalents that are substantially homologous to R. These include, for example, conservative substitutions. The amino acid sequence may include natural mutations (i.e., substitution of one or more amino acids with similar amino acids). For example, Conservative substitutions are substitutions of one amino acid with another within the same general class, e.g., an acidic amino acid with another one acidic amino acid with another basic amino acid, or one This refers to the substitution of one neutral amino acid with another neutral amino acid. Such techniques are well known in the art.

[0175] In another embodiment, the present invention provides antibodies comprising the antibody fragments, variable regions and CDRs described herein. A polypeptide having at least 90% sequence identity to any one or more of the polypeptide sequences. More preferably, the present invention contemplates a polypeptide sequence comprising an antibody as described herein. For any one or more of the polypeptide sequences of the fragment, variable region, and CDR, at least More preferably, the sequence identity is at least 95%, and even more preferably, the sequence identity is at least 98%. More preferably, polypeptide sequences having at least 99% sequence identity are intended. Methods for determining homology between nucleic acid and amino acid sequences are well known to those skilled in the art. be.

[0176] In another embodiment, the present invention further provides a compound as described herein that further has anti-CGRP activity. The above polypeptide homologs of the antibody fragments, variable regions and CDRs that are contemplated herein are also contemplated. Non-limiting examples of activities are described herein.

[0177] The present invention also relates to a method for the preparation of a polynucleotide sequence comprising the steps of: Anti-CGRP antibodies comprising any of the polypeptide or polynucleotide sequences described herein. For example, and without limitation, the present invention contemplates the use of any of the compounds described herein. The present invention also contemplates antibodies that include any combination of variable light and variable heavy chain sequences as described herein. Any of the CDR sequences described herein may be combined with any other CDR sequence described herein. Antibodies resulting from the substitution are contemplated.

[0178] Further exemplary embodiments of the present invention In another embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29 Selected from b7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, or Ab14 The anti-human CGRP antibody to be selected is a complete human CGRP polypeptide or a fragment thereof. , specifically bind to the same overlapping linear or conformational epitopes, and / or One or more anti-human CG antigens that compete for binding to the corresponding linear or conformational epitopes. Therapeutic methods using anti-RP antibodies or antibody fragments thereof are contemplated. The anti-CGRP antibody or fragment thereof may be expressed as Ab3, Ab6, Ab13, or Ab14. The same overlapping linear or conformational epitopes on a human CGRP polypeptide or a fragment thereof specifically bind to the same overlapping linear or conformational epitope and / or compete to match.

[0179] A preferred embodiment of the present invention is a method for the production of a CGRP-binding fragment thereof comprising: Chimeric or humanized antibodies and and therapeutic methods using fragments thereof, including Fab fragments. In embodiments, the chimeric or humanized anti-CGRP antibody is Ab3, Ab6, Ab13, or Ab 14 are selected.

[0180] In another embodiment of the invention, the anti-human CGRP antibody used in the described therapeutic methods is Epitopes using overlapping linear peptide fragments spanning the entire length of the native human CGRP polypeptide As confirmed by sequencing, Ab3, Ab6, Ab13, or Ab14 The same overlapping linear or is an antibody that specifically binds to a conformational epitope.

[0181] The present invention also relates to Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Anti-CGR selected from Ab9, Ab10, Ab11, Ab12, Ab13, or Ab14 As antibodies or antibody fragments disclosed herein, including but not limited to P antibodies, For binding to CGRP, the antibody binds to the same CGRP epitope and / or is an anti-CGRP antibody. The present invention relates to a method of treatment using anti-CGRP antibodies that compete with the body.

[0182] In another embodiment, the present invention also relates to: 3, 13, 23, 33, 43, 53, 63, 73, V selected from 83, 93, 103, 113, 123, or 133 H Polypeptide sequence or variants thereof, and / or one or more of the CDRs contained in: 1, 11, 21, 31, 4 1, 51, 61, 71, 81, 91, 101, 111, 121, or 131 RuV L An isolated polypeptide comprising one or more CDRs or variants thereof. The present invention also relates to therapeutic methods using anti-CGRP antibodies or antibody fragments.

[0183] In one embodiment of the present invention, the anti-human CGRP antibody discussed in the two previous paragraphs is Ab1. , Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab 11, Ab12, Ab13, or Ab14. At least two complementarity determining regions in each of the variable light and variable heavy chain regions are identical to Includes the CDR region.

[0184] In a preferred embodiment, the anti-human CGRP antibody used in the described therapeutic methods is , Ab3 or Ab6, respectively, in the variable light and variable heavy chain regions identical to those contained therein. In another embodiment, the antibody comprises at least two complementarity determining regions (CDRs) of the antibody discussed above. The entire CDR of the human CGRP antibody is Ab1, Ab2, Ab3, Ab4, Ab5, Ab6. , Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, or Ab14 The CDRs are identical to those contained in an anti-human CGRP antibody selected from the group consisting of the following: In one embodiment, all of the CDRs of the anti-human CGRP antibodies discussed above are selected from Ab3 or Ab6. The CDRs are identical to those contained in the anti-human CGRP antibody to be selected.

[0185] The present invention further provides that one or more of the anti-human CGRP antibodies discussed above is aglycosylated. or, if glycosylated, only mannosylated; effector function, Fc Regions Modified to Alter Half-Life, Proteolysis, and / or Glycosylation which is human, humanized, single chain or chimeric; derived from a rabbit (parent) anti-human CGRP antibody Exemplary mutations that impair glycosylation include No. 5,624,821, the entirety of which is incorporated herein by reference. As described above, the Asn residue at position 297 of the IgG heavy chain constant region, such as IgG1, It includes mutations to other amino acids such as la.

[0186] The present invention further relates to a framework region ( FR) are either unmodified or have one or more nucleotides in the variable light or heavy chain region, respectively. The FR residues are modified by replacement with the corresponding FR residues of the parent rabbit antibody. the human FR is a human FR, and the human FR is different from other human germline antibody sequences contained in the library. In comparison, based on the high level of homology to the corresponding rabbit variable heavy or light chain regions, The antibody is derived from human variable heavy and light chain antibody sequences selected from a library of human germline antibody sequences. The present invention contemplates one or more anti-human CGRP antibodies.

[0187] The present invention also relates to, for example, anti-migraine medications associated with overuse and / or triptans. and / or medication overuse headache, related to ergot and / or analgesic overuse The present invention relates to a method for the treatment or prevention of medication overuse headache, comprising administering to a subject suffering from or suffering from medication overuse headache, A therapeutically effective amount of at least one anti-human C-cell antigen-binding protein (AAC) as described herein is administered to a patient at risk of developing the AAC. The present invention also contemplates methods of treatment comprising administering a GRP antibody or fragment thereof. may include administration of two or more anti-CGRP antibodies or fragments thereof disclosed herein. It is contemplated that when two or more antibodies are administered to a patient, the antibodies may be administered simultaneously or concurrently. They may be administered developmentally or staggered in their administration. The anti-CGRP activity of the anti-CGRP antibodies and fragments thereof of the present invention having the binding specificity They can be described by their binding strength or their affinity for CGRP. In one embodiment, the anti-CGRP antibodies of the invention that have binding specificity for CGRP and The fragments are 5x10 -7 M, 10 -7 M, 5x10 -8 M, 10 -8 M, 5x10 -9 M. 10 -9 M, 5x10 -10 M, 10 -10 M, 5x10 -11 M, 10 -11 M, 5x 10 -12 M, 10 -12 M, 5x10 -13 M or 10 -13 The dissociation constant (K D ) binds to CGRP. Preferably, the anti-CGRP antibodies and fragments thereof bind to CGRP at 10-11 M , 5x10 -12 M or 10 -12 The compound of the present invention binds to CGRP with a dissociation constant of M. In an embodiment, the anti-CGRP antibodies and fragments thereof of the present invention have binding specificity for CGRP. The fragments bind to linear or conformational CGRP epitopes.

[0188] In another embodiment of the invention, an anti-CGRP molecule of the invention has binding specificity for CGRP. The anti-CGRP activity of the antibodies and their fragments was -4 S -1 , 5x10 -5 S -1 , 10 -5 S -1 , 5x10 -6 S -1 , 10 -6 S -1 , 5x10 -7 S -1 or 10 -7 S -1 Binds to CGRP with the following off-rate:

[0189] In a further embodiment of the invention, an anti-CGRP molecule of the invention has binding specificity for CGRP. The anti-CGRP activity of the P antibodies and fragments thereof prevents symptoms of CGRP-related diseases and disorders. By improving or reducing the symptoms of the disease or disorder, or by treating the disease or disorder, Non-limiting examples of CGRP-related diseases and disorders are described herein. It is listed as a treatment for headache and migraine disorders.

[0190] Polynucleotides encoding anti-CGRP antibody polypeptides As mentioned above, the present invention relates in particular to CDRs, VLs having the sequences specified in Figures 1A-12. As used herein, Ab comprises or consists of VH, CL, and CH polypeptides. The present invention includes the use of specific anti-CGRP antibodies and antibody fragments designated Ab1 to Ab14. The nucleic acid sequences encoding the VL, VH, CL, and CH polypeptides included in 14 are 1A-12. Particularly preferred anti-CGRP antibodies include the CDRs, VLs, and VLs of Ab6. Nucleic acid sequences encoding the H, CL, and CH polypeptides are further described below.

[0191] Antibody Ab6 The present invention further relates to a polypeptide encoding an antibody polypeptide having binding specificity for CGRP. In one embodiment of the invention, the polynucleotide of the invention has the sequence The polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO:222 is or consisting of: [ka]

[0192] In one embodiment of the invention, the polynucleotide of the invention is the light chain polypeptide of SEQ ID NO: 221. The present invention comprises or consists of the following polynucleotide sequence encoding the peptide sequence: [ka]

[0193] In another embodiment of the invention, the polynucleotide of the invention comprises the variable heavy chain of SEQ ID NO: 202 The polypeptide sequence is encoded by the following polynucleotide sequence: : [ka]

[0194] In one embodiment of the invention, the polynucleotide of the invention is the heavy chain polypeptide of SEQ ID NO: 201. The present invention comprises or consists of the following polynucleotide sequence encoding the peptide sequence: [ka]

[0195] In one embodiment of the invention, the polynucleotide of the invention is the heavy chain polypeptide of SEQ ID NO:566. The present invention comprises or consists of the following polynucleotide sequence encoding the peptide sequence: [ka]

[0196] In a further embodiment of the invention, a nucleic acid encoding an antibody fragment that has binding specificity for CGRP is provided. The polynucleotide having the light chain variable sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221 corresponding to a polynucleotide encoding the complementarity determining region (CDR, or hypervariable region) of , SEQ ID NO:234; SEQ ID NO:236; and one of the polynucleotide sequences of SEQ ID NO:238. It includes or consists of the above.

[0197] In a further embodiment of the invention, a nucleic acid encoding an antibody fragment that has binding specificity for CGRP is provided. The polynucleotide having the heavy chain variable sequence of SEQ ID NO: 202 or SEQ ID NO: 201 or A polyclonal antibody encoding the complementarity determining region (CDR, or hypervariable region) of the heavy chain sequence of SEQ ID NO:566. The polynucleotides corresponding to SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218 It comprises or consists of one or more of the nucleotide sequences.

[0198] The present invention also relates to one or more polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present invention, the polynucleotide sequence includes a polypeptide that is directed against CGRP. A polynucleotide encoding an antibody fragment having the binding specificity of The present invention comprises or consists of one, two, three or more of the following polynucleotides: Polynucleotide sequence encoding the light chain variable sequence of SEQ ID NO:232; SEQ ID NO:221 A polynucleotide encoding the light chain sequence of SEQ ID NO:231; a polynucleotide encoding the heavy chain variable region of SEQ ID NO:202 A polynucleotide encoding the heavy chain sequence of SEQ ID NO:201; Polynucleotide encoding the heavy chain sequence of SEQ ID NO:211; the light chain variable sequence of SEQ ID NO: 567; the light chain variable sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221 Encoding the complementarity determining regions (SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:238) and the heavy chain variable sequence of SEQ ID NO:202 or SEQ ID NO:201 or SEQ ID NO: The complementarity determining regions of the heavy chain sequence of SEQ ID NO:566 (SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO: 218).

[0199] In a preferred embodiment of the present invention, the polynucleotide of the present invention is a polypeptide that binds to CGRP. or a polynucleotide encoding a Fab (fragment antigen binding) fragment having specificity; In relation to the antibody Ab6, a polynucleotide encoding the full-length Ab6 antibody is SEQ ID NO:231 and SEQ ID NO:232, which encode the light chain sequence of SEQ ID NO:221, The polynucleotide sequence encoding the heavy chain sequence of SEQ ID NO:201 is SEQ ID NO:211 or SEQ ID NO:566. The polynucleotide encoding the heavy chain sequence comprises or consists of SEQ ID NO:567.

[0200] Another embodiment of the invention is directed to mammalian cells, such as CHO, NSO, HEK-293, or can be a fungal, insect, or microbial system, such as a yeast cell, e.g., the yeast Pichia It is contemplated that these polynucleotides may be incorporated into expression vectors for expression in Suitable Pichia species include Pichia pastoris. oris). One embodiment of the present invention described herein (below), the Fab fragment is synthesized as Ab6 after expression of the full-length polynucleotide in a suitable host. In another embodiment of the present invention, the ribozyme can be produced by enzymatic digestion (e.g., with papain) of Anti-CGRP antibodies, such as Ab6 or Fab fragments thereof, can be expressed in mammalian cells, such as CHO, N SO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (e.g., diploid Ab6 polynucleotides in diploid yeasts, e.g., diploid Pichia and other yeast strains Suitable Pichia species include Pichia Examples include, but are not limited to, Pichia pastoris.

[0201] In one embodiment, the present invention relates to a nucleic acid sequence encoding SEQ ID NO:2, SEQ ID NO:42, SEQ ID NO:82, SEQ ID NO:12 2, SEQ ID NO: 162, SEQ ID NO: 202, SEQ ID NO: 242, SEQ ID NO: 282, SEQ ID NO: 32 2, SEQ ID NO: 362, SEQ ID NO: 402, SEQ ID NO: 442, SEQ ID NO: 482, or SEQ ID NO: Anti-CGRP V selected from 522 H Antibody amino acid sequence H or a variant thereof The present invention relates to an isolated polynucleotide comprising a polynucleotide encoding an antibody, At least one framework residue (FR residue) is H Polypeptide The amino acid is replaced with an amino acid present at the corresponding position of the amino acid sequence, or with a conservative amino acid substitution.

[0202] In another embodiment, the present invention relates to SEQ ID NO: 22, SEQ ID NO: 62, SEQ ID NO: 102, SEQ ID NO: No. 142, SEQ ID NO: 182, SEQ ID NO: 222, SEQ ID NO: 262, SEQ ID NO: 302, SEQ ID NO: SEQ ID NO: 342, SEQ ID NO: 382, ​​SEQ ID NO: 422, SEQ ID NO: 462, SEQ ID NO: 502, or Anti-CGRP V in column 542 L Antibody amino acid sequence H Encoding the antibody amino acid sequence, or The present invention relates to an isolated polynucleotide comprising a polynucleotide sequence encoding the variant. wherein at least one framework residue (FR residue) is a nucleotide sequence identical to that of a rabbit anti-CGRP antibody. V L The amino acid present at the corresponding position in the polypeptide, or a conservative amino acid substitution. It is being done.

[0203] In yet another embodiment, the present invention relates to SEQ ID NO:22 and SEQ ID NO:2; SEQ ID NO:62 and SEQ ID NO: Sequence number 42; sequence number 102 and sequence number 82; sequence number 142 and sequence number 122; Row number 182 and sequence number 162; sequence number 222 and sequence number 202; sequence number 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: No. 462 and SEQ ID NO: 442; SEQ ID NO: 502 and SEQ ID NO: 482; or SEQ ID NO: 54 2 and one or more heterologous polypeptides comprising a sequence encoding the polypeptide contained in SEQ ID NO:522. Concerning rinucleotides.

[0204] In another embodiment, the present invention provides at least one CDR polypeptide derived from an anti-CGRP antibody. An isolated polynucleotide expressing a polypeptide comprising a peptide, The expressed polypeptide may be capable of specifically binding to CGRP alone or in combination with an anti-CGRP antibody. and expressing a polypeptide comprising at least one CDR polypeptide derived from When expressed in the context of a nucleotide sequence, the at least one Each 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: 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: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 Polypeptide The compounds are selected from those contained in the chid.

[0205] Host cells and vectors containing the polynucleotides are also contemplated.

[0206] The present invention further provides polynucleotides encoding the variable heavy and light chain polypeptide sequences, and vectors comprising individual complementarity determining regions (CDRs, or hypervariable regions) described herein. In one embodiment of the present invention, the present invention contemplates a vector comprising the vector, as well as a host cell comprising said vector sequence. The host cell is a yeast cell. In another embodiment of the invention, the yeast host cell is Pichia It belongs to the genus Chia.

[0207] Methods for Producing Antibodies and Fragments Thereof In another embodiment, the invention features methods for producing anti-CGRP antibodies and fragments thereof. FIG. 1 shows a polyploid, preferably diploid, strain of mating competent yeast. Methods for producing antibodies and fragments thereof secreted from Oligosaccharides or tetraploid strains are described, for example, in the literature. U.S. Patent Application No. 2009 / 0022659 to Gason et al. U.S. Patent No. 7,935,340 to Rcia-Martinez et al. (the disclosures of each of which are incorporated herein by reference in their entireties). Methods for producing antibodies and fragments thereof in mammalian cells, e.g., CHO cells, are described in the art. It is further well known in the art.

[0208] Other methods for producing antibodies are also known to those of skill in the art. For example, Methods for producing such proteins are now well known in the art (e.g., Cabilly et al. No. 4,816,567 to Morrison et al., P.O. .ASUSA,81:8651-55(1984);Neuberger,MS et al.,Nature,314:268-270(1985);Bouliann e, GLet al., Nature, 312:643-46 (1984) (each See, e.g., pp. 211-215, 2003, the disclosure of which is incorporated herein by reference in its entirety).

[0209] Similarly, other methods for producing humanized antibodies are now known in the art (e.g., U.S. Patent Nos. 5,530,101 and 5,585, Specification No. 089, Specification No. 5,693,762, and Specification No. 6,180,370 Nos. 5,225,539 and 6,548,644 to Winter; No. 6,054,297 to Carter et al.; Nos. 6,407,213 and 6,639,055 to Adair National Patent No. 6,632,927; Jones, PTet al, Nature ,321:522-525(1986);Reichmann,L.,et al,Na ture,332:323-327(1988);Verhoeyen,M,et al , Science, 239:1534-36 (1988) (the disclosures of each are incorporated by reference in their entirety). (see, for example, US Pat. No. 6,393,311, which is incorporated herein by reference). ).

[0210] As used herein, the term "opioid analgesic" refers to any opioid, natural or synthetic, that has a morphine-like effect. Synthetic and semi-synthetic opioid painkillers are classified into five chemical classes of compounds: phenyl Derivatives of phenylheptylamines, phenylpiperidines, morphinans, and benzomorphans. Exemplary opioid analgesics include codeine, morphine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levothyroxine, Lufanol, oxymorphone, alfentanil, buprenorphine, butorphanol ethanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxycycline, Examples include cyclosporine and pentazocine, or pharma- ceutically acceptable salts thereof.

[0211] The term "NSAID" refers to nonsteroidal anti-inflammatory compounds. They are classified according to their ability to inhibit cyclooxygenase 1 and cyclooxygenase 2. Cyclooxygenase 2 is the two major isoforms of cyclooxygenase, and most Most standard NSAIDs are mixed inhibitors of both isoforms. SAIDs belong to one of five structural categories: (1) Propionic acid derivatives , such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen (2) acetic acid derivatives, such as tolmetin and sulindac; (3) fenamic acid derivatives, (4) biphenylcarboxylic acid derivatives, such as mefenamic acid and meclofenamic acid; Diflunisal and Flufenisal; and (5) Oxicams, such as Piroxime, Sudo Oxicam and isoxicam. Another class of N-acetylglucosamines that selectively inhibit cyclooxygenase 2. SAIDs have been described. Cox-2 inhibitors are described, for example, in U.S. Pat. Specification No. 6,601; Specification No. 5,604,260; Specification No. 5,593,994 Specification No. 5,550,142; Specification No. 5,536,752; No. 5,52 Specification No. 1,213; Specification No. 5,475,995; Specification No. 5,639,780 Specification No. 5,604,253; Specification No. 5,552,422; No. 5,51 Specification No. 0,368; Specification No. 5,436,265; Specification No. 5,409,944 and US Pat. No. 5,130,311, all of which are incorporated herein by reference. Specific exemplary COX-2 inhibitors include celecoxib (SC-5863 5), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxamine 6-Naphthylacetic Acid (6-MNA), Rofecoxib, MK-966, Nabumetone (6- MNA prodrug), Nimesulide, NS-398, SC-5766, SC-5821 5, T-614; or combinations thereof.

[0212] In some embodiments, aspirin and / or acetaminophen are administered to a subject at least once a day to stimulate CGRP synthesis. Aspirin is another type of nonsteroidal anti-inflammatory drug. It is a disease-causing compound.

[0213] The subject to whom the pharmaceutical preparation is administered is, for example, a person in need of such treatment, prevention, and / or improvement. Any human or non-human aged person who requires or would benefit from the inhibition or attenuation of medication overuse headache. For example, the subject may be an individual diagnosed with medication overuse headache, or a person who is suffering from medication overuse headache. The present invention relates to a method for treating drug overuse headache. The present invention relates to a method for the treatment, prevention and / or amelioration of headache, comprising administering to a subject a composition comprising the composition disclosed herein. Further included are any of the uses in pharmaceutical formulations.

[0214] Administration In one embodiment of the present invention, an anti-CGRP antibody described herein, or a CGRP binding agent thereof, The antibody or antibody fragment combination, as well as the antibody or antibody fragment combination, is administered in an amount of about 0. In a preferred embodiment of the present invention, the subject is administered a concentration of 1 to 100.0 mg / kg. The anti-CGRP antibodies, or CGRP-binding fragments thereof, described herein, as well as The antibody fragment combination is administered at a concentration of about 0.4 mg / kg of body weight of the recipient subject, and and / or administered to the subject in a dose of 100 or 300 mg. In one embodiment, the present invention relates to an anti-CGRP antibody, or a CGRP-binding fragment thereof, as described herein, and Combinations of antibodies or antibody fragments may be administered once every 26 weeks or 6 months or less, or once every 16 weeks or once every 4 months or less, once every 8 weeks or 2 months or less, once every 4 weeks or 1 month or less , once every two weeks or half a month, once every week or less, or once every day or less Generally, administration of successive doses will be in accordance with the schedule set forth above. The administration schedule may vary by one or more days, e.g., every 3 months or every 12 weeks. Includes administration of doses that vary by plus or minus 1, 2, 3, 4, 5, 6, or 7 days. .

[0215] Fab fragments may be administered every 2 weeks or less, every week or less, every day or less, multiple times per day, and / or In one embodiment of the present invention, the patient is administered The effective dose is 1 mg / kg to 40 mg / kg / day of Fab fragments in 1 to 6 divided doses per day. , or in sustained release form.

[0216] The concentration of antibody or Fab administered to a given patient may be higher than the exemplary administration concentrations listed above. It should be understood that the amount of the saturation can be higher or lower.

[0217] Those skilled in the art will appreciate that, for example, the disclosures herein and Goodman, LS, Gilman, A .,Brunton,LL,Lazo,JS,& Parker,KL(2 006).Goodman & Gilman's pharmacology cal basis of therapeutics.New York:McGra w-Hill; Howland, RD, Mycek, MJ, Harvey, R. A., Champe, P. C., & Mycek, M. J. (2006). Pharma cology.Lippincott's illustrated reviews. Philadelphia: Lippincott Williams & Wilki ns;and Golan, DE(2008).Principles of ph armacology:the pathophysiologic basis of drug therapy.Philadelphia,Pa.,[etc.]:Li Guided by the teachings of Ppincott Williams & Wilkins Effective dosages and frequency of administration can be determined by routine experimentation.

[0218] In another embodiment of the invention, an anti-CGRP antibody as described herein, or a CGRP The binding fragments, as well as combinations of said antibodies or antibody fragments, are administered to subjects in pharmaceutical formulations.

[0219] "Pharmaceutical composition" refers to a chemical or biological composition suitable for administration to a mammal. Such compositions may be administered intravenously, buccally, epidermally, epidurally, by inhalation, intra-arterially, intracardially, intraventricularly, intradermally, intramuscularly, intravenously ... Intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, direct by enema or suppository Enteral, subcutaneous, subdermal, sublingual, transdermal, and and transmucosal, preferably intravenous. In addition, administration may be by injection, powder, liquid, gel, or liquid formulation. This can be done by drops, or other administration means.

[0220] A "pharmaceutical excipient" or "pharmaceutical acceptable excipient" is a substance in which an active therapeutic agent is formulated. In one embodiment of the present invention, the active therapeutic agent is a carrier, typically a liquid, as described herein. The excipient generally provides a pharmacologically active agent to the formulation. Although it does not provide any stability, it may provide chemical and / or biological stability and release characteristics. Exemplary formulations are available from, for example, Remington's Pharmaceuticals. Sciences, 19 th Ed., Grennaro, A., Ed., 1995 (see (incorporated by reference).

[0221] As used herein, a "pharmaceutically acceptable carrier" or "excipient" refers to a physiologically Any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic In one embodiment, the carrier is suitable for parenteral administration. Alternatively, The carrier may be suitable for intravenous, intraperitoneal, intramuscular, or sublingual administration. Possible carriers include sterile aqueous solutions or dispersions and for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharma- ceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, it is well known in the art. Supplementary active compounds may also be incorporated into the compositions. It can be incorporated.

[0222] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. The present invention contemplates that the pharmaceutical composition is in lyophilized form. , formulated as microemulsions, liposomes, or other ordered structures suitable for high drug concentration. The carrier may be, for example, water, ethanol, polyol (e.g., glycerol, proline, pyrene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The present invention further relates to a pharmaceutical composition comprising a stabilizer. Proper flowability is intended to, for example, maintain the required particle size in the case of a dispersion. This can be maintained by using surfactants and by applying a surfactant.

[0223] In many cases, isotonic agents, for example sugars, polyalcohols, for example mannitol, sorbitol, It may be preferable to include sodium chloride in the composition. Prolonged absorption can be achieved by including in the composition an agent which delays absorption, for example, monostearate salts and the like. In addition, alkaline polypeptides, e.g. For example, the active compound can be formulated into a time-release formulation in a composition that includes a slow-release polymer. The products include controlled release formulations, including implants and microencapsulated delivery systems. The compound can be prepared with a carrier that protects it from rapid release. Polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and and biodegradable, biocompatible polymers such as polylactic acid and polyglycolic acid copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art. be.

[0224] An exemplary composition includes an anti-CGRP antibody or fragment thereof (e.g., Ab6), Histidine, or a combination thereof in an aqueous solution. excipients such as thymine, isotonicity agents such as sorbitol, and surfactants such as polysorbate 80. For example, the composition may comprise, consist essentially of, or consist of a therapeutic agent. Histidine (L-histidine), sorbitol, polysorbate, with a pH of 5.8 80, for example, about 100 mg anti-CGRP antibody (e.g., Ab6) per mL volume, about 3 .1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polysol. 80, or approximately equal thereto, e.g., within 10% of these values, within 5% of these values Within 1% of these values, within 0.5% of these values, or within 0.1% of these values, and water. For example, the pH value can be within 10% of 5.8, i.e., 5.22 to 6.38. The variable light and heavy chain polypeptides of SEQ ID NO: 222 and SEQ ID NO: 202, respectively, No. 221 and SEQ ID NO: 201, or the variable light and heavy chain polypeptides of SEQ ID NO: 22 1 and SEQ ID NO: 566. The article will give rise to the aforementioned configuration when reconstituted with an aqueous solution or, for example, by the addition of water. It may also be in the form of a concentrate (e.g., lyophilized). An exemplary composition contains 1 00 mg of light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 201, respectively, 3.1 mg of L-histidine, about 40.5 mg of sorbitol, and about 0.15 mg of polysaccharide. Resorbate 80, and water QS, or approximately the same, e.g., 10% or less of these amounts. Within 5% of these amounts, within 1% of these amounts, within 0.5% of these amounts, or Another exemplary composition comprises 100 mg per mL of each of 221 and 566, about 3.1 mg of L- histidine, about 40.5 mg sorbitol, and about 0.15 mg polysorbate 80 , and water QS, or approximately its composition, e.g., within 10% of these amounts, 5%, within 1% of these amounts, within 0.5% of these amounts, or within 0.1% of these amounts The composition is suitable for intravenous or subcutaneous administration, preferably for intravenous administration. For example, the composition may be about 100 mg to about 100 mL of intravenous solution. For an amount of 300 mg of antibody, mix with an intravenous solution (e.g., 0.9% sodium chloride) Preferably, the composition has at least 1, 3, 6, 12, 18, or The product may be shelf-stable for up to 24 months, e.g., after storage at room temperature or after refrigeration at 4°C for a specified period. or in accelerated aging tests simulating storage for that period, the antibody or fragment The results show less than 5% or less than 10% aggregate formation.

[0225] For each of the embodiments listed, the compounds can be administered in a variety of dosage forms. Any biologically acceptable dosage form known to one of skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include reconstitutable powders, elixirs, solutions, suspensions, and the like. formulations, emulsions, powders, granules, particles, microparticles, dispersible granules, cachets, inhalants, aerosols Sol inhalation, patch, particle inhalation, implant, depot implant, injection (subcutaneous, Intramuscular, intravenous, and intradermal, preferably including intravenous), infusion, and combinations thereof. Examples of such methods include, but are not limited to,

[0226] The above description of various exemplary embodiments of the present invention is not intended to be exhaustive or to provide a complete understanding of the present invention. It is not intended to be exhaustive or to be limited to the precise form disclosed. While certain embodiments and examples are described herein, those skilled in the art will recognize that the present invention Various equivalent modifications are possible within the scope of the present invention. It may be applied for purposes other than those shown in the examples.

[0227] These and other changes can be made to the invention in light of the above detailed description. Generally, in the following claims, the terms used shall have the same meaning as defined in the specification and claims. However, the present invention should not be construed as being limited to the specific embodiments disclosed herein. Accordingly, the present invention is not limited by this disclosure, but instead the scope of the present invention is limited by the following claims. The scope of the claim should be determined entirely by the scope of the claim.

[0228] The invention may be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations of the present invention are possible in light of the above teachings. It is within the scope of the appended claims.

[0229] Certain CGRP antibody polynucleotides and polypeptides are disclosed in the sequence appended to this patent application. The disclosure of said Sequence Listing is incorporated herein by reference in its entirety.

[0230] Each of the references in the "Background Art", "Description of the Invention" and "Examples" Publication of documents (including patents, patent applications, journal articles, abstracts, manuals, books, or other disclosures) The entire disclosure is hereby incorporated by reference in its entirety.

[0231] The following examples are provided to those skilled in the art with a complete disclosure and description of how to make and use the present invention. These are provided for the convenience of the reader and are not intended to limit the scope of what is regarded as the invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, concentrations, etc.). Experimental results have been obtained, but some experimental error and deviation should be allowed for. As long as parts are parts by weight, molecular weight is average molecular weight, temperature is degrees Celsius, and pressure is atmospheric. The pressure is at or near the pressure.

[0232] Additional Exemplary Embodiments Further exemplary embodiments of the present invention are provided as follows.

[0233] S1. For the manufacture of a medicament for treating or preventing medication-overuse headache, at least one Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP - Use of antibody fragments.

[0234] S2. Treating or preventing probable medication overuse headache at least one anti-CGRP antibody or an anti-CGRP antibody for the manufacture of a medicament for Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0235] S3. The anti-CGRP antibody comprises any one of Ab1 to Ab14 or a fragment thereof; At least one anti-CGRP antibody or anti-CGRP according to any one of the above embodiments. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0236] S4. Any of the above embodiments, wherein the anti-CGRP antibody comprises Ab6 or an antibody fragment. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment according to any one of the preceding claims. Use of PR antibodies or anti-CGRP-R antibody fragments.

[0237] S5. The anti-CGRP antibodies are selected from the group consisting of SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO: 228 light chain complementarity determining region (CDR) 1, 2, and 3 polypeptide sequences, At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0238] S6. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO: 238, comprising the light chain CDR 1, 2, and 3 polypeptide sequences encoded by At least one anti-CGRP antibody or anti-CGRP according to any one of the embodiments Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0239] S7. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO: 208 heavy chain CDR 1, 2, and 3 polypeptide sequences, At least one anti-CGRP antibody or anti-CGRP according to any one of the above embodiments. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0240] S8. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:217. 218, comprising the heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by At least one anti-CGRP antibody or anti-CGRP according to any one of the embodiments Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0241] S9. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227. 228 and the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:204; SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:208. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0242] S10. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO: and the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238, respectively: Heavy chain CDRs encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218 1, 2 and 3 polypeptide sequences. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or the use of anti-CGRP-R antibody fragments.

[0243] S11. The anti-CGRP antibody, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222. At least one anti-CGRP antibody or anti-CGRP according to any one of the embodiments Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0244] S12. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. At least one anti-CGRP antibody according to any one of the above embodiments, or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment use.

[0245] S13. The anti-CGRP antibody, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202. At least one anti-CGRP antibody or anti-CGRP according to any one of the embodiments Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0246] S14. The anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO:212. At least one anti-CGRP antibody according to any one of the above embodiments, or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment use.

[0247] S15. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: 202 variable heavy chain polypeptides. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or Use of anti-CGRP-R antibody fragments.

[0248] S16. 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. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0249] S17. The above embodiment, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0250] S18. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231. At least one anti-CGRP antibody or Use of anti-CGRP antibody fragment, anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0251] S19. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. At least one anti-CGRP antibody or Use of anti-CGRP antibody fragment, anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0252] S20. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567. At least one of the above embodiments, comprising a heavy chain polypeptide comprising Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP - Use of antibody fragments.

[0253] S21. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 20 1 or a heavy chain polypeptide of SEQ ID NO: 566. At least one of the anti-CGRP antibodies or anti-CGRP antibody fragments or anti-CGRP-R antibodies described above. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0254] S22. 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. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0255] S23. The anti-CGRP antibody or anti-CGRP antibody fragment is a Pichia pastoris (P ichia pastoris or Pichia pastoris (Pichia Any of the above embodiments obtained by expression in hia pastoris. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment according to any one of the preceding claims. Use of PR antibodies or anti-CGRP-R antibody fragments.

[0256] S24. The anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells. Any one of the above embodiments, wherein the nucleotide sequence is expressed in a CHO cell or obtained by expression in a CHO cell. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP- Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0257] S25. Is the amount of the anti-CGRP antibody administered about 100 mg to about 300 mg? or about 100 mg, or about 300 mg. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP- Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0258] S26. The method of any one of the above embodiments, wherein the administered amount of the anti-CGRP antibody is 100 mg. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of the above, Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0259] S27. The method further comprises administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0260] S28. The method further comprises administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks. At least one anti-CGRP antibody or Use of anti-CGRP antibody fragment, anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0261] S29. The patient is a chronic migraine patient or an episodic migraine patient at risk of developing medication-overuse headache. At least one of the above embodiments, One anti-CGRP antibody or anti-CGRP antibody fragment, or one anti-CGRP-R antibody or anti-CG Use of RP-R antibody fragments.

[0262] S30. The patient has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and optionally, said acute medication use is continued for at least 28 days. At least one anti-CGR according to embodiment S29, determined over a time course. P antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of fragments.

[0263] S31. The patient uses acute headache medication at least 10 days per month, and optionally The acute drug use is determined over a baseline period of at least 28 days. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C2 Use of GRP-R antibodies or anti-CGRP-R antibody fragments.

[0264] S32. The acute medication is an ergot alkaloid, a triptan, a non-opioid analgesic, an acetonitrile, or a cerebrospinal fluid. Tonoaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics, or opioids At least one of the methods according to any one of the embodiments S30 to S31, comprising the use of an ooid. Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP - Use of antibody fragments.

[0265] S33. The medication-overuse headache is characterized by: (a) a 15-day course in the patient with an existing headache disorder; (b) acute and / or symptomatic treatment of headaches One or more drugs taken for the pulmonary emphysema treatment of said disease for more than 3 months At least one anti-CGR according to any one of the above embodiments, including abuse by a person. P antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of fragments.

[0266] S34. The method of claim 1, wherein the patient exhibits about 15 to about 22 migraine days per month prior to said administration. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0267] S35. The above-mentioned embodiment, wherein the patient exhibits headache days of about 15 to about 27 days per month prior to said administration. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0268] S36. The above-mentioned embodiment, wherein the patient exhibits about 17 to about 24 headache days per month prior to said administration. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0269] S37. Prior to said administration, the patient is experiencing about 15 to about 19 migraine days per month, or about 2 migraine days per month. The above embodiments showing 0 or about 21 headache days or about 16 migraine days per month. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0270] S38. The above method, wherein the patient was diagnosed with migraine headache at least 10 years prior to the administration. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0271] S39. The method according to any of the above, wherein the patient was diagnosed with migraine headaches at least 15 years prior to the administration. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of the embodiments Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0272] S40. The patient was diagnosed with migraine headaches at least 18 or at least 19 years prior to the administration. at least one anti-CGRP antibody or Use of anti-CGRP antibody fragment, anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0273] S41. The patient is administered a migraine headache treatment, the migraine headache treatment being compared to the baseline number of migraine days experienced by the patient prior to the administration. All patients had at least a 50% reduction in the number of migraine days in the month following administration of the antibody. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0274] S42. The patient is administered a migraine headache treatment, the migraine headache treatment being compared to the baseline number of migraine days experienced by the patient prior to the administration. All patients had at least a 75% reduction in the number of migraine days in the month following administration of the antibody. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0275] S43. The patient is administered a 20 mg / kg / day migraine headache supplement, the 20 mg / kg / day migraine headache supplement, or the 20 mg / kg / day migraine supplement. all of the above have a 100% reduction in the number of migraine days in the month following administration of the antibody. At least one anti-CGRP antibody or anti-CGRP according to any one of the embodiments Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0276] S44. The patient is administered a migraine headache treatment, the migraine headache treatment being compared to the baseline number of migraine days experienced by the patient prior to the administration. All patients had at least a 50% reduction in the number of migraine days over the 12 weeks following administration of the antibody. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0277] S45. The patient is administered a migraine headache treatment, the migraine headache treatment being compared to the baseline number of migraine days experienced by the patient prior to the administration. All patients had at least a 75% reduction in the number of migraine days over the 12 weeks following administration of the antibody. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0278] S46. The patient is administered a migraine headache treatment, the migraine headache treatment being compared to the baseline number of migraine days experienced by the patient prior to the administration. all of the above have a 100% reduction in migraine days over the 12 weeks following administration of the antibody. At least one anti-CGRP antibody or anti-CGRP according to any one of the embodiments Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0279] S47. About 12 weeks or about 3 months after said administration, said patient is administered a second dose of said anti-CGR The method of any one of the above embodiments further comprising administering a P antibody to the subject. One anti-CGRP antibody or anti-CGRP antibody fragment, or one anti-CGRP-R antibody or anti-CG Use of RP-R antibody fragments.

[0280] S48. The administration is at about 100 mg, at about 125 mg, at about 150 mg, at about 175 mg, at about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-C At least one of the methods according to any one of the above embodiments, comprising administering a GRP antibody. One anti-CGRP antibody or anti-CGRP antibody fragment, or one anti-CGRP-R antibody or anti-CG Use of RP-R antibody fragments.

[0281] S49. The anti-CGRP antibody or antibody fragment is aglycosylated, or Any of the above embodiments, only if glycosylated, contains only mannose residues. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody according to any one of the above. Use of CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0282] S50. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 20 1 or SEQ ID NO: 566. At least one of the anti-CGRP antibodies or anti-CGRP antibody fragments or anti-CGRP-R antibodies described above. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0283] S51. 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. at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0284] S52. The medication-overuse headache is characterized by: (a) a 15-day course in the patient with an existing headache disorder; and (b) headaches occurring more than once a month; and (b) taken for the acute and / or symptomatic treatment of headaches. Any of the above embodiments, including abuse by said patient of one or more drugs associated with At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody according to any one of the above. Use of CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0285] S53. The substance abuse includes ergotamine use for 10 days or more per month, thrombin use for 10 days or more per month, Use of liptan, one or more non-opioid analgesics (paracetamol (amycin)) for ≥15 days / month cetoaminophen), acetylsalicylic acid (aspirin), another NSAID, or another use of one or more combination analgesics (including non-opioid analgesics) for ≥10 days / month (referred to below) use of one or more opioids for 10 days or more per month; or use of one or more opioids for 10 days or more per month and the use of a combination of two or more drug classes (described further below) per month, The use of triptans is optionally selected from sumatriptan, zolmitriptan, naratriptan, One of rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally comprises the use of oxycodone , tramadol, butorphanol, morphine, codeine, and hydrocodone At least one anti-CGR antibody according to any one of the above embodiments, including the use of P antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of fragments.

[0286] S54. The medication-overuse headache is selected from the group consisting of ergotamine-overuse headache, triptan-overuse headache, and non-opioid Ipioid analgesic overuse headache, opioid overuse headache, complex analgesic overuse headache, complex analgesic overuse headache that is not individually abused Medication-overuse headache due to multiple drug classes, multiple drug classes unspecified or unspecified Medication-overuse headache caused by overuse of a prescribed drug or medication-overuse headache caused by other drugs, The use of triptans is optionally selected from sumatriptan, zolmitriptan, and naratriptan. , rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally includes one or more of oxycodone Of the following, morphine, tramadol, butorphanol, morphine, codeine, and hydrocodone At least one anti-CG according to any one of the above embodiments, including one or more uses RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of body fragments.

[0287] S55. The non-opioid analgesic overuse headache is caused by paracetamol (acetaminophen) Nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin) overuse headache, NSAID-overuse headache, or other non-opioid analgesic-overuse headache, according to the above embodiments. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of the above, Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0288] S56. The ergotamine-overuse headache is a headache occurring 15 days or more per month or a headache occurring for more than 3 months. Any one of the above embodiments, including use of ergotamine for 10 or more days per month. At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or the use of anti-CGRP-R antibody fragments.

[0289] S57. The triptan-overuse headache is headache occurring 15 days or more per month and headache occurring for more than 3 months. use of one or more triptans for 10 days or more per month, Selectively, sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan including the use of one or more of the following: triptans, almotriptan, and frovatriptan; At least one anti-CGRP antibody or anti-CGRP according to any one of the above embodiments. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0290] S58. The non-opioid analgesic overuse headache is a headache occurring 15 days or more per month and Use of one or more non-opioid analgesics (paracetamol, acetaminophen, etc.) for more than 15 days / month amiodarone), acetylsalicylic acid (aspirin), another NSAID, or another non-steroidal anti-inflammatory drug At least one of the methods according to any one of the above embodiments, including the use of a steroid analgesic (e.g., a steroid analgesic). One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C Use of GRP-R antibody fragments.

[0291] S59. The above-mentioned combination analgesic-overuse headache is headache occurring 15 days or more per month and headache occurring for more than 3 months. The use of one or more combined analgesics for 10 days or more per month, each of which is They have analgesic properties (e.g. paracetamol and codeine) or are adjuvants (e.g. ca and optionally, the composite analgesic drug comprises two or more agents that act as analgesics, Combination opioid analgesics, including at least one opioid (tramadol) ethanol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof ), including the use of barbiturates such as butalbital and / or caffeine, At least one anti-CGRP antibody or anti-CGRP according to any one of the embodiments Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0292] S60. The opioid-overuse headache is headache occurring 15 or more days per month and headache occurring for more than 3 months. Use of one or more opioids (oxycodone, tramadol, butorphanol) for 10 days or more per month use of morphine, codeine, hydrocodone, or any combination thereof) at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0293] S61. Medication-overuse headache caused by multiple drug classes that are not individually abused is present for 15 days. Headache occurring on at least one or more days / month and ergotamine-related , triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan, Eletriptan, almotriptan, frovatriptan, or any combination thereof ), non-opioid analgesics and / or opioids (oxycodone, tramadol, butorfinazole) any of the following: ethanol, morphine, codeine, hydrocodone, or any combination thereof At least one anti-CG according to any one of the above embodiments, comprising the use of a combination of RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of body fragments.

[0294] S62. Drug abuse resulting from unspecified or unidentified abuse of multiple drug classes Headache occurring on 15 or more days per month and headache occurring on at least 10 days per month for more than 3 months Rugotamine, Triptans (Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, triptan, eletriptan, almotriptan, frovatriptan, or any of these combinations), non-opioid analgesics and / or opioids (oxycodone, tramadol , butorphanol, morphine, codeine, hydrocodone, or any combination thereof. etc.), where the identity of these classes of drugs ( The identity, amount and / or pattern of use or abuse has been reliably established. at least one anti-CGRP antibody according to any one of the above embodiments or Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0295] S63. Medication-overuse headache caused by other drugs occurs on 15 or more days per month and is not associated with headaches of 3 or more days per month. taken for the acute or symptomatic treatment of headache on at least 10 days / month for more than three months The method of any one of the above embodiments, including the use of one or more drugs other than those listed above. At least one of the anti-CGRP antibodies or anti-CGRP antibody fragments or anti-CGRP-R antibodies described above. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0296] S64. The patient had a pre-existing primary headache disorder prior to the onset of the medication-overuse headache. Also, at least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0297] S65. Number of headache days and / or medication use days are reported by patient or relatives, by diary, by doctor's appointment, or by other means. Medical records, drug purchase history, prescription fulfillment, biomarkers of drug use, occurrence of drug toxicity, The above embodiments, as determined by the incidence of substance abuse and / or other indicators of the patient's drug use. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of the above aspects. or the use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0298] S66. The medication-overuse headache is classified as a headache disorder according to the International Classification of Headache Disorders (ICD). According to the third edition of the International Standardization of Headache Disorders and wherein said medication-overuse headache is, optionally, selected from the group consisting of ergotamine-overuse headache, trimethoprim-sulphonate headache, Butane overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache pain, medication-overuse headache due to multiple drug classes not individually abused, medication-overuse headache due to multiple drug classes Medication-overuse headache due to unspecified or unidentified abuse of other drugs At least one anti-CGRP according to any one of the above embodiments, including substance abuse headache. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Use of pieces.

[0299] S67. The anti-CGRP antibody or anti-CGRP antibody fragment is a histidine (L-histidine In a formulation comprising or consisting of sorbitol, polysorbate 80, and water at least one anti-CGRP antibody or a combination thereof according to any one of the above embodiments. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0300] S68. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0, or having an amount of each component within 10% of said value; 5. The small amount of the extract according to embodiment S67, having a pH of 8 or within + / - 10% of said value. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or the use of anti-CGRP-R antibody fragments.

[0301] S69. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each component within + / - 5% of said values; and / or has a pH of 5.8 or within + / - 5% of said value, embodiment S6. 7. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0302] S70. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each component within + / - 1% of said values; and / or having a pH of 5.8 or within 1% of said value. At least one of the anti-CGRP antibodies or anti-CGRP antibody fragments or anti-CGRP-R antibodies described above. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0303] S71. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each ingredient within + / - 0.5% of the above values. and / or has a pH of 5.8 or within 0.5% of said value. 67. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment according to 67. Use of PR antibodies or anti-CGRP-R antibody fragments.

[0304] S72. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 Contains or consists of 0, or has an amount of each component within + / - 0.1% of the above value. and / or has a pH of 5.8 or within 0.1% of said value. 67. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment according to 67. Use of PR antibodies or anti-CGRP-R antibody fragments.

[0305] S73. Histidine (L-histidine), sorbitol, polysorbate 80, and water In a formulation comprising or consisting of an anti-CGRP antibody or an anti-CGRP antibody fragment, or a pharmaceutical composition comprising them.

[0306] S74. The preparation contains 100 mg of anti-CGRP antibody per mL of volume in aqueous solution. , 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg poly Containing or consisting of Sorbate 80, or having an amount of each component within 10% of the above value. and having a pH of 5.8 or within + / - 10% of said value. The pharmaceutical composition described.

[0307] S75. The preparation contains 100 mg of anti-CGRP antibody per mL of volume in aqueous solution. , 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg poly Consists of or comprises Sorbate 80, or the amount of each ingredient is within + / - 5% of the above values and / or has a pH of 5.8 or within 5% of said value. 74. The pharmaceutical composition according to claim 73.

[0308] S76. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each component within + / - 1% of said values; and / or has a pH of 5.8 or within 1% of said value. The pharmaceutical composition described above.

[0309] S77. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each ingredient within + / - 0.5% of the above values. and / or has a pH of 5.8 or within 0.5% of said value. 74. The pharmaceutical composition according to claim 73.

[0310] S78. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 Contains or consists of 0, or has an amount of each component within + / - 0.1% of the above value. and / or has a pH of 5.8 or within 0.1% of said value. 74. The pharmaceutical composition according to claim 73.

[0311] S79. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227. The light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:228 and SEQ ID NO:20, respectively 4; SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:208. The pharmaceutical composition according to any one of embodiments S73 to S79, comprising a sequence.

[0312] S80. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:237. Light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238 and Heavy chains encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218, respectively. Any one of embodiments S73 to S79, comprising CDR 1, 2 and 3 polypeptide sequences. The pharmaceutical composition described above.

[0313] S81. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: 202 variable heavy chain polypeptide. Pharmaceutical compositions.

[0314] S82. 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. The pharmaceutical composition according to any one of S73 to S79.

[0315] S83. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 20 Any one of embodiments S73 to S79, comprising a heavy chain polypeptide of SEQ ID NO: 1 or SEQ ID NO: 566. The pharmaceutical composition described above.

[0316] S84. 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. , A pharmaceutical composition according to any one of embodiments S73 to S79.

[0317] S85. The anti-CGRP antibody or anti-CGRP antibody fragment is a Pichia pastoris (P ichia pastoris or Pichia pastoris (Pichia According to the embodiment S73 to S84, the method is obtained by expression in hia pastoris. 13. The pharmaceutical composition according to any one of claims 1 to 12.

[0318] S86. The anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells. or obtained by expression in CHO cells. The pharmaceutical composition described above.

[0319] S87. A method for the manufacture of a medicament for treating or preventing migraine, comprising administering to a subject a compound comprising at least one anti-C Use of anti-CGRP antibodies or anti-CGRP antibody fragments and / or at least one anti-CGRP- Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments in the treatment of ergot alkaloids, triptans, , non-opioid analgesics, acetaminophen, aspirin, NSAIDs, non-opioid analgesics Acute treatment of headaches, selected from the group consisting of analgesics, combination analgesics, or opioids; and / or The use further comprising the use of at least one additional drug taken for symptomatic treatment.

[0320] S88. The combined administration of (i) and (ii) reduces the medication-overuse headache symptoms in said patient. , at least one of the methods according to embodiment S87, which reduces the severity and / or episodes of Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP - Use of antibody fragments.

[0321] S89. The drug taken for acute and / or symptomatic treatment of headache is ergot alopecia. At least one anti-CGRP antibody or anti-CGRP antibody according to embodiment S87 or S88, comprising a kaloid. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0322] S90. The ergot alkaloid is ergotamine, nicergoline, methysergide, dihy At least one of the compounds according to embodiment S89 selected from droergotamine and the above combinations. One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C Use of GRP-R antibody fragments.

[0323] S91. The drug taken for acute and / or symptomatic treatment of headache is a tryptophan At least one anti-CGRP antibody or antibody according to embodiment S87 or S88, Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0324] S92. The triptan is sumatriptan, zolmitriptan, naratriptan, or ritriptan. Zatriptan, eletriptan, almotriptan, frovatriptan, and combinations of the above At least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0325] S93. The drug taken for acute and / or symptomatic treatment of headache is a non-opioid At least one anti-CGRP antibody according to embodiment S87 or S88, comprising an anti-CGRP analgesic. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment use.

[0326] S94. The non-opioid analgesic is paracetamol (acetaminophen) or At least one anti-CGRP antibody or anti-C-actin antibody according to embodiment S93, including spironolactone. Use of a GRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0327] S95. The drug taken for acute and / or symptomatic treatment of headache is an NSAI At least one anti-CGRP antibody according to embodiment S87 or S88, Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0328] S96. The NSAID is a salicylate, a propionate, d) Derivatives, enolic acid derivatives, anthranilic acid derivatives (fenamates), selective COX-2 inhibitors (coxibs), sulfones At least one compound according to embodiment S95 selected from the group consisting of anilides, and combinations thereof. Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP - Use of antibody fragments.

[0329] S97. The NSAID is aspirin (acetylsalicylic acid), diflunisal (Do lobid), salicylic acid and its salts, and salsalate (Disalcid) recylate; ibuprofen, dexibuprofen, naproxen, fenoprofen, Ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and Propionic acid derivatives such as xoprofen; indomethacin, tolmetin, sulindac, Acetate such as etodolac, ketorolac, diclofenac, aceclofenac, and nabumetone Acid derivatives, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam Enolic acid (oxicam) derivatives such as phenylbutazone (bute), isoxicam, and phenylbutazone (bute) derivatives; amides such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid Anthranilic acid derivatives (fenamates); celecoxib, rofecoxib, valdecoxib Selective C, such as parecoxib, lumiracoxib, etoricoxib, and firocoxib OX-2 inhibitors (coxibs); sulfonanilides such as nimesulide; clonixin, lycosides feron, H-harpagide or devil's claw, and combinations thereof. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to form S95 or an anti Use of CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0330] S98. The drug taken for acute and / or symptomatic treatment of headache is a non-opioid At least one anti-CGRP antibody according to embodiment S87 or S88, comprising an anti-CGRP analgesic. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment use.

[0331] S99. The drug taken for acute and / or symptomatic treatment of headache is a combined analgesic At least one anti-CGRP antibody or a combination thereof according to embodiment S87 or S88, Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0332] S100. The combination analgesic comprises a non-opioid analgesic and at least one opioid or includes combinations with barbiturates such as butalbital and / or caffeine, or acetaminophen, aspirin, and caffeine, e.g., EXCEDRIN or EXCEDRIN MIGRAINE® combination, or at least one non-analgesic drug, e.g., a vasoconstrictor such as pseudoephedrine; or a combination analgesic comprising an analgesic in combination with an antihistamine. At least one of the anti-CGRP antibodies or anti-CGRP antibody fragments or anti-CGRP-R antibodies described above. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0333] S101. The drug taken for acute and / or symptomatic treatment of headache is an opioid At least one anti-CGRP antibody or antibody according to embodiment S87 or S88, or the use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0334] S102. The opioid is oxycodone, tramadol, butorphanol, mol. Hine, codeine, hydrocodone, thebaine, oripavine, mixed opium alkaloids, e.g. For example, papaveretam, diacetylmorphine, nicomorphine, dipropanoylmorphine, di Acetyldihydromorphine, acetylpropionylmorphine, desomorphine, methyldeso Ruphine, dibenzoylmorphine, ethylmorphine, heterocodeine, buprenorphine , etorphine, hydromorphone, oxymorphone, fentanyl, α-methylphen Alfentanil, alfentanil, sufentanil, remifentanil, carfentanil ( carfentanyl), omefentanyl, pethidine (meperidine), ketobemide MPPP, Allylprozine, Prozine, PEPAP, Promedol, Diphenylprozine Pyramine, propoxyphene, dextropropoxyphene, dextromorphamide, The compound according to embodiment S101, which is selected from bezitramide, piritramide, and combinations thereof. At least one of the anti-CGRP antibodies or anti-CGRP antibody fragments or anti-CGRP-R antibodies described above. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0335] S103. The anti-CGRP antibody comprises any one of Ab1 to Ab14 or a fragment thereof. At least one anti-CGRP antibody according to any one of embodiments S87 to S102. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment use.

[0336] S104. The anti-CGRP antibody of any of embodiments S87 to S1, wherein the anti-CGRP antibody comprises Ab6 or a fragment thereof. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of claims 03 to 04. Use of a fragment thereof or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0337] S105. The anti-CGRP antibody is selected from SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227, respectively. The light chain complementarity determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 228 are included. At least one anti-CGRP antibody or Use of anti-CGRP antibody fragment, anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0338] S106. The anti-CGRP antibody is selected from SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:237, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238 and at least one anti-CGRP antibody or a combination thereof according to any one of embodiments S87 to S105. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0339] S107. The anti-CGRP antibody is selected from SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:207. The heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:208 are included in the embodiments S87 to S89. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of S106. Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0340] S108. The anti-CGRP antibody is selected from SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:217; The heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:218 and at least one anti-CGRP antibody or a combination thereof according to any one of embodiments S87 to S107. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0341] S109. The anti-CGRP antibody is selected from SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:228 and SEQ ID NO:2, respectively 04; SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptides of SEQ ID NO:208. At least one anti-CG according to any one of embodiments S87 to S108, comprising the sequence RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of body fragments.

[0342] S110. The anti-CGRP antibody is selected from SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:237, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238; and The overlap sequences encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218, respectively. Any of embodiments S87 to S109, comprising a CDR 1, 2, and 3 polypeptide sequence. or at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment according to any one of the preceding items. Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0343] S111. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222. At least one anti-CGRP antibody or or the use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0344] S112. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. At least one antibody according to any one of embodiments S87 to S111, comprising a peptide. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- Use of R antibody fragments.

[0345] S113. The anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202. At least one anti-CGRP antibody or or the use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0346] S114. The anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO: 212. At least one antibody according to any one of embodiments S87 to S113, comprising a peptide. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- Use of R antibody fragments.

[0347] S115. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and SEQ ID NO: 202, comprising the variable heavy chain polypeptide of any one of embodiments S87 to S114. At least one of the anti-CGRP antibodies or anti-CGRP antibody fragments or anti-CGRP-R antibodies described above. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0348] S116. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. and an embodiment comprising a variable heavy chain polypeptide encoded by SEQ ID NO:212. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of aspects S87 to S115. Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0349] S117. The embodiment in which the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of aspects S87 to S116. Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0350] S118. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231. At least one anti-CG according to any one of embodiments S87 to S117, comprising RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of body fragments.

[0351] S119. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. At least one anti-CG according to any one of embodiments S87 to S118, comprising RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Use of body fragments.

[0352] S120. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567. The method according to any one of embodiments S87 to S119, comprising administering to said patient a heavy chain polypeptide comprising: At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or use of anti-CGRP-R antibody fragments.

[0353] S121. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 2 Any of embodiments S87 to S120, comprising a heavy chain polypeptide of SEQ ID NO: 566 or SEQ ID NO: 567. or at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment according to any one of the preceding items. Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0354] S122. 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. At least one anti-CGRP antibody according to any one of embodiments S87 to S121. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment use.

[0355] S123. The anti-CGRP antibody or anti-CGRP antibody fragment is a Pichia pastoris ( It was expressed in Pichia pastoris or Pichia pastoris (Pi Embodiments S87 to S12, obtained by expression in chia pastoris 2. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of claims 1 to 2. or the use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0356] S124. The anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells. According to the embodiments S87 to S123, the nucleotide sequence of the present invention is expressed or obtained by expression in CHO cells. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of the above, Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0357] S125. The amount of the anti-CGRP antibody administered is about 100 mg to about 300 mg. or about 100 mg, or about 300 mg, of any of the embodiments S87 to S124. At least one anti-CGRP antibody or anti-CGRP antibody fragment according to any one of the above, Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0358] S126. Embodiment S87, in which the administered amount of the anti-CGRP antibody is 100 mg. At least one anti-CGRP antibody or anti-CGRP according to any one of claims 1 to 125. Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0359] S127.Further administering 100 mg of said anti-CGRP antibody intravenously every 12 weeks At least one anti-CGRP antibody according to any one of embodiments S87 to S126. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Use of.

[0360] S128.Further administering 300 mg of said anti-CGRP antibody intravenously every 12 weeks At least one anti-CGRP antibody according to any one of embodiments S87 to S127. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Use of.

[0361] S129. The patient is a chronic migraine sufferer or a sudden onset migraine sufferer at risk of developing medication-overuse headache. The patient is a patient with chronic migraine or cluster headache according to any one of embodiments S87 to S128. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or the use of an anti-CGRP-R antibody fragment.

[0362] S130. The patient has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1 0 days, and optionally, said acute medication use continues for at least 28 days. The method according to any one of embodiments S87 to S129, wherein the time period is determined over a baseline period. At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or the use of anti-CGRP-R antibody fragments.

[0363] S131. The patient uses acute headache medication at least 10 days per month, and optionally: The acute drug use is determined over a baseline period of at least 28 days. At least one anti-CGRP antibody according to any one of forms S87 to S130, or Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0364] S132. The medication-overuse headache is (a) 15-day follow-up in the patient with an existing headache disorder. and (b) headaches occurring for ≥ 10 days / month; and (b) taken for the acute and / or symptomatic treatment of headaches. The present invention relates to an embodiment S87 to an embodiment S88, which includes abuse by the patient of one or more drugs for more than three months. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of S131 Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0365] S133. Prior to said administration, the patient exhibits a migraine headache frequency of about 15 to about 22 days per month. At least one anti-CGRP antibody or anti-C antibody according to any one of forms S87 to S132. Use of a GRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0366] S134. Prior to said administration, the patient exhibits about 15 to about 27 headache days per month. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of aspects S87 to S133. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0367] S135. Prior to said administration, the patient exhibits about 17 to about 24 headache days per month. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of aspects S87 to S134. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0368] S136. Prior to said administration, the patient has between about 15 and about 19 migraine days per month, or between about 15 and about 19 migraine days per month. Embodiment S8, showing 20 or about 21 headache days or about 16 migraine days per month. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of S137 to S135. Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0369] S137. The embodiment, wherein the patient was diagnosed with migraine headaches at least 10 years prior to the administration. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of aspects S87 to S136. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0370] S138. The embodiment, wherein the patient was diagnosed with migraine headaches at least 15 years prior to the administration. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of aspects S87 to S137. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0371] S139. The patient has had a history of migraine headaches at least 18 or at least 19 years prior to the administration. Diagnosed with at least one anti-CGRP antibody according to any of embodiments S87 to S138. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Use of pieces.

[0372] S140. The patient is administered a baseline number of migraine days experienced by the patient prior to said administration, and Compared to placebo, the antibody reduced the number of migraine days by at least 50% in the month following administration. At least one anti-CGRP antibody or a combination thereof according to any one of embodiments S87 to S139. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0373] S141. The patient is administered a measurement of the baseline number of migraine days experienced by the patient prior to said administration. Compared to placebo, subjects who received the antibody had at least a 75% reduction in the number of migraine days in the month following treatment. At least one anti-CGRP antibody or a combination thereof according to any one of embodiments S87 to S140. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0374] S142. The patient is administered a baseline number of migraine days experienced by the patient prior to said administration, and The antibody has a 100% reduction in migraine days in the month following administration of the antibody, compared to the control group. At least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0375] S143. The patient is administered a measurement of the baseline number of migraine days experienced by the patient prior to said administration. Compared to placebo, subjects who received the antibody had at least a 50% reduction in the number of migraine days over the 12 weeks following treatment with the antibody. At least one anti-CGRP antibody or a combination thereof according to any one of embodiments S87 to S142. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0376] S144. The patient is administered a baseline number of migraine days experienced by the patient prior to said administration, and Compared to placebo, subjects who received the antibody had a reduction in the number of migraine days by at least 75% over the 12 weeks following treatment with the antibody. At least one anti-CGRP antibody or a combination thereof according to any one of embodiments S87 to S143. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0377] S145. The patient is administered a baseline number of migraine days experienced by the patient prior to said administration, and In comparison, the antibody has a 100% reduction in migraine days over the 12 weeks following administration of the antibody. At least one anti-CGRP antibody or anti- Use of a CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0378] S146. About 12 weeks or about 3 months after said administration, said patient is administered a second dose of said anti-CG The method according to any one of embodiments S87 to S145, further comprising administering an RP antibody. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or the use of an anti-CGRP-R antibody fragment.

[0379] S147. The administration is 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 antibody. According to any one of the embodiments S87 to S146, comprising administering a CGRP antibody. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or the use of an anti-CGRP-R antibody fragment.

[0380] S148. The anti-CGRP antibody or antibody fragment is aglycosylated or contains only mannose residues only if glycosylated, At least one anti-CGRP antibody or anti-CGRP antibody according to any one of S147. Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0381] S149. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 2 01 or the heavy chain polypeptide of SEQ ID NO: 566. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C Use of GRP-R antibodies or anti-CGRP-R antibody fragments.

[0382] S150. 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 At least one anti-CGRP antibody according to any one of embodiments S87 to S149. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Use of.

[0383] S151. The medication-overuse headache is (a) 15-day follow-up in the patient with an existing headache disorder. and (b) headache occurring for more than 3 months with one or more medications At least one anti-C-terminal peptide according to any one of embodiments S87 to S150, including abuse of GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Use of antibody fragments.

[0384] S152. The substance abuse is ergotamine use for 10 days or more per month, Use of triptans, one or more non-opioid analgesics (paracetamol ( acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or use of one or more combination analgesics (such as another non-opioid analgesic) for 10 days or more per month use of opioids (as described further below) for 10 days or more per month; use of 1 or more opioids for 10 days or more per month; The combination of two or more drug classes (described further below) is included in the above-mentioned The use of triptans is optionally selected from sumatriptan, zolmitriptan, and naratriptan. , rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally includes one or more of oxycodone Of the following, morphine, tramadol, butorphanol, morphine, codeine, and hydrocodone At least one of the embodiments S87 to S151, including one or more uses. One anti-CGRP antibody or anti-CGRP antibody fragment, or one anti-CGRP-R antibody or anti-CG Use of RP-R antibody fragments.

[0385] S153. The medication-overuse headache is ergotamine-overuse headache, triptan-overuse headache, or non-opioid Opioid analgesic overuse headache, opioid overuse headache, combined analgesic overuse headache, not individually abused Medication-overuse headache due to multiple drug classes, multiple drug classes unspecified or unspecified Medication-overuse headache caused by overuse of medication or medication-overuse headache caused by other drugs, The use of a triptan is optionally selected from sumatriptan, zolmitriptan, naratriptan, Among rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or the opioid use optionally includes one or more of oxycodone. Of the drugs listed below, morphine, tramadol, butorphanol, codeine, and hydrocodone, At least one of the methods according to any one of the embodiments S87 to S152, comprising the use of one or more of One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C Use of GRP-R antibody fragments.

[0386] S154. The non-opioid analgesic overuse headache is caused by paracetamol (acetaminophen ) Nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin) overuse headache, (NSAID)-overuse headache or other non-opioid analgesic-overuse headache, At least one anti-CGRP antibody or anti-CGRP according to any one of claims 1 to 53. Use of an antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0387] S155. The ergotamine-overuse headache is a headache occurring 15 or more days per month or Any of embodiments S87 to S154, including use of ergotamine for 10 days or more per month. or at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment according to any one of the preceding items. Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0388] S156. The triptan-overuse headache is headache occurring 15 days or more per month and headache occurring for more than 3 months. use of one or more triptans for at least 10 days / month, Optionally, sumatriptan, zolmitriptan, naratriptan, rizatriptan, Includes use of one or more of the following: Letriptan, Almotriptan, and Frovatriptan and at least one anti-CGRP antibody or a combination thereof according to any one of embodiments S87 to S155. or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment. For.

[0389] S157. The non-opioid analgesic overuse headache is a headache occurring 15 days or more per month and One or more non-opioid analgesics (paracetamol, acetaminophen, etc.) for ≥15 days / month for >2 months aminophen), acetylsalicylic acid (aspirin), another NSAID, or another nonsteroidal anti-inflammatory drug Any one of embodiments S87 to S156, including the use of an opioid analgesic. At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or the use of anti-CGRP-R antibody fragments.

[0390] S158. The above-mentioned combination analgesic-overuse headache is a headache occurring on 15 or more days per month or a headache occurring for more than 3 months. The use of one or more combination analgesics for 10 days or more per month, each of which is They have analgesic properties (e.g. paracetamol and codeine) or are supplementary (e.g. caffeine), and optionally the composite analgesic comprises: A combination of non-opioid analgesics, including at least one opioid (tramadol) ethanol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof and the like), a barbiturate such as butalbital, and / or caffeine. At least one anti-CGRP antibody or anti-C according to any one of S87 to S157 Use of a GRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0391] S159. The opioid-overuse headache is a headache occurring 15 days or more per month or a headache occurring for more than 3 months. Use of one or more opioids (oxycodone, tramadol, butorfa) for 10 days or more per month use of any of the following drugs: morphine, codeine, hydrocodone, or any combination thereof At least one anti-CGRP antibody according to any one of embodiments S87 to S158. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Use of.

[0392] S160. Medication-overuse headache caused by multiple drug classes that are not individually abused is 15 Headache occurring on at least days / month and ergotaneus headache occurring on at least 10 days / month in total over more than 3 months triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan , eletriptan, almotriptan, frovatriptan, or any combination thereof etc.), non-opioid analgesics and / or opioids (oxycodone, tramadol, butol any combination thereof) At least one of the embodiments S87 to S159, including the use of any combination thereof. One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C Use of GRP-R antibody fragments.

[0393] S161. The above drug is the result of abuse of multiple drug classes, either unspecified or unidentified. Overuse headache is defined as headache occurring ≥15 days / month and ≥10 days / month for >3 months. Ergotamines, triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan) Triptan, eletriptan, almotriptan, frovatriptan, or any of these combinations), non-opioid analgesics and / or opioids (oxycodone, tramadol, etc.) ethanol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof etc.), where the identity of these classes of drugs , the amount and / or pattern of use or abuse has not been reliably established, embodiment S8. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of S160 to S160. Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0394] S162. Medication-overuse headache caused by other medications occurs 15 days or more per month and Taken for the acute or symptomatic treatment of headache on at least 10 days per month for more than 3 months Any of the embodiments S87 to S161, including the use of one or more drugs other than those mentioned above. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C Use of GRP-R antibodies or anti-CGRP-R antibody fragments.

[0395] S163. The patient had a pre-existing primary headache disorder prior to the onset of the medication-overuse headache. At least one anti-CGRP antibody according to any one of embodiments S87 to S162. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Use of.

[0396] S164. Number of headache days and / or medication use days should be measured by patient or relative report, diary, or Medical records, drug purchasing history, prescription fulfillment, biomarkers of drug use, occurrence of drug toxicity, In embodiment S, the incidence of substance abuse and / or other indicators of the patient's substance use are determined. At least one anti-CGRP antibody or anti-CGRP antibody according to any one of S87 to S163. Use of an anti-CGRP antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0397] S165. The medication-overuse headache is classified as a headache disorder according to the International Classification of Headache Disorders (ICD). According to the 3rd edition of the "Standardization of Headache Disorders" and wherein said medication-overuse headache is, optionally, ergotamine-overuse headache, thromboembolism headache, Liptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse Headache, medication-overuse headache due to multiple drug classes not individually abused, multiple drug classes Medication-overuse headache resulting from unspecified or unidentified abuse of other drugs At least one of the methods according to any one of embodiments S87 to S164, including medication-overuse headache. Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP Use of PR antibody fragments.

[0398] S166. The anti-CGRP antibody or anti-CGRP antibody fragment is a histidine (L-his) A formulation comprising or consisting of sorbitol, polysorbate 80, and water. At least one anti-C according to any one of embodiments S87 to S165, GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Use of antibody fragments.

[0399] S167. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of CGRP antibody, and 100 mg of CGRP antibody per mL of volume. g L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80, or having an amount of each component within 10% of said value, As described in embodiment S166, having a pH of 0.8 or within + / - 10% of said value. At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or the use of anti-CGRP-R antibody fragments.

[0400] S168. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of CGRP antibody, and 100 mg of CGRP antibody per mL of volume. g L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or have amounts of each ingredient within + / - 5% of the above values. and / or has a pH of 5.8 or within + / - 5% of said value. 166. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody according to Use of anti-CGRP-R antibodies or anti-CGRP-R antibody fragments.

[0401] S169. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of CGRP antibody, and 100 mg of CGRP antibody per mL of volume. g L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or have amounts of each ingredient within + / - 1% of the above values. and / or has a pH of 5.8 or within 1% of said value, embodiment S166. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP- Use of an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0402] S170. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of CGRP antibody, and 100 mg of CGRP antibody per mL of volume. g L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or containing an amount of each ingredient within + / - 0.5% of the above value and / or having a pH of 5.8 or within 0.5% of said value. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C Use of GRP-R antibodies or anti-CGRP-R antibody fragments.

[0403] S171. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of CGRP antibody, and 100 mg of CGRP antibody per mL of volume. g L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or containing an amount of each ingredient within + / - 0.1% of the above value and / or having a pH of 5.8 or within 0.1% of said value. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C Use of GRP-R antibodies or anti-CGRP-R antibody fragments.

[0404] Further exemplary embodiments Further exemplary embodiments of the present invention are provided as follows.

[0405] E1. At least one anti-CG antibody for use in treating or preventing medication-overuse headache RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Body fragments.

[0406] E2. A combination of at least one anti-inflammatory drug for use in treating or preventing suspected medication-overuse headache. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- R antibody fragment.

[0407] E3. The anti-CGRP antibody comprises any one of Ab1 to Ab14 or a fragment thereof; At least one anti-CGRP antibody or or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0408] E4. Any of the above embodiments, wherein the anti-CGRP antibody comprises Ab6 or a fragment thereof. At least one anti-CGRP antibody or anti-CGRP antibody fragment for the use according to any one of claims 1 to 5. Or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0409] E5. The anti-CGRP antibody is selected from SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227, respectively. No. 228, comprising the light chain complementarity determining region (CDR) 1, 2, and 3 polypeptide sequences of said at least one anti-CGRP antibody or is an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0410] E6. The anti-CGRP antibody is selected from SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO: The light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238 are included in the above. At least one anti-CGRP antibody or or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0411] E7. The anti-CGRP antibody is selected from SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO: Any of the above embodiments, comprising the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:208. At least one anti-CGRP antibody or anti-CGRP antibody for any one of the uses described in fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0412] E8. The anti-CGRP antibody is selected from SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:217, respectively. The heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:218 are included in the above. At least one anti-CGRP antibody or or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0413] E9. The anti-CGRP antibody is selected from SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:228 and SEQ ID NO:204, respectively SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:208. At least one anti-CGR for use according to any one of the above embodiments, comprising P antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody piece.

[0414] E10. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:237; Light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238 and Heavy chains encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218, respectively. As described in any one of the above embodiments, comprising CDR 1, 2 and 3 polypeptide sequences. at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use in CGRP-R antibody or anti-CGRP-R antibody fragment.

[0415] E11. The anti-CGRP antibody, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222. at least one anti-CGRP antibody or is an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0416] E12. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO:232. At least one antibody for use according to any one of the above embodiments, comprising a peptide. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- R antibody fragment.

[0417] E13. The anti-CGRP antibody, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202. at least one anti-CGRP antibody or is an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0418] E14. The anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO:212. At least one antibody for use according to any one of the above embodiments, comprising a peptide. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- R antibody fragment.

[0419] E15. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: 202 variable heavy chain polypeptide. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody for Antibody or anti-CGRP-R antibody fragment.

[0420] E16. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. The above embodiment includes a variable heavy chain polypeptide encoded by the peptide and SEQ ID NO: 212. At least one anti-CGRP antibody or anti- CGRP antibody fragment, or anti-CGRP-R antibody, or anti-CGRP-R antibody fragment.

[0421] E17. The embodiment of any one of the above, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221. At least one anti-CGRP antibody or anti- CGRP antibody fragment, or anti-CGRP-R antibody, or anti-CGRP-R antibody fragment.

[0422] E18. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO:231. At least one anti-CG for use according to any one of the above embodiments, RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Body fragments.

[0423] E19. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. At least one anti-CG for use according to any one of the above embodiments, RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Body fragments.

[0424] E20. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567. The method according to any one of the above embodiments further comprises administering to said patient a heavy chain polypeptide comprising: At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or is an anti-CGRP-R antibody fragment.

[0425] E21. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 20 1 or SEQ ID NO: 566. at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use in CGRP-R antibody or anti-CGRP-R antibody fragment.

[0426] E22. 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. at least one anti-CGRP antibody for use according to any one of the above embodiments or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment.

[0427] E23. The anti-CGRP antibody or anti-CGRP antibody fragment is a Pichia pastoris (P ichia pastoris or Pichia pastoris (Pichia Any of the above embodiments obtained by expression in hia pastoris. At least one anti-CGRP antibody or anti-CGRP antibody fragment for the use according to any one of claims 1 to 5. Or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0428] E24. The anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells. Any one of the above embodiments, wherein the nucleotide sequence is expressed in a CHO cell or obtained by expression in a CHO cell. or at least one anti-CGRP antibody or anti-CGRP antibody fragment for the use according to An anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0429] E25. Is the amount of the anti-CGRP antibody administered about 100 mg to about 300 mg? or about 100 mg, or about 300 mg. or at least one anti-CGRP antibody or anti-CGRP antibody fragment for the use according to An anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0430] E26. The method of any one of the above embodiments, wherein the administered amount of the anti-CGRP antibody is 100 mg. At least one anti-CGRP antibody or anti-CGRP for the use according to any one of the preceding claims. An antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0431] E27. The method further comprises administering 100 mg of said anti-CGRP antibody intravenously every 12 weeks. at least one anti-CGRP antibody for use according to any one of the above embodiments. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0432] E28. The method further comprises administering 300 mg of said anti-CGRP antibody intravenously every 12 weeks. For the use according to any one of the embodiments E1 to E26, at least one anti-CG RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Body fragments.

[0433] E29. The patient is a chronic migraine patient or an episodic migraine patient at risk of developing medication-overuse headache. For the use according to any one of the above embodiments, the patient is a migraine or cluster headache sufferer. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or an anti-CGRP-R antibody fragment.

[0434] E30. The patient has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and optionally, said acute medication use is continued for at least 28 days. For the use according to embodiment E29, at least one One anti-CGRP antibody or anti-CGRP antibody fragment, or one anti-CGRP-R antibody or anti-CG RP-R antibody fragment.

[0435] E31. The patient uses acute headache medications at least 10 days per month, and optionally The acute drug use is determined over a baseline period of at least 28 days. At least one anti-CGRP antibody or anti-CGRP antibody for use according to aspect E29 fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0436] E32. The acute medication is an ergot alkaloid, a triptan, a non-opioid analgesic, an acetonitrile, or Tonoaminophen, aspirin, NSAIDs, non-opioid analgesics, combination analgesics, or opioids The use of any one of embodiments E30 to E31, including the use of an ointment, At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or is an anti-CGRP-R antibody fragment.

[0437] E33. The medication-overuse headache is: (a) within 15 days in the patient with an existing headache disorder; and (b) headaches occurring more than once a month; and (b) taken for the acute and / or symptomatic treatment of headaches. Any of the above embodiments, including abuse by said patient of one or more drugs associated with At least one anti-CGRP antibody or anti-CGRP antibody for the use according to any one of the preceding claims. an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0438] E34. The method of claim 1, wherein prior to said administration, the patient exhibits about 15 to about 22 migraine days per month. At least one anti-CGRP antibody or An anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0439] E35. Prior to said administration, the patient is experiencing headache days of about 15 to about 27 days per month. At least one anti-CGRP antibody or anti- CGRP antibody fragment, or anti-CGRP-R antibody, or anti-CGRP-R antibody fragment.

[0440] E36. Prior to said administration, the patient is experiencing about 17 to about 24 headache days per month. At least one anti-CGRP antibody or anti- CGRP antibody fragment, or anti-CGRP-R antibody, or anti-CGRP-R antibody fragment.

[0441] E37. Prior to said administration, the patient is experiencing about 15 to about 19 migraine days per month, or about 2 migraine days per month. The above embodiments showing 0 or about 21 headache days or about 16 migraine days per month. 2. The method according to claim 1, further comprising administering to said patient at least one anti-CGRP antibody or anti-CGRP antibody. P antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0442] E38. The method of any of the above, wherein the patient was diagnosed with migraine headaches at least 10 years prior to the administration. At least one anti-CGRP antibody or anti- CGRP antibody fragment, or anti-CGRP-R antibody, or anti-CGRP-R antibody fragment.

[0443] E39. The method of any of the above, wherein the patient was diagnosed with migraine headaches at least 15 years prior to the administration. At least one anti-CGRP antibody or anti- CGRP antibody fragment, or anti-CGRP-R antibody, or anti-CGRP-R antibody fragment.

[0444] E40. The patient was diagnosed with migraine headache at least 18 or at least 19 years prior to said administering. at least one anti-CG antibody for use according to any one of the above embodiments RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Body fragments.

[0445] E41. The patient is administered a migraine headache treatment, the number of days compared to the baseline number of days experienced by the patient prior to said administration. All patients had at least a 50% reduction in the number of migraine days in the month following administration of the antibody. at least one anti-CGRP antibody for use according to any one of the above embodiments Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0446] E42. The patient is administered a migraine headache treatment, the number of days compared to the baseline number of days experienced by the patient prior to said administration. All patients had at least a 75% reduction in the number of migraine days in the month following administration of the antibody. at least one anti-CGRP antibody for use according to any one of the above embodiments Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0447] E43. The patient is administered a migraine headache treatment, the number of days compared to the baseline number of days experienced by the patient prior to said administration. all of the above have a 100% reduction in the number of migraine days in the month following administration of the antibody. at least one anti-CGRP antibody or is an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0448] E44. The patient is administered a migraine headache treatment, the number of days compared to the baseline number of days experienced by the patient prior to said administration. All patients had at least a 50% reduction in the number of migraine days over the 12 weeks following administration of the antibody. at least one anti-CGRP antibody for use according to any one of the above embodiments Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0449] E45. The patient is administered a migraine headache treatment that is comparable to the baseline number of migraine days experienced by the patient prior to said administration. All patients had at least a 75% reduction in the number of migraine days over the 12 weeks following administration of the antibody. at least one anti-CGRP antibody for use according to any one of the above embodiments Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0450] E46. The patient is administered a migraine headache treatment, compared to the baseline number of migraine days experienced by the patient prior to said administration. all of the above have a 100% reduction in migraine days over the 12 weeks following administration of the antibody. at least one anti-CGRP antibody or is an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0451] E47. About 12 weeks or about 3 months after said administration, said patient is administered a second dose of said anti-CGR For use according to any one of the above embodiments, further comprising administering a P antibody. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or an anti-CGRP-R antibody fragment.

[0452] E48. The administration is at about 100 mg, at about 125 mg, at about 150 mg, at about 175 mg, at about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-C For the use according to any one of the above embodiments, comprising administering a GRP antibody. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or an anti-CGRP-R antibody fragment.

[0453] E49. The anti-CGRP antibody or antibody fragment is aglycosylated, or Any of the above embodiments, only if glycosylated, contains only mannose residues. At least one anti-CGRP antibody or anti-CGRP antibody for the use according to any one of the preceding claims. an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0454] E50. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 20 1 or SEQ ID NO: 566. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C for the above-mentioned use. GRP-R antibodies or anti-CGRP-R antibody fragments.

[0455] E51. 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. at least one anti-CGRP antibody for use according to any one of the above embodiments Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0456] E52. The medication-overuse headache is: (a) a 15-day course in the patient with an existing headache disorder; and (b) headaches occurring more than once a month; and (b) taken for the acute and / or symptomatic treatment of headaches. Any of the above embodiments, including abuse by said patient of one or more drugs associated with At least one anti-CGRP antibody or anti-CGRP antibody for the use according to any one of the preceding claims. an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0457] E53. The substance abuse includes ergotamine use for 10 days or more per month, thrombin use for 10 days or more per month, Use of liptan, one or more non-opioid analgesics (paracetamol (amycin)) for ≥15 days / month cetoaminophen), acetylsalicylic acid (aspirin), another NSAID, or another use of one or more combination analgesics (including non-opioid analgesics) for ≥10 days / month (referred to below) use of one or more opioids for 10 days or more per month; or use of one or more opioids for 10 days or more per month and the use of a combination of two or more drug classes (described further below) per month, The use of triptans is optionally selected from sumatriptan, zolmitriptan, naratriptan, One of rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally comprises the use of oxycodone , tramadol, butorphanol, morphine, codeine, and hydrocodone At least one of the above embodiments for use, including one or more uses. One anti-CGRP antibody or anti-CGRP antibody fragment, or one anti-CGRP-R antibody or anti-CG RP-R antibody fragment.

[0458] E54. The medication-overuse headache is ergotamine-overuse headache, triptan-overuse headache, or non-opioid Ipioid analgesic overuse headache, opioid overuse headache, complex analgesic overuse headache, complex analgesic overuse headache that is not individually abused Medication-overuse headache due to multiple drug classes, multiple drug classes unspecified or unspecified Medication-overuse headache caused by overuse of a prescribed drug or medication-overuse headache caused by other drugs, The use of triptans is optionally selected from sumatriptan, zolmitriptan, and naratriptan. , rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally includes one or more of oxycodone Of the following, morphine, tramadol, butorphanol, morphine, codeine, and hydrocodone At least one of the above embodiments for use, including one or more uses. One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C GRP-R antibody fragment.

[0459] E55. The non-opioid analgesic overuse headache is caused by paracetamol (acetaminophen). Nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin) overuse headache, NSAID-overuse headache, or other non-opioid analgesic-overuse headache, according to the above embodiments. At least one anti-CGRP antibody or anti-CGRP for the use according to any one of the preceding claims. An antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0460] E56. The ergotamine-overuse headache is a headache occurring 15 days or more per month or a headache occurring for more than 3 months. Any one of the above embodiments, including use of ergotamine for 10 or more days per month. at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use in CGRP-R antibody or anti-CGRP-R antibody fragment.

[0461] E57. The triptan-overuse headache is headache occurring 15 days or more per month and lasting for more than 3 months. use of one or more triptans for 10 days or more per month, Selectively, sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan including the use of one or more of the following: triptans, almotriptan, and frovatriptan; At least one anti-CGRP antibody or or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0462] E58. Non-opioid analgesic overuse headache is a headache occurring 15 days or more per month and Use of one or more non-opioid analgesics (paracetamol, acetaminophen, etc.) for more than 15 days / month amiodarone), acetylsalicylic acid (aspirin), another NSAID, or another non-steroidal anti-inflammatory drug For use according to any one of the above embodiments, including the use of a steroid analgesic (e.g., a steroid agonist, analgesic, etc.) At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0463] E59. The above-mentioned combination analgesic-overuse headache is headache occurring 15 days or more per month and headache occurring for more than 3 months. The use of one or more combined analgesics for 10 days or more per month, each of which is They have analgesic properties (e.g. paracetamol and codeine) or are adjuvants (e.g. ca and optionally, the composite analgesic drug comprises two or more agents that act as analgesics, Combination opioid analgesics, including at least one opioid (tramadol) ethanol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof ), barbiturates such as butalbital and / or caffeine, At least one anti-CGRP antibody or anti-C for use according to any one of the aspects. GRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment.

[0464] E60. The opioid-overuse headache is headache occurring ≥15 days / month and headache occurring for >3 months. Use of one or more opioids (oxycodone, tramadol, butorphanol) for 10 days or more per month use of morphine, codeine, hydrocodone, or any combination thereof) at least one anti-CGRP antibody for use according to any one of the above embodiments. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0465] E61. Medication-overuse headache caused by multiple drug classes that are not individually abused for 15 days Headache occurring on at least one or more days / month and ergotamine-related , triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan, Eletriptan, almotriptan, frovatriptan, or any combination thereof ), non-opioid analgesics and / or opioids (oxycodone, tramadol, butorfinazole) any of the following: ethanol, morphine, codeine, hydrocodone, or any combination thereof For the use according to any one of the above embodiments, the use of a combination of One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C GRP-R antibody fragment.

[0466] E62. Drug abuse resulting from unspecified or unidentified abuse of multiple drug classes. Headache occurring on 15 or more days per month and headache occurring on at least 10 days per month for more than 3 months Rugotamine, Triptans (Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, triptan, eletriptan, almotriptan, frovatriptan, or any of these combinations), non-opioid analgesics and / or opioids (oxycodone, tramadol , butorphanol, morphine, codeine, hydrocodone, or any combination thereof. etc.), where the identity of these classes of drugs, The above embodiments in which the amount and / or pattern of use or abuse has not been reliably established. 2. The method according to claim 1, further comprising administering to said patient at least one anti-CGRP antibody or anti-CGRP antibody. P antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0467] E63. Medication-overuse headache caused by other medications occurs on 15 or more days per month and occurs on 3 or more days per month. taken for the acute or symptomatic treatment of headache on at least 10 days / month for more than three months The method of any one of the above embodiments, including the use of one or more drugs other than those listed above. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C for the above-mentioned use. GRP-R antibodies or anti-CGRP-R antibody fragments.

[0468] E64. The patient had a pre-existing primary headache disorder prior to the onset of the medication-overuse headache. Also, at least one anti-CGRP antibody for use according to any one of the above embodiments. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0469] E65. Number of headache days and / or medication use days are reported by patient or relatives, by diary, by clinician, or by physician. Medical records, drug purchase history, prescription fulfillment, biomarkers of drug use, occurrence of drug toxicity, The above embodiments, as determined by the incidence of substance abuse and / or other indicators of the patient's drug use. The use according to any one of the aspects, RP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment.

[0470] E66. The medication-overuse headache is classified as a headache disorder according to the International Classification of Headache Disorders (ICD). According to the third edition of the International Standardization of Headache Disorders and wherein said medication-overuse headache is, optionally, selected from the group consisting of ergotamine-overuse headache, trimethoprim-sulphonate headache, Butane overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache pain, medication-overuse headache due to multiple drug classes not individually abused, medication-overuse headache due to multiple drug classes Medication-overuse headache due to unspecified or unidentified abuse of other drugs At least one of the above embodiments for use, including medication overuse headache. Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP PR antibody fragment.

[0471] E67. The anti-CGRP antibody or anti-CGRP antibody fragment contains histidine (L-histidine). In a formulation comprising or consisting of sorbitol, polysorbate 80, and water At least one anti-C for use according to any one of the above embodiments, GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0472] E68. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0, or having an amount of each component within 10% of said value; 5. The use according to embodiment E67, wherein the pH is 8 or within + / - 10% of said value. at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP for use in -R antibody or an anti-CGRP-R antibody fragment.

[0473] E69. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each component within + / - 5% of said values; and / or having a pH of 5.8 or within + / - 5% of said value, embodiment E6. 7. At least one anti-CGRP antibody or anti-CGRP antibody fragment or is an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0474] E70. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each component within + / - 1% of said values; and / or having a pH of 5.8 or within 1% of said value. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C for the above-mentioned use. GRP-R antibodies or anti-CGRP-R antibody fragments.

[0475] E71. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each ingredient within + / - 0.5% of the above values. and / or has a pH of 5.8 or within 0.5% of said value. 67. At least one anti-CGRP antibody or anti-CGRP antibody fragment for use according to claim 67. Or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0476] E72. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 Contains or consists of 0, or has an amount of each component within + / - 0.1% of the above value. and / or has a pH of 5.8 or within 0.1% of said value. 67. At least one anti-CGRP antibody or anti-CGRP antibody fragment for use according to claim 67. Or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0477] E73. Histidine (L-histidine), sorbitol, polysorbate 80, and water In a formulation comprising or consisting of an anti-CGRP antibody or an anti-CGRP antibody fragment, or a pharmaceutical composition comprising them.

[0478] E74. The formulation contains 100 mg of anti-CGRP antibody per mL volume in aqueous solution. , 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg poly Containing or consisting of Sorbate 80, or having an amount of each component within 10% of the above value. and having a pH of 5.8 or within + / - 10% of said value. The pharmaceutical composition described.

[0479] E75. The formulation contains 100 mg of anti-CGRP antibody per mL volume in aqueous solution. , 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg poly Consists of or comprises Sorbate 80, or the amount of each ingredient is within + / - 5% of the above values and / or has a pH of 5.8 or within 5% of said value. 74. The pharmaceutical composition according to claim 73.

[0480] E76. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each component within + / - 1% of said values; and / or having a pH of 5.8 or within 1% of said value. The pharmaceutical composition described above.

[0481] E77. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 0 or have amounts of each ingredient within + / - 0.5% of the above values. and / or has a pH of 5.8 or within 0.5% of said value. 74. The pharmaceutical composition according to claim 73.

[0482] E78. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 8 Contains or consists of 0, or has an amount of each component within + / - 0.1% of the above value. and / or has a pH of 5.8 or within 0.1% of said value. 74. The pharmaceutical composition according to claim 73.

[0483] E79. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227. The light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:228 and SEQ ID NO:20, respectively 4; SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:208. The pharmaceutical composition according to any one of embodiments E73 to E79, comprising a sequence.

[0484] E80. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:237; Light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238 and Heavy chains encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218, respectively. Any one of embodiments E73 to E79 comprising CDR 1, 2 and 3 polypeptide sequences. The pharmaceutical composition described above.

[0485] E81. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: 202 variable heavy chain polypeptide. Pharmaceutical compositions.

[0486] E82. 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. The pharmaceutical composition according to any one of E73 to E79.

[0487] E83. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 20 Any one of embodiments E73 to E79, comprising a heavy chain polypeptide of SEQ ID NO: 566 or SEQ ID NO: 567. The pharmaceutical composition described above.

[0488] E84. 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. , A pharmaceutical composition according to any one of embodiments E73 to E79.

[0489] E85. The anti-CGRP antibody or anti-CGRP antibody fragment is a Pichia pastoris (P ichia pastoris or Pichia pastoris (Pichia According to the embodiment E73 to E84, the method is obtained by expression in hia pastoris. 13. The pharmaceutical composition according to any one of claims 1 to 12.

[0490] E86. The anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells. or obtained by expression in CHO cells. The pharmaceutical composition described above.

[0491] E87. At least one anti-CGRP antibody for use in treating or preventing migraine antibody or anti-CGRP antibody fragment and / or at least one anti-CGRP-R antibody or The present invention relates to an anti-CGRP-R antibody fragment, and to an ergot alkaloid for treating or preventing migraine. triptans, non-opioid analgesics, acetaminophen, aspirin, NSAIDs, Acute pain relief for headaches, selected from the group including non-opioid analgesics, combination analgesics, or opioids The present invention further includes the use of at least one drug taken for therapeutic and / or symptomatic treatment. at least one anti-CGRP antibody or anti-CGRP antibody fragment and / or at least one An anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0492] E88. The combined administration of (i) and (ii) reduces the medication-overuse headache symptoms in said patient. For the use according to embodiment E87, which reduces the severity and / or episodes of At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or is an anti-CGRP-R antibody fragment.

[0493] E89. The drug taken for acute and / or symptomatic treatment of headache is ergot alopecia. At least one anti-C for use according to embodiment E87 or E88, comprising a kaloid. GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0494] E90. The ergot alkaloid is ergotamine, nicergoline, methysergide, dihy For the use according to embodiment E89, selected from droergotamine and the combinations described above. At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0495] E91. The drug taken for acute and / or symptomatic treatment of headache is a tryptophan At least one anti-CGRP antibody for use according to embodiment E87 or E88, Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Piece.

[0496] E92. The triptan is sumatriptan, zolmitriptan, naratriptan, or ritriptan. Zatriptan, eletriptan, almotriptan, frovatriptan, and combinations of the above At least one anti-CGRP antibody for use according to embodiment E91 is selected from Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0497] E93. The drug taken for acute and / or symptomatic treatment of headache is a non-opioid At least one anti-inflammatory drug for use according to embodiment E87 or E88, including an anti-inflammatory drug. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- R antibody fragment.

[0498] E94. The non-opioid analgesic is paracetamol (acetaminophen) or At least one anti-CGRP antibody for use according to embodiment E93, comprising aspirin. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment.

[0499] E95. The drug taken for acute and / or symptomatic treatment of headache is an NSAI At least one anti-CGRP antibody for use according to embodiment E87 or E88, comprising D. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Piece.

[0500] E96. The NSAID is a salicylate, propionate, d) Derivatives, enolic acid derivatives, anthranilic acid derivatives (fenamates), selective COX-2 inhibitors (coxibs), sulfones The at least one compound for use according to embodiment E95 is selected from the group consisting of anilides, and combinations thereof. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or is an anti-CGRP-R antibody fragment.

[0501] E97. The NSAID is aspirin (acetylsalicylic acid), diflunisal (Do lobid), salicylic acid and its salts, and salsalate (Disalcid) recylate; ibuprofen, dexibuprofen, naproxen, fenoprofen, Ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, and Propionic acid derivatives such as xoprofen; indomethacin, tolmetin, sulindac, Acetate such as etodolac, ketorolac, diclofenac, aceclofenac, and nabumetone Acid derivatives, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam Enolic acid (oxicam) derivatives such as phenylbutazone (bute), isoxicam, and phenylbutazone (bute) derivatives; amides such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid Anthranilic acid derivatives (fenamates); celecoxib, rofecoxib, valdecoxib Selective C, such as parecoxib, lumiracoxib, etoricoxib, and firocoxib OX-2 inhibitors (coxibs); sulfonanilides such as nimesulide; clonixin, lycosides feron, H-harpagide or devil's claw, and combinations thereof. At least one anti-CGRP antibody or anti-CGRP antibody for use according to form E95. an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0502] E98. The drug taken for acute and / or symptomatic treatment of headache is a non-opioid At least one anti-inflammatory drug for use according to embodiment E87 or E88, including an anti-inflammatory drug. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- R antibody fragment.

[0503] E99. The drug taken for acute and / or symptomatic treatment of headache is a combined analgesic At least one anti-CGRP drug for use according to embodiment E87 or E88. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Piece.

[0504] E100. The combination analgesic comprises a non-opioid analgesic and at least one opioid or includes combinations with barbiturates such as butalbital and / or caffeine, or acetaminophen, aspirin, and caffeine, e.g., EXCEDRIN or EXCEDRIN MIGRAINE® combination, or at least one non-analgesic drug, e.g., a vasoconstrictor such as pseudoephedrine; or a combination analgesic comprising an analgesic in combination with an antihistamine. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C for the above-mentioned use. GRP-R antibodies or anti-CGRP-R antibody fragments.

[0505] E101. The drug taken for acute and / or symptomatic treatment of headache is an opioid At least one anti-CGR antibody for use according to embodiment E87 or E88, comprising an antibody P antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody piece.

[0506] E102. The opioid is oxycodone, tramadol, butorphanol, mol. Hine, codeine, hydrocodone, thebaine, oripavine, mixed opium alkaloids, e.g. For example, papaveretam, diacetylmorphine, nicomorphine, dipropanoylmorphine, di Acetyldihydromorphine, acetylpropionylmorphine, desomorphine, methyldeso Ruphine, dibenzoylmorphine, ethylmorphine, heterocodeine, buprenorphine , etorphine, hydromorphone, oxymorphone, fentanyl, α-methylphen Alfentanil, alfentanil, sufentanil, remifentanil, carfentanil ( carfentanyl), omefentanyl, pethidine (meperidine), ketobemide MPPP, Allylprozine, Prozine, PEPAP, Promedol, Diphenylprozine Pyramine, propoxyphene, dextropropoxyphene, dextromorphamide, The compound according to embodiment E101, selected from bezitramide, piritramide, and combinations thereof. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C for the above-mentioned use. GRP-R antibodies or anti-CGRP-R antibody fragments.

[0507] E103. The anti-CGRP antibody comprises any one of Ab1 to Ab14 or a fragment thereof. At least one anti-cancer agent for use according to any one of embodiments E87 to E102. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- R antibody fragment.

[0508] E104. Embodiments E87-E1, wherein the anti-CGRP antibody comprises Ab6 or a fragment thereof. For the use according to any one of claims 03 to 03, at least one anti-CGRP antibody or anti-C GRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment.

[0509] E105. The anti-CGRP antibody is selected from SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227, respectively. The light chain complementarity determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 228 are included. At least one anti-CG for the use according to any one of the embodiments E87 to E104. RP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody Body fragments.

[0510] E106. The anti-CGRP antibody is selected from SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:237, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238 At least one anti-C for the use according to any one of the embodiments E87 to E105 GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0511] E107. The anti-CGRP antibody is selected from SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:207, respectively. The heavy chain CDR 1, 2, and 3 polypeptide sequences of sequence number 208 are included in the embodiment E87 to The use of any one of E106, comprising at least one anti-CGRP antibody or An anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0512] E108. The anti-CGRP antibody is selected from SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:217; The heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:218 or at least one anti-C for use according to any one of embodiments E87 to E107. GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0513] E109. The anti-CGRP antibody is selected from SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:227, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:228 and SEQ ID NO:2, respectively 04; SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptides of SEQ ID NO:208. For the use according to any one of embodiments E87 to E108, comprising the sequence One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C GRP-R antibody fragment.

[0514] E110. The anti-CGRP antibody is selected from SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:237, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238; and The overlap sequences encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218, respectively. Any of embodiments E87 to E109, comprising a CDR 1, 2, and 3 polypeptide sequence. or at least one anti-CGRP antibody or anti-CGRP antibody fragment for one of the uses described above. or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0515] E111. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222. At least one anti-CGR for use according to any one of the embodiments E87 to E110. P antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody piece.

[0516] E112. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. The use according to any one of embodiments E87 to E111, comprising a peptide At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or Anti-CGRP-R antibody fragment.

[0517] E113. The anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202. At least one anti-CGR for use according to any one of the embodiments E87 to E112. P antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody piece.

[0518] E114. The anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO: 212. At least one of the methods for use according to any one of embodiments E87 to E113, comprising administering to a subject a peptide comprising the steps of: At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or Anti-CGRP-R antibody fragment.

[0519] E115. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and SEQ ID NO: The method of any one of embodiments E87 to E114, comprising the variable heavy chain polypeptide of No. 202. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-C for the above-mentioned use. GRP-R antibodies or anti-CGRP-R antibody fragments.

[0520] E116. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. and an embodiment comprising a variable heavy chain polypeptide encoded by SEQ ID NO:212. At least one anti-CGRP antibody for use according to any one of the methods E87 to E115. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0521] E117. The embodiment in which the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221. At least one anti-CGRP antibody for use according to any one of the methods E87 to E116. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0522] E118. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231. For the use according to any one of embodiments E87 to E117, One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C GRP-R antibody fragment.

[0523] E119. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. For the use according to any one of the embodiments E87 to E118, One anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-C GRP-R antibody fragment.

[0524] E120. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567. The use according to any one of embodiments E87 to E119, comprising a heavy chain polypeptide at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP- R antibody or anti-CGRP-R antibody fragment.

[0525] E121. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 2 Any of embodiments E87 to E120, comprising a heavy chain polypeptide of SEQ ID NO: 566 or SEQ ID NO: 567. or at least one anti-CGRP antibody or anti-CGRP antibody fragment for one of the uses described above. or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0526] E122. 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. At least one anti-cancer agent for use according to any one of embodiments E87 to E121. CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP- R antibody fragment.

[0527] E123. The anti-CGRP antibody or anti-CGRP antibody fragment is a Pichia pastoris ( It was expressed in Pichia pastoris or Pichia pastoris (Pi Embodiments E87 to E12, obtained by expression in chia pastoris. 2. Use of at least one anti-CGRP antibody or anti-CGRP antibody according to any one of claims 1 to 2. RP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment.

[0528] E124. The anti-CGRP antibody or anti-CGRP antibody fragment is expressed in CHO cells. of embodiments E87 to E123, wherein the nucleotide sequence is expressed or obtained by expression in CHO cells. At least one anti-CGRP antibody or anti-CGRP for any one of the uses described herein. An antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0529] E125. The amount of the anti-CGRP antibody administered is about 100 mg to about 300 mg. or about 100 mg, or about 300 mg, of any of embodiments E87 to E124. At least one anti-CGRP antibody or anti-CGRP for any one of the uses described herein. An antibody fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0530] E126. Embodiment E87, in which the administered amount of the anti-CGRP antibody is 100 mg. 1. The method of claim 1, further comprising administering to said patient at least one anti-CGRP antibody or is an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0531] E127. A further administration of 100 mg of said anti-CGRP antibody intravenously every 12 weeks. At least one of the methods for use according to any one of embodiments E87 to E126, Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP -R antibody fragment.

[0532] E128. Further administering 300 mg of said anti-CGRP antibody intravenously every 12 weeks. At least one of the methods for use according to any one of embodiments E87 to E127, Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP -R antibody fragment.

[0533] E129. The patient is a chronic migraine sufferer or an episodic migraine sufferer at risk of developing medication-overuse headache. The patient according to any one of embodiments E87 to E128 is a patient suffering from chronic migraine or cluster headache. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use PR antibody or anti-CGRP-R antibody fragment.

[0534] E130. The patient has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1 0 days, and optionally, said acute medication use continues for at least 28 days. Any one of embodiments E87 to E129, wherein the baseline period is determined. at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use in CGRP-R antibody or anti-CGRP-R antibody fragment.

[0535] E131. The patient uses acute headache medication at least 10 days per month, and optionally: The acute drug use is determined over a baseline period of at least 28 days. At least one anti-CGRP compound according to any one of the forms E87 to E130. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment Piece.

[0536] E132. The medication-overuse headache is (a) 15 days after administration in the patient with an existing headache disorder and (b) headaches occurring for ≥ 10 days / month; and (b) taken for the acute and / or symptomatic treatment of headaches. The present invention relates to embodiments E87 to E89, which include abuse by said patient of one or more drugs for more than three months. The use of any one of E131, An anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0537] E133. Prior to said administration, the patient is experiencing migraine headaches on about 15 to about 22 days per month. At least one anti-CGRP antibody for use according to any of forms E87 to E132. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment.

[0538] E134. Prior to said administration, the patient exhibits about 15 to about 27 headache days per month. At least one anti-CGRP antibody or a combination thereof for use according to any one of aspects E87 to E133. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0539] E135. Prior to said administration, the patient exhibits about 17 to about 24 headache days per month. At least one anti-CGRP antibody or a combination thereof for use according to any one of aspects E87 to E134. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0540] E136. Prior to said administration, the patient has between about 15 and about 19 migraine days per month, or between about 15 and about 19 migraine days per month. Embodiment E8, which exhibits 20 or about 21 headache days or about 16 migraine days per month. At least one anti-CGRP antibody or An anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0541] E137. The patient was diagnosed with migraine headaches at least 10 years prior to the administration. At least one anti-CGRP antibody or a combination thereof for use according to any one of aspects E87 to E136. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0542] E138. The embodiment, wherein the patient was diagnosed with migraine headaches at least 15 years prior to the administration. At least one anti-CGRP antibody or a combination thereof for use according to any one of aspects E87 to E137. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0543] E139. The patient has had a migraine headache for at least 18 or at least 19 years prior to the administration. At least one of the methods for use according to any of the embodiments E87 to E138 has been diagnosed Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP PR antibody fragment.

[0544] E140. The patient is administered a test that measures the baseline number of migraine days experienced by the patient prior to said administration. Compared to placebo, the antibody reduced the number of migraine days by at least 50% in the month following administration. At least one anti-C for use according to any of the embodiments E87 to E139. GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0545] E141. The patient is administered a test to determine the baseline number of migraine days experienced by the patient prior to said administration. Compared to placebo, subjects who received the antibody had at least a 75% reduction in the number of migraine days in the month following treatment. At least one anti-C for use according to any of the embodiments E87 to E140. GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0546] E142. The patient is administered a baseline number of migraine days experienced by the patient prior to said administration. The antibody has a 100% reduction in migraine days in the month following administration of the antibody, compared to the control group. At least one anti-CGRP antibody for use according to any of the embodiments E87 to E141. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0547] E143. The patient is administered a test to determine the baseline number of migraine days experienced by the patient prior to said administration. Compared to placebo, subjects who received the antibody had at least a 50% reduction in the number of migraine days over the 12 weeks following treatment with the antibody. At least one anti-C for use according to any of the embodiments E87 to E142. GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0548] E144. The patient is administered a baseline number of migraine days experienced by the patient prior to said administration. Compared to placebo, subjects who received the antibody had a reduction in the number of migraine days by at least 75% over the 12 weeks following treatment with the antibody. At least one anti-C for use according to any of the embodiments E87 to E143. GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0549] E145. The patient is administered a test to determine the baseline number of migraine days experienced by the patient prior to said administration. In comparison, the antibody has a 100% reduction in migraine days over the 12 weeks following administration of the antibody. At least one anti-CGRP antibody for use according to any of the embodiments E87 to E144. Antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R antibody fragment .

[0550] E146. About 12 weeks or about 3 months after said administration, said patient is administered a second dose of said anti-CG The method of any one of embodiments E87 to E145, further comprising administering a RP antibody. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use PR antibody or anti-CGRP-R antibody fragment.

[0551] E147. The administration is 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 antibody. The method of any one of embodiments E87 to E146, comprising administering a CGRP antibody. At least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use PR antibody or anti-CGRP-R antibody fragment.

[0552] E148. The anti-CGRP antibody or antibody fragment is aglycosylated or contains only mannose residues only if glycosylated, The use of any one of E147, comprising at least one anti-CGRP antibody or An anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0553] E149. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 2 Any of embodiments E87 to E148, comprising a heavy chain polypeptide of SEQ ID NO: 566 or SEQ ID NO: 567. At least one anti-CGRP antibody or anti-CGRP antibody for any one of the uses described herein. fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0554] E150. 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 At least one of the methods for use according to any one of the embodiments E87 to E149. Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP -R antibody fragment.

[0555] E151. The medication-overuse headache is (a) 15 days after administration to the patient with an existing headache disorder and (b) headache occurring for more than 3 months with one or more medications For the use according to any one of embodiments E87 to E150, including abuse such as Another anti-CGRP antibody or anti-CGRP antibody fragment, or an anti-CGRP-R antibody or CGRP-R antibody fragment.

[0556] E152. The substance abuse includes use of ergotamine for 10 days or more per month, use of ergotamine for 10 days or more per month, Use of triptans, one or more non-opioid analgesics (paracetamol ( acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or use of one or more combination analgesics (such as another non-opioid analgesic) for 10 days or more per month use of opioids (as described further below) for 10 days or more per month; use of 1 or more opioids for 10 days or more per month; The combination of two or more drug classes (described further below) is included in the above-mentioned The use of triptans is optionally selected from sumatriptan, zolmitriptan, and naratriptan. , rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally includes one or more of oxycodone Of the following, morphine, tramadol, butorphanol, morphine, codeine, and hydrocodone For the use according to any one of the embodiments E87 to E151, including one or more uses At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or an anti-CGRP-R antibody fragment.

[0557] E153. The medication-overuse headache is ergotamine-overuse headache, triptan-overuse headache, or non-opioid Opioid analgesic overuse headache, opioid overuse headache, combined analgesic overuse headache, not individually abused Medication-overuse headache due to multiple drug classes, multiple drug classes unspecified or unspecified Medication-overuse headache caused by overuse of medication or medication-overuse headache caused by other drugs, The use of a triptan is optionally selected from sumatriptan, zolmitriptan, naratriptan, Among rizatriptan, eletriptan, almotriptan, and frovatriptan, and / or the opioid use optionally includes one or more of oxycodone. Of the drugs listed below, morphine, tramadol, butorphanol, codeine, and hydrocodone, For use according to any one of the embodiments E87 to E152, comprising the use of one or more of At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0558] E154. The non-opioid analgesic overuse headache is caused by paracetamol (acetaminophen ) Nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin) overuse headache, (NSAID)-overuse headache, or other non-opioid analgesic-overuse headache, in embodiment E87 1. The method of claim 1, further comprising administering to said patient at least one anti-CGRP antibody or is an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0559] E155. The ergotamine-overuse headache is a headache occurring 15 days or more per month or a headache occurring for more than 3 months. Any of embodiments E87 to E154, including use of ergotamine for 10 days or more per month. or at least one anti-CGRP antibody or anti-CGRP antibody fragment for one of the uses described above. or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0560] E156. The triptan-overuse headache is headache occurring 15 days or more per month and headache occurring for more than 3 months. use of one or more triptans for at least 10 days / month, Optionally, sumatriptan, zolmitriptan, naratriptan, rizatriptan, Includes use of one or more of the following: Letriptan, Almotriptan, and Frovatriptan At least one anti-C for the use according to any one of the embodiments E87 to E155 GRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP-R Antibody fragment.

[0561] E157. Non-opioid analgesic overuse headache is a headache occurring 15 days or more per month and One or more non-opioid analgesics (paracetamol, acetaminophen, etc.) for ≥15 days / month for >2 months aminophen), acetylsalicylic acid (aspirin), another NSAID, or another nonsteroidal anti-inflammatory drug Any one of embodiments E87 to E156, including the use of an opioid analgesic. at least one anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP antibody fragment for use in CGRP-R antibody or anti-CGRP-R antibody fragment.

[0562] E158. The above-mentioned combination analgesic-overuse headache is a headache occurring 15 days or more per month and a headache occurring for more than 3 months. The use of one or more combination analgesics for 10 days or more per month, each of which is They have analgesic properties (e.g. paracetamol and codeine) or are supplementary (e.g. caffeine), and optionally the composite analgesic comprises: A combination of non-opioid analgesics, including at least one opioid (tramadol) ethanol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof and the like), a barbiturate such as butalbital, and / or caffeine. At least one anti-CGRP antibody for use according to any one of E87 to E157. or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody, or an anti-CGRP-R antibody fragment.

[0563] E159. The opioid overuse headache is headache occurring 15 days or more per month and headache occurring for more than 3 months. Use of one or more opioids (oxycodone, tramadol, butorfa) for 10 days or more per month use of any of the following drugs: morphine, codeine, hydrocodone, or any combination thereof At least one of the methods for use according to any one of the embodiments E87 to E158, Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP -R antibody fragment.

[0564] E160. Medication-overuse headache caused by multiple drug classes that are not individually abused is 15 Headache occurring on at least days / month and ergotaneus headache occurring on at least 10 days / month in total over more than 3 months triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan , eletriptan, almotriptan, frovatriptan, or any combination thereof etc.), non-opioid analgesics and / or opioids (oxycodone, tramadol, butol any combination thereof) For the use according to any one of the embodiments E87 to E159, including the use of any combination thereof. At least one of the anti-CGRP antibody or anti-CGRP antibody fragment or anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0565] E161. Drugs of unspecified or unidentified classes resulting from abuse of the above drugs Overuse headache is defined as headache occurring ≥15 days / month and ≥10 days / month for >3 months. Ergotamines, triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan) Triptan, eletriptan, almotriptan, frovatriptan, or any of these combinations), non-opioid analgesics and / or opioids (oxycodone, tramadol, etc.) ethanol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof etc.), where the identity of these classes of drugs , the amount and / or pattern of use or abuse has not been reliably established, embodiment E8. At least one anti-CGRP antibody or or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0566] E162. Medication-overuse headache caused by other drugs occurs 15 days or more per month and Taken for the acute or symptomatic treatment of headache on at least 10 days per month for more than 3 months Any of the embodiments E87 to E161, including the use of one or more drugs other than those listed above. At least one anti-CGRP antibody or anti-CGRP antibody for any one of the uses described herein. fragment or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0567] E163. The patient had a pre-existing primary headache disorder prior to the onset of the medication-overuse headache. At least one of the methods for use according to any one of the embodiments E87 to E162 Anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or anti-CGRP -R antibody fragment.

[0568] E164. Number of headache days and / or medication use days are reported by patient or relatives, by diary, or by other means. Medical records, drug purchasing history, prescription fulfillment, biomarkers of drug use, occurrence of drug toxicity, As determined by the incidence of substance abuse and / or other indicators of the patient's substance use, embodiment E. 87 to E163, for the use of at least one anti-CGRP antibody or or an anti-CGRP antibody fragment, or an anti-CGRP-R antibody or an anti-CGRP-R antibody fragment.

[0569] E165. The medication-overuse headache is classified as a headache disorder according to the International Classification of Headache Disorders (ICD). According to the 3rd edition of the "Standardization of Headache Disorders" and wherein said medication-overuse headache is, optionally, ergotamine-overuse headache, thromboembolism headache, Liptan overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse Headache, medication-overuse headache due to multiple drug classes not individually abused, multiple drug classes Medication-overuse headache resulting from unspecified or unidentified abuse of other drugs A method for the use of any one of embodiments E87 to E164, including medication-overuse headache. At least one anti-CGRP antibody or anti-CGRP antibody fragment, or anti-CGRP-R antibody or or anti-CGRP-R antibody fragments.

[0570] E166. The anti-CGRP antibody or anti-CGRP antibody fragment is a histidine (L-his) A formulation comprising or consisting of sorbitol, polysorbate 80, and water. For the use according to any one of the embodiments E87 to E165 contained therein Another anti-CGRP antibody or anti-CGRP antibody fragment, or an anti-CGRP-R antibody or CGRP-R antibody fragment.

[0571] E167. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of CGRP antibody, and 100 mg of CGRP antibody per mL of volume. g L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80, or having an amount of each component within 10% of said value, As described in embodiment E166, having a pH of 0.8 or within + / - 10% of said value. at least one anti-CGRP antibody or anti-CGRP antibody fr...

Claims

1. A pharmaceutical composition comprising an anti-CGRP antibody for treating or preventing medication-overuse headache (MOH) in a patient, comprising: the anti-CGRP antibody (a) a light chain variable region (VL) polypeptide comprising the light chain complementarity-determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively; and (b) a heavy chain variable region (VH) polypeptide comprising the heavy chain CDR1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively; A pharmaceutical composition, wherein the medication-overuse headache is ergotamine-overuse headache. (a) the VL polypeptide comprises the amino acid sequence of SEQ ID NO: 222; and (b) the VH polypeptide comprises the amino acid sequence of SEQ ID NO:

202.

3. the anti-CGRP antibody (a) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 221; and (b) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 201 or SEQ ID NO: 566 3. The pharmaceutical composition of claim 1 or 2, comprising:

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the dosage of the anti-CGRP antibody is about 100 mg to about 300 mg, or 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, or 100 mg.

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