Acute treatment and rapid treatment of headache using Anti-CGRP antibodies

Abstract

To provide methods for rapid treatment of chronic migraine.SOLUTION: The present invention provides a method comprising administering to a patient in need thereof an effective amount of an anti-CGRP antibody, wherein the anti-CGRP antibody administration begins while the patient has a headache and within 30 hours of headache onset, preferably within 24 hours of headache onset.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application is a continuation of U.S. Provisional Patent Application No. 62 / 789,828, filed January 8, 2019. Specification (Attorney Reference Number 1143257.008600), issued on July 11, 2019 No. 62 / 872,989 (Attorney Docket No. 11432 57.009001), and U.S. Provisional Patent Application No. 62 / 8, filed May 2, 2019. Priority is claimed to be based on Specification No. 42,162 (Attorney Docket No. 1143257.009000). No. 6,399,423, 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 "1143257o008601.txt", and has 35 It is 7,494 bytes in size.

[0003] Background Fields The present invention relates to a method for the preparation of a compound that specifically binds to human calcitonin gene-related peptide (hereinafter referred to as "CGRP"). Acute treatment of headache disorders, including migraine, using antibodies and fragments thereof (including Fab fragments) The present invention also relates to a method for the treatment of human calcitonin gene-related peptide (hereinafter referred to as "CGRP"). The present invention relates to a method for treating headaches, such as chronic headaches, using an antibody or a fragment thereof (including a Fab fragment) that specifically binds to Regarding the rapid treatment of sexual migraines. [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 provides a method for the acute treatment of headache, the method comprising administering an effective amount of at least one anti-inflammatory drug to a patient. CGRP antibody or antibody fragment, or anti-CGRP-R antibody or antibody fragment, or and administering to a patient in need thereof one or more formulations comprising the antibody or antibody fragment disclosed herein. The antibody may be administered while the patient is suffering from a headache. Administration may be initiated within 1 to 6 hours of onset of the headache. The headache may be a migraine, For example, the headache may include episodic migraine or chronic migraine. The headache may include medication overuse headache. The anti-CGRP antibody or antibody fragment may, for example, be selected from the group consisting of SEQ ID NO: 224; SEQ ID NO: 226; and the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 228 and SEQ ID NO: 204 SEQ ID NO:206; and the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:208. or SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:238, respectively. the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:214; SEQ ID NO:216; and the heavy chain CDR 1, 2, and 3 polynucleotides encoded by SEQ ID NO:218. Any one of Ab1 to Ab14 or a Fab fragment thereof having a peptide sequence, for example, A b6 or a Fab fragment thereof. The anti-CG polypeptide may comprise a variable light chain polypeptide and a variable heavy chain polypeptide of SEQ ID NO: 202. The RP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO:232 and a variable light chain polypeptide encoded by SEQ ID NO:2 12. The anti-CGRP antibody may comprise a variable heavy chain polypeptide encoded by the sequence A light chain polypeptide of SEQ ID NO:221 and a heavy chain polypeptide of SEQ ID NO:201 or SEQ ID NO:566 The anti-CGRP antibody may comprise a light chain polypeptide encoded by SEQ ID NO: 231. and a heavy chain polypeptide encoded by SEQ ID NO:211 or SEQ ID NO:567. The anti-CGRP antibody may comprise a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: 2 isolated from a recombinant cell expressing a nucleic acid sequence encoding the variable heavy chain polypeptide of The antibody expression products may include polypeptides, which may optionally include human light and heavy chains. Constant region polypeptides, such as human IgG1, IgG2, IgG3 or IgG4 constant regions. These constant regions are optionally linked to a glycosylation or proteolysis domain. and the recombinant cell is optionally a yeast or mammalian cell. Animal cells, such as Pichia pastoris or CHO The anti-CGRP antibody comprises a light chain of SEQ ID NO: 221 and a light chain of SEQ ID NO: 201 or isolated from a recombinant cell expressing a nucleic acid sequence encoding the heavy chain polypeptide of No. 566. The recombinant cell may comprise an antibody expression product, the recombinant cell being a yeast or mammalian cell, e.g. For example, Pichia pastoris or CHO cells are optional. The constant region includes a region that controls glycosylation or proteolysis or other effector function. Any of the above-mentioned anti-CGRP antibodies or antibodies can be optionally modified to change The fragment, preferably Ab6, optionally comprises a histidine residue, e.g., having a pH of about 5.8. (L-histidine), sorbitol, polysorbate 80, e.g., about 1 per mL volume 00 mg of anti-CGRP antibody, approximately 3.1 mg of L-histidine, approximately 40.5 mg of sorbitol and about 0.15 mg of polysorbate 80. The dose of the antibody may be about 100 mg to about 300 mg, for example, about 100 The dosage may be about 300 mg, 100 mg, or 300 mg. Depending on the stage, for example, intravenously, for example, 0.9% of an appropriate volume (for example, 100 mL) It may be administered in a saline solution such as sodium chloride.

[0007] The patient has fewer than 25 headache days per month, fewer than 20 headache days per month, fewer than 15 headache days per month For example, the patient may exhibit headache days per month of 10 to 20 days, or less than 10 headache days per month. Number of headache days < 14, Number of headache days < 13, Number of headache days < 12, Number of headache days < 11 Number of days with pain, number of headache days less than 10, number of headache days less than 9, number of headache days less than 8, number of headache days less than 7 The patient may present with 2 to 15 headache days per month, or less than 6 headache days. Number of days, e.g., 3-14 headache days, 4-13 headache days, 5-12 headache days, It may show 6-11 headache days or 7-10 headache days.

[0008] The patient experiences fewer than 10 migraines per month, such as 1 to 9 migraines per month, e.g. 2-8 migraines per month, 3-7 migraines per month, 4-6 migraines per month, or The patient may experience about 5 migraines per month. The patient may experience, on average, less than 1 migraine headache per month. Pain, e.g., once every 2 months, once every 3 months, once every 4 or 6 months, or once every 3 months The migraine headache may be classified as occurring twice a day or twice a week. Thus, a diagnosis can be made.

[0009] In an exemplary embodiment, the headache may include a medication-overuse headache. The decision may be based on meeting the following criteria: (a) for patients with an existing headache disorder; (b) headache occurring on 15 or more days per month in a Excessive use of one or more drugs that can be taken for more than three months.

[0010] 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

[0011] 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.

[0012] The medication overuse headaches include ergotamine overuse headaches, triptan overuse headaches, non-opioid headaches, and Opioid analgesic overuse headache, Opioid overuse headache, Combination analgesic overuse headache, Individual Medication-overuse headache due to multiple drug classes not separately overused, multiple drug classes Medication-overuse headache due to unspecified or untested overuse of other medications This may include medication overuse headaches caused by

[0013] 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.

[0014] 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

[0015] In the methods herein, the ergot alkaloids are ergotamine, nicergoline, methicillin, It may comprise ergot derivatives, or dihydroergotamine.

[0016] 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.

[0017] 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.

[0018] In the methods herein, the NSAID is ibuprofen, naproxen, or indole. May include any NSAID or combination thereof, including but not limited to methacin .

[0019] 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 refers to drugs that each have an analgesic effect. Two or more classes of drugs (e.g. paracetamol and codeine), or adjuvants Preparations that combine an analgesic with an agent that acts as a sedative (e.g., caffeine) A commonly overused combination analgesic is one that contains at least one non-opioid analgesic. In combination with one opioid, a barbiturate, e.g. butalbital and / or caffeine In an exemplary embodiment, combination analgesic overuse headache is treated with acetaminophen , aspirin, and caffeine, such as EXCEDRIN® or EXCE DRIN MIGRAINE® combination. The analgesic agent may be at least one non-analgesic agent, e.g., a pseudoanesthetic agent for sinus-related preparations. Vasoconstrictors such as phenylalanine, antihistamines used to treat allergy sufferers This includes painkillers combined with antidepressants, etc.

[0020] 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.

[0021] Medication-overuse headaches resulting from multiple drug classes that are not individually overused are considered to be a common cause of headaches. Occurring ≥15 days / month in patients with chronic headaches and excess of a single drug or drug class Use of ergotamine, trimethoprim, or thrombomodulin for at least 10 days / month over a 3-month period without any associated use of Regular intake of any combination of opioids, non-opioid painkillers and / or opioids Consequences may include headaches.

[0022] 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.

[0023] Medication-overuse headache, resulting from unspecified or untested overuse of multiple drug classes, is a condition that has been Occurring ≥15 days / month in patients with primary headache and associated with a single drug or drug class Ergotamine, trimethoprim, or tetrahydrocannabinol (TCA) for at least 10 days / month for at least 3 months without excessive use of TCCA. Regular intake of any combination of opioids, non-opioid painkillers and / or opioids The identity, amount, and / or use of these classes of medications may include the resulting headaches. or patterns of overuse have not been reliably established.

[0024] Medication-overuse headache due to other medications occurred in 15 to 20 patients with pre-existing primary headaches. Occurring for ≥ 1 day / month and for at least 1 day over a ≥ 3 month period for acute or symptomatic treatment of headache Developed as a result of regular ingestion of one or more medications other than those listed above taken for 0 days / month May include headaches.

[0025] 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

[0026] 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.

[0027] Medication overuse headache (ergotamine overuse headache, triptan overuse headache, non-opioid headache) Opioid overuse headache, combination analgesic overuse headache, individual Medication-overuse headache due to multiple drug classes not overused in Medication-overuse headache due to unspecified or untested overuse or due to other medications Medication-overuse headache (e.g., headache caused by medication overuse) is classified as an International Classification. Diagnosed according to the International Commission on Headache Disorders, 3rd Edition (ICHD-3) Headache Classification Committee f the International Headache Society (IHS ),The International Classification of He adache disorder,3rd edition,Cephalalgia. 2018 Jan;38(1):1-211 (herein incorporated by reference in its entirety). ) for more information.

[0028] 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.

[0029] The present disclosure also provides a method for treating chronic migraine headaches, the method comprising administering from about 100 mg to about 300 mg of A first dose containing 10 mg of anti-CGRP antibody is administered intravenously to a patient in need thereof. and wherein the anti-CGRP antibody preferably comprises a light chain polypeptide of SEQ ID NO: 221, and comprising a heavy chain polypeptide of SEQ ID NO: 201 or 566, Within 24 hours, patients show at least a 50% reduction in migraine prevalence.

[0030] In another aspect, a method for treating chronic migraine is provided, the method comprising administering from about 100 mg to about 300 mg of A first dose containing 10 mg of anti-CGRP antibody is administered intravenously to a patient in need thereof. and wherein the anti-CGRP antibody preferably comprises a light chain polypeptide of SEQ ID NO: 221, and and comprising a heavy chain polypeptide of SEQ ID NO: 201 or 566, and the patient is diagnosed with a migraine headache the day after administration. Shows at least a 50% reduction in prevalence.

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

[0032] In another exemplary embodiment, the dose of the anti-CGRP antibody, e.g., the first dose, is: It may be 300 mg.

[0033] The method further comprises administering 100 mg of the anti-CGRP antibody every 10 to 14 weeks, preferably This may involve intravenous administration every 11 to 13 weeks, more preferably every 12 weeks.

[0034] The method further comprises administering 300 mg of the anti-CGRP antibody every 10 to 14 weeks, preferably This may involve intravenous administration every 11 to 13 weeks, more preferably every 12 weeks.

[0035] The antibody may be prepared, for example, from 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 of L-histidine, about 40.5 mg of sorbitol, and about 0.15 mg of polysaccharide. It may be provided or administered in a formulation disclosed herein that includes Resorbate 80.

[0036] Prior to the first dose, the patient is receiving about 10 to about 22 migraine days per month, e.g., In some cases, patients may experience about 13 to about 19 migraine days per month, for example, about 16 migraine days per month.

[0037] Prior to the first dose, the patient may receive about 14 to about 27 headache days per month, e.g., There may be about 17 to about 24 headache days, for example about 20 or about 21 headache days per month.

[0038] The patient may have received at least 10 years prior to the first dose, e.g., at least one dose of the first At least 15 years prior, e.g., at least 18 years prior or at least 19 years prior to the first dose. Migraines may have been diagnosed years prior.

[0039] The patient may have received at least one dose of the first agonist at least 5 years prior to the first dose, e.g., at least 8 years prior to the first dose, e.g., at least 11 years prior to the first dose or at least 12 years prior to the first dose. Patients may also be diagnosed with chronic migraine headaches.

[0040] The patient may have a headache upon administration of said first dose.

[0041] The patient may have a migraine headache, e.g., a migraine headache with aura, at the time of administration of the first dose. stomach.

[0042] The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 50% of the migraine days in the month following administration of the first dose There may be a decrease.

[0043] The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 75% of the migraine days in the month following administration of the first dose There may be a decrease.

[0044] The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, there was a 100% reduction in the number of migraine days in the month following administration of the first dose. You may do so.

[0045] The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 50% of migraine days are reduced in the 12 weeks following administration of the first dose. There may be a decrease.

[0046] The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 75% of migraine days are reduced in the 12 weeks following administration of the first dose. There may be a decrease.

[0047] The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, there was a 100% reduction in the number of migraine days over the 12 weeks following administration of the first dose. You may do so.

[0048] The method further comprises administering the compound to the patient for about 10 to 14 weeks, preferably 11 to 13 weeks, after the first dose. and, more preferably, within about 12 weeks or about 3 months, a second dose of the anti-CGRP antibody. to said patient, for example intravenously.

[0049] The first dose may be about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 2 00 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-CGR It may comprise a P antibody.

[0050] The patient is a chronic migraine sufferer or an episodic migraine sufferer who is at risk of developing medication-overuse headache. The patient may be receiving at least 1, 2, 3, 4, 5, 6, 7, 8, The patient may use acute headache medication on at least 10 days per month. Acute headache medication may be used. Optionally, the acute medication use is for a baseline period of at least 28 days. The acute medication use is determined by the patient, caregiver, or The acute medications may be reported based on records. opioid painkillers, acetaminophen, aspirin, NSAIDs, non-opioid painkillers, This may include the use of combination analgesics, or opioids.

[0051] Prior to said administration, the patient is experiencing about 15 to about 30 migraine days per month, e.g., about 1 6 to about 28 migraine days per month, e.g., about 17 to about 26 migraine days per month Approximately 16 migraine days may be present.

[0052] Prior to said administration, the patient is experiencing about 15 to about 27 headache days per month, e.g., about 1 There may be 7 to about 24 headache days, for example about 20 or about 21 headache days per month.

[0053] 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.

[0054] 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 or at least 12 years prior to said administration. It's fine.

[0055] 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.

[0056] 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 in the month following administration of the antibody. Good too.

[0057] 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.

[0058] 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 12 weeks after administration of the antibody. Good too.

[0059] 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.

[0060] 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.

[0061] The method further comprises administering the compound to the subject for approximately 10 to 14 weeks, preferably 11 to 13 weeks, after the administration. More preferably, a second dose of the anti-CGRP antibody is administered within about 12 weeks or about 3 months. This may involve administering to the patient, for example, intravenously.

[0062] 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.

[0063] The anti-CGRP antibody may be aglycosylated or glycosylated. In some cases, the mannose residues may be present alone.

[0064] 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

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] In another embodiment, about 100 mg of the anti-CGRP antibody or antibody fragment is administered.

[0072] In another embodiment, about 300 mg of the anti-CGRP antibody or antibody fragment is administered intravenously, e.g., intravenously. It is administered intravenously.

[0073] In an exemplary embodiment, the anti-human CGRP antibody or antibody fragment is administered at most every 10 to 14 weeks. , preferably every 11 to 13 weeks, more preferably every 3 months or every 12 weeks, for example, It is administered intravenously, and the antibody dose may be administered in a single formulation or divided into different formulations. This is approximately every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 3 months or The antibody doses will be administered in a single formulation or in different doses. The expression "divided into formulations" refers to the same or different routes of administration (e.g., vi, im). . and / or sc), for a relatively short period of time, e.g., a few hours, e.g. Administration of the recited amounts of antibodies within 1 to 8 hours, within about 1 day, within about 2 days, or within about 1 week. The term "different formulations" in this context refers to the pharmaceutical formulations in which each dose is administered. Regardless of whether the dosage is the same or different in terms of the chemical composition of the or antibody doses administered at different sites and / or by different routes; e.g., different concentrations, The vehicle, carrier, pH, etc. may be the same or different among the different dosages.

[0074] 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.

[0075] In another exemplary embodiment, the dose of the anti-human CGRP antibody or antibody fragment is administered in a single formulation. or divided into different formulations, which is administered approximately every 10 to 14 weeks, preferably once a day. It is administered every 1 to 13 weeks, more preferably every 12 weeks or every 3 months.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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 .

[0085] 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 .

[0086] 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 .

[0087] 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.

[0088] 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.

[0089] 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.

[0090] In another exemplary embodiment, the anti-human CGRP antibody used in the above method is administered systemically. will be done.

[0091] 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.

[0092] 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.

[0093] In other exemplary embodiments, the anti-human CGRP antibody has an in vivo half-life of at least 15 days. It has a period.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] In another exemplary embodiment, the anti-human CGRP antibody used in the aforementioned method is a human α- and binds to β-CGRP.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] In another preferred embodiment of the present invention, the CGRP-α-, CGRP-β-, and The present invention also contemplates 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.

[0110] 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]

[0111] [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] 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 of each of the individual features are provided. [Figure 7] Provided are polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features, including the variable regions and complementarity determining regions (CDRs), as well as the SEQ ID NO for each of the individual features. [Figure 8] Provided are the 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 for each of the individual features. [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

[0112] Detailed Description The use of anti-CGRP antibodies for the treatment of medication-overuse headache is described herein. Anti-CGRP antibodies are demonstrated herein to be effective in treating chronic migraine headaches. The treatment has a very rapid onset of action, with relief of migraine headaches observed as early as the first day after administration. It was shown that.

[0113] 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.

[0114] As used herein, the term "medication-overuse headache" refers to e Classification Committee of the Intern ational Headache Society (IHS), The Intern ational Classification of Headache Disor der,3rd edition,Cephalalgia.2018 Jan;38( 1):1-211). As defined by ICHD-3, for example, triptan overuse headache, non-opioid sedatives Includes subtypes of medication overuse headache such as medication overuse headache and opioid overuse headache.

[0115] As used herein, the term "reduction in migraine prevalence" refers to a reduction in migraine prevalence after a first dose of an antibody. , for a stated period, e.g., 18 hours, 20 hours, 24 hours, 28 hours, or 30 hours. Preferably, the antibody is administered within a 24-hour period, or within a 24-hour period following the day of antibody administration (i.e., after antibody administration is complete). A reduction in the likelihood that a patient will have a migraine headache on the first full day after completing the treatment (e.g., It refers to a percentage reduction, e.g., 50%). The patient may or may not have had migraines during that period. It is not necessary to have a reduced chance of survival, because the reduction in chance is consistent across the majority of patients, regardless of the outcome for each individual patient. This is because it may be observable at

[0116] 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 migraine days and / or headaches. It refers to a condition in which a person experiences, on average, fewer than 15 headache and / or migraine days per month.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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:

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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

[0127] 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.

[0128] 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.

[0129] 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

[0130] 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.

[0131] 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).

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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. so that after recombination, the att site consists of sequences contributed by each parent vector. Recombination can occur between DNA of any topology.

[0136] 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

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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 It contains antibody fragments such as bs, Fab’, F(ab’)2, etc. Streltsov VA ,et al.,Structure of a shark IgNAR antib ody variable domain and modeling of an e arly - developmental isotype,Protein Sci.2 005 Nov;14(11):2901 - 9.Epub 2005 Sep 30;G reenberg AS,et al.,A new antigen recepto 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.

[0141] 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 subjected to appropriate amplification of the 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.

[0142] 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.

[0143] 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.

[0144] 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 because the 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. .

[0145] 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 , can 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.

[0146] 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.

[0147] 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

[0148] 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.

[0149] "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.

[0150] 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.

[0151] "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.

[0152] 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 to 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] "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.

[0158] "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.

[0159] "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.

[0160] 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.

[0161] 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]

[0162] 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]

[0163] 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]

[0164] 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]

[0165] 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]

[0166] 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:

[0167] 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:

[0168] 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.

[0169] 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.

[0170] 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).

[0171] 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 antibody is Ab6, which has at least one of the following inhibitory activities:

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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

[0177] 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]

[0178] 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]

[0179] 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.

[0180] 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. Hand 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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( 125I), Carbon-14 ( 14 C), sulfur 35( 35 S), tritium ( 3 H) and phosphorus 32 ( 32 P), but are not limited to these.

[0190] 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.

[0191] 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)).

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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 comprising 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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 FRs are distinct 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.

[0207] The present invention also relates to, for example, anti-migraine medications associated with overuse and / or triptans. and / or for the treatment of medication-overuse headaches associated with ergotism and / or analgesic overuse. The present invention relates to a method for the treatment or prevention of medication-overuse headache, the method comprising administering to a patient exhibiting or at risk of developing medication-overuse headache, The patient is administered a therapeutically effective amount of at least one anti-human CGRP antibody or The present invention also contemplates a method of treatment comprising administering a fragment of the invention to a subject comprising administering to said subject a subject a fragment of the invention. It is contemplated that the method may include administration of two or more of the disclosed anti-CGRP antibodies or fragments thereof. When more than one antibody is administered to a patient, the antibodies may be administered simultaneously or concurrently. or may be staggered in their administration. The anti-CGRP activity of the anti-CGRP antibody and fragments thereof of the present invention having the activity against CGRP is also In one embodiment of the present invention, the binding strength of the The anti-CGRP antibodies and fragments thereof of the present invention having binding specificity for CGRP are 5x 10 -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, 5x10 -12 M , 10 -12 M, 5x10 -13 M or 10 -13 The dissociation constant (K D ) in CGR Preferably, the anti-CGRP antibodies and fragments thereof bind to 10 -11 M, 5x10 - 12 M or 10 -12 In another embodiment of the invention, the CGRP binding site is 100 μm. The anti-CGRP antibodies and fragments thereof of the present invention that have binding specificity for CGRP may be linear or binds to conformational CGRP epitopes.

[0208] 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:

[0209] 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.

[0210] 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.

[0211] 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]

[0212] 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]

[0213] 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]

[0214] 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]

[0215] 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]

[0216] 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.

[0217] 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.

[0218] 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 same binding specificity as the antibody fragment is 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).

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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 LThe amino acid present at the corresponding position in the polypeptide, or a conservative amino acid substitution. It is being done.

[0223] 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.

[0224] 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.

[0225] Host cells and vectors containing the polynucleotides are also contemplated.

[0226] 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.

[0227] 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.

[0228] 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).

[0229] 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). ).

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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 subject that 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 the treatment, prevention, and / or prophylaxis of medication-overuse headache. any of the pharmaceutical formulations disclosed herein in the manufacture of a medicament for the prevention and / or amelioration of The present invention further includes the use of

[0234] 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. .

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] "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.

[0240] 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).

[0241] As used herein, a "pharmaceutical acceptable carrier" or "excipient" refers to a physiologically suitable 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.

[0242] 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.

[0243] 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.

[0244] 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, about 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 its composition, 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.

[0245] For each of the embodiments listed, the compounds can be administered in a variety of dosage forms. Any biologically acceptable dosage form known to those 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,

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] Additional Exemplary Embodiments Additional exemplary embodiments of the present invention are as follows:

[0253] S1. Use of an anti-CGRP antibody for the manufacture of a medicament for treating acute migraine. While the patient has a headache and within 30 hours of headache onset, preferably within 24 hours of headache onset administering an anti-CGRP antibody to the patient within a period of time.

[0254] S2. Medication was administered within 18 hours, 12 hours, 6 hours, 5 hours, or less from the onset of headache. Within 4 hours, 3 hours, 2 hours, or 1 hour, e.g., 1 to 6 hours after headache onset 2. The use of an anti-CGRP antibody according to embodiment 1, for administration in

[0255] S3. The anti-CG drug of embodiment S1 or S2, wherein the drug is for intravenous or subcutaneous injection. Use of RP antibodies.

[0256] S4. The antibody of any one of embodiments S1 to S3, wherein the medicament is for intravenous infusion. Use of CGRP antibodies.

[0257] S5. The patient is headache-free 2 hours after completion of administration or infusion, according to embodiments S1-S 5. Use of an anti-CGRP antibody according to any one of claims 4 to 4.

[0258] S6. The patient is administered a Most Bothersome Symptom (MBS) score 2 hours after completion of administration or infusion. The use of an anti-CGRP antibody according to any one of embodiments S1 to S5, wherein the anti-CGRP antibody is free of

[0259] S7. The administration of said medication is monitored for the following: time to pain relief; time to pain relief; completion of infusion. Headache relief at 2 hours with persistent headache relief at 24 and 48 hours; 24 hours after infusion completion and use of rescue medication for up to 48 hours; absence of photophobia 2 hours after completion of infusion; Absence of phonophobia at 2 hours; absence of nausea at 2 hours after completion of infusion; headache effect test at 4 weeks Change from baseline in Headache Impact Test (HIT-6); or Week 4 Migraine Treatment Optimization Questionnaire-6 ) (MTOQ-6) 7. Use of an anti-CGRP antibody according to any one of 6.

[0260] S8. The anti-CGRP antibody comprises any one of Ab1 to Ab14. -S7. Use of an anti-CGRP antibody according to any one of claims 1 to 7.

[0261] S9. Any one of embodiments S1 to S8, wherein the anti-CGRP antibody comprises Ab6. Use of anti-CGRP antibodies.

[0262] S10. The anti-CGRP antibodies are, respectively, SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: No. 228, comprising the light chain complementarity determining region (CDR) 1, 2, and 3 polypeptide sequences of The use of an anti-CGRP antibody of any one of forms S1-S9.

[0263] S11. The anti-CGRP antibodies are, respectively, SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: The present invention relates to a method for the production of a light chain comprising the steps of: Use of an anti-CGRP antibody according to any one of embodiments S1 to S10.

[0264] S12. The anti-CGRP antibodies are, respectively, SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: No. 208. 2. Use of an anti-CGRP antibody according to any one of claims 1 to 11.

[0265] S13. The anti-CGRP antibodies are, respectively, SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: The heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:218 are Use of an anti-CGRP antibody according to any one of embodiments S1 to S12.

[0266] S14. The anti-CGRP antibodies are, respectively, SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 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. The use of an anti-CGRP antibody according to any one of embodiments S1 to S13.

[0267] S15. The anti-CGRP antibodies are, respectively, 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 according to any one of the embodiments S1 to S14. Use of the anti-CGRP antibodies listed above.

[0268] S16. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222. The use of an anti-CGRP antibody of any one of forms S1-S15.

[0269] S17. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. The use of an anti-CGRP antibody according to any one of embodiments S1 to S16, comprising a peptide.

[0270] S18. The anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202. The use of an anti-CGRP antibody of any one of forms S1 to S17.

[0271] S19. The anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO: 212. The use of an anti-CGRP antibody according to any one of embodiments S1 to S18, comprising a peptide.

[0272] S20. 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. Use of anti-CGRP antibodies.

[0273] S21. 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. Use of an anti-CGRP antibody according to any one of aspects S1 to S20.

[0274] S22. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221, Use of an anti-CGRP antibody according to any one of S1 to S21.

[0275] S23. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231. The use of an anti-CGRP antibody according to any one of embodiments S1 to S22, including

[0276] S24. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The use of an anti-CGRP antibody according to any one of embodiments S1 to S23, including

[0277] S25. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567. The anti-CGRP antibody of any one of embodiments S1 to S24, comprising a heavy chain polypeptide comprising Use of antibodies.

[0278] S26. 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 S1 to S25, comprising a heavy chain polypeptide of SEQ ID NO: 566 or a heavy chain polypeptide of SEQ ID NO: 566. 3. Use of an anti-CGRP antibody as described in claim 2.

[0279] S27. 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. Including the use of an anti-CGRP antibody according to any one of embodiments S1 to S26.

[0280] S28. The dose of the anti-CGRP antibody is about 100 mg to about 300 mg, or about 100 mg or about 300 mg, Use of the anti-CGRP antibodies listed above.

[0281] S29. The method of any one of embodiments S1 to S28, wherein the dose of the anti-CGRP antibody is 100 mg. 2. Use of an anti-CGRP antibody according to any one of claims 1 to 11.

[0282] S30. The medicine is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 1 In one embodiment, the anti-CGRP antibody is administered intravenously at a dose of 100 mg every two weeks. 20. Use of an anti-CGRP antibody according to any one of 1 to S29.

[0283] S31. The medicine is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every In one embodiment, the anti-CGRP antibody is administered intravenously at a dose of 300 mg every two weeks. 20. Use of an anti-CGRP antibody according to any one of 1 to S29.

[0284] S32. The patient is suffering from medication-overuse headache, any one of embodiments S1 to S31. 3. Use of an anti-CGRP antibody as described in claim 2.

[0285] S33. Before administration of the drug, the patient is required to take the drug 1 to 10 times a month in a 3-month period prior to administration. The use of an anti-CGRP antibody according to any one of embodiments S1 to S32, which is indicative of headache attacks.

[0286] S34. Prior to administration of the drug, the patient experienced 2 to 8 episodes of ectopic cranial nerve pain per month in the month or 3 months prior to administration. The use of an anti-CGRP antibody according to any one of embodiments S1 to S33, which is indicative of pain attacks.

[0287] S35. Prior to administration of the drug, the patient had 3 to 7 episodes of ectopic cranial nerve pain per month in the month or 3 months prior to administration. The use of an anti-CGRP antibody according to any one of embodiments S1 to S34, which is indicative of pain attacks.

[0288] S36. Prior to administration of the medication, the patient experienced fewer than 25 headaches per month in the month or 3 months prior to administration. The use of an anti-CGRP antibody according to any one of embodiments S1 to S35, indicating the number of days.

[0289] S37. Prior to administration of the medication, the patient experienced fewer than 20 headaches per month in the month or 3 months prior to administration. The use of an anti-CGRP antibody according to any one of embodiments S1 to S36, indicating the number of days.

[0290] S38. Prior to administration of the medication, the patient experienced fewer than 15 headaches per month in the month or 3 months prior to administration. The use of an anti-CGRP antibody according to any one of embodiments S1 to S37, indicating the number of days.

[0291] S39. Prior to administration of the medication, the patient experienced less than 10 headaches per month in the month or 3 months prior to administration. The use of an anti-CGRP antibody according to any one of embodiments S1 to S38, indicating the number of days.

[0292] S40. The patient was diagnosed with migraine headaches at least 10 years prior to administration of the medicament. Use of an anti-CGRP antibody according to any one of embodiments S1 to S39.

[0293] S41. The patient was diagnosed with migraine headaches at least 15 years prior to administration of the medicament. Use of an anti-CGRP antibody according to any one of embodiments S1 to S40.

[0294] S42. The patient has had ectopic prefrontal cortex at least 18 or at least 19 years prior to administration of the medicament. The use of an anti-CGRP antibody according to any one of embodiments S1 to S41 in patients diagnosed with pain.

[0295] S43. The patient is administered a baseline number of migraine days experienced by the patient prior to administration of the medication. at least 50% fewer migraine days in the month following administration of the antibody compared to the number of days prior to administration of the antibody The use of an anti-CGRP antibody according to any one of embodiments S1 to S42, having a reduction in

[0296] S44. The patient is administered the medication prior to the baseline number of migraine days experienced by the patient. at least 75% fewer migraine days in the month following administration of the antibody compared to the number of days prior to administration of the antibody The use of an anti-CGRP antibody according to any one of embodiments S1 to S43, having a reduction in

[0297] S45. The patient is administered the medication prior to the baseline number of migraine days experienced by the patient. showed a 100% reduction in the number of migraine days in the first month after administration of the antibody compared to the number of days before administration. 5. Use of an anti-CGRP antibody according to any one of embodiments S1 to S44,

[0298] S46. The patient is administered the medication prior to the baseline number of migraine days experienced by the patient. at least 50% fewer migraine days in the 12 weeks following administration of the antibody compared to the baseline The use of an anti-CGRP antibody according to any one of embodiments S1 to S45, having a reduction in

[0299] S47. The patient is administered the medication prior to the baseline number of migraine days experienced by the patient. at least 75% fewer migraine days in the 12 weeks following administration of the antibody compared to the baseline The use of an anti-CGRP antibody according to any one of embodiments S1 to S46, having a reduction in

[0300] S48. The patient is administered the medication prior to the baseline number of migraine days experienced by the patient. showed a 100% reduction in the number of migraine days over the 12 weeks following administration of the antibody compared to the baseline 5. The use of an anti-CGRP antibody according to any one of embodiments S1 to S47,

[0301] S49. The medicament may further be administered for about 10 to 14 weeks, preferably 11 to 13 weeks, after administration of the medicament. and administering the second dose of the anti-CGRP antibody for about 12 weeks, more preferably for about 12 weeks or about 3 months. The use of an anti-CGRP antibody according to any one of embodiments S1 to S48 for administration.

[0302] S50. The medicine 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 anti-C Use of an anti-CGRP antibody according to any one of embodiments S1 to S49, including a GRP antibody .

[0303] S51. The anti-CGRP antibody may be non-glycosylated or glycosylated. In the case of the above, the mannose residues are only contained. Use of anti-CGRP antibodies.

[0304] S52. 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 of embodiments S1 to S51, comprising a heavy chain polypeptide of SEQ ID NO: 1 or SEQ ID NO: 566. 1. Use of an anti-CGRP antibody according to claim 1.

[0305] S53. 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. The use of an anti-CGRP antibody according to any one of embodiments S1 to S52.

[0306] S54. The rescue medication is a triptan, a non-opioid analgesic (e.g., paracetamol). (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic), including one or more of a combination of two or more drug classes The triptan use is optionally selected from sumatriptan, zolmitriptan, naratriptan, Triptan, rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally includes one or more of the following: Of the following, morphine, tramadol, butorphanol, morphine, codeine, and hydrocodone The combination of two or more drug classes may include, optionally, one or more uses These drugs have analgesic effects (e.g. paracetamol and codeine) or act as adjuvants. Optionally, the combination analgesic agent comprises two drugs that act as an analgesic agent (e.g., caffeine), Combination opioid analgesics, including at least one opioid (e.g., tramadol, torphanol, morphine, codeine, hydrocodone, or any combination thereof) , barbiturates, such as butalbital and / or caffeine, 54. The use of an anti-CGRP antibody according to any one of S53.

[0307] S55. The headache or migraine is classified as a headache or migraine according to the International Classification 3rd edition of the International Classification of Headache Disorders The use of an anti-CGRP antibody according to any one of embodiments S1 to S54, For.

[0308] S56. The anti-CGRP antibody is a Pichia pastoris s) or in Pichia pastoris According to any one of the embodiments S1 to S55, Use of anti-CGRP antibodies.

[0309] S57. The anti-CGRP antibody is expressed in CHO cells or is expressed in CHO cells. The anti-CGRP antibody according to any one of embodiments S1 to S55, Use of antibodies.

[0310] S58. The anti-CGRP antibody or anti-CGRP antibody fragment contains histidine (L-histidine ), sorbitol, polysorbate 80, and water, or in a formulation consisting of these. The use of an anti-CGRP antibody according to any one of embodiments S1 to S57,

[0311] S59. The formulation contains 100 mg of anti-CGRP antibody and 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has an amount of each ingredient within + / - 10% of the above values; 5. According to embodiment S58, the composition has a pH of 8 or an amount within + / - 10% of said value. Use of anti-CGRP antibodies.

[0312] S60. The formulation contains 100 mg of anti-CGRP antibody and 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 containing or consisting of, or having amounts of each ingredient within + / - 5% of the aforementioned values; and / or 5.8, or an amount within + / - 5% of said value. Use of the anti-CGRP antibodies described.

[0313] S61. The formulation contains 100 mg of anti-CGRP antibody and 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 containing or consisting of, or having amounts of each ingredient within + / - 1% of the aforementioned values; and / or 5.8, or an amount within + / - 1% of said value. Use of the anti-CGRP antibodies described.

[0314] S62. The formulation contains 100 mg of anti-CGRP antibody and 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has an amount of each ingredient within + / - 0.5% of the above values; and and / or a pH of 5.8, or an amount within + / - 0.5% of said value. 5. The use of an anti-CGRP antibody according to S58.

[0315] S63. The formulation contains 100 mg of anti-CGRP antibody and 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has amounts of each ingredient within + / - 0.1% of the above values; and and / or a pH of 5.8, or an amount within + / - 0.1% of said value. 5. The use of an anti-CGRP antibody according to S58.

[0316] S64. Use of an anti-CGRP antibody for the manufacture of a medicament for treating chronic migraine. The medicament comprises a first dose of about 100 mg to about 300 mg of an anti-CGRP antibody. for intravenous administration, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 222. and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, In the first 24 hours after use, patients demonstrate at least a 50% reduction in migraine headache prevalence.

[0317] S65. Use of an anti-CGRP antibody for the manufacture of a medicament for treating chronic migraine. The medicament comprises a first dose of about 100 mg to about 300 mg of an anti-CGRP antibody. for intravenous administration, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 222. and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, and on the day following the administration, the patient is , use that shows at least a 50% reduction in migraine prevalence.

[0318] S66. The first dose of the anti-CGRP antibody is 100 mg, according to embodiment S64 or S66. The use of an anti-CGRP antibody according to embodiment S65.

[0319] S67. The first dose of the anti-CGRP antibody is 300 mg, according to embodiment S64 or S65. The use of an anti-CGRP antibody according to embodiment S65.

[0320] S68. The medicine is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every In one embodiment, the anti-CGRP antibody is administered intravenously at a dose of 100 mg every two weeks. 64, S65, or S66.

[0321] S69. The medicine is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 1 In one embodiment, the anti-CGRP antibody is administered intravenously at a dose of 300 mg every two weeks. 64, S65, or S67.

[0322] S70. Prior to said first dose, the patient is experiencing about 10 to about 22 migraine days per month. The use of an anti-CGRP antibody according to any one of embodiments S64 to S69.

[0323] S71. Prior to said first dose, the patient is experiencing about 13 to about 19 migraine days per month. The use of an anti-CGRP antibody according to any one of embodiments S64 to S70.

[0324] S72. Prior to said first dose, the patient exhibits about 16 migraine days per month. The use of an anti-CGRP antibody of any one of forms S64 to S71.

[0325] S73. Prior to said first dose, the patient is experiencing about 14 to about 27 headache days per month. , The use of an anti-CGRP antibody according to any one of embodiments S64 to S72.

[0326] S74. Prior to said first dose, the patient is experiencing about 17 to about 24 headache days per month. , The use of an anti-CGRP antibody according to any one of embodiments S64 to S73.

[0327] S75. Prior to said first dose, the patient is experiencing about 20 or about 21 headache days per month. The use of an anti-CGRP antibody according to any one of embodiments S64 to S74.

[0328] S76. The patient was diagnosed with migraine headaches at least 10 years prior to the first dose. Use of an anti-CGRP antibody according to any one of embodiments S64 to S75.

[0329] S77. The patient was diagnosed with migraine headaches at least 15 years prior to the first dose. The use of an anti-CGRP antibody according to any one of embodiments S64 to S76.

[0330] S78. The patient has a pre-existing condition at least 18 or at least 19 years prior to the first dose. The use of an anti-CGRP antibody according to any one of embodiments S64 to S77 in patients diagnosed with headache. For.

[0331] S79. The patient was diagnosed with chronic migraine headaches at least 5 years prior to the first dose. , The use of an anti-CGRP antibody according to any one of embodiments S64 to S78.

[0332] S80. The patient was diagnosed with chronic migraine headaches at least 8 years prior to the first dose. , The use of an anti-CGRP antibody according to any one of embodiments S64 to S79.

[0333] S81. The patient has chronic rheumatoid arthritis at least 11 or at least 12 years prior to the first dose. The anti-CGRP antibody according to any one of embodiments S64 to S80, which has been diagnosed as chronic migraine. Use of.

[0334] S82. The medicament is for administration of the first dose when the patient has a headache. Use of an anti-CGRP antibody according to any one of embodiments S64 to S81.

[0335] S83. The medicament is for administration of the first dose when the patient has a migraine. The use of an anti-CGRP antibody according to any one of embodiments S64 to S82.

[0336] S84. The medicament comprises administering the first dose when the patient has migraine with aura. The use of an anti-CGRP antibody according to any one of embodiments S64 to S83 for the treatment of

[0337] S85. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days during the month following administration of the first dose, compared to the number of days in the The anti-CGRP antibody of any one of embodiments S64 to S84, having a 50% reduction Use of.

[0338] S86. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days during the month following administration of the first dose, compared to the number of days in the The anti-CGRP antibody of any one of embodiments S64 to S85, having a 75% reduction Use of.

[0339] S87. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. 100% reduction in migraine days in the month following administration of the first dose compared to the number of days in the The use of an anti-CGRP antibody according to any one of embodiments S64 to S86, having a reduction in

[0340] S88. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days in the 12-week period following administration of the first dose, compared to the number of days in the The anti-CGRP antibody of any one of embodiments S64 to S87, having a 50% reduction Use of.

[0341] S89. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days in the 12-week period following administration of the first dose, compared to the number of days in the The anti-CGRP antibody of any one of embodiments S64 to S88, having a 75% reduction Use of.

[0342] S90. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. 100% reduction in migraine days over the 12 weeks following administration of the first dose compared to the number of days in the The use of an anti-CGRP antibody according to any one of embodiments S64 to 89, having a reduction in

[0343] S91. A second dose of the anti-CGRP antibody is administered about 12 weeks or about 3 months after the first dose. Any one of embodiments S64 to S90, further comprising administering to the patient an amount Use of anti-CGRP antibodies.

[0344] S92. The first dose is about 100 mg, about 125 mg, about 150 mg, about 175 mg g, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg The anti-CGRP antibody according to any one of embodiments S64 to S91, comprising the anti-CGRP antibody. Use of the body.

[0345] S93. The anti-CGRP antibody or antibody fragment is non-glycosylated or glycosylated. Any of embodiments S64 to S92, wherein the mannose residues are only present. 3. Use of an anti-CGRP antibody according to any one of claims 1 to 2.

[0346] S94. The anti-CGRP antibody is a light chain polypeptide of the light chain polypeptide of SEQ ID NO: 221. and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. 4. Use of an anti-CGRP antibody according to any one of claims 4 to S93.

[0347] S95. The anti-CGRP antibody is a Pichia pastoris s) or in Pichia pastoris According to any one of the embodiments S64 to S94, Use of anti-CGRP antibodies.

[0348] S96. The anti-CGRP antibody is expressed in CHO cells or is expressed in CHO cells. The anti-CGR antibody according to any one of embodiments S64 to S94, Use of P antibodies.

[0349] S97. The anti-CGRP antibody or anti-CGRP antibody fragment contains histidine (L-histidine ), sorbitol, polysorbate 80, and water, or in a formulation consisting of these. The use of an anti-CGRP antibody according to any one of embodiments S64 to S96,

[0350] S98. The formulation contains 100 mg of anti-CGRP antibody and 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has an amount of each ingredient within + / - 10% of the above values; 5. The method of embodiment S97, having a pH of 8 or an amount within + / - 10% of said value. Use of anti-CGRP antibodies.

[0351] S99. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 containing or consisting of, or having amounts of each ingredient within + / - 5% of the aforementioned values; and / or 5.8, or an amount within + / - 5% of said value. Use of the anti-CGRP antibodies described.

[0352] S100. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or having amounts of each component within + / - 1% of the aforementioned values; and and / or has a pH of 5.8 or an amount within + / - 1% of said value, embodiment S97. 2. Use of an anti-CGRP antibody as described in claim 1.

[0353] S101. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or having amounts of each component within + / - 0.5% of the above values, and / or has a pH of 5.8 or an amount within + / - 0.5% of said value. 2. Use of an anti-CGRP antibody according to claim 1, wherein the antibody is

[0354] S102. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or having amounts of each component within + / - 0.1% of the aforementioned values; and / or has a pH of 5.8, or an amount within + / - 0.1% of said value. 2. Use of an anti-CGRP antibody according to claim 1, wherein the antibody is

[0355] Further exemplary embodiments Further exemplary embodiments of the present invention are as follows:

[0356] E1. While the patient has a headache and within 30 hours of headache onset, preferably An anti-CGRP antibody for use in the treatment of acute migraine headaches of less than 24 hours.

[0357] E2. Anti-CGRP antibodies were detected within 18 hours, 12 hours, 6 hours, and 5 hours after headache onset. Within hours, within 4 hours, within 3 hours, within 2 hours, or within 1 hour, for example, from the onset of headache The anti-CGRP antibody for use according to embodiment E1, which is for administration in 1 to 6 hours.

[0358] E3. The method of any one of embodiments E1 to E2, wherein the anti-CGRP antibody is for intravenous or subcutaneous infusion. An anti-CGRP antibody for the described use.

[0359] E4. Any one of embodiments E1-E3, wherein the anti-CGRP antibody is for intravenous infusion. 2. An anti-CGRP antibody for use as described in claim 1.

[0360] E5. The patient is headache-free 2 hours after completion of administration or infusion. 5. An anti-CGRP antibody for use according to any one of claims 4 to 4.

[0361] E6. The patient's most bothersome symptom (MBS) 2 hours after completion of administration or infusion The anti-CGRP antibody for use according to any one of embodiments E1 to E5, wherein the anti-CGRP antibody is free of

[0362] E7. Administration of said anti-CGRP antibody determines: time to pain relief; time to pain elimination headache relief at 2 hours with persistent headache relief at 24 and 48 hours after infusion completion; infusion completion use of rescue medication for up to 24 and 48 hours after infusion; absence of photophobia 2 hours after completion of infusion; Absence of phonophobia 2 hours after completion of infusion; absence of nausea 2 hours after completion of infusion; headache at 4 weeks Change from baseline in the Pain Impact Study (HIT-6); or Migraine Treatment Optimization at Week 4 Improve one or more of the Change from Baseline in the Medication Osteoarthritis Questionnaire-6 (MTOQ-6), embodiments An anti-CGRP antibody for use according to any one of E1 to E6.

[0363] E8. Embodiment E1, wherein the anti-CGRP antibody comprises any one of Ab1-Ab14. An anti-CGRP antibody for use according to any one of claims 1 to 7.

[0364] E9. Any one of embodiments E1-E8, wherein the anti-CGRP antibody comprises Ab6. 4. An anti-CGRP antibody for use in

[0365] E10. The anti-CGRP antibodies are, respectively, SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: No. 228, comprising the light chain complementarity determining region (CDR) 1, 2, and 3 polypeptide sequences of The anti-CGRP antibody for use according to any one of forms E1-E9.

[0366] E11. The anti-CGRP antibodies are selected from SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: The present invention relates to a method for the production of a light chain comprising the steps of: An anti-CGRP antibody for use according to any one of embodiments E1 to E10.

[0367] E12. The anti-CGRP antibodies are selected from SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO: Embodiments E1 to E11, comprising the heavy chain CDR 1, 2, and 3 polypeptide sequences of No. 208. 2. An anti-CGRP antibody for use according to any one of the preceding claims.

[0368] E13. The anti-CGRP antibodies are, respectively, SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO: The heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:218 are An anti-CGRP antibody for use according to any one of embodiments E1 to E12.

[0369] E14. The anti-CGRP antibodies are 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. The anti-CGRP antibody for use according to any one of embodiments E1 to E13, comprising

[0370] E15. The anti-CGRP antibodies are selected from 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 according to any one of the embodiments E1 to E14. Anti-CGRP antibodies for use as described above.

[0371] E16. The anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222. The anti-CGRP antibody for use according to any one of forms E1-E15.

[0372] E17. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. An anti-CGRP antibody for use according to any one of embodiments E1 to E16, comprising a peptide body.

[0373] E18. The anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202. The anti-CGRP antibody for use according to any one of forms E1-E17.

[0374] E19. The anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO:212. An anti-CGRP antibody for use according to any one of embodiments E1 to E18, comprising a peptide body.

[0375] E20. 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. Anti-CGRP antibodies for use.

[0376] E21. 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. An anti-CGRP antibody for use according to any one of aspects E1 to E20.

[0377] E22. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221, An anti-CGRP antibody for use according to any one of E1 to E21.

[0378] E23. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231. The anti-CGRP antibody for use according to any one of embodiments E1 to E22, comprising

[0379] E24. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The anti-CGRP antibody for use according to any one of embodiments E1 to E23, comprising

[0380] E25. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567. For use according to any one of embodiments E1 to E24, comprising a heavy chain polypeptide comprising of anti-CGRP antibodies.

[0381] E26. 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 the heavy chain polypeptide of SEQ ID NO: 566. 2. An anti-CGRP antibody for use according to claim 1.

[0382] E27. 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. Including, an anti-CGRP antibody for use according to any one of embodiments E1 to E26.

[0383] E28. The dose of the anti-CGRP antibody is about 100 mg to about 300 mg, or about 100 mg or about 300 mg, Anti-CGRP antibodies for use as described above.

[0384] E29. The method of any one of embodiments E1 to E28, wherein the dose of the anti-CGRP antibody is 100 mg. 13. An anti-CGRP antibody for use according to any one of claims 1 to 12.

[0385] E30. The anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 to 14 weeks. Preferably, for intravenous administration of a dose of 100 mg of the anti-CGRP antibody every 12 weeks. An anti-CGRP antibody for use according to any one of embodiments E1 to E29.

[0386] E31. The anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 to 14 weeks. Preferably, the anti-CGRP antibody is administered intravenously at a dose of 300 mg every 12 weeks. The anti-CGRP antibody for use according to any one of embodiments E1 to E29,

[0387] E32. The patient is suffering from medication-overuse headache. 2. An anti-CGRP antibody for use according to claim 1.

[0388] E33. Prior to administration of the anti-CGRP antibody, the patient has had 1 to 3 months of chemotherapy or chemotherapy-induced hypercalcaemia. For the use according to any one of the embodiments E1 to E32, which indicates 10 migraine attacks Anti-CGRP antibody.

[0389] E34. Prior to administration of the anti-CGRP antibody, the patient has had 2 to 3 months of chemotherapy or chemotherapy-induced hypercalcaemia. Anti-inflammatory drugs for use according to any one of the embodiments E1 to E33, which show 8 migraine attacks CGRP antibody.

[0390] E35. Prior to administration of the anti-CGRP antibody, the patient has had 3 to 4 serotoninib daily for the month or 3 months prior to administration. Anti-inflammatory drugs for use according to any one of the embodiments E1 to E34, which show 7 migraine attacks CGRP antibody.

[0391] E36. Prior to administration of the anti-CGRP antibody, the patient has had 25 mg / month of CGRP therapy or ... For use according to any one of embodiments E1 to E35, the patient exhibits a number of headache days of less than GRP antibodies.

[0392] E37. Prior to administration of the anti-CGRP antibody, the patient has had 20 For use according to any one of embodiments E1 to E36, the patient exhibits a number of headache days of less than GRP antibodies.

[0393] E38. Prior to administration of the anti-CGRP antibody, the patient has had 15 or more CGRP-related For use according to any one of embodiments E1 to E37, the patient exhibits a number of headache days of less than GRP antibodies.

[0394] E39. Prior to administration of the anti-CGRP antibody, the patient has For use according to any one of embodiments E1 to E38, the patient exhibits a number of headache days of less than GRP antibodies.

[0395] E40. The patient is diagnosed with migraine headaches at least 10 years prior to administration of the anti-CGRP antibody. An anti-CGRP antibody for use according to any one of embodiments E1 to E39.

[0396] E41. The patient is diagnosed with migraine headaches at least 15 years prior to administration of the anti-CGRP antibody. An anti-CGRP antibody for use according to any one of embodiments E1 to E40.

[0397] E42. The patient has received at least 18 or at least 19 doses of the anti-CGRP antibody. For the use according to any one of the embodiments E1 to E41, Anti-CGRP antibody.

[0398] E43. The patient is administered the number of migraine days experienced by the patient prior to administration of the anti-CGRP antibody. A reduction in the number of migraine days during the month following administration of the antibody, compared to a baseline number For the use according to any one of the embodiments E1 to E42, Anti-CGRP antibody.

[0399] E44. The patient is administered the number of migraine days experienced by the patient prior to administration of the anti-CGRP antibody. A reduction in the number of migraine days during the month following administration of the antibody, compared to a baseline number For use according to any one of the embodiments E1 to E43, Anti-CGRP antibody.

[0400] E45. The patient is administered the anti-CGRP antibody and is then compared to the number of migraine days experienced by the patient prior to administration of the anti-CGRP antibody. 100% reduction in the number of migraine days in the month following administration of the antibody, compared to a baseline number of % reduction in the anti-CGR antibody for use according to any one of the embodiments E1 to E44 P antibody.

[0401] E46. The patient is administered the number of migraine days experienced by the patient prior to administration of the anti-CGRP antibody. A reduction in the number of migraine days over a 12-week period after administration of the antibody, compared to a baseline number of days For use according to any one of the embodiments E1 to E45, Anti-CGRP antibody.

[0402] E47. The patient is administered the number of migraine days experienced by the patient prior to administration of the anti-CGRP antibody. A reduction in the number of migraine days over a 12-week period after administration of the antibody, compared to a baseline number of days For use according to any one of the embodiments E1 to E46, Anti-CGRP antibody.

[0403] E48. The patient is administered the anti-CGRP antibody and is then compared to the number of migraine days experienced by the patient prior to administration of the anti-CGRP antibody. 100% reduction in the number of migraine days in the 12 weeks after administration of the antibody, compared to a baseline number of % reduction in the anti-CGR antibody for use according to any one of embodiments E1 to E47 P antibody.

[0404] E49. The use is continued for about 10 to 14 weeks after administration of the anti-CGRP antibody, preferably 1 After 1 to 13 weeks, more preferably after about 12 weeks or about 3 months, the patient is administered the anti-CGR The method of any one of embodiments E1 to E48, comprising administering a second dose of the P antibody. 4. An anti-CGRP antibody for use in

[0405] E50. The use is at about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-C The use of any one of embodiments E1 to E49, comprising administering a GRP antibody. Anti-CGRP antibodies for

[0406] E51. The anti-CGRP antibody is aglycosylated or, if glycosylated, Any one of embodiments E1 to E50, wherein the mannose residues are only present. 4. An anti-CGRP antibody for use in

[0407] E52. 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 of embodiments E1 to E51, comprising a heavy chain polypeptide of SEQ ID NO: 566 or a heavy chain polypeptide of SEQ ID NO: 566. 1. An anti-CGRP antibody for use as described in claim 1.

[0408] E53. 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. An anti-CGRP antibody for use according to any one of embodiments E1 to E52.

[0409] E54. The rescue medication is a triptan, a non-opioid analgesic (e.g., paracetamol). (acetaminophen), acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic), including one or more of a combination of two or more drug classes The triptan use is optionally selected from sumatriptan, zolmitriptan, naratriptan, Triptan, rizatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally includes one or more of the following: Of the following, morphine, tramadol, butorphanol, morphine, codeine, and hydrocodone The combination of two or more drug classes may include, optionally, one or more uses These drugs have analgesic effects (e.g. paracetamol and codeine) or act as adjuvants. Optionally, the combination analgesic agent comprises two drugs that act as an analgesic agent (e.g., caffeine), Combination opioid analgesics, including at least one opioid (e.g., tramadol, torphanol, morphine, codeine, hydrocodone, or any combination thereof) , barbiturates, such as butalbital and / or caffeine, An anti-CGRP antibody for use according to any one of claims 1 to 8.

[0410] E55. The headache or migraine is classified as a chronic headache or migraine according to the International Classification Diagnosed according to the 3rd edition of the International Standards of Headache Disorders. An anti-CGRP antibody for use according to any one of embodiments E1 to E54.

[0411] E56. The anti-CGRP antibody is a Pichia pastoris s) or in Pichia pastoris According to any one of the embodiments E1 to E55, Anti-CGRP antibodies for use.

[0412] E57. The anti-CGRP antibody is expressed in CHO cells or is For use according to any one of the embodiments E1 to E55, obtained by of anti-CGRP antibodies.

[0413] E58. The anti-CGRP antibody or anti-CGRP antibody fragment contains histidine (L-histidine ), sorbitol, polysorbate 80, and water, or in a formulation consisting of these. An anti-CGRP antibody for use according to any one of embodiments E1 to E57, comprising

[0414] E59. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has an amount of each ingredient within + / - 10% of the above values; 5. According to embodiment E58, having a pH of 8 or an amount within + / - 10% of said value. Anti-CGRP antibodies for use.

[0415] E60. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 containing or consisting of, or having amounts of each ingredient within + / - 5% of the aforementioned values; and / or 5.8, or an amount within + / - 5% of said value. An anti-CGRP antibody for the described use.

[0416] E61. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 containing or consisting of, or having amounts of each ingredient within + / - 1% of the aforementioned values; and / or 5.8, or an amount within + / - 1% of said value. An anti-CGRP antibody for the described use.

[0417] E62. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has an amount of each ingredient within + / - 0.5% of the above values; and and / or a pH of 5.8, or an amount within + / - 0.5% of said value. An anti-CGRP antibody for use as described in E58.

[0418] E63. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has amounts of each ingredient within + / - 0.1% of the above values; and and / or a pH of 5.8, or an amount within + / - 0.1% of said value. An anti-CGRP antibody for use as described in E58.

[0419] E64. An anti-CGRP antibody for use in the treatment of chronic migraine, said antibody comprising For intravenous administration in a first dose containing about 100 mg to about 300 mg of an anti-CGRP antibody. and 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 and a heavy chain polypeptide of SEQ ID NO: 566, Over time, patients show at least a 50% reduction in migraine prevalence, anti-CGRP antibodies.

[0420] E65. An anti-CGRP antibody for use in the treatment of chronic migraine, said antibody comprising For intravenous administration in a first dose containing about 100 mg to about 300 mg of an anti-CGRP antibody. and 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 and a heavy chain polypeptide of SEQ ID NO: 566, and on the day following the day of administration, the patient is Anti-CGRP antibodies showing at least a 50% reduction in

[0421] E66. The first dose of the anti-CGRP antibody is 100 mg. The anti-CGRP antibody for use according to embodiment E65.

[0422] E67. The first dose of the anti-CGRP antibody is 300 mg. The anti-CGRP antibody for use according to embodiment E65.

[0423] E68. The anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 to 14 weeks. Preferably, for intravenous administration of a dose of 100 mg of the anti-CGRP antibody every 12 weeks. The anti-CGRP antibody for use according to embodiment E64, E65, or E66.

[0424] E69. The anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 to 14 weeks. Preferably, for intravenous administration of a dose of 300 mg of the anti-CGRP antibody every 12 weeks. The anti-CGRP antibody for use according to embodiment E64, E65, or E67.

[0425] E70. Prior to said first dose, the patient is experiencing about 10 to about 22 migraine days per month. An anti-CGRP antibody for use according to any one of embodiments E64 to E69.

[0426] E71. Prior to said first dose, the patient is experiencing about 13 to about 19 migraine days per month. An anti-CGRP antibody for use according to any one of embodiments E64 to E70.

[0427] E72. Prior to said first dose, the patient exhibits about 16 migraine days per month. The anti-CGRP antibody for use according to any one of forms E64 to E71.

[0428] E73. Prior to said first dose, the patient is experiencing about 14 to about 27 headache days per month. , An anti-CGRP antibody for use according to any one of embodiments E64 to E72.

[0429] E74. Prior to said first dose, the patient is experiencing about 17 to about 24 headache days per month. An anti-CGRP antibody for use according to any one of embodiments E64 to E73.

[0430] E75. Prior to said first dose, the patient is experiencing about 20 or about 21 headache days per month. An anti-CGRP antibody for use according to any one of embodiments E64 to E74.

[0431] E76. The patient was diagnosed with migraine headache at least 10 years prior to the first dose. An anti-CGRP antibody for use according to any one of embodiments E64 to E75.

[0432] E77. The patient was diagnosed with migraine headache at least 15 years prior to the first dose. The anti-CGRP antibody for use according to any one of embodiments E64 to E76.

[0433] E78. The patient has a history of HIV infection at least 18 or at least 19 years prior to the first dose. Anti-CG for use according to any one of the embodiments E64 to E77, diagnosed with headache RP antibody.

[0434] E79. The patient was diagnosed with chronic migraine headaches at least 5 years prior to the first dose. , An anti-CGRP antibody for use according to any one of embodiments E64 to E78.

[0435] E80. The patient was diagnosed with chronic migraine headaches at least 8 years prior to the first dose. , An anti-CGRP antibody for use according to any one of embodiments E64 to E79.

[0436] E81. The patient has chronic rheumatoid arthritis at least 11 or at least 12 years prior to the first dose. The anti-inflammatory drug for use according to any one of the embodiments E64 to E80, which has been diagnosed as having chronic migraine. CGRP antibody.

[0437] E82. The anti-CGRP antibody is for administration of the first dose when the patient has a headache. The anti-CGRP antibody for use according to any one of embodiments E64 to E81,

[0438] E83. The anti-CGRP antibody is administered at the first dose when the patient has a migraine. The anti-CGRP antibody for use according to any one of embodiments E64 to E82, .

[0439] E84. The anti-CGRP antibody is administered in the first dose when the patient has migraine with aura. The anti-C antibody for use according to any one of the embodiments E64 to E83, for administration of a dose GRP antibodies.

[0440] E85. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days during the month following administration of the first dose, compared to the number of days in the 50% reduction in the use of any one of the embodiments E64 to E84. CGRP antibody.

[0441] E86. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days during the month following administration of the first dose, compared to the number of days in the 75% reduction in the anti-inflammatory effect of the present invention. CGRP antibody.

[0442] E87. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. 100% reduction in migraine days in the month following administration of the first dose compared to the number of days in the Anti-CGRP for use according to any one of embodiments E64 to E86, having a reduction antibody.

[0443] E88. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days in the 12-week period following administration of the first dose, compared to the number of days in the 50% reduction in the use of any one of the embodiments E64 to E87. CGRP antibody.

[0444] E89. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. at least one decrease in the number of migraine days in the 12-week period following administration of the first dose, compared to the number of days in the 75% reduction in the use of any one of the embodiments E64 to E88. CGRP antibody.

[0445] E90. The patient is administered a baseline number of migraine days experienced by the patient prior to the first dose. 100% reduction in migraine days over the 12 weeks following administration of the first dose compared to the number of days in the Anti-CGRP for use according to any one of embodiments E64 to E89, having a reduction antibody.

[0446] E91. A second dose of the anti-CGRP antibody is administered about 12 weeks or about 3 months after the first dose. The method of any one of embodiments E64 to E90, further comprising administering to the patient an amount 4. An anti-CGRP antibody for use in

[0447] E92. The first dose is about 100 mg, about 125 mg, about 150 mg, about 175 mg g, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg For use according to any one of the embodiments E64 to E91, comprising an anti-CGRP antibody. Anti-CGRP antibody.

[0448] E93. The anti-CGRP antibody or antibody fragment is non-glycosylated or glycosylated. Any of embodiments E64 to E92, wherein, if present, the mannose residues are only present. 3. An anti-CGRP antibody for use according to any one of claims 1 to 2.

[0449] E94. The anti-CGRP antibody is and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. 4 to E93. An anti-CGRP antibody for use according to any one of claims 4 to E93.

[0450] E95. The anti-CGRP antibody is a Pichia pastoris s) or in Pichia pastoris According to any one of the embodiments E64 to E94, 4. An anti-CGRP antibody for use in

[0451] E96. The anti-CGRP antibody is expressed in CHO cells or expressed in CHO cells For use according to any one of the embodiments E64 to E94, obtained by Anti-CGRP antibodies.

[0452] The anti-CGRP antibody or anti-CGRP antibody fragment contains histidine (L-histidine ), sorbitol, polysorbate 80, and water, or in a formulation consisting of these. The anti-CGRP antibody for use according to any one of embodiments E64 to E96,

[0453] E98. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 Contains or consists of, or has an amount of each ingredient within + / - 10% of the above values; 5. According to embodiment E97, the composition has a pH of 8 or an amount within + / - 10% of said value. Anti-CGRP antibodies for use.

[0454] E99. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L -histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 containing or consisting of, or having amounts of each ingredient within + / - 5% of the aforementioned values; and / or 5.8, or an amount within + / - 5% of said value. An anti-CGRP antibody for the described use.

[0455] E100. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or having amounts of each component within + / - 1% of the aforementioned values; and and / or having a pH of 5.8 or an amount within + / - 1% of said value. 2. An anti-CGRP antibody for use as described in claim 1.

[0456] E101. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or having amounts of each component within + / - 0.5% of the above values, and / or has a pH of 5.8 or an amount within + / - 0.5% of said value. 10. An anti-CGRP antibody for use according to aspect E97.

[0457] E102. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or having amounts of each component within + / - 0.1% of the aforementioned values; and / or has a pH of 5.8, or an amount within + / - 0.1% of said value. 10. An anti-CGRP antibody for use according to aspect E97. EXAMPLES

[0458] The following examples are provided to illustrate the invention but in no way limit the scope of the claims. should not be construed as

[0459] Example 1 Preparation of antibodies that bind to CGRP The preparation of exemplary anti-CGRP antibodies Ab1-Ab14 having the sequences of Figures 1A-12 can be performed using the Co-owned, published Nov. 29, 2012, the contents of which are incorporated herein by reference. This is disclosed in PCT application WO 2012 / 162243. The application relates to the development of these phenotypes in Pichia pastoris cells. The present application further illustrates the synthesis of anti-CGRP antibodies Ab1 to Ab1 in CHO cells. 4, specifically Ab6.

[0460] Example 2 Human clinical trials to evaluate the safety and efficacy of anti-CGRP antibodies according to the present invention Clinical Treatment Protocol The humanized anti-CGRP IgG1 antibody, identified herein as Ab6, was administered to treat migraine episodes. The ability to inhibit, reduce or prevent the number, duration and / or intensity of The Ab6 antibody was evaluated in SEQ ID NO: 222 and SEQ ID NO: 221, respectively. L And light The V chain polypeptide is represented by SEQ ID NO: 202 and SEQ ID NO: 201, respectively. H and heavy chain polypeptide The antibody contains an IgG1 constant region that contains a mutation in the heavy chain constant region (position 297 of asparagine residues to alanine residues, which substantially eliminates glycosylation and lytic activity. Substitution (see U.S. Pat. No. 5,624,821).

[0461] Specifically, the clinical efficacy of the Ab6 antibody was verified in a placebo-controlled, double-blind, randomized study. All individuals in the study were selected based on certain criteria. In particular, all were aged ≤50 years. The patient was diagnosed as a migraine patient (ICHD-II, 2004, Section 1) and further screening was performed. A history of migraine headaches of ≥12 months with ≥5 and ≤14 migraine days in each 28-day period during the 3 months preceding the study There was a medical history.

[0462] In addition, during the 3 months prior to screening and the 28 days prior to randomization, All individuals enrolled in the study were taking acute migraine medications on ≤14 days per 28 days. and within these days, had triptan use ≦10 days per 28 days.

[0463] Table 1 summarizes the demographic characteristics of the study population.

[0464] [Table 1]

[0465] Throughout the study, all individuals were required to record their migraine symptoms daily using an e-diary. In the e-diary, subjects in this study were asked to keep track of the number of migraine days / month, migraine episodes, and migraine headache duration / month, migraine headache severity, and use of any preventive medications such as triptans. It was required to be recorded.

[0466] In addition, study participants were asked to record their migraine symptoms for 28 days prior to treatment with the antibody or placebo. Use e-diaries to measure monthly migraine days / hours / episodes baseline This also required the study subjects to be able to use the e-diary. I was able to become familiar with.

[0467] After the 28-day experiment, the study subjects were divided into two groups containing 80 subjects each (Figure 17 In the first group, i.e., the antibody treatment group, (n=80), each subject in the group received a single 10 mg dose of Ab6. In the second group (n=80), i.e. the placebo group, Each elephant was given an intravenous injection containing only the aqueous antibody carrier solution.

[0468] Individuals in the treatment and placebo groups were evaluated 24 weeks after dosing. First, a 12-week An interim analysis was performed. After the 12-week interim analysis, a detailed analysis was performed. This detailed analysis was performed to determine the Addition or removal of patient data, e.g. according to a study protocol, e.g. This refinement included updating data that was not fully loaded from the database. It made a difference, but it didn't change the overall conclusion.

[0469] The efficacy of the antibody against the placebo was partially determined by the data recorded in the e-diary entries. For example, this analysis was based on the recorded mean age of subjects in the treatment and placebo groups. Comparisons were included for number of migraine days / month, migraine episodes / month, and migraine minutes / month. The proportion of responders in each group (i.e., 50%, 75%, and 100% reduction in migraine days) We also compared the results for a few subjects.

[0470] In addition, the response of Ab6 and placebo-treated subjects in both arms to the MSQ and HIT-6 questionnaires was The MSQ is a questionnaire that evaluates and compares responses to health-related quality of life (HRQL). It is a disease-specific tool that is frequently used to assess the impact of migraine. A 16-item migraine-specific qualifier developed by Wellcome Inc. The TheoLife Questionnaire (Version 1.0) was included. The MSQ included three parameters: (i) role functioning restriction; (ii) role functioning prevention; and (iii) emotional functioning. can be.

[0471] The HIT-6 or Functional Impact (also called the Headache Impact Test or HIT-6) is similarly This is a well-known tool for assessing headache intensity. Understand the impact of pain and its treatment on an individual's functional health and well-being.

[0472] Additionally, the pharmacokinetic (PK) properties and immunogenicity of CGRP antibodies have been investigated in Ab6 antibody treatment subjects. It is evaluated based on the above.

[0473] Clinical Results and Analysis The results of this human clinical trial and analysis of treated subjects over 12 weeks are summarized in Table 2 below. Can.

[0474] [Table 2]

[0475] In addition, the results of clinical trials were compared based on the number of responders in the treatment and placebo groups. As shown in Figure 13, the number of migraine days was 50, 75, or 100 for each month in the interim period. The number of subjects with a % reduction in Ab6 was compared between the treatment and placebo groups. 60% of the groups had at least a 50% reduction in headache days, and 31% of the Ab6-treated group had fewer headache days. and 15% of patients in the Ab6-treated group experienced a 100% reduction in headache days.

[0476] In contrast, 33% of patients in the placebo group experienced at least a 50% reduction in headache days; 9% of patients in the treatment group experienced at least a 75% reduction in headache days, while 0% of patients in the placebo group experienced no headaches. The number of days was reduced by 100%.

[0477] These results clearly demonstrated that the reduction in migraine days was much greater in the Ab6-treated group. Without a significant placebo effect, these differences would have been more significant. (The increase in the placebo effect is a phenomenon often very High, so not surprising.

[0478] In addition, the baseline number of migraine days per month in the placebo and Ab6 groups was significantly reduced As shown in Figure 14, the percent change in monthly mean blood glucose level in the placebo and Ab6 treatment groups was compared. The median (±QR) % change from baseline in the number of migraine days was measured after treatment in the two groups. These results were statistically significant (p=0.0078) and A The b6 group had a significantly lower number of headache days per month compared to baseline compared with the placebo group. The figures clearly show that the number of

[0479] Additionally, baseline number of migraine episodes per month in the placebo and Ab6 groups was As shown in Figure 15, the percent change from baseline in the placebo and Ab6-treated groups was Median (±QR) % change from baseline in number of migraine episodes per month was assessed by treatment These results showed that the Ab6 group had better outcomes than the placebo group. showed a significant increase in the number of migraine episodes per month compared with baseline .

[0480] Additionally, baseline migraine episode time per month in the placebo and Ab6 groups was As shown in Figure 16, the percent change from baseline in the placebo and Ab6 treatment groups was The median (±QR) % change from baseline in monthly migraine headache hours was These results showed that the Ab6 group had a significantly higher mortality rate than the placebo group over the 12-week period after treatment. showed a significant reduction in the number of migraine hours per month compared to baseline. do.

[0481] In addition, the HIT-6 results were compared between the two groups. As mentioned above, this questionnaire was Well-accepted use in assessing migraine status in individuals with chronic / sexual migraine FIG. 18 shows the results at baseline, 4 weeks after treatment, 8 weeks after treatment, and To compare HIT-6 responder analysis for Ab6-treated and placebo groups at 12 weeks post-treatment From the results at each time point, the Ab6 group showed a statistically significant increase in HIT compared with the placebo group. -6 score improvement, i.e., 54.4% with Ab6 treatment at week 4, compared with The rate was 30% with placebo (p=0.0023) and 51.3% with Ab6 treatment at week 8. 0.05% vs. 38.0% for placebo (p=0.1094), and 61.1% of patients with treatment had a 6-month survival rate compared with 33.3% of patients with placebo (p=0.001). Figure 19 shows the HIG-6 scores over time in the placebo and Ab6 treatment groups. The proportion of patients with some or little / no symptoms is shown (statistical significance is shown).

[0482] In addition, Figure 20 shows the results of a single dose of 1000 mg administered intravenously over a 24-week period following Ab6 administration. Pharmacokinetic (PK) profiles (in mg / mL) for administered Ab6 are included.

[0483] FIG. 21 shows the plasma free pharmacokinetics (PFR) of Ab6 for a single 1000 mg intravenous dose. PK) parameters N (number of patients), mean, standard deviation (SD) and parameters shown in the table The unit is C. max (μg / mL), AUC 0-∞ (mg*hr / mL), half-life (days), V z (L) and C L (mL / hr).

[0484] Further analysis was performed on patient data between weeks 12 and 24. Treatment groups were divided into control and The study continued to show a reduction in the number of migraine days compared with placebo, but the magnitude of the difference diminished over time. The control group had fewer migraine days per month than at baseline. In part, this is due to the fact that people who answer affirmatively to the question of whether they had a migraine on a given day Avoid the time and effort of answering further questions about the migraines that may result from This may lead to "diary fatigue," in which people may not report migraines on the days they actually occur. was thought to be caused by

[0485] Further analysis of the test results is shown in Figures 22-33. These results show that Ab6 (1000 mg iv) Change from baseline in number of migraine days per month (mean) vs. placebo Analysis of mean number of migraine days (+ / SEM) over time for the entire analysis population (Figure 22). In addition, the change in the mean mean mean SD for the Ab6 treatment group over the 1-4 week period is shown in Figure 23. Distribution of migraine days and changes in the number of days (Figure 24) and the actual number of days in the placebo group during weeks 1 to 4 Distribution of migraine days and changes (Figure 25), actual results for the Ab6 treatment group over the 5-8 week period Distribution of migraine days and changes (Figure 26), actual bias for the placebo group during weeks 5 to 8 Distribution of headache days and changes (Figure 27), actual data for the Ab6 treatment group during weeks 9-12 Distribution of migraine days and changes (Figure 28) and results for the placebo group during weeks 9 to 12 The distribution of migraine days and changes over time (Figure 29) is shown.

[0486] Responder rate analysis was also performed (Figures 30 to 32). These figures show the results for Ab6 and Plasma, respectively. The 50%, 75%, and 100% responder rates for the Sebo treatment groups are shown. Subjects who achieved a 50% or greater reduction in migraine frequency were considered 50% responders. Subjects who achieved a 100% reduction in migraine frequency were considered 75% responders. Subjects who achieve this are considered 100% responders.

[0487] In Figures 22 and 30-32, normalization is applied to the visit interval, and the observed frequency is multiplied by the inverse of the completion rate. An e-diary for days 21 to 27 was completed by multiplying the numbers.

[0488] Migraine severity was also analyzed. Figure 33 shows the time-averaged migraine severity for the entire analysis population. On the scale used, a mean migraine score of 3 represents a "moderate headache."

[0489] Figure 34 shows the number of days with migraine headaches, migraine episodes, migraine time, average migraine severity, and headache frequency. , as well as HIT-6 score, MSQ (Migraine-specific Quality of Life Questionnaire) RFP (Role function prevention), MSQ RFR (Role function restriction), and MSQ EF (Emotional functioning) Summarize changes from baseline in outcome measures including:

[0490] Example 3 A human clinical trial evaluating the safety and efficacy of anti-CGRP antibodies in patients with chronic migraine This example is a randomized controlled trial evaluating the safety and efficacy of Ab6 for the prevention of chronic migraine headaches. We describe a randomized, double-blind, placebo-controlled clinical trial. Ab6 (300 mg or 100 mg) or placebo administered by infusion once every 2 weeks To be eligible for the study, patients were randomized to receive at least Patients must meet the criteria of having experienced at least 15 headache days, of which at least 8 were migraines. Patients enrolled in the study had a mean migraine headache frequency of 16.1 days at baseline. The study endpoints were mean change from baseline in monthly number of migraine days, Reduction in migraine prevalence on day 1 and days 1-28, as well as in the average number of migraine days per month at least 50%, 75%, and 100% decrease from baseline in monthly average acute Change from baseline in number of migraine-specific medication days and Headache Impact Study (HIT -6) reduction from baseline in patient-reported impact scores on The antibody, Ab6, comprises a light chain polypeptide of SEQ ID NO:221 and a heavy chain polypeptide of SEQ ID NO:201. It is an anti-CGRP antibody consisting of thiocyanate.

[0491] Patient characteristics are summarized in Figure 39 and are compared between placebo, 100 mg antibody, or 300 mg antibody. There is a separate column for patients receiving the treatment. The average number of years since the patient's migraine diagnosis is 17.0 The mean duration of chronic migraine was 11.5-12.4 years. 44.3–45.2% were using at least one preventive medication. The average number of migraine days per month was 16.1 in both antibody treatment groups, compared with 16.1 in the placebo group. The average number of migraine days per episode was 16.2.

[0492] A specific percentage (50%, 75%, or 100%) of the average monthly number of migraine days from baseline Reduction is the number of patients in a treatment group who showed a given percentage reduction in the number of migraine days per month or For example, a patient who had 16 migraine days per month at baseline had If the number of migraine days per month is reduced by at least 12 days per month over a specified period of time, 75% will be responders.

[0493] The results are shown in Figures 35 to 39. Figure 35 shows the results of the 300 m test on the 1st, 7th, 14th, 21st, and 28th days. The percentage of patients with migraine headaches in the 100 mg, 100 mg, and placebo treatment groups is shown. The top line is the placebo result, the bottom line is the 300 mg dose result, and the middle line is the 100 mg dose result. Results are shown for mg doses.

[0494] As shown in Figure 35, on day 1, the reduction in migraine prevalence was 52.0% for the 300 mg dose. %, 50% with the 100 mg dose, and 27% with placebo. The differences were statistically significant compared to placebo for both the 300 mg and 300 mg treatment groups.

[0495] Figures 36-38 show the results at 1 month, over 1-3 months (after the first injection), and 4-5 months. Achieved a 50%, 75%, and 100% reduction in the number of migraine days over the course of 24 h (after the second injection), respectively. The percentage of patients in the 300 mg and 100 mg treatment groups who were Data bars, from left to right, show results for the 100 mg, 300 mg, and placebo groups. Statistical significance is as indicated. ++ indicates a statistically significant difference from placebo. + indicates statistically significant difference from placebo (unadjusted); § indicates statistically significant difference from placebo Show the difference (post hoc).

[0496] Example 4 A human clinical trial evaluating the safety and efficacy of anti-CGRP antibodies in patients with chronic or episodic migraine Baseline subgroup analysis for floor testing In the chronic migraine study described in Example 3, at the time of intake, each patient was screened for potential drug abuse. Headache (MOH) was evaluated in 39.9% (139 patients) of the 100 mg treatment group. 42.0% (147 patients) in the 300 mg treatment group, and 39.6% (1 patient) in the placebo group. Evaluation of treatment outcome in this subset of patients was based on anti-CGRP antibody therapy. The results showed that somatic therapy is effective for MOH (Figure 41). In the treatment group, patients with MOH at baseline had a higher mortality rate than those who received placebo. The mean number of migraine days per month for participants was -3.0 (95% CI, -4.56 to -1.52). Similarly, the 300 mg treatment group had a significantly lower venous thromboembolism rate than MOH patients who received placebo. Patients with MOH at baseline had a mean migraine headache day count of -3.2 days per month (95% confidence interval [CI] 0.01-0.05). I, -4.66 to -1.78 days). In contrast, patients without MOH at baseline For patients who did not receive placebo at baseline, the 100 mg treatment group had Compared with patients without H, the mean number of migraine days per month was -1.3 days (95% CI The change in HR was -2.43 to -0.16 days. For patients who received placebo, the 300 mg treatment group had MOH at baseline, whereas the placebo group had no MOH at baseline. Compared with patients who did not have the condition, the mean number of migraine days per month was -2.1 days (95% CI, - The mean number of days with migraine headaches (MM) was 17 days or less or 17 days or more. D) Patients with frequency, age at diagnosis 21 years or younger or over 21 years, and persistent migraine headaches Patients with a migraine history of 15 years or less or more than 15 years, and those suffering from migraine with or without aura Patients with or without previous prophylactic use, with or without concomitant prophylactic use and other patients with triptan use ≥33% or <33% of the days. Efficacy was also demonstrated for subgroups. In each case, efficacy was shown for each subgroup (Figure 41).

[0497] In another human clinical trial of patients with episodic migraines, in a double-blind, parallel study, patients Ab6 100 mg (n=221), 300 mg (n=222), or placebo (n= After a 28-day screening period, patients were randomized to receive 4 Patients received either drug or placebo intravenously every 3 months for a total of 1 infusion (Figure 40). was demonstrated over 1-3 months for both the 100 mg and 300 mg treatment groups, with The mean change in pain days was -3.9 in the 100 mg treatment group compared with -3.2 in the placebo group. The mean number of migraine days (M MD) frequency, age at diagnosis 21 years or younger or older than 21 years, and persistent migraine headaches Patients with a duration of 15 years or less or more than 15 years, and patients with migraine with aura or migraine without aura Efficacy was also shown for subgroups of patients, including those suffering from pain.

[0498] Example 5 Effect of Ab6 treatment on medication use in patients with chronic and episodic migraine headaches The study was conducted on patients with chronic migraine as described in Example 3 and patients with episodic migraine as described in Example 4. During the trial, patients were also asked to record their acute medication use in a daily e-diary and to take acute medications at their own discretion. Medications were permitted. Acute medications for migraines included ergot, triptans, and analgesics. pain relievers (e.g., NSAIDS, opioids, and caffeine-containing combination analgesics). It was being done.

[0499] For further analysis, subjects were randomly assigned to the study during the 28-day screening period (days 1–9 or ≥10; Patients were stratified by the number of days of acute medication use (i.e., days of acute medication use). Calculations are made for each type of acute drug and for combinations, i.e. when two or more types of drugs are used at the same time. If the medications were used on the same calendar day, they were counted as separate drug use days. If a pulmonary anesthetic and a triptan were taken on the same day, they were counted as 2 days of acute drug use. These analyses included at least 1 acute day of nausea and vomiting during the 28-day baseline screening period. Patients who had drug use days were included.

[0500] Patients with chronic and episodic migraine who used acute medication during a 28-day baseline period In both studies, Ab6 treatment showed greater efficacy than placebo as early as one month after dosing. , resulting in a mean reduction in monthly migraine days and acute medication days, across the two doses over six months Similar results were obtained at intervals.

[0501] Ab6 was associated with increased risk of developing chronic migraineurs who had taken acute medication for at least 1 day during baseline. and consistently demonstrated a greater reduction in the average number of monthly migraine days over a 6-month treatment period than placebo. The proportion of people with acute drug use at least 1 day per month during baseline was 18.4% (Figure 42). Patients with chronic migraine headaches were more likely to experience a placebo response as early as one month after treatment and throughout the treatment period. The study showed a greater reduction in acute drug use during baseline for days 1–9 than for baseline for the control group (Figure 43). In the subgroup of chronic migraineurs who were taking sexual medications, the baseline number of days of acute medication use was Changes from baseline were greater in the 300mg Ab6 group than in placebo over 6 months of treatment (Figure 44). In patients with at least 10 days of drug use at baseline, Over the entire 6-month period, the number of days of drug use per month was significantly greater in both Ab6 treatment arms compared with placebo. A clear reduction in the number of patients with acute drug use for ≥1 day at baseline was observed. Medication status at 1 and 6 months in subgroups of patients with chronic migraine headaches of 1-9 days and 10 days or more Change in substance use at 6 months in patients who used 1-9 days / month at baseline With the exception of Ab6 100 mg, Ab6 was more effective than placebo in reducing acute drug use. The results showed a greater therapeutic effect.

[0502] Similarly, over the 6-month interval between two doses, ≥1 day of acute medication use during baseline Patients with episodic migraine who used medications showed a significantly reduced mean number of monthly migraine days with Ab6 compared with placebo. All participants experienced a greater reduction in acute nausea and vomiting (Figure 46). Sudden onset migraine in patients with chronic drug use was observed as early as one month after treatment and throughout the treatment period. The study showed a greater reduction in acute drug use than placebo across the baseline and post-baseline periods (Figure 47). In a subgroup of patients with episodic migraine who had taken acute medication for 1 to 9 days during the treatment, The change from baseline in days of drug use was greater than placebo over 6 months of treatment The difference was larger in Ab6 (Figure 48). Patients who had taken acute medication for 10 days or more during baseline A similar pattern was observed in the subgroup of patients, but the small sample size may have contributed to the lack of clearer results over time. These findings may have contributed to the less consistent pattern of schizophrenia at baseline. In the subgroups of patients with episodic migraine who used sexual medication for ≥1 day, 1–9 days, or ≥10 days, Changes in drug use at 1 and 6 months are shown. With the exception of Ab6 100 mg at 6 months in patients who were receiving was greater in the Ab6-treated group than in the Sebo-treated group.

[0503] The results showed that patients with acute medication-overuse headache (≥10 days / month acute medication use) were at risk for idiopathic headache. Both headache and chronic migraine patients showed the greatest reduction in acute medication use, with Ab6 treatment being the most effective in reducing acute headaches compared with general showed that it produced a greater reduction in the number of drug use days than placebo.

[0504] The most frequently reported acute headache medication in >10% of subjects was tomapaline N (44.5 %) (combination of paracetamol, aspirin, and caffeine), ibuprofen ( 40.6%), sumatriptan (33.6%), and paracetamol (acetaminophen). (20.3%), and naproxen sodium (10.2%). The most frequently reported preventive headache medication among subjects was topiramate (12.5%). .

[0505] Example 6 Efficacy of anti-CGRP antibodies in subjects experiencing acute attacks of migraine This example describes a randomized controlled trial evaluating the safety and efficacy of Ab6 for the acute treatment of migraine headaches. We describe a randomized, double-blind, placebo-controlled clinical trial in which approximately 450 patients were randomly assigned to Patients were randomized 1:1 to receive either 0.00 mg Ab6 or placebo. During the training period (approximately 1-8 weeks), patients will be assessed for migraine frequency and medication use frequency. Eligible patients had migraine attacks of approximately 4 to 15 migraine days per month during the 3 months prior to screening. From medical history, the subject's typical migraine attacks, if untreated, range from moderate to severe The patients were likely to be associated with a headache of about 100 mg / kg / dose and most bothersome symptoms of nausea, photophobia, or phonophobia. To participate, subjects must be headache-free for at least 24 hours prior to the onset of a qualifying migraine episode. On the day of treatment, patients travel to the clinical trial site and receive treatment within approximately 1-6 hours of the onset of the seizure. Patients will begin receiving 100 mg of Ab6 or placebo intravenously at pre-screening. Other monoclonal antibodies (e.g., any CGRP antagonist antibody) within 6 months of has not received any support at all.

[0506] Coprimary endpoints were time to resolution of headache and time to resolution of most bothersome symptom. The co-secondary endpoint was The secondary endpoints were headache relief at 1 h and the most bothersome symptom at 2 h. time to headache reduction, headache relief at 2 hours with persistent headache relief at 24 and 48 hours, time and use of rescue medication up to 48 hours, disappearance of photophobia after 2 hours, phonophobia after 2 hours Elimination of fear, 2-hour nausea, baseline Headache Impact Test (HIT 6) at Week 4 Change from baseline and Migraine Treatment Optimization Questionnaire-6 (mTOQ-6) at Week 4 The exploratory endpoints were freedom from headache at all time points except 2 hours. , disappearance of photophobia at all time points except 2 hours, disappearance of phonophobia at all time points except 2 hours , resolution of nausea at all times except 2 hours, recurrence if headache is resolved after 2 hours, 4 weeks Patient Global Impression of Eye Change Scale (PGIC), and time to next migraine. Ratings were collected on a 4-point scale, with 3 being severe, 2 being moderate, 1 being mild, and 0 being no headache. Pain is the absence of headache (0) in the absence of rescue medication (investigational rescue medications are It should not be used for 2 hours after the end of the infusion to separate the effect of the antibody from the rescue medication. However, rescue medications may be used as an option during the normal course of use. (Note that medication use is collected as data.)

[0507] Statistical analysis was performed to assess differences in endpoints between patients receiving Ab6 or placebo. Significance was determined and endpoints included time to headache relief and time to most bothersome symptom. Time to resolution, as well as each of the other aforementioned endpoints, will be included.

[0508] Rescue medication use is any intervention (medical) provided to a subject to relieve migraine headaches. In this test, the effect of the antibody is separated from that of the rescue drug. For this reason, rescue medication should not be provided earlier than 2 hours after completion of study drug administration. Not contraindicated. The proportion of subjects who required rescue medication will be summarized in this study. Skewer medications include any drug that treats migraines or migraine-related symptoms, such as tryptophan, cerebrospinal fluid, and the like. analgesics, such as non-opioid or opioid / narcotic, acetaminophen, NSAI DS, combination drugs, such as EXCEDRIN® or EXCEDRIN M These include IGRAINE®, antiemetics, ergotamines, and ergot derivatives.

[0509] Disappearance of migraine pain-related symptoms (photophobia, phonophobia, and nausea) as reported by the subject refers to the absence or presence of each of the aforementioned migraine-related symptoms. The proportion of subjects who were symptom-free without any symptoms will be summarized in this study.

[0510] The Headache Impact Test (HIT-6) was assessed as the change from baseline in the total score. These will be summarized and compared between treatment groups in this study.

[0511] Migraine Treatment Optimization Questionnaire-6 (mTOQ-6) total score change from baseline These will be evaluated as outcomes and summarized and compared between treatment groups in the study.

[0512] Time to headache relief was the time period during which the subject reported headache relief, i.e., the subject's headache was relieved without the need for rescue medication. From moderate or severe (2 or 3) to mild or no headache (1 or 0) without administration of The first time point after the end of the infusion is evaluated.

[0513] Headache recurrence was assessed within 48 hours after drug administration in patients with no headache after 2 hours (0). Subjects with recurrent headache of any severity will be assessed as having a headache of any severity. Percentages are summarized in this study.

[0514] This study demonstrates that Ab6 is effective and safe for treating acute migraine headaches.

Claims

1. A method for the acute treatment of migraine headaches comprising administering to a patient in need thereof an effective amount of an anti-CGRP antibody. and administering the anti-CGRP antibody to the patient for at least 30 minutes between headache episodes while the patient has headaches. The method is initiated within 24 hours, preferably within 24 hours, of headache onset.

2. The administration of the anti-CGRP antibody is within 18 hours, within 12 hours, within 6 hours, or within 18 hours after the onset of headache. Within 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour, for example, headache onset The method of claim 1, wherein the incubation period is from 1 to 6 hours after the start of the incubation period.

3. 10. The method of any one of the preceding claims, wherein the injection is intravenous or subcutaneous.

4. 13. The method of any one of the preceding claims, wherein the injection is intravenous.

5. 2. The method according to claim 1, wherein the patient is headache-free 2 hours after completion of administration or infusion. The method according to claim 5.

6. The patient reported the most bothersome symptoms 2 hours after completion of the administration or infusion.

2. The method of any one of the preceding claims, wherein the patient is free of Membrane Stress Symptoms (MBS).

7. The administration was performed according to the following: time to pain relief; time to pain resolution; 24 hours after completion of the infusion; and headache relief at 2 hours with persistent headache relief for 48 hours; 24 and 48 hours after infusion was completed use of rescue medication until 2 h after completion of infusion; absence of photophobia 2 h after completion of infusion; absence of sound Absence of phonophobia; absence of nausea 2 hours after completion of infusion; headache effect study at 4 weeks (HIT-6 ) change from baseline; or Migraine Treatment Optimization Questionnaire-6 (MTOQ-6) at Week 4 6) improves one or more of the changes from baseline in How to.

8. The anti-CGRP antibody of any of the preceding claims includes any one of Ab1 to Ab14.

3. The method according to claim 1 .

9. 2. The method of any one of the preceding claims, wherein the anti-CGRP antibody comprises Ab6.

10. The anti-CGRP antibodies are SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:228, respectively. The polypeptide sequence of claim 1, comprising light chain complementarity determining regions (CDRs) 1, 2 and 3 of the present invention.

2. The method according to any one of claims 1 to 11.

11. The anti-CGRP antibodies are SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:238, respectively. The light chain CDR 1, 2, and 3 polypeptide sequences encoded by 2. The method according to claim 1 .

12. The anti-CGRP antibodies are SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:208, respectively.

2. The heavy chain CDR 1, 2 and 3 polypeptide sequence of any one of the preceding claims. Method of posting.

13. The anti-CGRP antibodies are SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218, respectively. The heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by 2. The method according to claim 1 .

14. The anti-CGRP antibodies are SEQ ID NO:224; SEQ ID NO:226; and SEQ ID NO:228, respectively. and the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:204; SEQ ID NO:2 06; and the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:

208.

13. A method according to any one of the preceding claims.

15. The anti-CGRP antibodies are SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:238, respectively. and the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO:216; and heavy chain CDRs 1, 2 encoded by SEQ ID NO:218 and three polypeptide sequences.

16. The anti-CGRP antibody of the preceding claim comprises a variable light chain polypeptide of SEQ ID NO:

222.

2. The method according to any one of claims 1 to 11.

17. The anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO:

232.

13. The method of any one of the preceding claims, comprising:

18. The anti-CGRP antibody of the preceding claim comprises a variable heavy chain polypeptide of SEQ ID NO:

202.

2. The method according to any one of claims 1 to 11.

19. The anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO:

212.

13. The method of any one of the preceding claims, comprising:

20. The anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable light chain polypeptide of SEQ ID NO: 20 2. The method of claim 1, comprising:

21. The anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO:

232. and the variable heavy chain polypeptide encoded by SEQ ID NO:

212. The method according to any one of the items.

22. The anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO:

221. The method according to any one of claims 1 to 5.

23. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO:

231.

10. A method according to any one of the preceding claims.

24. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO:201 or SEQ ID NO:566 10. A method according to any one of the preceding claims.

25. The anti-CGRP antibody has a heavy chain encoded by SEQ ID NO:211 or SEQ ID NO:

567.

13. A method according to any one of the preceding claims comprising a polypeptide.

26. 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 566. The method of claim 1, further comprising administering to said patient a heavy chain polypeptide of sequence number 566.

27. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO:231 and a sequence and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO:

567.

10. The method according to any one of claims 1 to 9.

28. The dose of the anti-CGRP antibody is about 100 mg to about 300 mg, or about 100 mg.

10. The method of any one of the preceding claims, wherein the amount of the administered dose is about 300 mg or about 300 g.

29. 2. The method of claim 1, wherein the dosage of the anti-CGRP antibody is 100 mg. The method described.

30. Further, 100 mg of the anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks. Any of the preceding claims, including intravenous administration every week, more preferably every 12 weeks.

3. The method according to claim 1 .

31. and 300 mg of the anti-CGRP antibody every 10 to 14 weeks, preferably every 11 to 13 weeks.

30. The method according to any one of claims 1 to 29, further comprising administering the compound intravenously every week, more preferably every 12 weeks. The method according to any one of claims 1 to 5.

32. 10. The method of any one of the preceding claims, wherein the patient is suffering from medication-overuse headache.

33. Prior to said administration, said patient had between 1 and 10 migraine attacks per month in the month or three months prior to said administration.

13. The method according to any one of the preceding claims, wherein:

34. Prior to said administration, said patient had between 2 and 8 migraine attacks per month in the month or three months prior to said administration.

4. A method according to any one of the preceding claims.

35. Prior to said administration, said patient had between 3 and 7 migraine attacks per month in the month or three months prior to said administration.

4. A method according to any one of the preceding claims.

36. Prior to said administration, said patient experienced fewer than 25 headache days per month in the month or three months prior to said administration.

2. A method according to any one of the preceding claims.

37. Prior to said administration, said patient experienced less than 20 headache days per month in the month or three months prior to said administration.

2. A method according to any one of the preceding claims.

38. Prior to said administration, said patient experienced fewer than 15 headache days per month in the month or three months prior to said administration.

2. A method according to any one of the preceding claims.

39. Prior to said administration, said patient experienced less than 10 headache days per month in the month or three months prior to said administration.

2. A method according to any one of the preceding claims.

40. The patient is diagnosed with migraine headaches at least 10 years prior to the administration. The method according to any one of claims 1 to 5.

41. The patient is diagnosed with migraine headaches at least 15 years prior to the administration. The method according to any one of claims 1 to 5.

42. The patient was diagnosed with migraine headaches at least 18 or at least 19 years prior to the administration.

10. A method according to any one of the preceding claims.

43. 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.

10. A method according to any one of the preceding claims.

44. 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 in the month following administration of the antibody.

10. A method according to any one of the preceding claims.

45. 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 a 100% reduction in the number of migraine days in the month following administration of the antibody.

2. The method according to claim 1 .

46. 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 12 weeks after administration of the antibody.

10. A method according to any one of the preceding claims.

47. 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.

10. A method according to any one of the preceding claims.

48. 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 a 100% reduction in the number of migraine days 12 weeks after administration of the antibody.

2. The method according to claim 1 .

49. Further, after said administration, the patient is maintained for about 10 to 14 weeks, preferably 11 to 13 weeks, more preferably administering a second dose of the anti-CGRP antibody to the patient at about 12 weeks or about 3 months.

13. A method according to any one of the preceding claims, comprising:

50. 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.

13. A method according to any one of the preceding claims, comprising administering to the body

51. The anti-CGRP antibody may be aglycosylated or, if glycosylated, may be a glycosylated antibody.

2. The method of any one of the preceding claims, wherein the nucleic acid sequence only comprises non-sheathed residues.

52. 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 566. The method of claim 1, further comprising administering to said patient a heavy chain polypeptide of sequence number 566.

53. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO:231 and a sequence and a heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO:

567.

13. A method according to any one of the preceding claims.

54. The rescue medication may be a triptan, a non-opioid analgesic (e.g., paracetamol (acetaminophen)), ampicillin), acetylsalicylic acid (aspirin), another NSAID, or another non-steroidal anti-inflammatory drug. analgesic), one or more of a combination of two or more drug classes, Triptan use is optional, with sumatriptan, zolmitriptan, naratriptan, and One of zatriptan, eletriptan, almotriptan, and frovatriptan and / or the opioid use optionally includes oxycodone, trametinib, One or more of the following: madol, butorphanol, morphine, codeine, and hydrocodone and / or the combination of two or more drug classes optionally includes the use of analgesia. They have an effect (e.g. paracetamol and codeine) or act as adjuvants (e.g. Optionally, the combination analgesic agent comprises two drugs, a non-opioid drug, such as caffeine, Combine with at least one opioid (e.g., tramadol, butorfa) morphine, codeine, hydrocodone, or any combination thereof), barbiturates, Any of claims 7 to 53, comprising a turate, e.g. butalbital and / or caffeine.

3. The method according to claim 1 .

55. The headache or migraine is classified as a headache or migraine according to the International Classification of Headaches and Headaches. Diagnosed according to the 3rd edition of the Guidelines for Headache Disorders.

10. The method according to any one of claims 1 to 9.

56. The anti-CGRP antibody was found to be capable of inhibiting the expression of CGRP in Pichia pastoris. or expressed in Pichia pastoris.

13. A method according to any one of the preceding claims, obtained by

57. The anti-CGRP antibody is expressed in CHO cells or is produced by expression in CHO cells. A method according to any one of claims 1 to 55, wherein

58. The anti-CGRP antibody or anti-CGRP antibody fragment may contain histidine (L-histidine), sol In a formulation comprising or consisting of bitol, polysorbate 80, and water, 10. A method according to any one of the preceding claims.

59. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. or consisting of, or having amounts of each component within + / - 10% of the aforementioned values, and a pH of 5.

8. or has a pH within + / - 10% of said value.

60. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. or consisting of, or having amounts of each component within + / - 5% of the aforementioned values; and / or 4.

59. The method of claim 58, having a pH of 8 or within + / - 5% of said value. 。

61. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. and / or 4. consists of or has an amount of each component within + / - 1% of the aforementioned values; 59. The method of claim 58, having a pH of 8 or within + / - 1% of said value. 。

62. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. and / or 59. The method of claim 58, having a pH of 5.8 or within + / - 0.5% of said value. Method of posting.

63. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. and / or 59. The method of claim 58, having a pH of 5.8 or within + / - 0.1% of said value. Method of posting.

64. A method for treating chronic migraine comprising administering to a patient from about 100 mg to about 300 mg of an anti-CGRP antibody. administering a first dose intravenously to a patient in need thereof, The subject is a human having a light chain polypeptide of SEQ ID NO:221 and a heavy chain polypeptide of SEQ ID NO:201 or SEQ ID NO:

566. and a polypeptide comprising: A method showing at least a 50% reduction in pain prevalence.

65. A method for treating chronic migraine comprising administering to a patient from about 100 mg to about 300 mg of an anti-CGRP antibody. administering a first dose intravenously to a patient in need thereof, The subject is a human having a light chain polypeptide of SEQ ID NO:221 and a heavy chain polypeptide of SEQ ID NO:201 or SEQ ID NO:

566. and a polypeptide comprising: A method for showing a decrease.

66. 64. The method of claim 63, wherein the first dose of the anti-CGRP antibody is 100 mg.

65. The method according to claim 65.

67. 64. The method of claim 63, wherein the first dose of the anti-CGRP antibody is 300 mg.

65. The method according to claim 65.

68. Further, 100 mg of the anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks. 64, 65 or 66, comprising administering the compound intravenously to a patient every week, more preferably every 12 weeks.

66. The method according to claim 66.

69. and 300 mg of the anti-CGRP antibody every 10 to 14 weeks, preferably every 11 to 13 weeks. 64, 65 or 66, comprising administering the compound intravenously to a patient every week, more preferably every 12 weeks.

67. The method according to claim 67.

70. Prior to said first dose, said patient experiences about 10 to about 22 migraine days per month.

70. The method according to any one of claims 64 to 69.

71. Prior to said first dose, said patient experiences about 13 to about 19 migraine days per month.

71. The method according to any one of claims 64 to 70.

72. 7. The method of claim 6, wherein prior to the first dose, the patient exhibits about 16 migraine days per month.

4. The method according to any one of claims 4 to 71.

73. Prior to said first dose, said patient exhibits about 14 to about 27 headache days per month. The method according to any one of claims 64 to 72.

74. Prior to said first dose, said patient exhibits about 17 to about 24 headache days per month. The method according to any one of claims 64 to 73.

75. Prior to the first dose, the patient experiences about 20 or about 21 headache days per month.

75. The method according to any one of claims 64 to 74.

76. 7. The patient was diagnosed with migraine headaches at least 10 years prior to the first dose.

76. The method according to any one of claims 4 to 75.

77. 7. The patient was diagnosed with migraine headaches at least 15 years prior to the first dose.

77. The method according to any one of claims 4 to 76.

78. The patient has been diagnosed with migraine headaches at least 18 or at least 19 years prior to the first dose. The method of any one of claims 64 to 77, wherein

79. 4. The patient was diagnosed with chronic migraine headaches at least 5 years prior to the first dose. 64-78. The method of any one of claims 64 to 78.

80. 4. The patient was diagnosed with chronic migraine headaches at least 8 years prior to the first dose.

80. The method of any one of claims 64 to 79.

81. The patient has had a chronic migraine headache for at least 11 or at least 12 years prior to the first dose. The method according to any one of claims 64 to 80, wherein the patient has been diagnosed with

82. 82. Any one of claims 64 to 81, wherein the patient has a headache upon administration of the first dose. The method according to claim 5.

83. 83. Any of claims 64 to 82, wherein the patient has a migraine headache at the time of administration of the first dose.

13. The method according to claim 1.

84. 64 - Claim 64, wherein the patient has migraine with aura at the time of administration of the first dose.

83. The method of any one of claims 83.

85. The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 50% of the migraine days in the month following administration of the first dose 85. The method of any one of claims 64 to 84, having a decrease.

86. The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 75% of the migraine days in the month following administration of the first dose 86. The method of any one of claims 64 to 85, having a decrease.

87. The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, there was a 100% reduction in the number of migraine days in the month following administration of the first dose. The method according to any one of claims 64 to 86,

88. The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 50% of migraine days are reduced in the 12 weeks following administration of the first dose.

88. The method of any one of claims 64 to 87, having a decrease.

89. The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, at least 75% of migraine days are reduced in the 12 weeks following administration of the first dose.

89. The method of any one of claims 64 to 88, having a decrease.

90. The patient is assessed for the baseline number of migraine days experienced by the patient prior to the first dose. In comparison, there was a 100% reduction in the number of migraine days in the 12 weeks following administration of the first dose. The method according to any one of claims 64 to 89,

91. about 12 weeks or about 3 months after the first dose, a second dose of the anti-CGRP antibody is administered to the patient.

91. The method of any one of claims 64 to 90, further comprising administering to a patient.

92. The first dose may be about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 2 00 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of the anti-CG The method of any one of claims 64 to 91, comprising an RP antibody.

93. The anti-CGRP antibody or antibody fragment may be non-glycosylated or glycosylated. The method according to any one of claims 64 to 92, wherein the mannose residues are the only residues present. Method of posting.

94. The anti-CGRP antibody has a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of the sequence Any one of claims 64 to 93, comprising a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO:

566. The method according to any one of claims 1 to 5.

95. The anti-CGRP antibody was found to be capable of inhibiting the expression of CGRP in Pichia pastoris. or expressed in Pichia pastoris.

95. The method according to any one of claims 64 to 94, obtained by

96. The anti-CGRP antibody is expressed in or obtained by expression in CHO cells. The method according to any one of claims 64 to 94,

97. The anti-CGRP antibody or anti-CGRP antibody fragment may contain histidine (L-histidine), sol In a formulation comprising or consisting of bitol, polysorbate 80, and water, 97. The method according to any one of claims 64 to 96.

98. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. or consisting of, or having amounts of each component within + / - 10% of the aforementioned values, and a pH of 5.

8. or has a pH within + / - 10% of said value.

99. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. or consisting of, or having amounts of each component within + / - 5% of the aforementioned values; and / or 4.

98. The method of claim 97, having a pH of 8 or within + / - 5% of said value. 。

100. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. and / or 4. consists of or has an amount of each component within + / - 1% of the aforementioned values; 98. The method of claim 97, having a pH of 8 or within + / - 1% of said value. 。

101. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. and / or 98. The method of claim 97, having a pH of 5.8 or within + / - 0.5% of said value. Method of posting.

102. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histidine per mL volume. 40.5 mg sorbitol, and 0.15 mg polysorbate 80. and / or 98. The method of claim 97, having a pH of 5.8 or within + / - 0.1% of said value. Method of posting.

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