Treatment of headache with Anti-CGRP antibodies

Abstract

To provide a method for immediate relief of migraine or headache, or a method for prevention thereof.SOLUTION: The present invention relates to methods of intravenously administering compositions comprising antibodies and fragments thereof (including Fab fragments) that specifically bind to human calcitonin gene-related peptide (CGRP) to patients in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application is a joint application of International Patent Application No. PCT / US2020 / 0 filed on January 8, 2020. 12781, which is a continuation-in-part of U.S. Provisional Patent No. 12781, filed January 8, 2019. Patent Application No. 62 / 789,828 (Attorney Docket No. 1143257.008600); U.S. Provisional Patent Application No. 62 / 872,989, filed July 11, 2019 (Attorney General) No. 1143257.009001); and U.S. Provisional Patent Application No. 1143257.009001 filed May 2, 2019. Patent Application No. 62 / 842,162 (Attorney Docket No. 1143257.009000) No. 60 / 699,999, filed on Oct. 1, 2003, and claims priority to US Pat. No. 6,699,999, all of which are incorporated herein by reference in their entireties. is used as a reference.

[0002] Sequence Listing Disclosure 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 February 14th, named "1143257o009200txt", and has 357, It is 541 bytes in size.

[0003] The present invention relates to a method for producing a compound that specifically binds to human calcitonin gene-related peptide (hereinafter referred to as "CGRP"). and the treatment of headache disorders such as migraine using antibodies and fragments thereof (including Fab fragments) that bind to the The present invention also relates to a method for the production of human calcitonin gene-related peptide (hereinafter "CGRP"). ") and fragments thereof (including Fab fragments) are used to treat headaches, e.g. , and also for the immediate treatment of chronic migraines. [Background technology]

[0004] 2. Description of Related Art 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 enzymes in humans and have similar activities. CGRP is produced in many tissues, including the trigeminal nerve. When activated, neuropeptides are released within 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 active action of CGRP is mediated by the receptor-related CGRP receptor (CGRP-R), which consists of seven transmembrane domains. CGRP-R is mediated by binding to the receptor for membrane-associated protein (RAMP). The receptor component, TA, is essential for efficient coupling to the associated adenylate 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) anti-CGRP antibodies and anti-CGRP antibodies for use in the treatment or prevention of migraine The assignee has developed an RP-R antibody called "ANTI-CGRP COMPOSITION and Use Thereof,” filed on May 21, 2012. PCT Application International Publication No. 2012 / 162243 Pamphlet, "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,” 201 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 "METABOLISM USING ANTI-CGRP ANTIBODIES" PCT application WO 2015 / 003122 filed July 3, 2014 No. 5,999,499, filed on Oct. 1, 2002, all of which applications are incorporated by reference in their entirety. Patent applications relating to GRP antibodies and their uses have been filed previously. Summary of the Invention

[0006] In one aspect, the present disclosure provides a method for treating migraine or headache symptoms in need of immediate relief. for the treatment of migraines or headaches in patients with 1. A method for the prevention of migraines or headaches in a patient in need of prophylactic treatment of , to patients in need, 100 or 300 mg 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, respectively, and the sequence SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively. and a polypeptide sequence of 3. do.

[0007] In some embodiments, the patient has at least one headache and / or migraine at the time of administration. Headache symptoms may occur.

[0008] In some embodiments, the at least one headache and / or migraine symptom is pain, nausea, The symptoms may include one or more of: anxiety, photophobia, or phonophobia.

[0009] In some embodiments, the at least one headache and / or migraine symptom is a headache pain).

[0010] In some embodiments, the most bothersome symptoms occur within 1 day after administration, within 12 hours after administration, within 24 hours after administration, within 14 hours after administration, within 2 ... Within 6 hours after administration, within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, and 2 hours after administration Within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration , may be alleviated after said administration.

[0011] In some embodiments, the patient is diagnosed with rhesus malabsorption within 1 day after administration, within 12 hours after administration, or within 6 hours after administration. Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, Or within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration, etc. After administration you will no longer have migraines.

[0012] In some embodiments, the anti-CGRP antibody is SEQ ID NO: 234; SEQ ID NO: 23 6; and the light chain CDR 1, 2, and 3 polypeptide encoded by SEQ ID NO:238 and SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively. and heavy chain CDR 1, 2, and 3 polypeptide sequences.

[0013] In some embodiments, the anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222. may include:

[0014] In some embodiments, the anti-CGRP antibody is encoded by SEQ ID NO:232. It may comprise a variant light chain polypeptide.

[0015] In some embodiments, the anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202. may include:

[0016] In some embodiments, the anti-CGRP antibody is encoded by SEQ ID NO:212. It may comprise a variable heavy chain polypeptide.

[0017] In some embodiments, the anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222. and the variable heavy chain polypeptide of SEQ ID NO: 202.

[0018] In some embodiments, the anti-CGRP antibody is encoded by SEQ ID NO:232. A variable light chain polypeptide and a variable heavy chain polypeptide encoded by SEQ ID NO: 212. It can be seen.

[0019] In some embodiments, the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221. It can be seen.

[0020] In some embodiments, the anti-CGRP antibody is a light antibody encoded by SEQ ID NO: 231. The polypeptide may comprise a chain.

[0021] In some embodiments, the anti-CGRP antibody has the amino acid sequence of SEQ ID NO: 201 or SEQ ID NO: 566. The polypeptide may comprise a chain.

[0022] In some embodiments, the anti-CGRP antibody is selected from the group consisting of SEQ ID NO: 211 and SEQ ID NO: 567. The heavy chain polypeptide may comprise a heavy chain polypeptide encoded by

[0023] In some embodiments, the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221 and It may comprise the heavy chain polypeptide of SEQ ID NO:201 or SEQ ID NO:566.

[0024] In some embodiments, the anti-CGRP antibody is a light antibody encoded by SEQ ID NO: 231. The heavy chain polypeptide encoded by SEQ ID NO:211 or SEQ ID NO:567 The compound may contain peptides.

[0025] In some embodiments, the intravenous administration is infused over a period of about 30 to 60 minutes. It can be done.

[0026] In some embodiments, headache or migraine symptoms are relieved within 1 day after administration, within 12 hours after administration, Within 6 hours after administration, within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration Within 1 hour, within 30 minutes, or 1 to 6 hours after administration and the like may be reduced or eliminated immediately after administration.

[0027] In some embodiments, the patient may be headache-free 2 hours after completion of the infusion.

[0028] In some embodiments, the method is administered every 10-14 weeks, preferably every 11-13 weeks. and more preferably, administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks. It may further include:

[0029] In some embodiments, the method is administered every 10-14 weeks, preferably every 11-13 weeks. and more preferably, 300 mg of the anti-CGRP antibody is administered intravenously every 12 weeks. It may further include:

[0030] In some embodiments, the anti-CGRP antibody is a histidine (L-histidine), sorbitol, or PEG-14. It may be included in a formulation that includes or consists of ethanol, polysorbate 80, and water. .

[0031] In some embodiments, the formulation contains 100 mg of anti-CGRP antibody per mL volume. 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg polyisoprene. It may comprise or consist of Polysorbate 80 or The amount of each ingredient is within + / - 10% of the stated value, and the pH is 5.8 or + / - 10% of the stated value. % pH.

[0032] In some embodiments, the formulation contains 100 mg of anti-CGRP antibody per mL volume. 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg polyisoprene. may comprise or consist of Rubate 80, or each component within + / - 5% of the above values and / or has a pH of 5.8 or within + / - 5% of said value.

[0033] In some embodiments, the formulation contains 100 mg of anti-CGRP antibody per mL volume. 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg polyisoprene. may comprise or consist of Rubate 80, or each component within + / - 1% of the above values and / or has a pH of 5.8 or within + / - 1% of said value.

[0034] In some embodiments, the formulation contains 100 mg of anti-CGRP antibody per mL volume. 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg polyisoprene. may contain or consist of Benzyl Alcohol 80 or each of the above values ​​within + / - 0.5% and / or a pH of 5.8 or within + / - 0.5% of said value. Has.

[0035] In some embodiments, the formulation contains 100 mg of anti-CGRP antibody per mL volume. 3.1 mg L-histidine, 40.5 mg sorbitol, and 0.15 mg polyisoprene. may contain or consist of Benzyl Alcohol 80 or each of the above values ​​within + / - 0.1% and / or a pH of 5.8 or within + / - 0.1% of said value. Has.

[0036] In some embodiments, the L-histidine in the formulation is L-histidine and L-hydidine. The 3.1 mg of histidine in the formulation contains a mixture of L-histidine and L-histidine monohydrate. It may also contain a mixture of L-histidine (1 mg) and L-histidine monohydrate (2.8 mg). This amounts to 3.1 mg of L-histidine free base in the final formulation.

[0037] In some embodiments, the formulation is contained in a 100 mg / mL single dose vial. Well, where each mL contains 100 mg of anti-CGRP antibody, L-histidine, at a pH of 5.8. (1 mg), L-histidine hydrochloride monohydrate (2.8 mg), polysorbate 80 (0 0.15 mg), sorbitol (40.5 mg), and water for injection, USP.

[0038] In some embodiments, the formulation is contained in a 300 mg / mL single dose vial. Well, where each mL contains 300 mg of anti-CGRP antibody, L-histidine, at a pH of 5.8. (1 mg), L-histidine hydrochloride monohydrate (2.8 mg), polysorbate 80 (0 0.15 mg), sorbitol (40.5 mg), and water for injection, USP.

[0039] In some embodiments, the migraine or headache is an acute migraine or headache, with or without aura. Migraine with or without migraine, chronic migraine, episodic migraine, chronic / episodic migraine, hemiplegic migraine Headache, cluster headache, migraine-like neuralgia, chronic headache, tension headache, general headache, root of head and neck Headaches caused by structural problems, sinus headaches (e.g., those related to sinusitis) and allergy-induced headache or migraine.

[0040] In some embodiments, the patient has a VRS-4 score of at least 1.0 at the time of administration of the antibody. Both can present with pain levels of 2.

[0041] In some embodiments, the patient has a VRS-4 score of at least 1.0 at the time of administration of the antibody. Both can present with a pain level of 3.

[0042] In some embodiments, the patient is diagnosed with rhesus malabsorption within 1 day after administration, within 12 hours after administration, or within 6 hours after administration. Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, Or within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration, etc. Immediately after the procedure, patients may experience a pain level of 2 or less on the VRS-4 scale.

[0043] In some embodiments, the patient is diagnosed with rhesus malabsorption within 1 day after administration, within 12 hours after administration, or within 6 hours after administration. Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, Or within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration, etc. Immediately after the procedure, patients may experience a pain level of 1 or less on the VRS-4 scale.

[0044] In some embodiments, the patient receives the drug within 15 minutes, 30 minutes, 1 hour, or 24 hours before or after administration. Within 2 hours, within 3 hours, within 4 hours, within 5 hours, or within 6 hours before said administration. No acute migraine medications should be administered within the following specified period.

[0045] In some embodiments, the acute migraine medication is a triptan, an analgesic, e.g., a non-opioid or opioids / narcotics, acetaminophen, NSAIDs, combinations The antihistamines may include antihistamines, ergotamine, or ergot derivatives.

[0046] In some embodiments, the non-opioid analgesic is paracetamol (acetaminophen). acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic The triptans may include sumatriptan, zolmitriptan, naratriptan, triptan, rizatriptan, eletriptan, almotriptan, or frovatriptan The opioid may include the use of one or more of the following: oxycodone, tramadol, Includes the use of one or more of the following: butorphanol, morphine, codeine, and hydrocodone The combination drug may be two drugs with analgesic effect (e.g., paracetamol, and codeine), analgesics and adjuvants (e.g., paracetamol and caffeine). and / or the combination analgesic may comprise at least one opioid (tramadol). Dhol, butorphanol, morphine, codeine, hydrocodone, or any combination thereof combinations), barbiturates, e.g., butalbital, and / or caffeine and / or the combination analgesic may be acetylsalicylic acid (aspirin), Racetamol and caffeine (EXCEDRIN®, EXCEDRIN MI) GRAINE®).

[0047] In some embodiments, the patient is receiving or has been receiving an additional migraine medication. is possible.

[0048] In some embodiments, the patient is administered a steroid hormone (SEQ ID NO: 1) prior to, concurrently with, or after administration of an anti-CGRP antibody. Additional migraine medication may be administered.

[0049] In some embodiments, the patient is administered the anti-CGRP antibody within 15 minutes, 30 minutes, or both before and after the administration. , within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, etc. In addition, an additional migraine medication may be administered within a predetermined period before or after administration of the anti-CGRP antibody.

[0050] In some embodiments, the additional migraine medication may include acute and / or chronic migraine medication. .

[0051] In some embodiments, the additional migraine medication is a triptan, an analgesic, e.g., a non-opioid or opioids / narcotics, acetaminophen, NSAIDs, combination medications, It may contain gothamine, or an ergot derivative.

[0052] In some embodiments, the non-opioid analgesic is paracetamol (acetaminophen). acetylsalicylic acid (aspirin), another NSAID, or another non-opioid analgesic The triptans may include sumatriptan, zolmitriptan, naratriptan, triptan, rizatriptan, eletriptan, almotriptan, or frovatriptan The opioid may be oxycodone, tramadol, butorfu use of one or more of the following: benzodiazepines, morphine, codeine, and hydrocodone; Combination medications are drugs that contain two drugs with analgesic effects (e.g., paracetamol and codeine). ), analgesics and adjuvants (e.g., paracetamol and caffeine), and / or The combination analgesic contains at least one opioid (tramadol, butorphanol, , morphine, codeine, hydrocodone, or any combination thereof), barbiturates and / or caffeine, and / or combinations thereof. Painkillers include acetylsalicylic acid (aspirin), paracetamol and caffeine ( Includes CEDRIN®, EXCEDRIN MIGRAINE® .

[0053] In some embodiments, the anti-CGRP antibody is isolated from Pichia pastoris (Pichia p astoris or Pichia pastoris It is obtained by expression in Bacillus subtilis (L. toris).

[0054] In some embodiments, the anti-CGRP antibody is expressed in CHO cells or Obtained by expression in HO cells.

[0055] In some embodiments, the patient receives 100 mg or 300 mg of the anti-CG every three months. RP antibodies may be administered.

[0056] In some embodiments, the methods may provide immediate relief from migraine or headache symptoms.

[0057] In some embodiments, the methods may provide immediate prophylactic treatment of migraines or headaches. .

[0058] The present disclosure provides a method for the immediate treatment of headaches, comprising administering to a patient in need thereof an effective amount of the compound described herein. at least one anti-CGRP antibody or antibody fragment or anti-CGRP-R antibody disclosed in administering an antibody or antibody fragment, or one or more formulations containing said antibody or antibody fragment. and in some embodiments, the antibody is administered to the patient while the patient is experiencing a headache. In some embodiments, the antibody administration is within 1 to 6 hours of the onset of the headache. In some embodiments, the headache is a migraine, e.g., an episodic migraine or The headache may include chronic migraine. The headache may include medication overuse headache. In some embodiments, The anti-CGRP antibody or antibody fragment Ab6 or a Fab fragment thereof is SEQ ID NO: 224; SEQ ID NO:226; and the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO:228, respectively. and heavy chain CDRs 1, 2, and 3 of SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:208. and 3 polypeptide sequences; or SEQ ID NO:234; SEQ ID NO:236; and and the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 238. , encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences. The CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202. The anti-CGRP antibody may comprise a polypeptide encoded by SEQ ID NO: 232. A variable light chain polypeptide and a variable heavy chain polypeptide encoded by SEQ ID NO: 212 The anti-CGRP antibody may comprise a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 20. In some embodiments, the anti-CG heavy chain polypeptide may comprise SEQ ID NO: 1 or SEQ ID NO: 566. The RP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a light chain polypeptide encoded by SEQ ID NO: 211 or the heavy chain polypeptide encoded by SEQ ID NO: 567. wherein 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: 20 Antibodies isolated from recombinant cells expressing nucleic acid sequences encoding variable heavy chain polypeptides of the two These polypeptides may optionally comprise human light and heavy constant region polypeptide, e.g., human IgG1, IgG2, IgG3, or IgG4 constant region These constant regions are optionally linked to each other and are optionally glycosylated or proteolyzed. The recombinant cell may optionally be a yeast or mammalian cell. Animal cells, such as Pichia pastoris or CHO In some embodiments, the anti-CGRP antibody comprises a light chain and a sequence of SEQ ID NO: 221. A composition for expressing a nucleic acid sequence encoding the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The recombinant cell may optionally comprise an antibody expression product isolated from the recombinant cell. , yeast or mammalian cells, such as Pichia pastoris ris) or CHO cells, the constant region of which is optionally glycosylated or protein-modified. It may also be modified to alter protein degradation or other effector function. In such a case, any of the aforementioned anti-CGRP antibodies or antibody fragments, preferably Ab6, may be used. Alternatively, for example, histidine (L-histidine), sorbitol, polysorbate 80, for example, about 100 mg of anti-CGRP antibody per 1 mL volume, about 3.1 mg of L-histidine, about 40.5 mg of sorbitol, and about 0.15 mg of Polysorbate 80 may also be included in the formulations disclosed herein. In one embodiment, the dose of the antibody is about 100 mg to about 300 mg, for example, about 100 mg. g, about 300 mg, 100 mg, or 300 mg. The dosage can be administered by different means, for example intravenously, in an appropriate volume (e.g. 1 It may be administered in saline, such as 0.9% sodium chloride (0.00 mL).

[0059] In some embodiments, the patient has fewer than 25 headache days per month, fewer than 20 headache days per month, The number of headache days per month may be shown, or fewer than 15 headache days per month, or fewer than 10 headache days per month. For example, The patient has fewer than 14 headache days per month, fewer than 13 headache days, fewer than 12 headache days per month , fewer than 11 headache days, fewer than 10 headache days, fewer than 9 headache days, fewer than 8 headache days The number of headache days may be less than 7, or less than 6. The patient has 2 to 15 headache days, e.g., 3 to 14 headache days, 4 to 13 headache days. days, 5-12 headache days, 6-11 headache days, or 7-10 headache days per month It can be shown.

[0060] In some embodiments, the patient experiences fewer than 10 migraines per month, e.g., 1-9 migraines per month. Headaches, e.g., 2-8 migraines per month, 3-7 migraines per month, 4-6 migraines per month, or In some embodiments, the patient may experience about 5 migraines per month. migraines less than once every two months, for example, once every three months, once every four or six months In some embodiments, the bias may be displayed monthly, or twice every three months, or the median value. Headaches may be diagnosed according to ICHD-3 guidelines.

[0061] 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 a pre-existing headache disorder; headache occurring 15 or more days per month in the setting of a headache; and (b) for the acute and / or symptomatic treatment of headache. Abuse of one or more drugs that can be taken for more than three months.

[0062] In some embodiments, the abuse is ergot alkaloid abuse for 10 or more days per month. use of steroid alkoids (e.g., ergotamine), triptans for 10 or more days / month Use of one or more non-opioid analgesics (paracetamol, acetaminophen) for ≥15 days / month acetaminophen, acetylsalicylic acid (aspirin), another NSAID, or another non-opioid use of one or more combination analgesics (see below) for 10 days or more per month; use of one or more opioids for ≥10 days / month or ≥10 days / month may include the use of a combination of two or more drug classes (described further below) per month .

[0063] In the methods herein, the triptans include, among others, sumatriptan, zolmitri triptan, naratriptan, rizatriptan, eletriptan, almotriptan, and The drug may include any one or any combination of triptans such as lobatriptan. Not limited to these.

[0064] In some embodiments, the medication-overuse headache is ergotamine-overuse headache, triptan-overuse headache, or pain, non-opioid analgesic overuse headache, opioid overuse headache, combination analgesic overuse headache, individual Medication-overuse headache due to multiple drug classes not separately abused, Medication-overuse headache due to unidentified or untested overuse of other drugs May include substance overuse headache.

[0065] In some embodiments, the non-opioid analgesic overuse headache is caused by paracetamol (acetaminophen). Minophen overuse headache, nonsteroidal anti-inflammatory drug (NSAID) overuse headache, e.g., acetaminophen Aspirin-overuse headache or ibuprofen-overuse headache, or another non-opioid This may include painkiller overuse headaches.

[0066] In some embodiments, the ergotamine-overuse headache is a headache that is present in patients with pre-existing primary headaches. ≥15 days / month for more than 3 months, and This may include headaches that develop as a result of regular use of horn alkaloids.

[0067] In the methods herein, the ergot alkaloids are ergotamine, nicergoline, metronidazole, methadone ... It may contain tisergide, or dihydroergotamine, or may contain ergot derivatives. .

[0068] In some embodiments, the triptan-overuse headache is occurring on ≥15 days / month for more than 3 months and on ≥1 triptan for ≥10 days / month for more than 3 months This may include headaches that develop as a result of regular use.

[0069] In some embodiments, the non-opioid analgesic overuse headache is a pre-existing primary headache. Occurring in patients on ≥15 days / month for >3 months, with ≥1 non-onset Hydroxygen-containing analgesics (paracetamol (acetaminophen), acetylsalicylic acid (aspirin) Regular use of antihistamines (e.g., ibuprofen, another NSAID, or another non-opioid pain reliever) May include headaches that develop as a result of use.

[0070] In the methods herein, the NSAID is ibuprofen, naproxen, or ibuprofen. Any NSAID or combination thereof, including but not limited to endomethacin obtain.

[0071] In some embodiments, the combination analgesic-overuse headache occurs on 10 or more days for more than 3 months. Occurs as a result of regular use of one or more combination analgesics per month, 15 days or more per month In the context of medication overuse headache, the term combination analgesic Two or more classes of drugs (e.g., paracetamol and coadministration) each have an analgesic effect. or painkillers combined with drugs that act as adjuvants (e.g., caffeine). A commonly abused combination analgesic is a non-opioid analgesic. , at least one opioid, a barbiturate, such as butalbital, and / or a cuff In an exemplary embodiment, the combination analgesic overuse headache is combined with acetaminophen. minophen, aspirin, and caffeine, e.g., EXCEDRIN® or Other known combinations of EXCEDRIN and MIGRAINE® The combination analgesic agent may contain at least one non-analgesic agent, e.g., a prodrug for sinus-related preparations. vasoconstrictors such as pseudoephedrine, antihistamines used to treat allergy sufferers, This includes painkillers combined with antihistamines.

[0072] In some embodiments, the opioid-overuse headache is a headache in patients with pre-existing primary headache. Occurring on ≥15 days / month for more than 3 months and involving ≥1 opioid on ≥10 days / month for more than 3 months This may include headaches that develop as a result of regular use.

[0073] In some embodiments, the drug abuse caused by multiple drug classes that are not individually abused. Drug-induced headache occurs ≥15 days / month in patients with pre-existing primary headache and is associated with a single drug or is an excess of at least 10 days / month total over a 3-month period without abuse of a single drug class. Any combination of rugotamine, triptans, non-opioid analgesics and / or opioids This may include headaches that develop as a result of regular intake of

[0074] In the methods herein, the opioid may be, among others, oxycodone, tramadol, Butorphanol, morphine, codeine, hydrocodone, thebaine, oripavine, mixed Hexane alkaloids, e.g., papaveretum, diacetylmorphine, nicomorphine, dipropionate Neoylmorphine, diacetylhydromorphine, acetylpropionylmorphine, desomol Morphine, methyldesorphine, dibenzoylmorphine, ethylmorphine, heterocodeine, Buprenorphine, etorphine, hydromorphone, oxymorphone, fentanyl , α-methylfentanyl, alfentanil, sufentanil, remifentanil, Lufentanil, omefentanil, pethidine (meperidine), ketobemidone, MPP P, allylprodine, prodine, PEPAP, promedol, diphenylpropylamine , propoxyphene, dextropropoxyphene, dextromoramide, vegetramide any one or more of the following opioid drugs, including but not limited to benzodiazepine, ... It can be a combination of:

[0075] In some embodiments, the use of drugs from unspecified or untested drug classes The medication-overuse headache occurs 15 or more days per month in patients with pre-existing primary headache. ergotamine, triptan, or non-opioid agonist for at least 10 days / month for more than 3 months Headaches that occur as a result of regular intake of any combination of painkillers and / or opioids and the identity, quantity, and / or use or abuse patterns of these drug classes. has not been firmly established.

[0076] In some embodiments, the medication-overuse headache caused by another drug is associated with a pre-existing primary headache. Occurring 15 or more days per month in patients with headache for acute or symptomatic treatment within 3 months Regular use of one or more medications other than those listed above taken at least 10 days / month for more than Symptoms may include headaches that develop as a result of ingestion.

[0077] The amount and duration of drug use were determined based on patient or relative-reported use, diaries, and medical records. Medical records, drug purchasing history, prescription fulfillment, biomarkers of drug use, and drug toxicity known methods, such as incidence rates, incidence rates of drug overdose, and / or other indicators of patient drug use; can be determined using

[0078] The present disclosure provides a method for treating or preventing headaches associated with potential medication abuse, comprising administering to a person in need thereof administering to the patient an effective amount of an anti-CGRP antibody or anti-CGRP antibody fragment disclosed herein or administering one or more formulations containing the anti-CGRP antibody or anti-CGRP antibody fragment. In some embodiments, the anti-CGRP antibody Ab6 is selected from the group consisting of SEQ ID NO: 22 4; SEQ ID NO:226; and the light chain CDR 1, 2, and 3 polynucleotides of SEQ ID NO:228, respectively. Peptide sequences and heavy chain CDRs of SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:208 1, 2, and 3 polypeptide sequences; or SEQ ID NO: 234; SEQ ID NO: 236; and the light chain CDR 1, 2, and 3 polypeptide encoded by SEQ ID NO: 238. The peptide sequences are coded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively. and heavy chain CDR 1, 2, and 3 polypeptide sequences encoded therein. 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 The anti-CGRP antibody may comprise a variable heavy chain polypeptide coded by SEQ ID NO: 232. a variable light chain polypeptide encoded thereby and a variable heavy chain poly peptide encoded by SEQ ID NO: 212. The anti-CGRP antibody may comprise a light chain polypeptide of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. In some embodiments, 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. In some embodiments, the anti-CGRP antibody is an antibody expression product isolated from a recombinant cell expressing a nucleic acid sequence encoding a variable light chain polypeptide of SEQ ID NO: 222 and a variable heavy chain polypeptide of SEQ ID NO: 202, and these polypeptides are optionally linked to human light and heavy constant region polypeptides, such as human IgG1, IgG2, IgG3 or IgG4 constant regions, respectively, and these constant regions may optionally be modified to alter glycosylation or proteolysis, and the recombinant cell optionally comprises yeast or mammalian cells, such as Pichia pastoris or CHO cells. The anti-CGRP antibody may comprise an antibody expression product isolated from a recombinant cell expressing a nucleic acid sequence encoding a light chain of SEQ ID NO: 221 and a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, and the recombinant cell optionally comprises yeast or mammalian cells, such as Pichia pastoris or <e000646>CHO cells, and its constant region may optionally be modified to alter glycosylation or proteolysis or other effector functions. The anti-CGRP antibody described above or ] ​​​​​​​​​or antibody fragment, preferably Ab6, optionally at a pH of, for example, about 5.8. histidine (L-histidine), sorbitol, polysorbate 80, for example , approximately 100 mg of anti-CGRP antibody, approximately 3.1 mg of L-histidine per 1 mL volume, The present invention comprises about 40.5 mg of sorbitol and about 0.15 mg of polysorbate 80. The antibody may be contained in a formulation disclosed in the specification. The dose of the antibody is about 100 mg to about 30 mg. The dose may be 0 mg, for example, about 100 mg, about 300 mg, 100 mg, or 300 mg. The dosage can be administered by different means, for example, intravenously, in an appropriate volume (e.g., 100 mL). It may be administered in saline, such as 0.9% sodium chloride. Potential headaches are those in which criteria (a) and (b) are not fully met, e.g., At least 80% or less of the specified headache days and / or medication days per 90% of all diagnoses and / or optionally no other ICHD-3 diagnosis, Refers to a lack of fulfillment over a shorter period of time, such as at least two months.

[0079] In some embodiments, the medication overuse headache (ergotamine overuse headache, triptan Overuse headache, non-opioid analgesic overuse headache, opioid overuse headache, combination Analgesic overuse headache, a drug overuse caused by multiple drug classes that are not individually overused Medication-related headaches, resulting from unspecified or untested overuse of multiple drug classes Overuse headache, or medication overuse headache caused by other drugs, is an International onal Classification of Headache Disorder Headache can be diagnosed according to the 3rd edition of the ICHD-3. cation Committee of the International He adache Society(IHS),The International Cl assification of Headache Disorder,3rd ed. ition,Cephalalgia.2018 Jan;38(1):1-211(all (The entirety of which is incorporated herein by reference).

[0080] Here, the criterion for headache occurring as a "result" of drug overuse is the relationship between drug overuse and headache. A clear association between, for example, drug overuse and headaches, so that a causal relationship can be inferred , refers to the presence at the specified frequency above.

[0081] The present disclosure also provides a method of treating chronic migraine, comprising administering to a patient in need thereof an amount of about 10 and administering intravenously a first dose comprising 0 mg to about 300 mg of an anti-CGRP antibody. , wherein the anti-CGRP antibody preferably comprises a light chain polypeptide of SEQ ID NO: 221 and a light chain polypeptide of SEQ ID NO: 201 or 566 heavy chain polypeptides, and wherein the patient exhibits at least a 50% reduction in migraine prevalence.

[0082] In another aspect, the present disclosure provides a method of treating chronic migraine, comprising administering to a patient in need thereof a first dose containing about 100 mg to about 300 mg of an anti-CGRP antibody is intravenously administered to the patient. wherein the anti-CGRP antibody preferably comprises a light chain polypeptide of SEQ ID NO: 221 and and a heavy chain polypeptide of SEQ ID NO: 201 or 566, and on day 1 after the day of administration, the patient , which shows at least a 50% reduction in migraine prevalence.

[0083] In some exemplary embodiments, the dose of the anti-CGRP antibody, e.g., the first dose The amount may be 100 mg.

[0084] In another exemplary embodiment, the dose of the anti-CGRP antibody, e.g., the first dose, is: It can be 300 mg.

[0085] In another exemplary embodiment, the method is repeated every 10-14 weeks, preferably every 11-13 weeks. and administering 100 mg of the anti-CGRP antibody intravenously every 12 weeks, more preferably every 12 weeks. It may further include:

[0086] In another exemplary embodiment, the method is repeated every 10-14 weeks, preferably every 11-13 weeks. and administering 300 mg of the anti-CGRP antibody intravenously every 12 weeks, more preferably every 12 weeks. It may further include:

[0087] The antibody has a pH of about 5.8, e.g., histidine (L-histidine), sorbitol ol, polysorbate 80, e.g., about 100 mg of anti-CGRP antibody per 1 mL volume , about 3.1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg The composition may be provided or administered in a formulation disclosed herein that includes polysorbate 80.

[0088] Prior to the first administration, the patient has about 10 to about 22 migraine days per month, for example about 1 to about 1 month. It may present with 3 to about 19 migraine days per month, for example about 16 migraine days per month.

[0089] Prior to the first administration, the patient has about 14 to about 27 headache days per month, for example about 17 headache days per month. The patient may present with up to about 24 headache days, for example about 20 or about 21 headache days per month.

[0090] In some embodiments, the patient has received at least 10 years of treatment prior to said first administration, e.g. at least 15 years prior to said first administration, for example at least 18 years prior to said first administration or have been diagnosed with migraines for at least 19 years.

[0091] In some embodiments, the patient has been receiving steroid therapy for at least 5 years prior to said first administration, e.g., at least 8 years prior to said first administration, e.g., at least 11 or Have been diagnosed with chronic migraines for at least 12 years.

[0092] In some embodiments, the patient may have a headache when the first dose is administered. do.

[0093] In some embodiments, the patient experiences a migraine headache, e.g., migraine headache, when the first dose is administered. They may have migraines with aura.

[0094] In some embodiments, the patient is administered a migraine headache treatment for the number of migraine days the patient experiences prior to said first administration. at least one month after the first dose is administered compared to baseline Both can have a 50% reduction in migraine days.

[0095] In some embodiments, the patient is administered a migraine headache treatment for the number of migraine days the patient experiences prior to said first administration. at least one month after the first dose is administered compared to baseline Both can have a 75% reduction in migraine days.

[0096] In some embodiments, the patient is administered a migraine headache treatment for the number of migraine days the patient experiences prior to said first administration. 100% reduction in serotonin levels during the 1-month period after the first dose is administered compared to baseline. % reduction in migraine days.

[0097] In some embodiments, the patient is administered a migraine headache treatment for the number of migraine days the patient experiences prior to said first administration. fewer than 12 weeks after the first dose is administered compared to baseline There may be a reduction in the number of migraine days of at least 50%.

[0098] In some embodiments, the patient is administered a migraine headache treatment for the number of migraine days the patient experiences prior to said first administration. fewer than 12 weeks after the first dose is administered compared to baseline There may be at least a 75% reduction in the number of migraine days.

[0099] In some embodiments, the patient is administered a migraine headache treatment for the number of migraine days the patient experiences prior to said first administration. a 10-week period after the first dose is administered compared to a baseline of 10 0% reduction in migraine days.

[0100] In some embodiments, the method includes, for example, administering the second dose of the anti-CGRP antibody: Approximately 10 to 14 weeks, preferably 11 to 13 weeks, more preferably about 10 to 14 weeks, after the first administration. The method can further comprise administering the compound intravenously to said patient within about 12 weeks or about 3 weeks.

[0101] In some embodiments, the first dose is about 100 mg, about 125 mg, about 15 mg, or about 20 mg. 0mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, or may contain about 300 mg of the anti-CGRP antibody.

[0102] In some embodiments, the patient is at risk for developing medication-overuse headache due to chronic unitemporal headache. The patient may have at least 1, 2, 3, 4, or 5 headaches per month. The patient may use acute headache medication for at least 5, 6, 7, 8, 9, or 10 days per month. Optionally, the acute medication use may be for at least 2 days. The acute drug use will be determined over an 8-day baseline period. The acute drugs may be reported by the doctor or on record. acetaminophen, aspirin, NSAIDs, non-opioid analgesics This may include the use of antihistamine analgesics, combination analgesics, or opioids.

[0103] In some embodiments, prior to said administration, the patient experiences about 15 to about 30 migraine days per month. Number of migraine days per month, e.g., about 16 to about 28 days per month, e.g., about 17 to about 26 days per month The number of pain days may be indicated, for example, about 16 migraine days per month.

[0104] In some embodiments, prior to said administration, the patient has between about 15 and about 27 headache days per month, For example, about 17 to about 24 headache days per month, for example, about 20 or about 21 headache days per month. The number of days may be indicated.

[0105] In some embodiments, the patient has had a history of at least 10 years prior to the administration, e.g., at least 15 years prior to administration, for example at least 18 years or at least 19 years prior to said administration Migraines may have been diagnosed years ago.

[0106] In some embodiments, the patient has been taking anticoagulants for at least 5 years prior to the administration, e.g., at least 8 years prior to said administration, e.g., at least 11 years or at least 12 years prior to said administration. may have been diagnosed with chronic migraine.

[0107] In some embodiments, the patient is assessed for the number of migraine days experienced by the patient prior to the administration. a reduction in the number of migraine days in the first month after administration of the antibody compared to a baseline number of days Both may have a 50% reduction.

[0108] In some embodiments, the patient is assessed for the number of migraine days experienced by the patient prior to the administration. a reduction in the number of migraine days in the first month after administration of the antibody compared to a baseline number of days Both may have a 75% reduction.

[0109] In some embodiments, the patient is assessed for the number of migraine days experienced by the patient prior to the administration. 100% reduction in the number of migraine days in the month after administration of the antibody compared to a baseline number of % reduction.

[0110] In some embodiments, the patient is assessed for the number of migraine days experienced by the patient prior to the administration. a reduction in the number of migraine days during the 12 weeks after administration of the first dose compared to a baseline number of There may be at least a 50% reduction.

[0111] In some embodiments, the patient is assessed for the number of migraine days experienced by the patient prior to the administration. A reduction in the number of migraine days over the 12 weeks after administration of the antibody compared to a baseline number of days Both may have a 75% reduction.

[0112] In some embodiments, the patient is assessed for the number of migraine days experienced by the patient prior to the administration. 100% reduction in migraine days over the 12 weeks after administration of the antibody compared to a baseline number of % reduction.

[0113] In some embodiments, the method further comprises administering, preferably within about 10 to 14 weeks, Preferably, the antibody is administered within about 11 to 13 weeks, more preferably within about 12 weeks or about 3 months. This may include administering a second dose of a CGRP antibody to the patient, for example, intravenously.

[0114] In some embodiments, the administration is about 100 mg, about 125 mg, about 150 mg, About 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 30 0 mg of the anti-CGRP antibody.

[0115] In some embodiments, the anti-CGRP antibody may be aglycosylated; may contain only mannose residues only if glycosylated.

[0116] In some embodiments, the anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221. and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The P antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231 and a light chain polypeptide encoded by SEQ ID NO: 211 or may consist of a heavy chain polypeptide encoded by SEQ ID NO:567.

[0117] 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 and / or a variable light chain encoded by SEQ ID NO: 232. or comprising a variable heavy chain encoded by SEQ ID NO:212.

[0118] 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.

[0119] In some embodiments, the anti-CGRP antibody comprises the V of SEQ ID NO: 222. L Polypeptides and V of SEQ ID NO: 202 H From recombinant cells expressing nucleic acid sequences encoding the polypeptides. These polypeptides may optionally be human immunoglobulins. and a heavy constant region polypeptide, such as human IgG1, IgG2, IgG3, or IgG4 Each is linked to a constant region, which may optionally be glycosylated or protein-modified. The recombinant cell may optionally be a yeast or is a mammalian cell, e.g., Pichia pastoris or Includes CHO cells.

[0120] In some embodiments, the anti-CGRP antibody has a light chain of SEQ ID NO: 221 and a light chain of SEQ ID NO: 201 or SEQ ID NO: 566. The recombinant cells may include an antibody expression product isolated from a yeast or mammalian cell. Animal cells, such as Pichia pastoris or CHO The cells optionally contain constant regions that are resistant to glycosylation or proteolysis or other effects. The vector can be optionally modified to alter its function.

[0121] In some embodiments, any of the aforementioned anti-CGRP antibodies or antibody fragments is administered intracellularly, e.g., Histidine (L-histidine), sorbitol, polysorbate, with a pH of approximately 5.8 80, for example, about 100 mg of anti-CGRP antibody and about 3.1 mg of L-his stigma, about 40.5 mg sorbitol, and about 0.15 mg polysorbate 80 The antibody or fragment may be administered by different means. For example, an appropriate volume (for example, 100 mL) of 0.9% sodium chloride may be administered intravenously. It may be administered in saline, such as thorium.

[0122] 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.

[0123] In another embodiment, about 100 mg of the anti-CGRP antibody or antibody fragment is administered.

[0124] In another embodiment, about 300 mg of the anti-CGRP antibody or antibody fragment is administered intravenously, e.g., intravenously. It is administered intravenously.

[0125] In an exemplary embodiment, the anti-human CGRP antibody or antibody fragment is administered for at most 10 to 14 weeks. every 11 to 13 weeks, more preferably every 3 months or every 12 weeks, for example For example, the antibody may be 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. The antibody dose may be administered in a single formulation or every 12 weeks. The expression "is divided into different formulations" may refer 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, For example, the recited amounts of the anti- The term "different formulations" in this context refers to the administration of each dose to the body. Whether the dosage is the same or different in terms of the chemical composition of the pharmaceutical preparation, refers to antibody doses administered between and / or at different sites and / or by different routes; e.g., Concentrations, excipients, carriers, pH, etc. may be the same or different between different dosages. stomach.

[0126] 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 are administered approximately every 8 weeks or every 2 months. It is given.

[0127] 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 It is administered every 11 to 13 weeks, more preferably every 12 weeks or every 3 months.

[0128] 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. It is administered.

[0129] 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. It is administered.

[0130] 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. It is administered.

[0131] 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. It is administered.

[0132] 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. It is administered.

[0133] 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. It is administered.

[0134] 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. It is administered.

[0135] 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. It is administered.

[0136] 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 .

[0137] 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 .

[0138] 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 .

[0139] 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 are administered approximately every 15 to 18 months. will be done.

[0140] 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 are administered approximately every 18 to 21 months. will be done.

[0141] In another exemplary embodiment, the anti-human CGRP antibody dose or anti-human CGRP antibody dose used in the aforementioned methods The body fragments may be administered in a single formulation or divided into different formulations, which may be administered approximately every two years. It is administered frequently.

[0142] In another exemplary embodiment, the anti-human CGRP antibody used in the foregoing method is administered systemically. will be done.

[0143] 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-described method is administered by the following mode of administration: The CGRP antibody or antibody fragment is administered intravenously.

[0144] In another exemplary embodiment, the anti-human CGRP antibody used in the foregoing method comprises at least also has an in vivo half-life of 10 days.

[0145] In another exemplary embodiment, the anti-human CGRP antibody has an in vivo half-life of at least 15 days. It has a period.

[0146] In another exemplary embodiment, the anti-human CGRP antibody used in the foregoing method comprises at least also has an in vivo half-life of 20 days.

[0147] In another exemplary embodiment, the anti-human CGRP antibody used in the foregoing method comprises at least It also has an in vivo half-life of 20 to 30 days.

[0148] 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.

[0149] In another exemplary embodiment, the anti-human CGRP antibody used in the foregoing method is human α- and binds to β-CGRP.

[0150] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than the antibody dose. Inhibition of vasodilation induced by topically applied capsaicin after at least 30 days bring about.

[0151] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than the antibody dose. Inhibition of vasodilation induced by topically applied capsaicin after at least 60 days bring about.

[0152] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than the antibody dose. Inhibition of vasodilation induced by topically applied capsaicin after at least 90 days bring about.

[0153] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than the antibody dose. Inhibition of vasodilation induced by topically applied capsaicin after at least 120 days. results.

[0154] In another exemplary embodiment, the administered anti-human CGRP antibody dose is less than the antibody dose. Inhibition of vasodilation induced by topically applied capsaicin after at least 150 days. results.

[0155] In another exemplary embodiment, the administered anti-CGRP antibody dose is at least 100 mg / kg of the antibody dose. The inhibition of vasodilation induced by topically applied capsaicin was also observed after 180 days. Drop.

[0156] 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.

[0157] 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.

[0158] In another exemplary embodiment, the administered anti-human CGRP antibody dose is It provides sustained pharmacodynamic (PK) activity that is maintained for at least 2-3 months, where anti-human C PK analysis of GRP antibodies is derived from plasma concentrations.

[0159] In another exemplary embodiment, the administered anti-human CGRP antibody dose is about 100 mg to Approximately 300 mg or more, which is administered no more frequently than every two months.

[0160] The present invention further provides 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 compound capable of binding to CGRP and / or Biological activities mediated by the 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 may be used in combination with recombinant proteins, optionally in combination with recombinant constructs engineered to express them. recombinant cells, optionally yeast or mammalian cells, and further optionally Pichia pastoris (Pi chia pastoris) and CHO cells.

[0161] In another preferred embodiment of the present invention, the CGRP-α-, CGRP-β-, and The present invention contemplates full-length antibodies and Fab fragments thereof that inhibit rat CGRP-driven production. In a further preferred embodiment, the compound of formula (I) reduces vasodilation in a recipient after administration. Full length and Fab fragments thereof are contemplated.

[0162] 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 chimeric or P antibody and binding fragment conjugates thereof. The use of humanized anti-CGRP or anti-CGRP / CGRP-R complex antibodies and their binding fragments is intended. In one embodiment, the binding fragments include Fab, Fab', F(ab'), Fv, s cFv fragments, SMIPs (small molecule immunopharmaceuticals), camelbodies, nano These include, but are not limited to, human IgNARs, human IgB-like cells, and human IgNARs. [Brief explanation of the drawings]

[0163] [Figure 1-1] 1A-1F provide the polypeptide sequences of the full-length heavy chains of antibodies Ab1-Ab14, clearly showing their 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, clearly showing their framework regions (FR), complementarity determining regions (CDR), and constant region sequences. [Figure 2-2] Same as above. [Figure 3-1] 3A-3P provide the polynucleotide sequences of the full-length heavy chains of antibodies Ab1-Ab14, clearly showing their framework regions (FR), complementarity determining regions (CDR), and constant region coding sequences. [Figure 3-2] Same as above. [Figure 3-3] Same as above. [Figure 3-4] Same as above. [Figure 3-5] Same as above. [Figure 3-6] Same as above. [Figure 3-7] Same as above. [Figure 3-8] Same as above. [Figure 4-1]4A-4I provide the polynucleotide sequences of the full-length light chains of antibodies Ab1-Ab14, clearly showing their 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. [Figure 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 of each of the individual features. [Figure 6] The polypeptide sequence coordinates within the full-length heavy chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features, including framework regions (FR) and constant regions, are provided, as well as the SEQ ID NO of each of the individual features. [Figure 7] Provided are polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibodies Ab1-Ab14 of sequence features, including variable regions and complementarity determining regions (CDRs), as well as the SEQ ID NO of each of the individual features. [Figure 8] 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, are provided, 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 the variable regions and complementarity determining regions (CDRs), are provided, as well as the SEQ ID NOs 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 individual feature, 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 the variable regions and complementarity determining regions (CDRs), are provided, as well as the SEQ ID NOs 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 for each of the individual features, are provided. [Figure 13] Figure 1 shows the number of subjects in the human clinical trial described in Example 2 treated with either Ab6 (treatment group) or placebo who experienced a 50%, 75%, or 100% reduction in migraine headaches at each monitoring point throughout the period. The graph on the right of each group corresponds to patients who received 1000 mg of Ab6, and the graph on the left of each group corresponds to the corresponding placebo control. Within each response rate group, patients who received Ab6 had a significantly greater response rate than placebo-treated controls, with p-values ​​of 0.0155, 0.0034, and 0.0006 in the respective groups, 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] 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 represent 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 represent 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 the number of migraine hours per month in the placebo and Ab6-treated groups over 12 weeks of treatment. The upper (red) and lower (blue) lines represent 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] The figures show 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" impact from migraines. At each subsequent time point, a significantly greater proportion of patients receiving 1000 mg Ab6 had only "somewhat" or "little / nothing" HIT-6 impact (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 for Ab6 (1000 mg iv) versus placebo as a single dose for the study described in Example 2. [Figure 23]Hourly mean number of migraine days (+ / -SD) is shown for the entire analysis population for the study described in Example 2. Normalization was applied to the visit interval, and 21- to 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. [Figure 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. [Figure 30] Figure 1 shows the 50% responder rates for the 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- to 27-day e-diaries were completed by multiplying the observed frequency by the inverse of the completion rate. [Figure 31] Figure 3 shows the 75% responder rates for the 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. [Figure 32]Figure 3 shows the 100% responder rates for the Ab6 and placebo treatment groups for the study described in Example 2. Subjects who experience a 100% reduction in migraine frequency are considered 100% responders. Normalization was applied as described in Figure 30. [Figure 33] Figure 1 shows the time-averaged migraine severity for the entire analysis population for the study described in Example 2. On the scale used, a mean migraine score of 3 represents a "moderate headache." [Figure 34] 1 summarizes the changes from baseline in measured attributes for the placebo and treatment groups in the study described in Example 2. [Figure 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. [Figure 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 represent results for the 100 mg, 300 mg, and placebo groups from left to right. 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. [Figure 40] Difference from placebo in change from baseline in mean number of migraine days (MMD) over months 1-3 by baseline subgroup in a human clinical trial of patients with chronic migraine. In the graph, data points represent the mean value, and lines indicate the 95% confidence interval (CI) of the change from placebo for the 100 mg (upper line) or 300 mg (lower line) treatment group for each subgroup indicated on the far left. [Figure 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. [Figure 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). [Figure 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). [Figure 44]Change from baseline in acute medication use by subgroups of patients with chronic migraine who had 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 but <10 days of acute medication use per month at baseline. Triangles: placebo. Circles: 100 mg Ab6 / dose. Squares: 300 mg Ab6 / dose. [Figure 45] Overview of acute medication days by subgroup in chronic migraineurs with baseline acute medication use. [Figure 46] Change from baseline in mean number of migraine days (MMD) over 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 but <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. [Figure 50] Migraine data includes Day -1. Day 0 is defined as the day of infusion. Therefore, data for Day 0 represent the treatment effect after infusion. DETAILED DESCRIPTION OF THE INVENTION

[0164] Detailed Description Described herein is the use of anti-CGRP antibodies for the treatment of headache. P antibodies are demonstrated herein to be effective for the treatment of chronic migraine. Treatment has a very rapid onset of efficacy, with migraine relief observed as early as day 1 after administration. It has been shown that

[0165] 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 this document is for the purpose of describing particular embodiments only and is 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" , includes plural referents unless the context clearly indicates otherwise. 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 skilled in the art. All technical and scientific terms used herein are those of the present invention unless expressly stated otherwise. It has the same meaning as commonly understood by a person skilled in the art to which the invention belongs.

[0166] As used herein, the term "medication overuse headache" refers to a headache disorder as defined by ICHD-3 (Headache Disorders and Neuropsychiatric Disorders). che Classification Committee of the Inte rnational Headache Society(IHS), The Inte National Classification of Headache Dis order,3rd edition,Cephalalgia.2018 Jan;3 8(1):1-211). as defined by ICHD-3, e.g., triptan overuse headache, non-opioid headache Subtypes of medication overuse headache, such as analgesic overuse headache and opioid overuse headache, include.

[0167] As used herein, the term "reduced migraine prevalence" refers to a reduction in the incidence of migraines after the first administration of an antibody. For a fixed period of time, such as 18 hours, 20 hours, 24 hours, 28 hours, or 30 hours, preferably or in a 24-hour period or on the first day after antibody administration (i.e., after antibody administration is completed). the first full day after the first dose), a reduction in the patient's likelihood of having a migraine (e.g., 50% or more), The reduction in probability refers to the outcome for an individual patient. Regardless, if it can be observed in a large number of patients, a given patient may experience eccentricity during that period. It should be understood that the patient may or may not have pain.

[0168] As used herein, the term "chronic migraine" refers to a condition in which the patient experiences, on average, at least one migraine headache per month. The term "episodic migraine" refers to a condition in which a person experiences at least 15 migraine and / or headache days. refers to a condition in which patients experience, on average, fewer than 15 headache and / or migraine days per month.

[0169] As used herein, the term "diagnosed with chronic migraine" refers to a condition that has not been formally diagnosed with chronic migraine. This refers to a patient meeting the criteria for chronic migraine, regardless of whether or not a diagnosis is made.

[0170] As used herein, the term "intravenously administered" 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 human circulation, most typically into the venous circulation. The substance 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 within 6 hours, most preferably within 1-2 hours), in a single formulation or in multiple formulations. Good too.

[0171] As used herein, the term "baseline number of migraine days" refers to the number of migraine days over a specified period of time. This refers to the number of migraine days reported by the patient, e.g., before treatment. The number of headaches can be calculated by recording whether or not a migraine occurred on each day, for example, over a period of one month. can be determined.

[0172] As used herein, the term "immediate relief" refers to the relief of headache or migraine in a patient. Symptoms, such as headaches or migraine associated with acute migraines or chronic / episodic migraines Relief of another headache or migraine condition associated with frequent headache or migraine episodes It is intended to mean that the alleviation of symptoms occurs rapidly or immediately after anti-CGRP antibody treatment. For example, relief of one or more symptoms may occur within a short period of time after infusion of Ab6, e.g., several Within minutes or hours, e.g., 10 minutes, 20 minutes, 30 minutes, 60 minutes, 1 hour, 2 hours, or 6 hours , experienced by the patient within, say, a day at most.

[0173] As used herein, the term "immediate preventative treatment" refers to the treatment of headache or unilateral headache in a patient. Prevention of pain symptoms, e.g., acute migraine or chronic / episodic migraine or other headache or migraine It is intended to mean the prevention of headache or migraine symptoms associated with a headache condition. In this context, "immediate preventative treatment" reduces the likelihood of a subject developing a headache or migraine. It refers to the prophylactic treatment of subjects at risk of developing migraines or headaches. Because of the patient's history of headache or migraine episodes, a new headache or migraine episode in the patient There is a high risk of developing encephalopathy. Typically, symptom prevention occurs rapidly after anti-CGRP antibody treatment. or immediately experienced, e.g., prevention of one or more symptoms within a short period of time after infusion of Ab6; For example, within a few minutes or hours, for example, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 1 hour, 2 hours or is experienced by the patient within 6 hours, or at most, say, one day.

[0174] As used herein, the term "four-point scale" or "four-point pain scale" or "VRS" or "VRS-4" is a 4-point verbal rating scale used to measure pain. Refers to the International Cl (VRS) (VRS-4) assification of Headache Disorders,3rd e dition”,Cephalalgia,2018,Vol.38(1)1-211, See pg. 210 ("Intensity of pain"). Patients are asked to verbally rate their pain on a 4-point scale (0-3), with 3 being 0 is no pain, 1 is severe, 2 is moderate, 1 is mild, and 0 is no pain. The functional outcome can be scored on a verbal rating scale: 0, no pain; 1, 1. Mild pain, not interfering with daily activities; 2. Moderate pain, not completely interfering with daily activities 3, severe pain, interfering with all activities;

[0175] As used herein, the term "monthly headache days" refers to the number of days 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 migraine days per month refers to the number of days on which a migraine occurred. can be determined by

[0176] As used herein, the term "headache days per month" refers to the number of days a patient has headaches, i.e. That is, the number of days per month on which the patient has symptoms that meet the clinical definition of headache at any time on that day. The number of headache days per month was determined by recording whether or not a headache occurred on each day. It can be done.

[0177] Calcitonin gene-related peptide (CGRP): as used herein, CGRP is a subsidiary of American Peptides (Sunnyvale, CA) and Bache The following Homo sapiens (H. sapiens) strains are available from Pharmacia (Torrance, CA): iens) CGRP-α and Homo sapiens CGRP-β It not only encompasses 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), where 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, homologs and mutations The same goes for the body.

[0178] Expression vectors: These DNA vectors are used to express the expression vectors in target host cells, such as yeast or mammalian cells. 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 selectable marker. A selectable marker will contain sequences to facilitate such manipulation, including It encodes a protein necessary for the survival or growth of transformed host cells grown in a 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) complement an auxotrophic deficiency, or (c) 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 ry Press.

[0179] 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 mother or mammalian specific sequence. It can be used to amplify the copy number of a vector.

[0180] The coding sequence for the polypeptide of interest is expressed in a host cell, e.g., Pichia pastoris (Pichia pastoris). Transcription and transcription processes providing expression of polypeptides in ia pastoris or 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. Because vectors often integrate into the host cell genome, yeast or mammalian origins of replication are In one embodiment of the present invention, the polypeptide of interest is isolated from yeast diploid cells. The polypeptide is operably linked or fused to a sequence that provides for optimized secretion of the polypeptide.

[0181] A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence, e.g. The signal sequence DNA is expressed as a preprotein involved in the secretion of the polypeptide. When a promoter or enhancer is used, it 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 enhancer is in reading frame with the adjacent The fragment 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. PCR / recombination methods (Gateway® Technology; Inv This is achieved through the use of a steroid drug (Protein, Carlsbad, California). If such sites do not exist, synthetic oligonucleotide adaptors or linkers may be used. It is used in accordance with the practice of

[0182] 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 the structural gene (generally about 100-100 These promoters are classified into several classes. Inducible, constitutive, and repressible promoters (transcriptional in response to the absence of a repressor) Inducible promoters increase the expression level of a gene by some change in culture conditions, e.g., nutrient DNA fragments are produced under the control of the presence or absence of nutrients or temperature changes. It can initiate increased levels of transcription.

[0183] 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 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 AOX and FLD1 promoters. The motor is inductive.

[0184] Other yeast promoters include ADH1, alcohol dehydrogenase II, and GAL 4, PHO3, PHO5, Pyk, and chimeric promoters derived from these. In addition, non-yeast promoters, such as those from mammals, insects, plants, reptiles, amphibians, viruses, 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:

[0185] Examples of mammalian promoters include, among others, promoters from cytomegalovirus (CMV). Motor, chicken 3-actin (CBM)-derived promoter, adenomatous polyposis coli A 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 rsu (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 promoters described above. A combination of two or more of these 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 undesired. Inducible promoters provide a molecular switch that can turn off expression when the promoter is not present. Examples include the metallothionine promoter, the glucocorticoid promoter, and the progestin promoter. These include, but are not limited to, the tetracycline promoter and the tetracycline promoter. do not have.

[0186] 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 budding yeast (S. cerevisiae) α-factor promoter is ReproSignal is a signaling molecule that encodes 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 essential for diploid yeast expression. The system can be engineered to provide enhanced secretion in mammalian and yeast cells. The secretion signal used may be heterologous to the protein to be secreted, or Included are mammalian signal sequences, which may be the native sequence of the protein to be secreted. The sequence includes a pre-peptide sequence and, in some instances, may also 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 those for the human Ig light chain, human Ig light chain, etc. For example, Hashimoto et al. Protein Eng 11(2)75 (1998); and Kobayashi et.al. Therapeutic Aph See Eresis 2(4)257(1998).

[0187] 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 long. Transcriptional enhancers are proteins 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. Enhancers are located 5' and 3' to the coding sequence. It can be spliced ​​into the expression vector at a site 5' from the promoter, but preferably Located in.

[0188] Expression vectors used in eukaryotic host cells contain the necessary amino acids for the termination of transcription and stabilization of mRNA. Such sequences may be derived from eukaryotic or viral DNA or cDNA. These are generally available in the untranslated region 3' of the translation termination codon. The region is a set of nucleotides that are transcribed as polyadenylated fragments in the untranslated portion of the mRNA. Contains fragments.

[0189] Construction of suitable vectors 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 then can be digested, tailored, and religated in the form desired to produce the required plasmid, or or produced via recombinant methods. Confirm the correct sequence in the constructed plasmid. The ligation mixture is used to transform host cells and the appropriate In some cases, successful transformation is indicated by antibiotic resistance (e.g., ampicillin or zeocin). Select the transformants. Prepare the plasmids from the transformants and digest them with restriction endonucleases. Further analysis and / or sequencing.

[0190] Att site and recombinase-based recombination as an alternative to fragment restriction and ligation Methods can be used to insert a DNA sequence into a vector. For example, see 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.

[0191] Att sites allow for ligation of the sequence of interest into an appropriate vector; use of specific primers Generate a PCR product containing an attB site by: The sequence of interest can be identified by, for example, generating a cDNA library cloned into can be introduced into

[0192] 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.

[0193] 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. Preferably, the expression level is sufficient for the desired expression pattern. Sequences containing transcriptional regulatory elements are stably integrated into the yeast genome by targeted methodologies. can be.

[0194] For example, eukaryotic PDIs mediate 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 sulfide bonds. Expression of cyclophilins, cyclophilins, and the like is also of interest. In this state, each of the monoploid parent strains expresses a different folding enzyme, e.g., one strain expresses BIP. Other strains may express PDI or a combination thereof.

[0195] The terms "protein of interest" or "antibody of interest" are used interchangeably and generally refer to a target Specific parent antibodies, i.e., CGRP or chimeric or humanized antibodies as described herein. The term "antibody" refers to a molecule 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 where one or more non-covalent interactions stabilize the complex between the molecular structure and the epitope. The prototypic antibody molecule is an immunoglobulin, which can be found in all sources, e.g., human, rodent, and mouse. All species 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." A preferred source for producing antibodies useful as starting materials according to the present invention is The source is rabbit. Numerous antibody coding sequences have been described; others are available in the art. They 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 (single-chain antibody derived from shark), small modular immunopharmaceutical (SMIP), and Fa This includes antibody fragments such as bs, Fab', and F(ab')2. Streltsov VA ,et al.,Structure of a shark IgNAR antib ody variable domain and modeling of an e early-developmental isotype,Protein Sci.2 005 Nov;14(11):2901-9.Epub 2005 Sep 30;G reenberg AS, et al., A new antigen receptor r gene family that undergoes rearrangeme nt and extensive somatic diversification in sharks,Nature.1995 Mar 9;374(6518):1 68-73;Nuttall SD,et al.,Isolation of the new antigen receptor from wobbegong sha rks,and use as a scaffold for the displa y of protein loop libraries, Mol Immunol. 2001 Aug;38(4):313-26;Hamers-Casterman C ,et al.,Naturally occurring antibodies d evoid of light chains,Nature.1993 Jun 3; 363(6428):446-8;Gill DS,et al.,Biopharma ceutical drug discovery using novel prot ein scaffolds,Curr Opin Biotechnol.2006 Dec;17(6):653-8. Epub 2006 Oct 19.

[0196] 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. PCR amplification was performed using messenger RNA isolated from somatic cells as a template. 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 used to identify the appropriate vector for 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 vector carrying these genes is then introduced into the host. Co-transfect the cells. Antibody gene synthesis occurs in the transfected host. When induced, the heavy and light chain proteins self-assemble and react with antigens or immunogens. The resulting antibody produces active antibodies that can be detected by screening.

[0197] 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 those 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. to alter the function of the cysteine ​​residues, or by substitution or deletion of one or more cysteine ​​residues not required for function. The amino acid substitutions may be conservative amino acid substitutions to minimize misfolding due to the mutation. The enhanced activity of specific regions of proteins (e.g., functional domains, catalytic amino acid residues, etc.) Variants 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.

[0198] 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 methods that produce antibodies with predominantly human domains. To generate such antibodies, rodent or rabbit variable regions and human constant regions are utilized. The 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 entire contents of which are incorporated herein by reference. Furthermore, the human constant regions of the chimeric antibodies of the present invention may be It is contemplated that the constant regions may be selected from IgG1, IgG2, IgG3, and IgG4 constant regions. do.

[0199] Humanized antibodies are antibodies engineered to contain more human-like immunoglobulin domains and are more readily available than animal antibodies. Only the complementarity determining regions of the derived antibody are incorporated. This is because the This is 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. .

[0200] Contains whole immunoglobulins (or their recombinant counterparts) plus epitope binding sites Immunoglobulin fragments (e.g., Fab', F(ab')2, or other fragments) can be synthesized. "Fragments," or minimal immunoglobulins, are those engineered 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.

[0201] Immunoglobulins and fragments thereof can be linked to effector moieties such as, for example, chemical linkers, fluorescent Detectable moieties such as dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties It may be post-translationally modified to add a molecule, or may be streptavidin, avidin, or Specific binding moieties, such as ribonucleotides or biotin, may be used in the methods and compositions of the invention. Examples of effector molecules are provided below.

[0202] A polynucleotide sequence is a sequence of a polypeptide that is generated by translation of the polynucleotide sequence according to the genetic code. A polynucleotide sequence "corresponds" to a polypeptide sequence (i.e., a polynucleotide sequence is , "encodes" a polypeptide sequence), and two sequences encode the same polypeptide sequence. One polynucleotide sequence "corresponds to" another polynucleotide sequence if:

[0203] A "heterologous" region or domain of a DNA construct is one found in association with a larger, naturally occurring molecule. It is an identifiable segment of DNA within a larger DNA molecule that is not distinct from the rest of the DNA. 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 mammalian genomic DNA. Another example of a heterologous region is a The coding sequence itself is a construct not found in nature (e.g., a genomic coding sequence is introduced cDNA containing codons, or synthetic sequences with codons different from the native gene). or naturally occurring mutational events that give rise to a heterologous region of DNA as defined herein. No.

[0204] "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. If they encode amino acid sequences, they correspond to each other. Coding sequences associated with appropriate regulatory sequences can be transcribed and translated into a polypeptide. Polyadenylation signal and transcription termination sequence A "promoter sequence" is a sequence that is used to initiate transcription in a cell. Able to bind RNA polymerase and initiate transcription of downstream (3' direction) coding sequences 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 within the cell and transcribes the coding sequence into mRNA is "under the control of" or "operably linked to" a promoter sequence if The mRNA is then translated into the protein encoded by the coding sequence.

[0205] A vector is a vector that transfers 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., which contain separate polynucleotide segments can be joined together to bring about the replication of the joined 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 starts transcription of mRNA. and ribosome binding sites and initiation signals direct translation of mRNA into polypeptides. This means inserting the gene into an expression vector at the appropriate site and in the correct reading frame. Incorporation of the polynucleotide sequence followed by 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.

[0206] "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 described in a review article by PCR is a prototype of nucleic acid amplification, and its use herein is exemplary of other suitable amplification techniques. should be considered as an indication.

[0207] 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 a molecular weight of 53,000-70,000. The four chains are: The light chains are linked by disulfide bonds in a "Y" configuration. The "branch" part of the "Y" configuration wraps around the heavy chain, starting from the mouth. 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 conformation to the C-terminus at the bottom of the conformation. The variable region has specificity for a given antigen, is about 100 amino acids in length, and is identical to the light chain. There is slight variation between heavy chains and from antibody to antibody.

[0208] The variable region is linked in each chain to a constant region that extends the remainder of the chain and gives the antibody its characteristic The specificity of the antibody (ie, the antigen that elicits it) does not vary. 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 constants IgG, IgM, IgA, IgD, and IgE) corresponding to the constant region. 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 targeting of the antibody; Light chains are classified as either κ (kappa) or λ (lambda). The antibody can be prepared with either kappa or lambda light chains. The immunoglobulins are covalently linked to each other and are produced by either hybridomas or B cells. When the heavy chains are coupled together, the "tail" portions of the two heavy chains are bound to each other by covalent disulfide bonds. do.

[0209] 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 ) and This is followed by a number of constant domains. Each light chain has a variable domain (V L ) and other 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.

[0210] The terms "complementarity determining region," "hypervariable region," or "CDR" refer 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. ("Sequences of Pro teins of Immunological Interest,” Kabat E., et al., US Dept. of Health and Human Se hypervariable region, or the three-dimensional structure of an antibody, as defined by (Vices, 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. CDRs from the other chain are held in close proximity by the CDRs 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 described as selectivity determining regions (SDRs) (Kashmiri iri, S., Methods, 36:25-34 (2005)). When a particular antibody amino acid or nucleic acid residue is referred to by 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.

[0211] 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., Sequ 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 within the variable region.

[0212] "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 it. The solid components are separated by centrifugation or other means to obtain serum (blood cells and clotting factors). and then analyzed by ELISA or other methods known in the art. The concentration of the analyte in the serum is detected by other means known in the art.

[0213] "AUC" is mg / mL x hr (or equivalently mg x hr / mL) unless otherwise specified. AUC refers to the area under the concentration-time curve, expressed in units of 0-t " is the time from time=0 to the AUC refers to the area under the concentration-time curve up to the point where a quantifiable concentration is reached. 0-inf " is the time = Area under the concentration-time curve extrapolated from 0 to infinity.

[0214] "I max " compared with responses elicited by lower anti-CGRP antibody doses. CGRP antibody dosage, preferably 350 mg or more, more typically at least 750 or This refers to the maximum pharmacodynamic response elicited by a dose of 1000 mg, e.g. The response can be detected by inhibition of vasodilation following topical application of capsaicin.

[0215] Anti-CGRP antibodies and their binding fragments with binding specificity to CGRP The present invention provides specific anti-CGRP antibodies and anti- 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, antibodies comprising or consisting of L, CH polypeptide sequences. The polypeptides included in b6 are further described below.

[0216] Antibody Ab6 In a preferred exemplary embodiment, the present invention provides a method for the treatment of CGRP-associated leukemias, comprising administering to said leukemia patients: and humanized antibodies having a variable light chain sequence comprising the sequence set forth below: [ka]

[0217] The present invention also provides a light chain having binding specificity for CGRP and comprising the sequence set forth below. The humanized antibody has the sequence: [ka]

[0218] The present invention also provides a variant polypeptide having binding specificity for CGRP and comprising the sequence set forth below. and a humanized antibody having the heavy chain sequence: [ka]

[0219] The present invention also provides a heavy chain having binding specificity for CGRP and comprising the sequence set forth below. The humanized antibody has the sequence: [ka]

[0220] Alternatively, the heavy chain of Ab6 may lack the C-terminal lysine of SEQ ID NO: 201, i.e., the heavy chain The sequences include those set forth below: [ka]

[0221] The present invention further provides 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 region (CDR, or hypervariable region); 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) It includes or consists of a combination of (including

[0222] 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 containing the polypeptide sequence of SEQ ID NO: 202 or SEQ ID NO: 201 or SEQ ID NO: 566 It consists of:

[0223] In a further embodiment of the invention, the fragment of the antibody that has binding specificity for CGRP is 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.

[0224] In a further embodiment of the invention, the fragment of the antibody that has binding specificity for CGRP is 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, corresponding 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.

[0225] The present invention also contemplates antibody fragments comprising one or more of the antibody fragments described herein. In one embodiment of the present invention, the fragment of the antibody having binding specificity for CGRP is SEQ ID NO: 22. 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: No. 208).

[0226] In particularly preferred embodiments of the invention, the humanized anti-CGRP antibody has the sequence SEQ ID NO: 221 and SEQ ID NO: 222. SEQ ID NO: 201 or SEQ ID NO: 566, The Ab6 has at least one of the following therapeutic activities:

[0227] In a further particularly preferred embodiment of the invention, the antibody fragment has binding specificity for CGRP. In relation to antibody Ab6, it comprises or consists of a Fab (fragment antigen-binding) fragment having The Fab fragment contains 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 present invention further provides a method for the production of CGRP-specific CGRP-binding proteins comprising: Additions, deletions, and variants of SEQ ID NO: 222 and / or SEQ ID NO: 202 in Fab are intended. Figure.

[0228] 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 also include antibody expression products isolated from recombinant cells expressing them. optionally human light and heavy constant region polypeptides, e.g., human IgG1, IgG2 , IgG3 or IgG4 constant regions, respectively, which may optionally be linked to IgG4, IgG5, or IgG6 constant regions. The recombinant cell may be modified to alter glycosylation or proteolysis, Optionally, yeast or mammalian cells, such as Pichia pastoris pastoris) or CHO cells.

[0229] 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 also provides nucleic acid sequences encoding the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. The antibody may 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 action or other effector functions.

[0230] In another particularly preferred embodiment of the invention, any of the aforementioned anti-CGRP antibodies or antibody fragments or, 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 1 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.

[0231] 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). RP antibodies, such as Ab6 or Fab fragments thereof, can be cultured in mammalian cells, such as CHO, NSO or can be expressed in HEK 293 cells, fungi, insects, 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:

[0232] In another embodiment, the antibody fragment may exist in one or more of the following non-limiting forms: Fab', F(ab')2, Fv and single chain Fv antibody formats. The anti-CGRP antibodies described herein may further comprise a kappa constant light chain sequence comprising the sequence set forth below. Contains columns: [ka]

[0233] In another preferred embodiment, the anti-CGRP antibodies described herein further comprise one or more of the following: or a carboxy-terminal lysine residue. and SEQ ID NO: 564 and SEQ ID NO: 565, respectively, containing the same sequences lacking: [ka] [ka]

[0234] 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: 1 including a C-terminal lysine. 564, or may comprise the constant region of SEQ ID NO: 565 lacking the C-terminal lysine. Therefore, all disclosure herein of the heavy chain of SEQ ID NO: 201 refers to that 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 containing a C-terminal lysine in the heavy chain may be cloned. The coding sequence can be expressed in a cell line, e.g., CHO cells, to prevent proteolysis. Therefore, an antibody lacking said C-terminal lysine or a mixture of heavy chains containing or lacking said C-terminal lysine is also provided. Compounds can be produced.

[0235] 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 variants thereof. H polypeptide sequence; and further: sequence 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 variants 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 substituted 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 It may comprise an Fc derived from an IgG2, IgG3, or IgG4 constant region.

[0236] In one embodiment of the present invention, an antibody or V H or V L Polypeptides are referred to herein as The humanized B cells are derived from or derived from one or more rabbit B cell populations prior to the initiation of the humanization process. be selected.

[0237] In another embodiment of the present 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 specificity for C In another embodiment of the present invention, an anti-CGRP antibody inhibits the association of GRP with CGRP-R. and fragments thereof, which may be used in combination with CGRP and CGRP-R and / or additional proteins and / or multiple proteins thereof. inhibits the association with the dimer and / or antagonizes its biological effect.

[0238] As described herein, antibodies and fragments thereof may 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, e.g., streptavidin, avidin, Functional moieties such as biotin, cytotoxins, cytotoxic materials, and radioactive materials may be added.

[0239] The antibody or fragment thereof may also be used to characterize 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 immunogenicity 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 binding chemical moieties.

[0240] 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 1.01 to 1.25, for ease of handling and manufacturing. The molecular weight is about 1 kDa to about 100 kDa (the term "about" refers to the preparation of polyethylene glycol). In this case, some molecules are heavier than the stated molecular weight and some are lighter. the desired therapeutic profile (e.g., the desired duration of sustained release, the desired biological activity, efficacy (if any), ease of handling, degree or lack of antigenicity, and therapeutic protein Other sizes may be used depending on other known effects of polyethylene glycol on proteins or analogs. For example, polyethylene glycol can be used in the range of 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 polymer 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 disclosure of each of which is incorporated herein by reference.

[0241] There are numerous methods of attachment available to those skilled in the art. See European Patent No. 0 401 384 (details of PEG-linked G-CSF). Concatenation). Malik et al.,Exp.Hematol.20:1028-103 5(1992)(reporting pegylation of GM-CSF u See also polyethylene glycol (PEG). The carboxyl groups are covalently linked to amino acid residues via reactive groups such as free amino or carboxyl groups. The 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 residue 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.

[0242] As alluded to above, polyethylene glycol can be substituted with 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 are selected from specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid) or cysteine), or two or more types of amino acid residues (e.g., lysine, histidine, Glutamic acid, aspartic acid, cysteine, and combinations thereof) Good too.

[0243] Alternatively, the antibody or fragment thereof may be bound to albumin (recombinant human serum albumin or a fragment thereof or and variants thereof (e.g., those incorporated herein by reference in their entirety). No. 5,876,969, issued March 2, 1999, which is incorporated herein by reference. EP 0 413 622 and the patent application published on June 16, 1998. See U.S. Pat. No. 5,766,883) or other circulating blood proteins , e.g., with increased in vivo half-life via fusion with transferrin or ferritin. In a preferred embodiment, the polypeptides and / or antibodies of the present invention (fragments 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) which 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.

[0244] Further exemplary enzymes for detectable moieties 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 enzymes. Further exemplary radioactive materials include, but are not limited to, quorine. Iodine 125( 125 I), carbon-14 ( 14 C), sulfur 35( 35 S), tritium ( 3 H) and phosphorus 32( 32 P), but are not limited to these.

[0245] With respect to functional moieties, exemplary cytotoxic agents include methotrexate, aminopteris, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil deca Rubazine; alkylating agents such as mechlorethamine, thioepa, chloramphenicol Bucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (C CNU), 1-methylnitrosourea, cyclothosphatamide mide), mechlorethamine, busulfan, dibromomannitol, streptozotocin Cisplatin, mitomycin C, cis-dichlorodiamineplatinum(II) (DDP), and and carboplatin (Paraplatin); anthracyclines include daunorubicin (formerly daunorubicin Unomycin), doxorubicin (adriamycin), detorubicin, carminomycin antibiotics, including idarubicin, epirubicin, mitoxantrone, and bisantrene; dactinomycin (actinomycin D), bleomycin, calicheamicin, mitochondrial and antimitotic agents, such as thromycin, thromycin, and anthramycin (AMC); These include, but are not limited to, vinca 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, dihydroxyanthracin dione, 1-de Hydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, Propranolol, puromycin, procarbazine, hydroxyurea, asparagina azepam, corticosteroids, mitotane (O,P'-(DDD)), interferon, and mixtures of these cytotoxic agents.

[0246] 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 of plant and bacterial origin, such as lysozymes, Diphtheria toxin, diphtheria toxin, and Pseudomonas toxin were humanized and or chimeric antibodies, or binding fragments thereof, to produce 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)).

[0247] Other cytotoxic agents include those disclosed by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the present invention include cytotoxic ribonucleases as described in the specification. Also, radionuclides that emit alpha or beta particles may be used with or without complexing agents. Regardless, the present invention relates to radioimmunoconjugates that are stably bound to antibodies or binding fragments thereof. Radionuclides such as β-emitters, e.g., phosphorus-32( 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.

[0248] See, e.g., 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.

[0249] The embodiments described herein include antibodies, antibody fragments, diabodies, and the like described herein. 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 amino acid within the same general class, e.g., one acidic amino acid with another substitution of one acidic amino acid with another basic amino acid, or substitution of one basic amino acid with another basic amino acid. This refers to the substitution of one neutral amino acid for another. Such techniques are well known in the art.

[0250] In another embodiment, the present invention provides antibody fragments, variable regions and CDRs described herein. It has at least 90% sequence identity to one or more of the polypeptide sequences. More preferably, the present invention contemplates polypeptide sequences comprising the antibodies described herein. For any one or more of the polypeptide sequences of the fragment, variable region, and CDR, at least 95% or more sequence identity, even more preferably at least 98% or more sequence identity, More preferably, polypeptide sequences having at least 99% or more 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.

[0251] In another embodiment, the present invention further provides a compound described herein that further has anti-CGRP activity. Antibody fragments, variable regions, and CDRs of the above polypeptide homologs are contemplated. Non-limiting examples of activities are described herein.

[0252] The present invention also relates to the use of the polynucleotides of the present invention, which are substituted with any of the other polynucleotide sequences described herein. Anti-CGRP antibodies comprising any of the polypeptide or polynucleotide sequences described herein. For example, but not by way of 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. of any CDR sequence described herein with any other CDR sequence described herein Antibodies resulting from the substitution are contemplated.

[0253] Further exemplary embodiments of the present invention In another embodiment, the present invention provides 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, Ab30, Ab31, Ab32, Select from Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, or Ab14 The anti-human CGRP antibody selected is a compound selected from the group consisting of a complete human CGRP polypeptide and a fragment thereof. , specifically bind to the same overlapping linear or conformational epitopes, and / or one or more anti-human CGs 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 in its entirety as Ab3, Ab6, Ab13, or Ab14. The same overlapping linear or conformational epitopes on a suitable human CGRP polypeptide or fragment thereof specifically bind to the same overlapping linear or conformational epitope and / or compete to match.

[0254] A preferred embodiment of the present invention is a method for the production of CGRP-binding fragments having binding specificity for CGRP and CGR of CGRP. 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 to be selected.

[0255] In another embodiment of the invention, the anti-human CGRP antibody used in the described methods of treatment is Epitope synthesis using overlapping linear peptide fragments spanning the entire length of the native human CGRP polypeptide As confirmed by profiling, Ab3, Ab6, Ab13, or Ab14 The same overlapping linear or is an antibody that specifically binds to a conformational epitope.

[0256] In another embodiment, the present invention also provides: 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 contained in the polypeptide sequence, or variants thereof. and methods of treatment using anti-CGRP antibodies or antibody fragments.

[0257] 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.

[0258] In a preferred embodiment, the anti-human CGRP antibody used in the described methods of treatment is , Ab3, or Ab6, in each of the variable light and variable heavy chain regions identical to those contained in Ab6. In another embodiment, the antibody fragments of the antibody fragments discussed above comprise at least two complementarity determining regions (CDRs). All of the CDRs of the human CGRP antibody are Ab1, Ab2, Ab3, Ab4, Ab5, and 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: In some embodiments, 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 selected anti-human CGRP antibody.

[0259] The present invention further provides an anti-human CGRP antibody, wherein one or more of the anti-human CGRP antibodies discussed above are aglycosylated. or, if glycosylated, only mannosylated; effector function, Fc regions modified to alter half-life, proteolysis, and / or glycosylation human, humanized, single chain, or chimeric; derived from rabbit (parent) anti-human CGRP antibody Contemplated therapeutic methods include humanized antibodies that: 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, This includes mutation to another amino acid, such as la.

[0260] The present invention further provides a method for producing a nucleotide sequence comprising the steps of: FR) are unmodified or contain one or more human nucleotides in the variable light or heavy chain region, respectively. The FR residues are modified by substituting them with the corresponding FR residues of the parent rabbit antibody. the human FRs are human FRs, and the human FRs are identical to 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, 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.

[0261] The present invention also relates to the treatment of headache disorders associated with, for example, the overuse of anti-migraine medications and / or triptans. and / or medication overuse headaches related to ergot and / or analgesic overuse A method for the treatment or prevention of medication overuse headache, comprising administering to a patient who is experiencing or has developed medication overuse headache. A therapeutically effective amount of at least one anti-human C-cell antigen-antibody described herein is administered to a patient at risk of developing the disease. The present invention also contemplates methods of treatment comprising administering a GRP antibody or fragment. that the present invention may involve the administration of two or more anti-CGRP antibodies or fragments thereof disclosed herein. It is contemplated that when two or more antibodies are administered to a patient, the antibodies may be administered simultaneously or concurrently. They may be administered sequentially or staggered in their administration. The anti-CGRP activity of the anti-CGRP antibodies and fragments thereof of the present invention having the binding specificity They can be described by their binding strength or their affinity for CGRP. In one embodiment, the anti-CGRP antibodies of the invention that have binding specificity for CGRP and their The fragments are 5x10 -7 M, 10 -7 Medium, 5x10 -8 M, 10 -8 Medium, 5x10 -9 M. 10 -9 Medium, 5x10 -10 M, 10 -10 Medium, 5x10 -11 M, 10 -11 M, 5x 10 -12 M, 10 -12 Medium, 5x10 -13 M or 10 -13 The dissociation constant (K D ) binds to CGRP. Preferably, the anti-CGRP antibodies and fragments thereof bind to CGRP at 10 -11 M , 5x10 -12 M or 10 -12 It binds to CGRP with a dissociation constant of M. In embodiments, the anti-CGRP antibodies of the present invention and fragments thereof that have binding specificity for CGRP are The fragments bind to linear or conformational CGRP epitopes.

[0262] In another embodiment of the invention, an anti-CGRP molecule of the invention has binding specificity for CGRP. The anti-CGRP activity of the antibody and its 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 -1Binds to CGRP with the following off-rate:

[0263] In a further embodiment of the invention, an anti-CGRP molecule of the invention has binding specificity for CGRP. The anti-CGRP activity of P antibodies and their fragments prevents symptoms of CGRP-related diseases and disorders. by improving or reducing the effects of, or treating, this disease or disorder. Non-limiting examples of CGRP-associated diseases and disorders are described herein. It includes headache and migraine disorders.

[0264] Polynucleotides encoding anti-CGRP antibody polypeptides As mentioned above, the present invention particularly relates to CDRs, VLs, and nucleotides having the sequences identified in Figures 1A-12. Ab as used herein comprises or consists of VH, CL, and CH polypeptides. This includes the use of specific anti-CGRP antibodies and antibody fragments designated Ab1 to Ab14. Nucleic acid sequences encoding the aforementioned VL, VH, CL, and CH polypeptides included in 14 are 1A-12. The CDRs, VL, and VL of a particularly preferred anti-CGRP antibody, Ab6, are also included in Figures 1A-12. Nucleic acid sequences encoding the H, CL, and CH polypeptides are further described below.

[0265] Antibody Ab6 The present invention further provides a polypeptide encoding an antibody polypeptide having binding specificity for CGRP. In one embodiment of the present invention, the polynucleotide of the present invention has the sequence The polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO:222 is: or consisting of: [ka]

[0266] In one embodiment of the invention, the polynucleotide of the invention is the light chain polypeptide of SEQ ID NO: 221. The present invention further comprises or consists of the following polynucleotide sequence encoding the peptide sequence: [ka]

[0267] In another embodiment of the invention, the polynucleotide of the invention comprises the variable heavy chain sequence of SEQ ID NO: 202. comprising or consisting of the following polynucleotide sequence encoding the polypeptide sequence: : [ka]

[0268] In one embodiment of the invention, the polynucleotide of the invention is the heavy chain polypeptide of SEQ ID NO: 201. The present invention further comprises or consists of the following polynucleotide sequence encoding the peptide sequence: [ka]

[0269] In one embodiment of the invention, the polynucleotide of the invention is the heavy chain polypeptide of SEQ ID NO: 566. The present invention further comprises or consists of the following polynucleotide sequence encoding the peptide sequence: [ka]

[0270] In a further embodiment of the invention, a nucleic acid encoding an antibody fragment having binding specificity for CGRP is provided. The polynucleotide for this purpose is 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.

[0271] In a further embodiment of the invention, a nucleic acid encoding an antibody fragment having 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 The polynucleotides encoding the complementarity determining regions (CDRs, or hypervariable regions) of the heavy chain sequence of SEQ ID NO: 566 are The polynucleotides of 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.

[0272] The present invention also provides one or more of the polynucleotide sequences encoding the antibody fragments described herein. In one embodiment of the present invention, a polynucleotide sequence comprising one or more of: A polynucleotide encoding an antibody fragment having the binding specificity of and / or comprising one, two, three or more of the following polynucleotides: Polynucleotide sequence encoding the light chain variable sequence of SEQ ID NO:222; SEQ ID NO:232; SEQ ID NO:221 Polynucleotide encoding the light chain sequence of SEQ ID NO: 231; heavy chain variable region of SEQ ID NO: 202 Polynucleotide sequence 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) polynucleotide; 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).

[0273] In a preferred embodiment of the present invention, the polynucleotide of the present invention is a polypeptide having a binding activity to CGRP. or a polynucleotide encoding a Fab (fragment antigen binding) fragment having specificity; In relation to antibody Ab6, a polynucleotide encoding the full-length Ab6 antibody The polynucleotide sequence of SEQ ID NO: 231 encoding the light chain sequence of SEQ ID NO: 221 and SEQ ID NO: The polynucleotide 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.

[0274] Another embodiment of the present 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 converted to Ab6 after expression of the full-length polynucleotide in a suitable host. In another embodiment of the present invention, the soluble ... 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.

[0275] In one embodiment, the present invention provides 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 mutation thereof The present invention relates to an isolated polynucleotide comprising a polynucleotide encoding an antibody, At least one framework residue (FR residue) is present in the rabbit anti-CGRP antibody V H Polypeptide The amino acid is substituted with the amino acid present at the corresponding position of the amino acid sequence, or with a conservative amino acid substitution.

[0276] In another embodiment, the present invention provides 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 number 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 of a rabbit anti-CGRP antibody. V L The amino acid present at the corresponding position in the polypeptide, or a conservative amino acid substitution, It is being done.

[0277] In yet another embodiment, the present invention provides 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; Sequence 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: SEQ ID 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.

[0278] In another embodiment, the present invention provides a method for the production of at least one CDR polypeptide derived from an anti-CGRP antibody. an isolated polynucleotide expressing a polypeptide comprising a peptide, The expressed polypeptides may bind specifically to CGRP alone or in combination with anti-CGRP antibodies. and another polypeptide expressing a polypeptide comprising at least one CDR polypeptide derived from When expressed in the context of a nucleotide sequence, it specifically binds to CGRP and 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: 522L or V H Polypep It is selected from those included in the chid.

[0279] Host cells and vectors containing the polynucleotides are also contemplated.

[0280] 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, as well as a host cell containing the vector sequence. The host cell is a yeast cell. In another embodiment of the invention, the yeast host cell is Pichia (Pi chia) genus.

[0281] Methods for producing antibodies and fragments thereof In another embodiment, the present invention features methods for producing anti-CGRP antibodies and fragments thereof. Mating competent yeast polyploids, preferably diploids, are used. Methods for producing antibodies and fragments thereof secreted from tetraploid or tetraploid strains are described, for example, in Ol U.S. Patent Application No. 2009 / 0022659 to son et al., and Ga U.S. Patent No. 7,935,340 to Rcia-Martinez et al. (the disclosure of each is incorporated herein by reference in its entirety). 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.

[0282] Other methods for producing antibodies are also known to those skilled in the art. For example, methods for producing chimeric antibodies Methods for producing such proteins are now well known in the art (see, for example, Cabilly et al. U.S. Patent No. 4,816,567 to Morrison et al., P.N. .ASUSA,81:8651-55(1984);Neuberger,MS et al.,Nature,314:268-270(1985);Bouliann e, GLet et al., Nature, 312:643-46 (1984) (each See, e.g., pp. 111-114, the disclosure of which is incorporated herein by reference in its entirety).

[0283] 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, to Queen et al. 089, 5,693,762, and 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; U.S. Patent No. 6,407,213 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, e.g., U.S. Pat. No. 6,113,399, incorporated herein by reference). ).

[0284] As used herein, the term "opioid analgesic" refers to any analgesic, natural or synthetic, that has morphine-like action. Synthetic and semi-synthetic opioid analgesics are compounds from five chemical classes: phenylalanine, ... Derivatives of phenylheptylamine, phenylpiperidine, morphinan, and benzomorphan and benzodiazepines, all of which are within the scope of the term. Exemplary opioid analgesics include codeine, benzodiazepines, and benzodiazepines. dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levo Irfanol, oxymorphone, alfentanil, buprenorphine, butorfane ethanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxycycline Examples include cyclosporine and pentazocine, or pharmaceutically acceptable salts thereof.

[0285] The term "NSAID" refers to a nonsteroidal anti-inflammatory compound. They are classified by their ability to inhibit cyclooxygenases. Cyclooxygenase 2 is one of 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 are described in, for example, U.S. Pat. No. 5,616,616. Cox-2 inhibitors are described in, for example, 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-methoxamer C-2-naphthylacetic acid (6-MNA), rofecoxib, MK-966, nabumetone (6- MNA prodrug), nimesulide, NS-398, SC-5766, SC-5821 5, T-614; or a combination thereof.

[0286] In some embodiments, aspirin and / or acetaminophen may be administered to a subject in need of CGRP stimulation. Aspirin is another type of nonsteroidal anti-inflammatory drug. It is a disease compound.

[0287] 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 requiring or who 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 suffering from medication overuse. The present invention relates to the treatment of overuse headache in individuals who are at risk of developing drug overuse headache.

[0023] In the manufacture of a medicament for the treatment, prevention and / or amelioration of headache, Further included are any of the uses of pharmaceutical formulations.

[0288] Administration In one embodiment of the present invention, an anti-CGRP antibody described herein, or a CGRP binding 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 dose 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 anti-CGRP antibody described herein, or a CGRP-binding fragment thereof, and The antibody or antibody fragment combination may be administered once every 26 weeks or 6 months or less, or once every 16 weeks or Once every four months or less, once every eight weeks or two months or less, once every four weeks or one 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 is performed in a plan from the schedule described above. The administration schedule may vary by one or more days, e.g., every 3 months or every 12 weeks. Includes administration of doses varying from 1, 2, 3, 4, 5, 6, or 7 days .

[0289] Fab fragments may be administered every two weeks or less, every week or less, every day or less, multiple times per day, and / or It may be administered every few hours. In one embodiment of the present invention, the patient is given an effective Effective Fab fragments are administered at 1 mg / kg to 40 mg / kg / day in 1 to 6 divided doses daily. , or in sustained release form.

[0290] 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

[0291] Those skilled in the art will appreciate, for example, from 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 Pincott Williams & Wilkins Effective dosages and frequency of administration will be determined by routine experimentation.

[0292] In another embodiment of the invention, an anti-CGRP antibody described herein, or a CGRP The binding fragments, as well as the combination of said antibodies or antibody fragments, are administered to subjects in pharmaceutical formulations.

[0293] "Pharmaceutical composition" refers to a chemical or biological composition suitable for administration to a mammal. Such compositions may be administered buccally, extradermally, epidurally, by inhalation, intra-arterially, intracardially, intracerebroventricularly, intradermally, intramuscularly, 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 via injection, powder, liquid, gel, or other suitable means. This can be done by drops, or other means of administration.

[0294] A "pharmaceutical excipient" or "pharmaceutically 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 the pharmaceutical agent with pharmacological activity. 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 (Reference (incorporated by reference).

[0295] As used herein, a "pharmaceutically 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 pharmaceutically 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.

[0296] 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 concentrations The carrier may be, for example, water, ethanol, polyol (e.g., glycerol, proline, polyethylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The present invention further provides a pharmaceutical composition comprising a stabilizer. Suitable 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 adding water.

[0297] In many cases, isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, It may be preferable to include sodium chloride in the composition. Prolonged absorption can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and the like. This can be achieved by including gelatin. For example, it can be formulated into a time-release formulation in a composition that includes a sustained-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. esters, 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.

[0298] An exemplary composition includes an anti-CGRP antibody or fragment thereof (e.g., Ab6), His, in 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, e.g., about 100 mg anti-CGRP antibody (e.g., Ab6), about 3 0.1 mg L-histidine, approximately 40.5 mg sorbitol, and approximately 0.15 mg polysol 80, or approximately therewith, 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, SEQ ID NO: 221 and SEQ ID NO: 201, or the variable light and heavy chain polypeptides of SEQ ID NO: 22, respectively. 1 and SEQ ID NO: 566. The product will undergo 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 mL of 00 mg of light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 201, respectively, about 3.1 mg L-histidine, about 40.5 mg sorbitol, and about 0.15 mg polysaccharide. Resorbate 80, and water QS, or approximately the same, e.g., 10% or more of these amounts. Within these amounts, 5% of these amounts, 1% of these amounts, 0.5% of these amounts, or Another exemplary composition comprises 100 mg per mL of each of , light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 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, for example, within 10% of these amounts, 5%, within 1% of these amounts, within 0.5% of these amounts, or 0.1% or more of these amounts The composition is suitable for intravenous or subcutaneous administration, preferably for intravenous administration. For example, the composition may contain from about 100 mg to about 100 mL of intravenous solution. For a dose of 300 mg of antibody, to be mixed with an intravenous solution (e.g., 0.9% sodium chloride): Preferably, the composition has at least 1, 3, 6, 12, 18, or may be shelf-stable for 24 months, e.g., after storage at room temperature or after refrigeration at 4°C for a specified period. or in accelerated degradation tests simulating storage for that period, the antibody or fragment The results show that 5% or less or 10% or less of the sample exhibits aggregate formation.

[0299] For each of the enumerated embodiments, the compounds can be administered in a variety of dosage forms. Any biologically acceptable dosage form known to those skilled in the art, and combinations thereof, are contemplated. Examples of such dosage forms include reconstitutable powders, elixirs, solutions, suspensions, and formulations, emulsions, powders, granules, particles, fine particles, dispersible granules, cachets, inhalants, aerosols Sol inhalants, patches, particle inhalants, implants, depot implants, injections (subcutaneous, Intramuscular, intravenous, and intradermal, preferably including intravenous), injection, and combinations thereof Examples include, but are not limited to:

[0300] The above description of various exemplary embodiments of the present invention is not intended to be exhaustive or to limit the scope 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 to other purposes than the examples.

[0301] 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 be consistent with the principles of the present specification and claims. The present invention should not be construed as being limited to the particular embodiments disclosed therein. Accordingly, the present invention is not limited by this disclosure; 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.

[0302] 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.

[0303] Certain CGRP antibody polynucleotides and polypeptides are described in the sequence appended to this patent application. The disclosure of said Sequence Listing is incorporated herein by reference in its entirety.

[0304] Each of the references cited in the "Background," "Description of the Invention," and "Examples" Publication of literature (including patents, patent applications, journal articles, abstracts, manuals, books, or other disclosures) The entire disclosure is incorporated herein by reference in its entirety.

[0305] The following examples are provided to those skilled in the art to provide a complete disclosure and description of how to make and use the present invention. It is set forth for the purpose of providing an understanding of the present invention and is 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.). Although experimental results have been obtained, 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.

[0306] Additional Exemplary Embodiments S1. Migraine or headache in patients requiring immediate relief of migraine or headache symptoms For treating headaches or for patients needing immediate preventative treatment of migraines or headaches Use of an anti-CGRP antibody for the manufacture of a medicament for the prevention of migraine or headache in The agent is administered intravenously at a dose of 100 or 300 mg of the anti-CGRP antibody. wherein the anti-CGRP antibody is SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 227. The respective light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 2 SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO:208. and a polypeptide sequence.

[0307] S2. The medication is administered to a patient who is experiencing at least one headache and / or migraine symptom. The anti-CGRP antibody of embodiment S1 for use in patients with use.

[0308] S3. The at least one headache and / or migraine symptom is pain, nausea, photophobia, or The use of an anti-CGRP antibody of embodiment S2, wherein the treatment is one or more of the following: phonophobia.

[0309] S4. The anti-CGRP antibody of embodiment S3, wherein the pain is head pain. use.

[0310] S5. The most troublesome symptoms occurred within 1 day after administration, within 12 hours after administration, within 6 hours after administration, Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or Within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration. The use of an anti-CGRP antibody of any one of embodiments S2 to S4, wherein the anti-CGRP antibody is ameliorated.

[0311] S6. The patient is administered within 1 day, 12 hours, 6 hours, or 24 hours after administration. Within 5 hours, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or after administration Within 1 hour, within 30 minutes after administration, or 1 to 6 hours after administration The use of an anti-CGRP antibody according to any one of embodiments S2 to S5 in the absence of migraines.

[0312] S7. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: The use of an anti-CGRP antibody according to any one of the above embodiments, comprising the light chain CDR 1, 2, and 3 polypeptide sequences encoded by No. 238, and each respectively, the heavy chain CD R 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218. The use of an anti-CGRP antibody according to any one of the above embodiments, comprising the light chain CDR 1, 2, and 3 polypeptide sequences encoded by No. 238, and each

[0313] S8. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222.

[0314] S9. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232.

[0315] S10. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202.

[0316] S11. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO: 212. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0317] S12. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein the anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202.

[0318] S13. The use of an anti-CGRP antibody according to any one of the above embodiments, wherein 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 use of an anti-CGRP antibody according to any one of the above embodiments, wherein 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 use of an anti-CGRP antibody according to any one of the above embodiments, wherein 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.

[0319] S14. The above embodiment, wherein 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 the embodiments.

[0320] S15. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231. 3. Use of an anti-CGRP antibody according to any one of the preceding embodiments, including

[0321] S16. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. 3. Use of an anti-CGRP antibody according to any one of the preceding embodiments, including

[0322] S17. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567. CGRP antibody according to any one of the preceding embodiments, comprising a heavy chain polypeptide comprising use.

[0323] S18. 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 the preceding embodiments, comprising a heavy chain polypeptide of SEQ ID NO: 1 or SEQ ID NO: 566. Use of anti-CGRP antibodies.

[0324] S19. 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 the above embodiments.

[0325] S20. The method of claim 1, wherein the intravenous administration is infused over a period of about 30 to 60 minutes. 10. Use of an anti-CGRP antibody according to any one of embodiments 1 to 9.

[0326] S21. Headache or migraine symptoms occur within 1 day, 12 hours, or 6 hours after administration. Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration. The anti-CGRP antibody of any one of the above embodiments is immediately reduced or eliminated. Use of the body.

[0327] S22. Any of the above embodiments, wherein the patient is headache-free 2 hours after completion of the infusion. Use of an anti-CGRP antibody according to any one of claims 1 to 4.

[0328] S23. The drug is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 to 14 weeks. or for intravenous administration at a dose of 100 mg of said anti-CGRP antibody every 12 weeks. 3. The use of an anti-CGRP antibody according to any one of the preceding embodiments.

[0329] S24. The drug is administered every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 to 14 weeks. or for intravenous administration at a dose of 300 mg of said anti-CGRP antibody every 12 weeks. The use of an anti-CGRP antibody according to any one of embodiments S1 to S22.

[0330] S25. The anti-CGRP antibody is a compound selected from the group consisting of histidine (L-histidine), sorbitol, poly(aminopropyl methylcellulose), and the like. The above embodiments are contained in a formulation comprising or consisting of sorbate 80 and water. 2. Use of an anti-CGRP antibody according to any one of claims 1 to 11.

[0331] S26. 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 an amount of each component within + / - 10% of the aforementioned values, As described in embodiment S25, having a pH of 5.8 or within + / - 10% of said value. Use of anti-CGRP antibodies.

[0332] S27. 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 an amount of each ingredient within + / - 5% of the aforementioned values; and and / or a pH of 5.8 or within + / - 5% of said value, embodiment S25. Use of an anti-CGRP antibody as described in

[0333] S28. 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 an amount of each ingredient within + / - 1% of the aforementioned values; and and / or a pH of 5.8 or within + / - 1% of said value, embodiment S25. Use of an anti-CGRP antibody as described in

[0334] S29. 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 an amount of each ingredient within + / - 0.5% of the above values. and / or having a pH of 5.8 or within + / - 0.5% of said value, 10. The use of an anti-CGRP antibody according to aspect S25.

[0335] S30. 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 an amount of each ingredient within + / - 0.1% of the above values. and / or having a pH of 5.8 or within + / - 0.1% of said value, 10. The use of an anti-CGRP antibody according to aspect S25.

[0336] S31. The L-histidine in the formulation is L-histidine and L-histidine monohydrate. The anti-CGRP antibody of any one of embodiments S25 to S30, including a mixture of monohydrates. use.

[0337] S32. The 3.1 mg of histidine in the formulation is L-histidine (1 mg) and L-histidine monohydrate (2.8 mg) in a mixture, which in the final formulation Any of embodiments S25 to S30, totaling 3.1 mg of L-histidine free base. 1. Use of an anti-CGRP antibody according to claim 1.

[0338] S33. The formulation is contained in a 100 mg / mL single dose vial, wherein each mL The solution was prepared at a pH of 5.8, containing 100 mg of anti-CGRP antibody, L-histidine (1 mg), and L-histidine. Stidine hydrochloride monohydrate (2.8 mg), polysorbate 80 (0.15 mg), sorbitol of embodiments S26 to S32, containing 100 mg of ethanol (40.5 mg), and water for injection, USP. 10. Use of an anti-CGRP antibody according to any one of claims 1 to 9.

[0339] S34. The formulation is contained in a 300 mg / mL single-dose vial, each mL containing 5. At a pH of 8, 300 mg of anti-CGRP antibody, L-histidine (1 mg), L-histidine Hydrochloride monohydrate (2.8 mg), polysorbate 80 (0.15 mg), sorbitol ( 40.5 mg), and Water for Injection, USP. 1. Use of an anti-CGRP antibody according to claim 1.

[0340] S35. The migraine or headache is accompanied or not accompanied by acute migraine or headache, aura, Non-migraine, chronic migraine, episodic migraine, chronic / episodic migraine, hemiplegic migraine, cluster Headache, migraine-like neuralgia, chronic headache, tension headache, general headache, underlying structural problems of the head and neck headaches due to problems, sinus headaches (e.g., those associated with sinusitis), and allergies Any one of the above embodiments, wherein the headache is selected from the group comprising ghee-induced headache or migraine. Use of an anti-CGRP antibody as described in

[0341] S36. The agent is administered to a patient with a VRS-4 score of at least 2 at the time of administration of the antibody. any one of the preceding embodiments, wherein the antibody is for administration to a patient exhibiting a level Use of anti-CGRP antibodies.

[0342] S37. The agent is administered to a patient with a pain response of at least 3 on the VRS-4 scale at the time of administration of the antibody. any one of the preceding embodiments, wherein the antibody is for administration to a patient exhibiting a level Use of anti-CGRP antibodies.

[0343] S38. The drug is administered within 1 day, within 12 hours, within 6 hours, or Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or VR immediately after administration, such as within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration In embodiments, the method is for administration to patients who experience a pain level of 2 or less on S-4. Use of an anti-CGRP antibody according to any one of S1 to S37.

[0344] S38. The drug is administered within 1 day, within 12 hours, within 6 hours, or Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or VR immediately after administration, such as within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration The above-mentioned embodiment is for administration to patients who have a pain level of 1 or less in S-4. Use of an anti-CGRP antibody according to any one of the embodiments.

[0345] S40. The drug is administered within 15 minutes, 30 minutes, 1 hour, or 2 hours before or after administration. Within 3 hours, 4 hours, 5 hours, or 6 hours before or after the administration. The above-mentioned method is intended for administration to patients who have not received any acute migraine medication within a certain period of time. Use of an anti-CGRP antibody according to any one of the embodiments.

[0346] S41. The acute migraine medication is a triptan, an analgesic, e.g., a non-opioid or opioid. oids / narcotics, acetaminophen, NSAIDs, combination medications, ergotamine, or The use of an anti-CGRP antibody of embodiment S40, which comprises an ergot derivative.

[0347] S42. The non-opioid analgesic is paracetamol (acetaminophen), acetaminophen, Contains salicylic acid (aspirin), another NSAID, or another non-opioid pain reliever; The triptans are sumatriptan, zolmitriptan, naratriptan, and rizatriptan. , eletriptan, almotriptan, or frovatriptan The opioid may be oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone; Two drugs with analgesic effects (e.g., paracetamol and codeine), analgesics and adjuvants (e.g. paracetamol and caffeine), and / or the combination analgesic , at least one opioid (tramadol, butorphanol, morphine, codeine) , hydrocodone, or any combination thereof), barbiturates, e.g., butal and / or caffeine, and / or the combined analgesic agent contains acetyl Salicylic acid (aspirin), paracetamol and caffeine (EXCEDRIN®) The invention described in embodiment S41 includes the use of the steroid hormone agonist (SEQ ID NO: 1), the use of the steroid hormone agonist (SEQ ID NO: 2), and the use of the steroid hormone agonist (SEQ ID NO: 3). Use of the anti-CGRP antibodies described above.

[0348] S43. Patient is taking or has taken additional migraine medication, The use of the anti-CGRP antibody of any one of forms S1-S39.

[0349] S44. The patient experiences additional migraines before, during, or after administration of an anti-CGRP antibody. The anti-CGRP antibody of any one of embodiments S1 to S39 or S43 is administered Use of the body.

[0350] S45. The patient is administered the anti-CGRP antibody within 15 minutes, 30 minutes, or 1 hour before or after the administration. , within 2 hours, within 3 hours, within 4 hours, within 5 hours, or within 6 hours, etc. In embodiments S1-S3, an additional migraine medication is administered within a predetermined period before or after administration of the RP antibody. Use of an anti-CGRP antibody according to any one of S9 or S43 to S44.

[0351] S46. Embodiment S44 wherein the additional migraine medication comprises an acute and / or chronic migraine medication. or the use of an anti-CGRP antibody according to any one of S45.

[0352] S47. The additional migraine medication is a triptan, an analgesic, e.g., a non-opioid or opioid. Pneumococcal / narcotic drugs, acetaminophen, NSAIDs, combination medications, ergotamine, or The anti-CGRP antibody of any one of embodiments S44 to S46, wherein the anti-CGRP antibody comprises an ergot derivative. use.

[0353] S48. The non-opioid analgesic is paracetamol (acetaminophen), acetaminophen, Contains salicylic acid (aspirin), another NSAID, or another non-opioid pain reliever; The triptans are sumatriptan, zolmitriptan, naratriptan, and rizatriptan. , eletriptan, almotriptan, or frovatriptan The opioid may be oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone; Two drugs with analgesic effects (e.g., paracetamol and codeine), analgesics and adjuvants (e.g. paracetamol and caffeine), and / or the combination analgesic , at least one opioid (tramadol, butorphanol, morphine, codeine) , hydrocodone, or any combination thereof), barbiturates, e.g., butal and / or caffeine, and / or the combined analgesic agent contains acetyl Salicylic acid (aspirin), paracetamol and caffeine (EXCEDRIN®) The invention described in embodiment S47 includes the use of the steroid hormone agonist (SEQ ID NO: 1), the use of the steroid hormone agonist (SEQ ID NO: 2), and the use of the steroid hormone agonist (SEQ ID NO: 3). Use of the anti-CGRP antibodies described above.

[0354] S49. The anti-CGRP antibody is a Pichia pastori s) or Pichia pastoris 3. The anti-CGRP antibody of any one of the preceding embodiments, obtained by expression in Use of.

[0355] S50. The anti-CGRP antibody is expressed in or expressed in CHO cells. an anti-CGRP antibody according to any one of embodiments S1 to S48, obtained by expression in a mammalian subject; Use of the body.

[0356] S51. The patient is administered 100 mg or 300 mg of the anti-CGRP antibody every 3 months. 3. The use of an anti-CGRP antibody according to any one of the preceding embodiments,

[0357] S52. The method of any of the above embodiments, wherein the method provides immediate relief of migraine or headache symptoms. 10. Use of an anti-CGRP antibody according to any one of claims 1 to 9.

[0358] S53. The above embodiments wherein the method provides immediate, preventative treatment of migraines or headaches. 10. Use of an anti-CGRP antibody according to any one of claims 1 to 9.

[0359] Additional Exemplary Embodiments E1. Migraine or headache in patients requiring immediate relief of migraine or headache symptoms For use in treating headaches or when immediate preventative treatment of migraines or headaches is required an anti-CGRP antibody for use in preventing migraine or headache in a patient wherein the anti-CGRP antibody is administered at a dose of 100 or 300 mg of the anti-CGRP antibody. wherein the anti-CGRP antibody is selected from the group consisting of SEQ ID NO: 224; SEQ ID NO: 2 26; and the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 228, respectively. , SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, 2, and 3 polypeptide sequences.

[0360] E2. The anti-CGRP antibody is administered to a patient in whom the patient has at least one headache and / or paralysis at the time of administration. The use according to embodiment E1, wherein the use is for use in patients presenting with headache symptoms. Anti-CGRP antibodies for

[0361] E3. The at least one headache and / or migraine symptom is pain, nausea, photophobia, or The anti-CGRP antibody for use according to embodiment E2, including one or more of the following: phonophobia .

[0362] E4. Anti-C for use according to embodiment E3, wherein the pain is head pain. GRP antibody.

[0363] E5. The most troublesome symptoms occurred within 1 day after administration, within 12 hours after administration, within 6 hours after administration, Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or Within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration. The anti-CGRP antibody for use according to any one of embodiments E2 to E4, .

[0364] E6. The patient is diagnosed with steroid steroids within 1 day after administration, within 12 hours after administration, within 6 hours after administration, or within 12 hours after administration. Within 5 hours, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or after administration Within 1 hour, within 30 minutes after administration, or 1 to 6 hours after administration Anti-CGRP for use according to any one of embodiments E2 to E5 in the absence of migraines antibody.

[0365] E7. The anti-CGRP antibody is selected from the group consisting of SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 237, respectively. and the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO:238, respectively. heavy chain CD4 encoded by SEQ ID NO:214; SEQ ID NO:216; and SEQ ID NO:218 1, 2, and 3 polypeptide sequences. Anti-CGRP antibodies for use.

[0366] E8. The antibody described above, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO: 222. 10. An anti-CGRP antibody for use according to any one of embodiments.

[0367] E9. The anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO: 232. 3. The anti-CGRP antibody for use according to any one of the preceding embodiments, comprising a CGRP antibody.

[0368] E10. The anti-CGRP antibody, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO: 202. 1. An anti-CGRP antibody for use according to any one of embodiments 1 to 5.

[0369] E11. The anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO: 212. 3. The anti-CGRP antibody for use according to any one of the preceding embodiments, comprising a peptide.

[0370] E12. 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: 223. 202 variable heavy chain polypeptide. Anti-CGRP antibodies.

[0371] E13. 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. 10. An anti-CGRP antibody for use according to any one of the embodiments.

[0372] E14. The method of any one of the above embodiments, wherein the anti-CGRP antibody comprises a light chain polypeptide of SEQ ID NO: 221. 10. An anti-CGRP antibody for use according to any one of the embodiments.

[0373] E15. The anti-CGRP antibody comprises a light chain polypeptide encoded by SEQ ID NO: 231. 3. The anti-CGRP antibody for use according to any one of the preceding embodiments, comprising

[0374] E16. The anti-CGRP antibody comprises a heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. 3. The anti-CGRP antibody for use according to any one of the preceding embodiments, comprising

[0375] E17. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0033] The anti-C antibody for use according to any one of the above embodiments, comprising a heavy chain polypeptide GRP antibody.

[0376] E18. 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 the preceding embodiments, comprising a heavy chain polypeptide of SEQ ID NO: 1 or SEQ ID NO: 566. 1. An anti-CGRP antibody for use in

[0377] E19. 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 the preceding embodiments.

[0378] E20. The method of claim 1, wherein the intravenous administration is infused over a period of about 30 to 60 minutes. 1. An anti-CGRP antibody for use according to any one of embodiments 1 to 5.

[0379] E21. Headache or migraine symptoms occur within 1 day, 12 hours, or 6 hours after administration. Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration. for the use according to any one of the above embodiments, wherein the Anti-CGRP antibody.

[0380] E22. The patient is headache-free 2 hours after completion of the infusion. 3. An anti-CGRP antibody for use according to any one of claims 1 to 2.

[0381] E23. The anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks. More preferably, intravenously at a dose of 100 mg of said anti-CGRP antibody every 12 weeks. an anti-CGRP antibody for use according to any one of the above embodiments, body.

[0382] E24. The anti-CGRP antibody is administered every 10 to 14 weeks, preferably every 11 to 13 weeks. More preferably, intravenously administered at a dose of 300 mg of said anti-CGRP antibody every 12 weeks. anti-CG for use according to any one of embodiments E1 to E22, RP antibody.

[0383] E25. The anti-CGRP antibody is a compound selected from the group consisting of histidine (L-histidine), sorbitol, poly(aminopropyl methylcellulose), and the like. The above embodiments are contained in a formulation comprising or consisting of sorbate 80 and water. 10. An anti-CGRP antibody for use according to any one of claims 1 to 9.

[0384] E26. 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 an amount of each component within + / - 10% of the aforementioned values, As described in embodiment E25, having a pH of 5.8 or within + / - 10% of said value. 1. An anti-CGRP antibody for use in

[0385] E27. 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 an amount of each ingredient within + / - 5% of the aforementioned values; and and / or a pH of 5.8 or within + / - 5% of said value. 2. An anti-CGRP antibody for use as described in .

[0386] E28. 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 an amount of each ingredient within + / - 1% of the aforementioned values; and and / or a pH of 5.8 or within + / - 1% of said value. 2. An anti-CGRP antibody for use as described in .

[0387] E29. 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 an amount of each ingredient within + / - 0.5% of the above values. and / or having a pH of 5.8 or within + / - 0.5% of said value, 10. An anti-CGRP antibody for use according to aspect E25.

[0388] E30. 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 an amount of each ingredient within + / - 0.1% of the above values. and / or having a pH of 5.8 or within + / - 0.1% of said value, 10. An anti-CGRP antibody for use according to aspect E25.

[0389] E31. The L-histidine in the formulation is L-histidine and L-histidine monohydrate. The anti-C for use according to any one of embodiments E25 to E30, comprising a mixture of hydrates. GRP antibody.

[0390] E32. The 3.1 mg of histidine in the formulation is L-histidine (1 mg) and L-histidine monohydrate (2.8 mg) in a mixture, which in the final formulation Any of embodiments E25 to E30, totaling 3.1 mg of L-histidine free base 1. An anti-CGRP antibody for use according to claim 1.

[0391] E33. The formulation is contained in a 100 mg / mL single dose vial, wherein each mL The solution was prepared at a pH of 5.8, containing 100 mg of anti-CGRP antibody, L-histidine (1 mg), and L-histidine. Stidine hydrochloride monohydrate (2.8 mg), polysorbate 80 (0.15 mg), sorbitol of embodiments E26 to E32, containing 100 mg of methylprednisolone (40.5 mg), methylprednisolone (40.5 mg), and water for injection, USP. 10. An anti-CGRP antibody for use according to any one of claims 1 to 9.

[0392] E34. The formulation is contained in a 300 mg / mL single-dose vial, each mL containing 5. At a pH of 8, 300 mg of anti-CGRP antibody, L-histidine (1 mg), L-histidine Hydrochloride monohydrate (2.8 mg), polysorbate 80 (0.15 mg), sorbitol ( Any of embodiments E26-E32 containing 40.5 mg), and water for injection, USP. 1. An anti-CGRP antibody for use according to claim 1.

[0393] E35. The migraine or headache is accompanied or not by acute migraine or headache, aura, Non-migraine, chronic migraine, episodic migraine, chronic / episodic migraine, hemiplegic migraine, cluster Headache, migraine-like neuralgia, chronic headache, tension headache, general headache, underlying structural problems of the head and neck headaches due to problems, sinus headaches (e.g., those associated with sinusitis), and allergies Any one of the above embodiments, wherein the headache is selected from the group comprising ghee-induced headache or migraine. 2. An anti-CGRP antibody for use as described in .

[0394] E36. The anti-CGRP antibody is administered to a subject with a serum creatinine level of at least 100 mg / kg / day in VRS-4 at the time of administration of the antibody. Any of the above embodiments is for administration to a patient presenting with a pain level of at least 2. 1. An anti-CGRP antibody for use according to claim 1.

[0395] E37. The anti-CGRP antibody is administered to a subject with a ≥100% CI of at least 100 mg / kg / day in VRS-4 at the time of administration of the antibody. Any of the above embodiments is for administration to a patient presenting with a pain level of at least 3. 1. An anti-CGRP antibody for use according to claim 1.

[0396] E38. The anti-CGRP antibody is administered within 1 day, 12 hours, or 6 hours after administration. Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration. For administration to patients who immediately experience a pain level of 2 or 3 or less on the VRS-4 3. The anti-CGRP antibody for use according to any one of the preceding embodiments, wherein

[0397] E39. The anti-CGRP antibody is administered within 1 day, 12 hours, or 6 hours after administration. Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration. For administration to patients who immediately present with a pain level of 1 or less on the VRS-4 , an anti-CGRP antibody for use according to any one of the preceding embodiments.

[0398] E40. The anti-CGRP antibody is administered within 15 minutes, 30 minutes, 1 hour, or 2 hours before or after administration. before or after the administration, such as within 3 hours, 4 hours, 5 hours, or 6 hours is for administration to patients who have not received any acute migraine medication within a prescribed period of time. , an anti-CGRP antibody for use according to any one of the preceding embodiments.

[0399] E41. The acute migraine medication is a triptan, an analgesic, e.g., a non-opioid or opioid oids / narcotics, acetaminophen, NSAIDs, combination medications, ergotamine, or The anti-CGRP antibody for use according to embodiment E40, which comprises an ergot derivative.

[0400] E42. The non-opioid analgesic is paracetamol (acetaminophen), acetaminophen, Contains salicylic acid (aspirin), another NSAID, or another non-opioid pain reliever; The triptans are sumatriptan, zolmitriptan, naratriptan, and rizatriptan. , eletriptan, almotriptan, or frovatriptan The opioid may be oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone; Two drugs with analgesic effects (e.g., paracetamol and codeine), analgesics and adjuvants (e.g. paracetamol and caffeine), and / or the combination analgesic , at least one opioid (tramadol, butorphanol, morphine, codeine) , hydrocodone, or any combination thereof), barbiturates, e.g., butal and / or caffeine, and / or the combined analgesic agent contains acetyl Salicylic acid (aspirin), paracetamol and caffeine (EXCEDRIN®) The method of embodiment E41, including (registered trademark), EXCEDRIN MIGRAINE® Anti-CGRP antibodies for use as described above.

[0401] E43. Patient is taking or has taken additional migraine medication, The use of the anti-CGRP antibody of any one of forms E1-E39.

[0402] E44. The patient experiences additional migraines before, during, or after administration of anti-CGRP antibodies. The anti-CGRP antibody of any one of embodiments E1 to E39 or E43 is administered Use of the body.

[0403] E45. The patient is administered the anti-CGRP antibody within 15 minutes, 30 minutes, or 1 hour before or after the administration. , within 2 hours, within 3 hours, within 4 hours, within 5 hours, or within 6 hours, etc. Embodiments E1-S3, in which an additional migraine medication is administered within a predetermined period before or after administration of the RP antibody. Use of an anti-CGRP antibody according to any one of E9 or E43 to E44.

[0404] E46. Embodiment E44 wherein the additional migraine medication comprises an acute and / or chronic migraine medication. or the use of an anti-CGRP antibody according to any one of E45.

[0405] E47. The further migraine medication is a triptan, an analgesic, e.g., a non-opioid or opioid Pneumococcal / narcotic drugs, acetaminophen, NSAIDs, combination medications, ergotamine, or The anti-CGRP antibody of any one of embodiments E44 to E46, wherein the antibody comprises an ergot derivative. use.

[0406] E48. The non-opioid analgesic is paracetamol (acetaminophen), acetaminophen, Contains salicylic acid (aspirin), another NSAID, or another non-opioid pain reliever; The triptans are sumatriptan, zolmitriptan, naratriptan, and rizatriptan. , eletriptan, almotriptan, or frovatriptan The opioid may be oxycodone, tramadol, butorphanol, morphine, codeine, and hydrocodone; Two drugs with analgesic effects (e.g., paracetamol and codeine), analgesics and adjuvants (e.g. paracetamol and caffeine), and / or the combination analgesic , at least one opioid (tramadol, butorphanol, morphine, codeine) , hydrocodone, or any combination thereof), barbiturates, e.g., butal and / or caffeine, and / or the combined analgesic agent contains acetyl Salicylic acid (aspirin), paracetamol and caffeine (EXCEDRIN®) The method of embodiment E47, including (registered trademark), EXCEDRIN MIGRAINE® Use of the anti-CGRP antibodies described above.

[0407] E49. The anti-CGRP antibody is a Pichia pastori s) or Pichia pastoris an antibody for use according to any one of the above embodiments, obtained by expression in CGRP antibody.

[0408] E50. The anti-CGRP antibody is expressed in or expressed in CHO cells. for use according to any one of embodiments E1 to E39, obtained by expression in Anti-CGRP antibody.

[0409] E51. The patient is receiving 100 mg or 300 mg of the anti-CGRP antibody every 3 months. 3. The use of an anti-CGRP antibody according to any one of the preceding embodiments,

[0410] E52. The method of any of the above embodiments, wherein the method provides immediate relief of migraine or headache symptoms. 10. Use of an anti-CGRP antibody according to any one of claims 1 to 9.

[0411] E53. The above embodiments wherein the method provides immediate, preventative treatment of migraines or headaches. 10. Use of an anti-CGRP antibody according to any one of claims 1 to 9. [Example]

[0412] The following examples are provided to illustrate the invention but in no way limit the scope of the claims. should not be construed as

[0413] 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 November 29, 2012, the contents of which are incorporated herein by reference. This is disclosed in PCT application WO 2012 / 162243. The application describes the growth 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, and specifically Ab6.

[0414] 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 patients with migraine headache. The ability to inhibit, reduce, or prevent the number, duration, and / or intensity of steroid hormones in human subjects has been evaluated. The Ab6 antibody was evaluated in the V sequence of SEQ ID NO: 222 and SEQ ID NO: 221, respectively. L and light and SEQ ID NO: 202 and SEQ ID NO: 201, respectively. H and heavy chain polypeptide This antibody contains an IgG1 constant region containing 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).

[0415] Specifically, the clinical efficacy of Ab6 antibody was verified in a placebo-controlled, double-blind, randomized trial. All individuals in the study were selected based on specific criteria. In particular, all were aged ≤50 years. He was diagnosed as a migraine patient (ICHD-II, 2004 Section 1) and further screening ≥12 months of migraine headache with ≥5 and ≤14 migraine days in each 28-day period in the 3 months prior to the test There was a medical history.

[0416] Furthermore, in the 3 months before screening and the 28 days before randomization, All individuals enrolled in the study were taking acute migraine medications on ≤14 days per 28 days. and had triptan use ≤10 days per 28 days within these days.

[0417] Table 1 summarizes the demographic characteristics of the study population.

[0418] [Table 1]

[0419] 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 headaches / month, migraine hours / month, migraine severity, and use of any preventive medications such as triptans It was required to be recorded.

[0420] In addition, study participants were asked to record their migraine symptoms for 28 days before treatment with the antibody or placebo. Use e-diary to measure monthly migraine days / hours / episodes baseline This also required the study subjects to be familiar with the use of e-diaries. I was able to become familiar with.

[0421] After the 28-day experiment, the study subjects were divided into two groups containing 80 subjects each (Figure 17 In the first group, 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.

[0422] Individuals in the treatment and placebo groups were evaluated 24 weeks after dose administration. First, at 12 weeks An interim analysis was performed. After the 12-week interim analysis, a detailed analysis was performed. This detailed analysis was performed to assess the potential potentially adding or removing patient data according to, for example, a study protocol, e.g., e-diary This refinement involved updating data that had not been fully loaded from the database. It made a difference, but it didn't change the overall conclusion.

[0423] The efficacy of the antibody compared to placebo was partially determined by the data recorded in the e-diary entries. For example, this analysis was based on the recorded data for subjects in the treatment and placebo groups. Comparisons included the number of migraine days / month, migraine episodes / month, and migraine hours / month. The proportion of responders in each group (i.e., 50%, 75%, and 100% reduction in migraine days) We also compared the results of a few subjects.

[0424] In addition, the response of Ab6 and placebo-treated subjects in both groups to the MSQ and HIT-6 questionnaires was The MSQ is a measure of health-related quality of life (HRQL). It is a disease-specific tool frequently used to assess the impact of migraine. Laxo: A 16-item migraine-specific quality index developed by Wellcome Inc. The MSQ includes the Theology of Life Questionnaire (version 1.0). The MSQ measures three parameters: (ii) role function prevention; and (iii) emotional functioning. can be.

[0425] The HIT-6 or Functional Impact (also called the Headache Impact Test or HIT-6) is similarly This test uses six questions to assess headache intensity. Understand the impact of pain and its treatment on an individual's functional health and well-being.

[0426] In addition, the pharmacokinetic (PK) properties and immunogenicity of CGRP antibodies have been investigated in Ab6 antibody treatment subjects. It is evaluated based on this.

[0427] 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. Meru.

[0428] [Table 2]

[0429] As shown in the figure, 60% of the Ab6 treatment group had at least 50 headache days. % reduction in headache days, 31% of the Ab6-treated group had at least a 75% reduction in headache days, and 10% of the Ab6-treated group had at least a 75% reduction in headache days. 15% had a 100% reduction in headache days.

[0430] In contrast, 33% of the placebo group experienced at least a 50% reduction in headache days; 9% of the patients in the treatment group experienced a reduction in headache days of at least 75%, while 0% of the placebo group experienced no headaches. The number of days was reduced by 100%.

[0431] 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 pronounced. (The placebo effect is enhanced because the phenomenon is often very High, so not surprising).

[0432] Additionally, the number of migraine days per month in the placebo and Ab6 groups decreased from baseline to As shown in Figure 14, the percent change in serotonin levels per month 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 for 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 than the placebo group. This clearly shows that the number of cases has decreased to 100.

[0433] 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 The median (±QR) % change from baseline in the number of migraine episodes per month was assessed by treatment These results showed that the Ab6 group showed better survival than the placebo group. showed a significant increase in the number of migraine episodes per month compared with baseline .

[0434] Furthermore, baseline migraine episode time per month in the placebo and Ab6 groups was The percent change from baseline was compared. As shown in Figure 16, the percent change in the placebo and Ab6 treatment groups The median (±QR) % change from baseline in migraine hours per month was measured for the two groups. These results showed that the Ab6 group had a significantly higher mortality rate than the placebo group. showed a significant reduction in the number of migraine hours per month compared to baseline. do.

[0435] In addition, the HIT-6 results were compared between the two groups. As mentioned above, this questionnaire is a frequently asked question. Well-accepted use in assessing migraine status in individuals with chronic / sexual migraines Figure 18 shows the results at baseline, 4 weeks after treatment, 8 weeks after treatment, and HIT-6 responder analysis was compared between Ab6-treated and placebo groups at 12 weeks post-treatment. The results at each time point showed that the Ab6-treated group had 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. 38.0% in the placebo group (p=0.1094), and Ab The mortality rate was 61.1% for the 6-treatment group compared with 33.3% for the placebo group (p=0.0 007). 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).

[0436] In addition, Figure 20 shows the results of a single 1000 mg intravenous dose of Ab6 administered over 24 weeks. Pharmacokinetic (PK) profiles (in mg / mL) for administered Ab6 are included.

[0437] Figure 21 shows the plasma-free pharmacokinetics (PPK) of Ab6 for a single 1000 mg intravenous dose. PK) parameters N (number of patients), mean, standard deviation (SD) of the parameters shown in the table and The unit is C max (μg / mL), AUC 0-∞ (mg*hr / mL), half-life (days), V z (L) and C L (mL / hr).

[0438] 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 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 answered 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 giving 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

[0439] 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 migraine days (+ / SEM) over time for the entire analysis population (Figure 22). In addition, the changes in the Ab6 treatment group over the 1-4 week period (SD) were included (Figure 23). Distribution of migraine days and changes in the number of migraine days (Figure 24), actual results for the placebo group during weeks 1 to 4 Distribution of migraine days and changes (Figure 25), actual data for Ab6 treatment group during weeks 5-8 Distribution of migraine days and change (Figure 26), actual bias for the placebo group during weeks 5-8 Distribution of headache days and change (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 9-12 The distribution of migraine days and changes over time (Figure 29) is shown.

[0440] Responder rate analysis was also performed (Figures 30-32). 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 experienced a 50% or greater reduction in migraine frequency were considered 50% responders. Subjects who achieve a 100% reduction in migraine frequency are considered 75% responders. A few subjects are considered 100% responders.

[0441] 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. The e-diary for days 21 to 27 was completed by multiplying the numbers.

[0442] 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."

[0443] Figure 34 shows the number of days with migraines, migraine episodes, migraine duration, 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 the change from baseline in outcome measures of the included outcomes.

[0444] Example 3 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. This study describes 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 one IV bolus per month. The criteria for a headache must be 15 days, of which at least 8 days were migraines. Patients enrolled in the trial had an average of 16.1 migraine days at baseline. The study endpoints were the mean change from baseline in the number of monthly 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% reduction from baseline in monthly average acute Change from baseline in number of migraine-specific medication days and the Headache Impact Study (HIT) The study included a reduction from baseline in patient-reported impact scores on the 6-point scale. 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 thiol.

[0445] Patient characteristics are summarized in Figure 39 and are compared between patients receiving placebo, 100 mg antibody, or 300 mg antibody. There is a separate column for patients receiving the medication. The average number of years since the patient's migraine diagnosis is 17.0 The average duration of chronic migraine was 11.5-12.4 years. 44.3% to 45.2% were using at least one preventive medication. In both antibody treatment groups, the average number of migraine days per month was 16.1, while in the placebo group, The average number of migraine days per episode was 16.2.

[0446] 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 had 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 16 migraine days per month. 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.

[0447] The results are shown in Figures 35 to 39. Figure 35 shows the results of the 300m 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.

[0448] As shown in Figure 35, on day 1, the percent reduction in migraine prevalence was 52% for the 300 mg dose. %, 50% with the 100 mg dose, and 27% with placebo. The difference was statistically significant compared to placebo for both the 300 mg and 300 mg treatment groups.

[0449] 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 hours (after the second infusion), respectively. The graphs show the proportion 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 a statistically significant difference from placebo (unadjusted); § indicates a statistically significant difference from placebo Show the difference (post hoc).

[0450] 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, each patient was screened for potential drug overdose at the time of intake. MOH was assessed in 39.9% (13%) of the 100 mg treatment group. 9 patients), 42.0% (147 patients) in the 300 mg treatment group, and 39.6% in the placebo group. (145 patients). Evaluation of treatment outcome in this subset of patients was performed using anti-CGR We demonstrated that treatment with P antibody is effective for MOH (Figure 41). gIn the treatment group, more patients had MOH at baseline compared with patients with MOH who received placebo Patients with a history of migraine headaches had a mean monthly migraine headache of -3.0 days (95% CI, -4.56 to -1.52). Similarly, in the 300 mg treatment group, there was a significant difference compared with MOH patients who received placebo. , mean number of migraine days per month in patients with MOH at baseline was -3.2 days (95% CI, -4.66 to -1.78 days). In contrast, those with MOH at baseline For patients who did not receive placebo at baseline, the 100 mg treatment group Compared with patients without MOH, the mean number of migraine days per month was -1.3 (95% CI, -2.43 to -0.16 days). For patients who received placebo at baseline, the 300 mg treatment group had a higher incidence of MO than those who received placebo at baseline. Compared with patients without H, the mean number of migraine days per month was -2.1 days (95% CI The mean number of migraine days (<17 days or ≥17 days) changed from -3.24 to -0.88 days. patients with a high incidence of migraine headaches, patients under 21 years of age at diagnosis or over 21 years of age, and patients with a high incidence of migraine headaches Patients with a duration of 15 years or less or more than 15 years, migraine with aura or migraine without aura Patients with or without previous prophylactic use, concomitant or Including non-concomitant patients and patients with triptan use ≥ 33% ​​or < 33% of the time. Efficacy was also demonstrated in other subgroups. In each case, efficacy was demonstrated in each subgroup. (Figure 41).

[0451] 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 Drug or placebo was administered intravenously every 3 months for a total of 1 infusion (Figure 40). was demonstrated over 1 to 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) was 9 or less and 9 or more in the 300 mg treatment group. Patients with a high frequency of migraines, patients under 21 years of age at diagnosis or over 21 years of age, and patients with persistent migraines Patients with a duration of 15 years or less or more than 15 years, and patients with migraine with or without aura Efficacy was also demonstrated for subgroups of patients, including those suffering from pain.

[0452] Example 5 Effect of Ab6 treatment on medication use in patients with chronic and episodic migraine 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 also recorded their acute medication use in a daily e-diary and were asked 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.

[0453] For further analysis, patients were randomly assigned to the 28-day screening period (days 1–9 or ≥10; “baseline” Patients were stratified by the number of days of acute medication use (i.e., "sline"). Calculations are made for each type of acute drug and for combinations, i.e., two or more types of drugs at the same time. If the medications were used on the same calendar day, they were counted as separate drug use days. If a steroid and a triptan were taken on the same day, they were counted as two days of acute drug use. These analyses required at least 1 day of acute steroid use during the 28-day baseline screening period. Patients with drug use days were included.

[0454] Patients with chronic and episodic migraine who used acute medication during the 28-day baseline period In both studies, Ab6 treatment demonstrated a significant improvement over placebo as early as 1 month after administration. , resulting in a mean reduction in monthly migraine days and acute medication days, and Similar results were obtained at intervals.

[0455] Ab6 was associated with a significant improvement in patients with chronic migraine who had taken acute medication for at least 1 day during baseline. consistently demonstrated a greater reduction in the average number of monthly migraine days over the 6-month treatment period than placebo The data are shown in Figure 42. Patients with acute drug use at least 1 day per month during baseline Patients with chronic migraine headaches were significantly more likely to experience a placebo response as early as one month after treatment and throughout the treatment period. showed a greater reduction in acute drug use than did the control group (Figure 43). In the subgroup of chronic migraineurs who were taking sexual medications, the number of days of acute medication use was significantly higher than in the control group. Changes from baseline were significantly greater in the 300mg Ab6 group than in placebo over 6 months of treatment (Figure 44) In patients with at least 10 days of medication use at baseline, Over the entire 6-month period, both Ab6 treatment groups had significantly fewer drug days per month compared with placebo. Figure 45 shows that patients with acute drug use for ≥1 day at baseline and 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 significantly more effective than placebo in reducing acute drug use. showed a greater therapeutic effect.

[0456] 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 significant difference in the mean number of migraine days per month with Ab6 compared with placebo. experienced a greater reduction than did the control group (Figure 46). Sudden migraine patients with sexual drug use experienced a significant decrease in pain as early as one month after treatment and throughout the treatment period. 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, Change from baseline in number of 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 time-dependent changes. This may have contributed to the less consistent pattern of variability at baseline. In the subgroups of patients with episodic migraine who had used sexual medication for ≥1 day, 1–9 days, and ≥10 days, Changes in drug use at 1 month and 6 months are shown. The reduction in acute drug use was consistent with placebo, except for Ab6 100 mg at 6 months in patients who were taking was greater in the Ab6-treated group than in the Sebo-treated group.

[0457] The results showed that those at risk for medication overuse headache (≥10 days / month of acute medication use) had a higher risk of developing sudden onset of medication overuse headache. Both acute and chronic migraineurs showed the greatest reduction in acute medication use, with Ab6 therapy Generally, these treatments have been shown to result in a greater reduction in drug use days than placebo.

[0458] The most frequently reported acute headache medication in >10% of subjects was tomapirin N (44.5%). %) (combination of paracetamol, aspirin, and caffeine), ibuprofen ( 40.6%), sumatriptan (33.6%), paracetamol (acetaminophen) (20.3%), and naproxen sodium (10.2%). The most frequently reported preventive headache medication among subjects was topiramate (12.5%). .

[0459] Example 6 Efficacy of anti-CGRP antibodies in subjects experiencing acute migraine attacks This example describes a randomized controlled trial evaluating the safety and efficacy of Ab6 for the acute treatment of migraine. A randomized, double-blind, placebo-controlled clinical trial is described. In this trial, approximately 450 patients Patients will be randomized 1:1 to receive either 100 mg of Ab6 or placebo. During the screening period (approximately 1-8 weeks), patients were asked to report their migraine frequency and medication use. Eligible patients had migraines approximately 4-15 days per month for the 3 months prior to screening. According to medical history, the subject's typical migraine attacks were If not treated, headache of moderate to severe intensity and the most severe symptoms of nausea, photophobia, or phonophobia may occur. To participate in the study, subjects must have had a migraine headache prior to the onset of the target migraine. You must be headache-free for at least 24 hours. Patients will attend a study site and receive an intravenous injection of 100 mg of Ab6 or a placebo until the onset of seizures. The test begins approximately 1-6 hours after the initial screening. Patients must not have had any other Not receiving monoclonal antibodies (e.g., any CGRP antagonist antibody) stomach.

[0460] The co-primary endpoints were time to headache relief and time to relief of the most bothersome symptom. The key co-secondary endpoints were the absence of headache at 2 hours, and The secondary endpoints were the absence of the most bothersome symptom at 2 hours. time at 0, absence of headache at 2 hours, and absence of persistent headache over 24 and 48 hours , use of rescue medications up to 24 and 48 hours, absence of photophobia at 2 hours, absence of phonophobia at 1 hour, absence of nausea at 2 hours, absence of headache at 4 weeks Changes from baseline in Impact Test (HIT 6) and bias at 4 weeks Change from baseline in the headache treatment optimization questionnaire-6 (mTOQ-6). The objective endpoints were absence of headache at all time points except 2 hours, absence of photophobia at all time points except 2 hours, absence of phonophobia at all time points except 2 hours Absence of nausea at all time points, subject's absence of headache at 2 hours, recurrence of pain onset, Patient Global Impression of Change (PGIC) at 4 weeks, and time to next migraine Headaches were collected on a 4-point scale, with 3 being severe, 2 being moderate, and 1 being mild. , where 0 is no pain. Absence of pain is no pain (0) without rescue medication. (In the study, rescue medication was administered at the time of injection to separate the effect of the antibody from the rescue medication.) During the course of normal use, rescue medications may be taken at any time, but should not be used for 2 hours after completion. It may be used selectively; note that any use of rescue medications will be collected as data. (will be done).

[0461] Statistical analysis was performed on time to pain relief and time to relief of most bothersome symptoms, as well as on the and each of the other aforementioned endpoints. This is done to determine the significance of differences in endpoints between the two groups.

[0462] Rescue medication use is any therapeutic intervention given to a subject to provide relief from migraine headaches. In this study, this refers to comparing the effectiveness of the antibody with that of the rescue drug. To separate, rescue medication should be provided no earlier than 2 hours after completion of study medication administration. The proportion of subjects requiring rescue medication was summarized in this study. Acute rescue medications include any drug for treating migraine or migraine-related symptoms, such as thrombus. Liptan, pain relievers such as non-opioid or opioid / narcotic, acetaminophen , NSAIDS, combination drugs such as EXCEDRIN® or EXCED RIN MIGRAINE®, an antiemetic, contains ergotamine, an ergot derivative, etc. .

[0463] Absence of migraine-related symptoms (photophobia, phonophobia, and nausea) was reported by the subject. This refers to the absence or presence of each of the aforementioned migraine-related symptoms. The proportion of symptom-free subjects will be summarized in this study.

[0464] The Headache Impact Test (HIT-6) was evaluated as the change from baseline in the total score. The results will be evaluated, summarized in the study, and compared between treatment groups.

[0465] Migraine Treatment Optimization Questionnaire-6 (mTOQ-6) total score change from baseline These will be assessed as, summarized in the study, and compared between treatment groups.

[0466] Time to headache relief was the time it took for a subject's headache to become moderate or severe (2 or 3) to mild or no pain (1 or 0). Relief of pain was reported and assessed as the first time point after completion of the infusion.

[0467] Pain recurrence was determined by any occurrence within 48 hours of drug administration in patients with no headache (0) at 2 hours. The severity of headache was assessed as the occurrence of headache of any severity. The proportion of participants will be summarized in this study.

[0468] This study demonstrates that Ab6 is effective and safe for the treatment of acute migraine headaches.

[0469] Example 7 In the pivotal clinical trial, patients received either 100 mg or 3 mg of ribozyme as described in Example 3. Patients were administered Ab6 at a dose of 0.00 mg. Statistical analysis included day -1 (after Ab6 infusion). By including it, when the treatment effect is evaluated, a clear treatment effect is present immediately after the injection. In the figure, day 0 is defined as the day of injection, and day -1 is Data represent pre-infusion conditions. A significant reduction in the percentage of headaches is evident. Furthermore, the magnitude of the effect is The 300 mg dose was higher than the 1 g dose, and both showed greater efficacy than the placebo group.

Claims

1. Migraine or headache relief in patients needing immediate relief of migraine or headache symptoms For the treatment or immediate prophylactic treatment of migraines or headaches in patients requiring A method for headache or headache prevention, comprising administering to a patient in need thereof 100 or 30 0 mg of each of the light chain CD4s of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228 R 1, 2, and 3 polypeptide sequences and SEQ ID NO:204; SEQ ID NO:206; and SEQ ID NO: and the heavy chain CDR 1, 2, and 3 polypeptide sequences of each of the heavy chains of No.

208. The method comprises administering the antibody intravenously.

2. wherein the patient is experiencing at least one headache and / or migraine symptom at the time of administration. The method according to claim 1.

3. The at least one headache and / or migraine symptom is pain, nausea, photophobia, or phonophobia. The method of claim 2 , including one or more of the following:

4. 4. The method of claim 3, wherein the pain is a head pain.

5. The most troublesome symptoms occurred within 1 day after administration, within 12 hours after administration, within 6 hours after administration, Within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or Within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration, The method according to any one of claims 2 to 4, wherein the amount of the ion exchange is reduced.

6. The patient is administered within 1 day, 12 hours, 6 hours, or 5 hours after administration. Within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or 1 hour after administration The patient is no longer experiencing migraines after administration, such as within 30 minutes of administration, or within 1 to 6 hours after administration. The method according to any one of claims 2 to 5, wherein the method does not have

7. The anti-CGRP antibodies are SEQ ID NO:234; SEQ ID NO:236; and SEQ ID NO:23 8 and the light chain CDR 1, 2, and 3 polypeptide sequences encoded by the sequences SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218 10. The method of any one of the preceding claims, comprising two, two, and three polypeptide sequences.

8. 2. The method of claim 1, wherein the anti-CGRP antibody comprises a variable light chain polypeptide of SEQ ID NO:

222.

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

9. the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO:232 10. The method of any one of the preceding claims, comprising:

10. 20. The method of claim 1, wherein the anti-CGRP antibody comprises a variable heavy chain polypeptide of SEQ ID NO:

202.

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

11. the anti-CGRP antibody comprises a variable heavy chain polypeptide encoded by SEQ ID NO:212 10. The method of any one of the preceding claims, comprising:

12. the anti-CGRP antibody comprising a variable light chain polypeptide of SEQ ID NO: 222 and a variable light chain polypeptide of SEQ ID NO: 202 10. The method of any one of the preceding claims, comprising a variable heavy chain polypeptide.

13. the anti-CGRP antibody comprises a variable light chain polypeptide encoded by SEQ ID NO:232 and and a variable heavy chain polypeptide encoded by SEQ ID NO:

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

14. 2. The anti-CGRP antibody of claim 1, wherein the anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO:

221.

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

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

231.

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

16. the anti-CGRP antibody comprises the heavy chain polypeptide of SEQ ID NO:201 or SEQ ID NO:566 10. The method of any one of the preceding claims, comprising:

17. The anti-CGRP antibody is encoded by SEQ ID NO: 211 or SEQ ID NO:

567.

10. The method of any one of the preceding claims, comprising a heavy chain polypeptide.

18. the anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221 and the light chain polypeptide of SEQ ID NO: 201 or and a heavy chain polypeptide of SEQ ID NO:

566. 。

19. the anti-CGRP antibody and the light chain polypeptide encoded by SEQ ID NO:231 and the heavy chain polypeptide encoded by SEQ ID NO:211 or SEQ ID NO:

567.

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

20. The method of the preceding claim, wherein the intravenous administration is infused over a period of about 30 to 60 minutes.

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

21. The headache or migraine symptoms occur within 1 day, 12 hours, or 6 hours after administration. , within 5 hours after administration, within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or Immediately after administration, such as within 1 hour after administration, within 30 minutes after administration, or 1 to 6 hours after administration 10. The method of any one of the preceding claims, wherein the number of steps is reduced or eliminated to

22. 10. The method of claim 9, wherein the patient is headache-free 2 hours after completion of the infusion. How to post.

23. Every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 weeks 10. The method of claim 1, further comprising intravenously administering 100 mg of said anti-CGRP antibody.

10. The method according to claim 1.

24. every 10 to 14 weeks, preferably every 11 to 13 weeks, more preferably every 12 weeks 23. The method of any one of claims 1 to 22, further comprising intravenously administering 100 mg of said anti-CGRP antibody. The method according to any one of claims 1 to 5.

25. The anti-CGRP antibody is preferably a soluble form of histidine (L-histidine), sorbitol, polysorbate 80, and water. The method described in paragraph .

26. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histoconazole per mL volume. stigma, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or consisting of, or having an amount of each component within + / - 10% of the aforementioned values; and 26. The method of claim 25, having a pH of 5.8 or within + / - 10% of said value. Law.

27. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histoconazole per mL volume. stigma, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 and / or consisting of, or having amounts of each component within + / - 5% of the aforementioned values; 26. The method of claim 25, wherein the pH is 5.8 or within + / - 5% of said value. Law.

28. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histoconazole per mL volume. stigma, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 and / or consisting of, or having amounts of each component within + / - 1% of the aforementioned values; 26. The method of claim 25, wherein the pH is 5.8 or within + / - 1% of said value. Law.

29. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histoconazole per mL volume. stigma, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or consisting of, or having an amount of each component within + / - 0.5% of the aforementioned values; and and / or a pH of 5.8 or within + / - 0.5% of said value. The method described.

30. The formulation contains 100 mg of anti-CGRP antibody, 3.1 mg of L-histoconazole per mL volume. stigma, 40.5 mg sorbitol, and 0.15 mg polysorbate 80 or consisting of, or having an amount of each component within + / - 0.1% of the aforementioned values; and and / or a pH of 5.8 or within + / - 0.1% of said value. The method described.

31. The L-histidine in the formulation is a mixture of L-histidine and L-histidine monohydrate. The method of any one of claims 25 to 30, comprising a mixture of

32. The 3.1 mg of histidine in the formulation is composed of L-histidine (1 mg) and L-histidine (1 mg). The final formulation contained a mixture of 2.8 mg of thiazolidine monohydrate and 2.8 mg of thiazolidine monohydrate, which totaled 3 1 mg of L-histidine free base. Law.

33. The formulation is contained in a 100 mg / mL single dose vial, where each mL contains 5. At a pH of 8, 100 mg of anti-CGRP antibody, L-histidine (1 mg), L-histidine Hydrochloride monohydrate (2.8 mg), polysorbate 80 (0.15 mg), sorbitol ( 40.5 mg), and water for injection, USP. The method described.

34. The formulation is contained in a 300 mg / mL single dose vial, where each mL contains 5. At a pH of 8, 300 mg of anti-CGRP antibody, L-histidine (1 mg), L-histidine Hydrochloride monohydrate (2.8 mg), polysorbate 80 (0.15 mg), sorbitol ( 40.5 mg), and water for injection, USP. The method described.

35. The migraine or headache is an acute migraine or headache, an aura-associated migraine or headache, pain, chronic migraine, episodic migraine, chronic / episodic migraine, hemiplegic migraine, cluster headache, migraine Headache-like neuralgia, chronic headache, tension headache, general headache, caused by underlying structural problems in the head and neck headaches associated with sinusitis, sinus headaches (e.g., those associated with sinusitis), and allergy-induced headaches 10. The method according to any one of the preceding claims, wherein the headache is selected from the group comprising headache, sexual headache or migraine. 。

36. The patient has a pain level of at least 2 on the VRS-4 at the time of administration of the antibody.

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

37. The patient has a pain level of at least 3 on the VRS-4 at the time of administration of the antibody.

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

38. The patient is administered within 1 day, 12 hours, 6 hours, or 5 hours after administration. Within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or 1 hour after administration VRS-4 immediately after administration, such as within 30 minutes after administration, or 1 to 6 hours after administration.

38. The method of any one of claims 1 to 37, wherein the patient presents with a pain level of 2 or less in a pain assessment.

39. The patient is administered within 1 day, 12 hours, 6 hours, or 5 hours after administration. Within 4 hours after administration, within 3 hours after administration, within 2 hours after administration, or 1 hour after administration VRS-4 immediately after administration, such as within 30 minutes after administration, or 1 to 6 hours after administration.

10. The method of any one of the preceding claims, wherein the patient presents a pain level of 1 or less in the

40. The patient is given the following information within 15 minutes, 30 minutes, 1 hour, 2 hours, or 3 hours before or after administration: Within a predetermined period before or after the administration, such as within 4 hours, 5 hours, or 6 hours.

10. The method of any one of the preceding claims, wherein no acute migraine medication is administered.

41. The acute migraine medication is a triptan, an analgesic, e.g., a non-opioid or opioid / Narcotics, acetaminophen, NSAIDs, combination medications, ergotamine, or ergot derivatives 41. The method of claim 40, comprising a body.

42. The non-opioid analgesic is paracetamol (acetaminophen), acetylsalicylic acid, or the like. triproline (aspirin), another NSAID, or another non-opioid analgesic; The drugs include sumatriptan, zolmitriptan, naratriptan, rizatriptan, and eret including the use of one or more of triptan, almotriptan, or frovatriptan; The opioids are oxycodone, tramadol, butorphanol, morphine, and codeine. and hydrocodone; wherein the combination drug provides an analgesic effect. two drugs (e.g. paracetamol and codeine), analgesics and adjuvants (e.g. , paracetamol and caffeine), and / or said combination analgesic comprises at least Each opioid (tramadol, butorphanol, morphine, codeine, hydrochloride) codon, or any combination thereof), barbiturates, e.g., butalbital and / or caffeine, and / or the combined analgesic agent is acetylsalicyl acid (aspirin), paracetamol and caffeine (EXCEDRIN®, E 42. The method of claim 41, comprising XCEDRIN MIGRAINE®.

43. 10. The method of claim 1, wherein the patient is receiving or has received an additional migraine medication.

40. The method according to any one of claims 1 to 39.

44. the patient experiences an additional migraine headache before, concurrently with, or after administration of the anti-CGRP antibody 44. The method of any one of claims 1 to 39 or 43, wherein a drug is administered.

45. The patient is administered the anti-CGRP antibody within 15 minutes, 30 minutes, 1 hour, 2 hours, or 2 minutes before or after the administration. within 3 hours, within 4 hours, within 5 hours, or within 6 hours, Claims 1 to 39 or 43, wherein an additional migraine medication is administered within a predetermined period before or after administration of the antibody.

45. The method according to any one of claims 1 to 44.

46. 46. ​​The method of claim 44 or 45, wherein the additional migraine medication comprises an acute and / or chronic migraine medication. How to post.

47. The additional migraine medication may be a triptan, an analgesic, e.g., a non-opioid or an opioid. / Narcotics, acetaminophen, NSAIDs, combination medications, ergotamine, or ergot allergies The method of any one of claims 44 to 46, comprising a conductor.

48. The non-opioid analgesic is paracetamol (acetaminophen), acetylsalicylic acid, or the like. triproline (aspirin), another NSAID, or another non-opioid analgesic; The drugs include sumatriptan, zolmitriptan, naratriptan, rizatriptan, and eret including the use of one or more of triptan, almotriptan, or frovatriptan; The opioids are oxycodone, tramadol, butorphanol, morphine, and codeine. and hydrocodone; wherein the combination drug provides an analgesic effect. two drugs (e.g. paracetamol and codeine), analgesics and adjuvants (e.g. , paracetamol and caffeine), and / or said combination analgesic comprises at least Each opioid (tramadol, butorphanol, morphine, codeine, hydrochloride) codon, or any combination thereof), barbiturates, e.g., butalbital and / or caffeine, and / or the combined analgesic agent is acetylsalicyl acid (aspirin), paracetamol and caffeine (EXCEDRIN®, E 48. The method of claim 47, comprising XCEDRIN MIGRAINE®.

49. The anti-CGRP antibody is capable of inhibiting the growth of Pichia pastoris. or in Pichia pastoris 10. The method according to any one of the preceding claims, obtained by expression.

50. The anti-CGRP antibody is expressed in CHO cells or The method according to any one of claims 1 to 48, wherein the method is obtained by

51. The patient receives 100 mg or 300 mg of the anti-CGRP antibody every three months.

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

52. 10. Any one of the preceding claims, wherein the method provides immediate relief of migraine or headache symptoms. The method described below.

53. 10. The method of claim 1, wherein the method provides immediate prophylactic treatment of migraines or headaches. The method described in paragraph .

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