Use of an antibody in the preparation of a medicament for treating or preventing migraine

Abstract

The present invention relates to the use of an antibody in the preparation of a medicament for treating or preventing migraine. The present invention relates to a method for preventing migraine using an anti-CGRP receptor antibody or binding fragment. Specifically, the present invention discloses a method for preventing or reducing the occurrence of migraine in a patient in need thereof, the method comprising administering to the patient an anti-CGRP receptor or binding fragment according to a specific dosage regimen. The present invention also describes a pharmaceutical composition and an administration device comprising an anti-CGRP receptor antibody or binding fragment for use in the method.

Description

[0001] This application is a divisional application. The filing date of the original application is August 10, 2015, the application number is 201580081186.0 (PCT / US2015 / 044479), and the invention title is "Use of Antibodies in the Preparation of a Medicament for the Treatment or Prevention of Migraine".

[0002] Cross - reference to related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 152,708, filed on April 24, 2015, which is incorporated herein by reference in its entirety.

[0004] Description of text files submitted electronically

[0005] This application contains a sequence listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. A machine - readable copy of the sequence listing was created on August 3, 2015, named A - 1945 - WO - PCT_ST25.txt and is 134 kilobytes in size. Field of the invention

[0006] The present invention relates to the fields of neurology and biopharmaceutics. Specifically, the present invention relates to the prophylactic treatment of migraine using antibodies that selectively inhibit the human calcitonin gene - related peptide (CGRP) receptor. Background of the invention

[0007] Migraine is a complex and common neurological disorder characterized by severe, paroxysmal attacks of headache and associated features, which may include nausea, vomiting, sensitivity to light, sound, or movement. In some patients, sensory warning signs or symptoms (i.e., aura) occur before or accompany the headache. In certain patients, the headache can be severe and also unilateral. Migraine attacks are disruptive to daily life and cost billions of dollars annually in terms of missed workdays and impaired performance (Modi and Lowder, Am. Fam. Physician, Vol. 73:72 - 78, 2006).

[0008] Migraine is a very prevalent disorder worldwide, with approximately 15% of the European population and 12% of the US population suffering from migraine attacks (Lipton et al., Neurology, Vol. 68:343-349, 2007). Additionally, migraine has been found to be associated with a variety of mental and medical comorbidities, such as depression and vascular disorders (Buse et al., Neurol. Neurosurg. Psychiatry, Vol. 81:428-432, 2010; Bigal et al., Neurology, Vol. 72:1864-1871, 2009).

[0009] Migraine is typically acutely treated primarily with analgesics and a class of drugs called triptans (Humphrey et al., Ann NY Acad Sci., Vol. 600:587-598, 1990; Houston and Vanhoutte, Drugs, Vol. 31:149-163 1986). Triptans are selective serotonin 5-HT1B / 1D agonists, are effective drugs for acute migraine and are generally well tolerated, but are contraindicated in the presence of cardiovascular disease due to the potential to cause coronary vasoconstriction. Additionally, many migraine patients do not have a favorable response to triptans. In a meta-analysis of 53 trials, up to one-third of all people with migraine and 40% of all migraine attacks do not respond to triptans (Ferrari et al., Lancet, Vol. 358:1668-1675, 2001).

[0010] Migraine prophylaxis is an area of unmet need. Approximately 40% of the migraine patient population would benefit from prophylactic therapy (Lipton et al., Neurology, Vol. 68:343 - 349, 2007). However, only about 12% of patients receive any prophylactic therapy, in part due to the limited efficacy of available prophylactic therapies and significant tolerability and safety issues. In the United States, topiramate, an anticonvulsant that blocks voltage - dependent sodium channels and certain glutamate receptors (AMPA - kainate), is the most commonly used drug for migraine prophylaxis. Topiramate is the only migraine prophylaxis agent shown to be effective in episodic and chronic migraine patients in randomized placebo - controlled trials (Diener et al., Cephalalgia, Vol. 27:814 - 823, 2007; Silberstein et al., Headache, Vol. 47:170 - 180, 2007). However, approximately 50% of patients do not respond to topiramate and it has poor tolerability. Common adverse events associated with topiramate treatment include paresthesia, anorexia, and cognitive adverse events, including psychomotor retardation, somnolence, language difficulties, and difficulties with memory and concentration (Brandes et al., JAMA, Vol. 291:965 - 973, 2004; Adelman et al., Pain Med., Vol. 9:175 - 185, 2008; Silberstein et al., Arch Neurol., Vol. 61:490 - 495, 2004). In an open - label, variable - dose study, 20% of patients discontinued topiramate due to adverse effects (Nelles et al., Headache, Vol. 49:1454 - 1465, 2009).

[0011] Accordingly, there is a pressing need for more effective and / or tolerable treatment options for migraine patients. SUMMARY OF THE INVENTION

[0012] The present invention is based in part on the identification of a treatment regimen for effectively reducing the frequency, severity, and / or duration of migraine in patients in need, with no or minimal adverse side effects. Accordingly, in one embodiment, the present invention provides a method for preventing or reducing the occurrence of migraine in a patient in need, the method comprising administering to the patient an anti - CGRP receptor antibody or antigen - binding fragment thereof in a dose of about 35 mg to about 210 mg per month. In some embodiments, the present invention provides a method for prophylactically treating migraine in a patient, the method comprising administering to the patient an anti - CGRP receptor antibody or antigen - binding fragment thereof in a dose of about 35 mg to about 210 mg per month.

[0013] In some embodiments of the method, the dose of the anti-CGRP receptor antibody or binding fragment thereof administered to the patient is sufficient to reduce the number of migraine days per month experienced by the patient compared to the number of migraine days per month prior to treatment or the number of migraine days per month experienced by a patient not receiving the anti-CGRP receptor antibody or binding fragment thereof. In some embodiments, the dose of the anti-CGRP receptor antibody or binding fragment thereof administered to the patient is sufficient to reduce the number of migraine days per month experienced by the patient by at least 50% compared to the number of days prior to treatment or the number of days experienced by a patient not receiving the anti-CGRP receptor antibody or binding fragment thereof.

[0014] In certain embodiments of the method, the dose of the anti-CGRP receptor antibody or binding fragment thereof administered to the patient is sufficient to reduce the number of migraine hours per month experienced by the patient compared to the number of migraine hours per month prior to treatment or the number of migraine hours per month experienced by a patient not receiving the anti-CGRP receptor antibody or binding fragment thereof. In certain other embodiments of the method, the dose of the anti-CGRP receptor antibody or binding fragment thereof administered to the patient is sufficient to reduce the number of days of use of migraine-specific medications per month experienced by the patient compared to the number of days of use of migraine-specific medications per month prior to treatment or the number of days of use of migraine-specific medications per month experienced by a patient not receiving the anti-CGRP receptor antibody or binding fragment thereof.

[0015] In some embodiments of the method, the dose of the anti-CGRP receptor antibody or binding fragment thereof administered to the patient is sufficient to reduce the number of days of physical impairment due to migraine experienced by the patient compared to the number of days prior to treatment or the number of days experienced by a patient not receiving the anti-CGRP receptor antibody or binding fragment thereof. In other embodiments, the dose of the anti-CGRP receptor antibody or binding fragment thereof administered to the patient is sufficient to reduce the impact of migraine on daily activities compared to the impact prior to treatment or the impact experienced by a patient not receiving the anti-CGRP receptor antibody or binding fragment thereof. The physical impairment due to migraine and the impact of migraine on daily activities can be evaluated using a variety of validated questionnaires as described herein.

[0016] In certain embodiments of the method, the dose sufficient to reduce the number of migraine days per month, the number of migraine hours per month, the number of days of migraine-specific medication use per month, the physical impairment due to migraine, and / or the impact of migraine on daily activities in a patient in need thereof is from about 35 mg to about 210 mg per month. In some embodiments, the sufficient dose is from about 70 mg to about 140 mg per month. In one specific embodiment, the sufficient dose is about 70 mg per month. In another specific embodiment, the sufficient dose is about 140 mg per month. In these and other embodiments, the dose of the anti-CGRP receptor antibody or binding fragment thereof is administered once monthly (QM).

[0017] In some embodiments of the methods described herein, administration of the described dosages of an anti-CGRP receptor antibody or binding fragment thereof does not substantially cause adverse side effects in a patient. Specifically, administration of the described dosages of an anti-CGRP receptor antibody or binding fragment thereof does not substantially cause adverse side effects associated with other migraine prophylactic treatments, including adverse side effects associated with anti-seizure medications, β-blockers, and antidepressants. In certain embodiments, the number and type of adverse side effects associated with administration of an anti-CGRP receptor antibody or binding fragment are not statistically different from the number and type of adverse side effects associated with administration of a placebo.

[0018] In certain embodiments of the methods described herein, an anti-CGRP receptor antibody or binding fragment thereof is administered to a patient parenterally. In a particular embodiment, the anti-CGRP receptor antibody or binding fragment thereof is administered to the patient by subcutaneous injection. In one embodiment, the subcutaneous injection is a rapid injection administered to the patient once a month. The subcutaneous injection can be delivered to the patient using a prefilled syringe or an autoinjector containing a monthly dose of the anti-CGRP receptor antibody or binding fragment thereof.

[0019] In some embodiments, a patient to whom an anti-CGRP receptor antibody or binding fragment thereof is to be administered according to the methods of the invention has or has been diagnosed with episodic migraine. The episodic migraine can be low-frequency episodic migraine or high-frequency episodic migraine. In other embodiments, a patient to whom an anti-CGRP receptor antibody or binding fragment thereof is to be administered according to the methods of the invention has or has been diagnosed with chronic migraine.

[0020] In certain embodiments of the methods of the invention, a patient to whom an anti-CGRP receptor antibody or binding fragment thereof is to be administered has not previously received any prophylactic therapy for migraine (i.e., the patient is treatment-naïve). In other embodiments of the methods of the invention, a patient to whom an anti-CGRP receptor antibody or binding fragment thereof is to be administered has failed or is intolerant to at least one other migraine prophylactic therapy. Thus, in some embodiments, a patient to whom an anti-CGRP receptor antibody or binding fragment thereof is to be administered has failed or is intolerant to at least one anti-seizure medication (e.g., topiramate, valproic acid), a tricyclic antidepressant (e.g., amitriptyline), a β-blocker (e.g., propranolol, timolol), or botulinum toxin A. In one embodiment, the patient has failed or is intolerant to two previous migraine prophylactic therapies. In another embodiment, the patient has failed or is intolerant to three previous migraine prophylactic therapies.

[0021] In any embodiment of the methods disclosed herein, the anti-CGRP receptor antibody or antigen-binding fragment thereof specifically binds to an epitope formed by amino acids in the human CRLR and human RAMP1 polypeptide components of the human CGRP receptor and selectively inhibits the human CGRP receptor as compared to the human AM1, AM2, and / or amylin receptors. In some embodiments, the anti-CGRP receptor antibody or antigen-binding fragment specifically binds to the human CGRP receptor and K D ≤ 100 nM. In other embodiments, the anti-CGRP receptor antibody or antigen-binding fragment specifically binds to the human CGRP receptor and K D ≤ 10 nM.

[0022] In one embodiment, the anti-CGRP receptor antibody or antigen-binding fragment thereof administered to a patient according to the method of the invention comprises a CDRH1 having the sequence of SEQ ID NO:14, a CDRH2 having the sequence of SEQ ID NO:23, a CDRH3 having the sequence of SEQ ID NO:34, a CDRL1 having the sequence of SEQ ID NO:44, a CDRL2 having the sequence of SEQ ID NO:55, and a CDRL3 having the sequence of SEQ ID NO:65. In another embodiment, the anti-CGRP receptor antibody or antigen-binding fragment thereof administered to a patient according to the method of the invention comprises a CDRH1 having the sequence of SEQ ID NO:15, a CDRH2 having the sequence of SEQ ID NO:29, a CDRH3 having the sequence of SEQ ID NO:35, a CDRL1 having the sequence of SEQ ID NO:45, a CDRL2 having the sequence of SEQ ID NO:61, and a CDRL3 having the sequence of SEQ ID NO:66.

[0023] The anti-CGRP receptor antibody or binding fragment thereof suitable for use in the methods of the invention may comprise a heavy chain variable region having the sequence of SEQ ID NO:92 and a light chain variable region having the sequence of SEQ ID NO:80. In some embodiments, the anti-CGRP receptor antibody or binding fragment thereof for use in the methods of the invention comprises a heavy chain variable region having the sequence of SEQ ID NO:98 and a light chain variable region having the sequence of SEQ ID NO:84. In certain embodiments, the anti-CGRP receptor antibody has a human IgG1 constant region or a human IgG2 constant region. In one embodiment, the anti-CGRP receptor antibody comprises a heavy chain having the sequence of SEQ ID NO:105 and a light chain having the sequence of SEQ ID NO:123. In another embodiment, the anti-CGRP receptor antibody comprises a heavy chain having the sequence of SEQ ID NO:111 and a light chain having the sequence of SEQ ID NO:127.

[0024] Any of the specific antibodies or antigen-binding fragments thereof described in Table 7 herein can be used in the methods of the present invention. In certain embodiments, the anti-CGRP receptor antibody or binding fragment administered to a patient according to the methods of the present invention is the 4E4 antibody or a binding fragment thereof. In other embodiments, the anti-CGRP receptor antibody or binding fragment administered to a patient according to the methods of the present invention is the 9F5 antibody or a binding fragment thereof.

[0025] The present invention also provides pharmaceutical compositions of anti-CGRP receptor antibodies or binding fragments thereof for use in the methods described herein. The pharmaceutical compositions can comprise one or more pharmaceutically acceptable diluents, carriers, or excipients, including buffers, surfactants, and stabilizers. In certain embodiments, the pharmaceutical composition comprises an anti-CGRP receptor antibody or binding fragment thereof, a buffer, a surfactant, and a stabilizer. In one embodiment, the pharmaceutical composition comprises an anti-CGRP receptor antibody or binding fragment thereof, an acetate buffer, polysorbate 20 or polysorbate 80, and sucrose. Any of the pharmaceutical compositions described herein can be incorporated into a self-administration device, such as a prefilled syringe or an autoinjector, for administration to a patient (e.g., subcutaneously) according to the methods described herein.

[0026] Accordingly, the present invention also includes a prefilled syringe or an autoinjector for prophylactically treating migraine in a patient in need thereof, the prefilled syringe or autoinjector comprising a pharmaceutical composition comprising an anti-CGRP receptor antibody or binding fragment thereof, an acetate buffer, sucrose, and polysorbate. In some embodiments, the pharmaceutical composition comprised in the prefilled syringe or autoinjector comprises from about 70 mg / ml to about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, from about 10 mM to about 15 mM sodium acetate, from about 0.008% to about 0.012% w / v polysorbate, and from about 8% to about 9% w / v sucrose, and has a pH of from about 4.8 to about 5.5. In certain embodiments, the injection volume of the prefilled syringe or autoinjector is about 1 ml or less.

[0027] In some embodiments, the present invention also provides kits comprising the pharmaceutical compositions or self-administration devices disclosed herein and instructions regarding the use of the pharmaceutical compositions or self-administration devices, e.g., to deliver a therapeutically effective dose by subcutaneous injection to prophylactically treat migraine in a patient in need thereof. In embodiments where the pharmaceutical composition is provided in a lyophilized or dry powder form, the kit can comprise a diluent and instructions regarding reconstitution of the pharmaceutical composition prior to administration.

[0028] Specifically covered is the use of an anti-CGRP receptor antibody or a binding fragment thereof, which is for any of the methods disclosed herein or for the preparation of a medicament for administration according to any of the methods disclosed herein. For example, the present invention includes an anti-CGRP receptor antibody or a binding fragment thereof in a method for preventing or reducing the occurrence of migraine in a patient in need thereof, wherein the method comprises administering to the patient a dose of the anti-CGRP receptor antibody or a binding fragment thereof of about 35 mg to about 210 mg per month. The present invention also includes an anti-CGRP receptor antibody or a binding fragment thereof in a method for prophylactically treating migraine in a patient, wherein the method comprises administering to the patient a dose of the anti-CGRP receptor antibody or a binding fragment thereof of about 35 mg to about 210 mg per month.

[0029] The present invention also includes the use of an anti-CGRP receptor antibody or a binding fragment thereof for the preparation of a medicament for preventing or reducing the occurrence of migraine in a patient in need thereof, wherein the dose of the anti-CGRP receptor antibody or binding fragment is about 35 mg to about 210 mg per month. The present invention further includes the use of an anti-CGRP receptor antibody or a binding fragment thereof for the preparation of a medicament for prophylactically treating migraine in a patient, wherein the dose of the anti-CGRP receptor antibody or binding fragment is about 35 mg to about 210 mg per month. Brief Description of the Drawings

[0030] Figure 1 Shows the percentage inhibition of capsaicin-induced dermal blood flow (DBF) as a function of serum concentration of AMG 334 monoclonal antibody in healthy human subjects and migraine patients.

[0031] Figure 2 Illustrates the percentage inhibition of capsaicin-induced dermal blood flow (DBF) and the serum concentration of AMG 334 monoclonal antibody as a function of time after single and repeated doses (once every four weeks; Q4W) of AMG 334 were administered subcutaneously (SC) to healthy human subjects and migraine patients. The duration of maximum DBF inhibition conforms to the dose-concentration - DBF relationship.

[0032] Figure 3A Shows the mean serum AMG 334 concentration-time curves in healthy human subjects (HS) and migraine patients (MP) receiving single escalating doses of AMG 334 or matching placebo subcutaneously (SC) or intravenously (IV).

[0033] Figure 3B Shows the mean serum AMG 334 concentration-time curves in healthy human subjects (HS) and migraine patients (MP) receiving multiple doses of AMG 334 or placebo subcutaneously (SC) on Day 1, Day 29, and Day 57.

[0034] Figure 4A Shows the percentage of capsaicin-induced inhibition of skin blood flow in healthy subjects and migraine patients four days after a single subcutaneous (SC) dose of AMG 334 or placebo in a single ascending dose study.

[0035] Figure 4B Shows the percentage of capsaicin-induced inhibition of skin blood flow in healthy subjects and migraine patients eight days after the first of three subcutaneous (SC) doses of AMG 334 or placebo in a multiple-dose study.

[0036] Figure 5 Shows the change in the mean number of monthly migraine days relative to baseline in episodic migraine patients receiving placebo or one of three monthly subcutaneous doses (7 mg, 21 mg, or 70 mg) of AMG 334, a human monoclonal antibody against the CGRP receptor.

[0037] Figure 6 Shows the change in the number of days of use of acute migraine-specific medications (e.g., triptans, ergotamines) relative to baseline in episodic migraine patients receiving placebo or one of three monthly subcutaneous doses (7 mg, 21 mg, or 70 mg) of a human monoclonal antibody against the CGRP receptor (AMG 334).

[0038] Figure 7A Shows the change in the mean number of monthly migraine days relative to baseline in patients with infrequent episodic migraine (fewer than 8 migraine days at baseline) and frequent episodic migraine (8 or more migraine days at baseline) receiving placebo or monthly subcutaneous injection of 70 mg of an anti-CGRP receptor antibody (AMG 334).

[0039] Figure 7B Shows the change in the mean number of monthly migraine days relative to baseline in episodic migraine patients who are untreated or have failed previous prophylactic migraine treatment and who receive placebo or monthly subcutaneous injection of 70 mg of an anti-CGRP receptor antibody (AMG 334).

[0040] Figure 8Shows the change in mean monthly migraine days relative to baseline in patients with episodic migraine who received either placebo or one of three monthly subcutaneous doses (7 mg, 21 mg, or 70 mg) of an anti-CGRP receptor antibody (AMG 334). After the 12-week double-blind period of the study, patients in each of the four treatment groups received a 70 mg subcutaneous dose of the anti-CGRP receptor antibody monthly during the open-label extension period of the study. Data are shown as least mean squares and standard errors during the double-blind period and as means and standard errors during the open-label extension period.

[0041] Figure 9A Shows the change in mean monthly headache days relative to baseline in patients with episodic migraine who received either placebo or one of three monthly subcutaneous doses (7 mg, 21 mg, or 70 mg) of an anti-CGRP receptor antibody (AMG 334). After the 12-week double-blind period of the study, patients in each of the four treatment groups received a 70 mg subcutaneous dose of the anti-CGRP receptor antibody monthly during the open-label extension period of the study. Data are shown as least mean squares and standard errors during the double-blind period and as means and standard errors during the open-label extension period.

[0042] Figure 9B Shows the change in days of use of migraine-specific medications (e.g., triptans, ergotamine) relative to baseline in patients with episodic migraine who received either placebo or one of three monthly subcutaneous doses (7 mg, 21 mg, or 70 mg) of an anti-CGRP receptor antibody (AMG 334). After the 12-week double-blind period of the study, patients in each of the four treatment groups received a 70 mg subcutaneous dose of the anti-CGRP receptor antibody monthly during the open-label extension period of the study. Data are shown as least mean squares and standard errors during the double-blind period and as means and standard errors during the open-label extension period. Detailed description

[0043] Current therapies available for treating migraine in human patients have a poor risk-benefit profile due to adverse side effects that many patients cannot tolerate or refuse to tolerate. The present invention addresses this problem in part by providing novel anti-CGRP receptor antibody regimens that provide effective migraine prophylaxis and have no or minimal side effects. The methods of the present invention described herein can effectively reduce the frequency, severity, and / or duration of migraine in patients suffering from episodic migraine as well as chronic migraine.

[0044] Migraine is a recurrent headache that lasts from about 4 to about 72 hours, characterized by unilateral, pulsating, and / or moderate to severe pain and / or pain exacerbated by physical activity. Migraine is often accompanied by nausea, vomiting, and / or sensitivity to light (photophobia), sound (phonophobia), or smell. In some patients, an aura occurs before a migraine attack. An aura is usually a visual, sensory, language, or motor disturbance that signals the impending onset of a headache. The methods described herein prevent, treat, or improve one or more symptoms of migraine in human patients, with or without an aura.

[0045] In one embodiment, the present invention provides a method for preventing or reducing the occurrence of migraine in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or an antigen-binding fragment thereof. The term "patient" includes human patients. As used herein, "preventing or reducing the occurrence of migraine" means reducing the frequency, duration, or severity of migraine compared to the frequency, duration, or severity of migraine before administration of the composition or compared to the frequency, duration, or severity of migraine in patients who have not received the composition (i.e., control subjects). Thus, in certain embodiments, the present invention provides a method for prophylactically treating migraine in a patient, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or an antigen-binding fragment thereof. "Prophylactic treatment" refers to a treatment designed to be administered before the onset of a migraine attack to reduce the frequency, severity, and / or duration of migraine in a patient. In some embodiments, prophylactic treatment may increase the effectiveness of acute migraine-specific medications or the patient's response to acute migraine-specific medications.

[0046] In some embodiments of the methods of the present invention, administration of an anti-CGRP receptor antibody or a binding fragment thereof reduces the number of migraine days experienced by the patient within one month compared to the number of days before administration of the anti-CGRP receptor antibody or binding fragment (i.e., pre-treatment baseline) and / or compared to the number of days experienced by patients who have not received the anti-CGRP receptor antibody or binding fragment. "Migraine days" includes any calendar day on which a patient experiences an attack, persistence, or recurrence of "migraine", with or without an aura lasting more than 30 minutes. "Migraine" is a headache accompanied by nausea or vomiting or sensitivity to light or sound, and / or a headache characterized by at least two of the following pain characteristics: unilateral pain, throbbing pain, moderate to severe pain intensity, or pain exacerbated by physical activity. The pre-treatment baseline can be established by measuring relevant parameters (such as migraine days) in the one month, two months, three months, four months, five months, or six months or longer before administration of the anti-CGRP receptor antibody or binding fragment. In some embodiments, the pre-treatment baseline is established based on measurements of a specific parameter in the three months before administration of the anti-CGRP receptor antibody or binding fragment.

[0047] In certain embodiments, the number of monthly migraine days experienced by a patient after administration of an anti-CGRP receptor antibody or binding fragment is reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% or about 60% compared to the pre-treatment baseline and / or a control subject (i.e., a patient who has not received the antibody or binding fragment). In some embodiments, the number of monthly migraine days experienced by a patient after administration of an anti-CGRP receptor antibody or binding fragment is reduced by 65% or more, such as at least about 70%, at least about 75% or at least about 80%, compared to the pre-treatment baseline and / or a control subject. In one embodiment, the number of monthly migraine days experienced by a patient after administration of an anti-CGRP receptor antibody or binding fragment is reduced by at least 50%. In another embodiment, the number of monthly migraine days experienced by a patient after administration of an anti-CGRP receptor antibody or binding fragment is reduced by at least 75%.

[0048] Reduction in migraine occurrence can also be evaluated by a reduction in the number of migraine hours experienced by a patient in a month compared to the number of hours experienced at pre-treatment baseline and / or by a patient who has not received an anti-CGRP receptor antibody or binding fragment. "Migraine hours" are any hours during which a patient experiences a "migraine" attack, persists or recurs, with or without aura. In certain embodiments, administration of an anti-CGRP receptor antibody or its binding fragment reduces the number of monthly migraine hours experienced by a patient by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% or at least about 70% compared to the number in a pre-treatment baseline and / or a control subject who has not received an anti-CGRP receptor antibody or binding fragment.

[0049] The efficacy of the treatment regimens described herein can also be evaluated based on the number of days of acute treatment with migraine-specific medications as needed by the patient, the number of days the patient is physically or functionally impaired due to migraine, or the number of migraine attacks experienced by the patient. For example, in some embodiments, administration of an anti-CGRP receptor antibody or a binding fragment thereof results in a decrease in the number of days of acute migraine treatment needed by the patient within one month compared to the pre-treatment baseline and / or the number of days experienced by patients not receiving the anti-CGRP receptor antibody or binding fragment. As used herein, the term "days of acute migraine-specific medication treatment" or "days of acute migraine-specific medication use" refers to any calendar day on which the patient takes a migraine-specific medication. Acute migraine-specific medications include, but are not limited to, triptans (e.g., almotriptan, frovatriptan, rizatriptan, sumatriptan, naratriptan, eletriptan, and zolmitriptan), ergotamines (e.g., dihydroergotamine and ergotamine with caffeine), non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic acid, ibuprofen, naproxen, indomethacin, and diclofenac), and opioid medications (e.g., codeine, morphine, hydrocodone, fentanyl, meperidine, and oxycodone). After administration of an anti-CGRP receptor antibody or a binding fragment thereof, the number of days of acute migraine-specific medication treatment per month can be reduced by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%. In certain embodiments, administration of an anti-CGRP receptor antibody or a binding fragment thereof completely eliminates the need for use of acute migraine-specific medications.

[0050] In some embodiments, administration of an anti-CGRP receptor antibody or a binding fragment thereof according to the methods described herein can reduce patient-reported physical impairment or quality-of-life impact scores, compared to pre-treatment baseline and / or patients not receiving an anti-CGRP receptor antibody. Migraine typically affects a patient's quality of life and prevents participation in leisure and daily activities, and causes loss of productivity at work. Validated questionnaires and surveys, such as the Modified Migraine Disability Assessment Scale (MIDAS), the Headache Impact Test-6 (HIT-6), the Migraine-Specific Quality of Life Questionnaire (MSQ), the Migraine Functional Impact Questionnaire (MFIQ), and the Migraine Physical Function Impact Diary (MPFID) can be used to assess these impacts. Thus, as evaluated by one or more of these questionnaires, the methods of the invention improve one or more aspects of a patient's quality of life and / or reduce the impact of migraine on one or more aspects of the patient's physical, social, or emotional functioning.

[0051] The MIDAS is a 5-item self-administered questionnaire that summarizes the number of productive days lost in the workplace and at home in the past month. The MIDAS also assesses disability in home, social, and leisure activities. The MIDAS score is the sum of the following days: days missed from paid work, household chores, and non-work (home, social, leisure) activities due to headache; and days with at least a 50% reduction in productivity at paid work or household chores. The score is divided into 4 severity categories: Category I = 0-5 points (defined as minimal or infrequent disability), Category II = 6-10 points (mild or infrequent disability), Category III = 11-20 (moderate disability), and Category IV = 21 points and higher (severe disability). In certain embodiments, administration of an anti-CGRP receptor antibody or a binding fragment thereof according to the methods of the invention results in a reduction in the patient's MIDAS score (i.e., a reduction in severity category / a reduction in the frequency or severity of disability caused by migraine), compared to the patient's score before treatment or the score of patients not receiving an anti-CGRP receptor antibody or binding fragment.

[0052] The MSQ is a 14-item self-administered tool that measures (i) how migraine restricts a patient's daily social and work-related activities (role function restriction), (ii) how migraine prevents these activities (role function prevention), and (iii) the emotions associated with the patient's migraine (emotional function). The patient responds to the items using a 6-point scale: "no time", "very little time", "some time", "a lot of time", "most of the time", and "all of the time", assigned scores of 1 to 6 respectively. The raw dimension score is calculated as the sum of the item responses and is re-scaled to a 0 to 100 scale such that a higher score indicates a better quality of life. In some embodiments, administration of an anti-CGRP receptor antibody or a binding fragment thereof according to the methods of the invention increases the patient's score on the MSQ (i.e., improves the patient's quality of life) compared to the patient's score prior to treatment or compared to the score of a patient who has not received an anti-CGRP receptor antibody or a binding fragment thereof.

[0053] The MFIQ is a 26-item self-administered tool that measures the impact of migraine on broader functions. Specifically, it measures the impact of the patient's migraine on physical function, common activities, social function, and emotional function. The subject responds to the items using a 5-point scale assigned scores of 1 to 5, where 5 represents the greatest burden. The score is calculated as the sum of the item responses and the sum is re-scaled according to a 0-100 scale, where a higher score indicates a greater burden. In certain embodiments, administration of an anti-CGRP receptor antibody or a binding fragment thereof according to the methods of the invention decreases the patient's score on the MFIQ (i.e., reduces the impact of migraine on the patient's functions) compared to the patient's score prior to treatment or compared to the score of a patient who has not received an anti-CGRP receptor antibody or a binding fragment thereof.

[0054] The MPFID is a 13-item self-administered tool that measures physical function. It assesses the impact on daily activities and physical impairment. Subjects respond to items using a 5-point scale, where difficulty items range from "no difficulty at all" to "unable to perform", and frequency items range from "no time" to "all the time". These items are assigned scores from 1 to 5, where a score of 5 represents the greatest burden. The score is calculated as the sum of the item responses, and the sum is re-scaled according to a 0 - 100 scale, where a higher score indicates a greater impact of migraine (i.e., a higher burden). In some embodiments, administration of an anti-CGRP receptor antibody or a binding fragment thereof according to the methods of the invention results in a lower score for the patient on the MPFID (i.e., a reduced impact of migraine on the patient's physical function or daily activities) compared to the score of the patient before treatment or the score of a patient who has not received an anti-CGRP receptor antibody or binding fragment. In one particular embodiment, administration of an anti-CGRP receptor antibody or a binding fragment thereof to a patient results in at least a about 50% reduction in the patient's physical impairment score compared to the score of the patient before treatment or a control subject (i.e., a subject who has not received an anti-CGRP receptor antibody or binding fragment). In some embodiments, the average number of days of physical impairment per month for a patient after administration of an anti-CGRP receptor antibody or a binding fragment thereof is reduced compared to the number of days before treatment or the average number of days of physical impairment per month for a control subject, as measured by the MPFID. In another particular embodiment, administration of an anti-CGRP receptor antibody or a binding fragment thereof to a patient results in at least a about 50% reduction in the impact on the patient's daily activity score compared to the score of the patient before treatment or the score of a control subject, as measured by the MPFID. In some embodiments, the average number of days per month that have an impact on the patient's daily activities after administration of an anti-CGRP receptor antibody or a binding fragment thereof is reduced compared to the number of days before treatment or the average number of days per month that have an impact on the daily activities of a control subject, as measured by the MPFID.

[0055] In certain embodiments of the methods of the present invention, the number of migraine attacks experienced by a patient after administration of an anti-CGRP receptor antibody or antigen-binding fragment thereof is reduced compared to the number of migraine attacks experienced by the patient prior to treatment or the number of migraine attacks experienced by a control subject. As used herein, the term "migraine attack" refers to any migraine event as defined herein. Migraine attacks that are interspersed with sleep or temporarily abate and then recur within 48 hours are generally considered a single attack. Similarly, migraine attacks that are successfully treated with an acute migraine-specific drug but recur within 48 hours are also considered a single attack. In some embodiments, the number of migraine attacks experienced by a patient after administration of an anti-CGRP receptor antibody or antigen-binding fragment thereof is reduced by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 75% compared to the number of attacks prior to treatment or the number of attacks in a control subject.

[0056] In some embodiments, the treatment regimens of the present invention improve one or more migraine-related symptoms in a patient in need thereof. By way of example, administration of an anti-CGRP receptor antibody or antigen-binding fragment thereof to a patient according to the methods described herein reduces the occurrence or treats one or more symptoms in the patient compared to a control subject (i.e., a subject not receiving an anti-CGRP receptor or binding fragment). Symptoms that can be improved or treated with the methods of the present invention include, but are not limited to, vasomotor symptoms (such as hot flashes, facial flushing, sweating, and night sweats), photophobia (sensitivity to light), phonophobia (sensitivity to sound), sensitivity to odors, dizziness, vertigo, nausea, vomiting, and headache.

[0057] In some aspects, the methods of the present invention comprise administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or antigen-binding fragment thereof. "Therapeutically effective amount" means an amount sufficient to remedy a migraine or symptom, particularly a condition or symptom associated with migraine, or otherwise prevent, impede, arrest, or reverse a migraine or the development of any other undesirable symptom in any way associated with migraine. In certain embodiments, a therapeutically effective amount is an amount sufficient to prevent or delay the onset or recurrence of a migraine attack, or to reduce the likelihood of the onset or recurrence of a migraine or its symptoms.

[0058] Thus, in some embodiments, an anti-CGRP receptor antibody or antigen-binding fragment thereof is administered to a patient at a total monthly dose of from about 35 mg to about 210 mg. By way of example, the dose of the anti-CGRP receptor antibody or binding fragment thereof can be about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg or about 210 mg per month. Also covered are ranges between any and all of these endpoints, such as from about 35 mg to about 70 mg, from about 40 mg to about 90 mg, from about 50 mg to about 80 mg, from about 35 mg to about 140 mg, from about 70 mg to about 140 mg, from about 50 mg to about 100 mg, from about 70 mg to about 210 mg, from about 140 mg to about 210 mg or from about 150 mg to about 200 mg per month. In some such embodiments, the monthly dose of the anti-CGRP receptor antibody or binding fragment thereof is similar among patients, regardless of body weight. In other words, in these embodiments, the monthly dose of the anti-CGRP receptor antibody or binding fragment thereof is the total dose and is not adjusted for the patient's body weight. In one embodiment, an anti-CGRP receptor antibody or binding fragment thereof is administered to a patient at a total monthly dose of from about 70 mg to about 140 mg. In certain embodiments of the methods described herein, an anti-CGRP receptor antibody or binding fragment thereof is administered to a patient at a total monthly dose of about 70 mg. In other embodiments, an anti-CGRP receptor antibody or binding fragment thereof is administered to a patient at a total monthly dose of about 140 mg.

[0059] In certain embodiments, the monthly dose of an anti-CGRP receptor antibody or a binding fragment thereof can be based on the patient's body weight. For example, in some embodiments, the monthly dose of an anti-CGRP receptor antibody or a binding fragment thereof can be in the range of about 0.3 mg to about 3.5 mg per kilogram of body weight, about 0.5 mg to about 3 mg per kilogram of body weight, or about 1 mg to about 2.5 mg per kilogram of body weight. For example, the monthly dose of an anti-CGRP receptor antibody or a binding fragment thereof can be about 0.3 mg, about 0.4 mg, 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, or about 3.5 mg per kilogram of body weight. In one embodiment, the monthly dose of an anti-CGRP receptor antibody or a binding fragment thereof is about 0.8 mg to about 1.2 mg per kilogram of body weight. In another embodiment, the monthly dose of an anti-CGRP receptor antibody or a binding fragment thereof is about 1.6 mg to about 2.2 mg per kilogram of body weight.

[0060] A dose of an anti-CGRP receptor antibody or an antigen-binding fragment thereof can be administered as a single administration or in multiple administrations over a dosing frequency cycle. For example, in certain embodiments, a therapeutically effective dose of an anti-CGRP receptor antibody or a binding fragment thereof is administered as a single administration within each frequency cycle. Thus, in some embodiments, a dose of any of the anti-CGRP receptor antibodies or binding fragments described herein can be administered to a patient once a month (QM dosing). According to the QM dosing regimen, an anti-CGRP receptor antibody or a binding fragment thereof is typically administered to a patient every 24 to 36 days, preferably every 28 to 35 days, more preferably every 28 to 31 days, or even more preferably every 28 days or every 30 days. In these and other embodiments, for example, a monthly dose is administered to a patient by rapid injection using a self-injecting device as described herein. For example, a 70 mg monthly dose can be administered to a patient by a single rapid injection of 70 mg using, optionally, an autoinjector, pen injector, or prefilled syringe containing a 70 mg dose. In certain embodiments, a monthly dose is administered as two or more consecutive injections. For example, a 70 mg monthly dose can be administered to a patient by two consecutive injections of 35 mg using, optionally, two injection devices (e.g., autoinjectors, pen injectors, or prefilled syringes) containing a 35 mg dose. Similarly, a 140 mg monthly dose can be administered to a patient by two consecutive injections of 70 mg using, optionally, two injection devices (e.g., autoinjectors, pen injectors, or prefilled syringes) containing a 70 mg dose. Consecutive injections given within a single day are considered a single administration. In other words, for example, a single rapid injection of 70 mg within a single day and two consecutive injections of 35 mg are both considered a single administration of a 70 mg dose.

[0061] In alternative embodiments, a dose of an anti-CGRP receptor antibody or a binding fragment thereof is divided into two or more administrations over the course of a dosing frequency cycle. For example, for a one-month dosing frequency cycle, a monthly dose can be divided into four doses and administered once a week, or divided into two doses and administered once every two weeks. Any of the doses of the anti-CGRP receptor antibodies or binding fragments described herein can be divided into two or more administrations. The number of administrations and the intervening time intervals can be adjusted for a particular patient depending on the type and severity of the migraine (e.g., episodic or chronic), the age of the patient, the general health of the patient, co-treatment with other medications, and / or the presence of other medical conditions.

[0062] In certain embodiments, the dosing frequency period of the dose of the anti-CGRP receptor antibody or binding fragment thereof described herein is monthly. In other words, the dose of the anti-CGRP receptor antibody or binding fragment thereof is a monthly dose, but can be administered as a single administration (i.e., once a month; QM dosing), or divided into multiple administrations within the month (e.g., administer ½ of the monthly dose every two weeks). In some embodiments, the dosing frequency is once every 2 months (Q2M dosing). In other embodiments, the dosing frequency is once every 3 months (Q3M dosing).

[0063] In some embodiments of the methods of the invention, an anti-CGRP receptor antibody or binding fragment is administered to a patient over a fixed treatment period. The "treatment period" begins upon administration of the first dose of the anti-CGRP receptor antibody or binding fragment and ends upon administration of the last dose of the anti-CGRP receptor antibody or binding fragment. The treatment period can comprise from about 1 month to about 36 months, such as about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, or about 33 months. In some embodiments, the treatment period is about 6 months. In other embodiments, the treatment period is about 7 months. In other embodiments, the treatment period is about 12 months. In certain embodiments, the treatment period can exceed 36 months, such as 48 or 60 or 64 months or longer. In one particular embodiment, the treatment period is at least about 6 months and results in a statistically significant reduction in the frequency, duration, or severity of the patient's migraines as compared to an untreated subject.

[0064] Administration of an anti-CGRP receptor antibody or binding fragment thereof according to the methods of the invention preferably causes few or no adverse side effects in a patient. As used herein, the term "adverse side effect" refers to any abnormal, defective, mutated, damaging, degenerative, harmful or undesirable reaction, symptom or injury that may be caused by taking a drug. In some embodiments, administration of an anti-CGRP receptor antibody or binding fragment thereof does not substantially cause one or more adverse side effects associated with other migraine prophylactic treatments (e.g., amitriptyline, divalproex, valproic acid, propranolol, timolol, topiramate, and botulinum toxin A). Side effects associated with other migraine prophylactic treatments include, but are not limited to, fatigue, nausea, dizziness, insomnia, depression, reduced exercise tolerance, tremors, paresthesia, teratogenicity, and cognitive difficulties. In other embodiments, administration of an anti-CGRP receptor antibody or binding fragment thereof is associated with a lower rate or number of adverse side effects compared to the rate or number of adverse side effects associated with other migraine prophylactic treatments. In other embodiments, administration of an anti-CGRP receptor antibody or binding fragment thereof is associated with a lower rate of treatment discontinuation due to adverse side effects compared to the rate of treatment discontinuation due to adverse side effects associated with other migraine prophylactic treatments. In certain embodiments, the number and type of adverse side effects associated with administration of an anti-CGRP receptor antibody or binding fragment are not statistically different from the number and type of adverse side effects associated with administration of a placebo. In some embodiments, administration of an anti-CGRP receptor antibody or binding fragment thereof is not associated with adverse events greater than grade 2, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. In other embodiments, administration of an anti-CGRP receptor antibody or binding fragment thereof is not associated with adverse events greater than grade 1, as assessed by the CTCAE.

[0065] In certain embodiments, a patient to be treated according to the methods of the invention has, suffers from, or is diagnosed with episodic migraine. Episodic migraine is diagnosed when a patient with a history of migraine (e.g., at least five migraine attacks in a lifetime) has 14 days or fewer migraine days per month as defined herein. In some embodiments, a patient having, suffering from, or diagnosed with episodic migraine has an average of at least four but fewer than 15 migraine days per month. In related embodiments, a patient having, suffering from, or diagnosed with episodic migraine has fewer than 15 headache days per month. As used herein, "headache days" are any calendar days on which a patient experiences a migraine as defined herein or any headache lasting more than 30 minutes or requiring acute headache treatment. In some embodiments, a patient may be classified as having or suffering from high-frequency episodic migraine. High-frequency episodic migraine may be characterized by 8 to 14 migraine days per month. In other embodiments, a patient may be classified as having or suffering from low-frequency episodic migraine. Low-frequency episodic migraine may be characterized by fewer than 8 migraine days per month.

[0066] In some embodiments, a patient to be treated according to the methods of the invention has, suffers from, or is diagnosed with chronic migraine. Chronic migraine is diagnosed when a migraine patient (i.e., a patient with at least five migraine attacks in a lifetime) has 15 days or more headache days per month and at least 8 of those headache days are migraine days. In some embodiments, a patient having, suffering from, or diagnosed with chronic migraine has an average of 15 days or more migraine days per month. In certain embodiments of the methods described herein, administration of an anti-CGRP receptor antibody or a binding fragment thereof prevents, reduces, or delays the development of episodic migraine to chronic migraine in a patient.

[0067] In certain embodiments of the methods described herein, the patient is treatment-naive. In one embodiment, a patient is treatment-naive if the patient has not previously received treatment for migraine. In another embodiment, a patient is treatment-naive if the patient has not been administered a therapeutic agent for treating migraine. In some embodiments, a patient is treatment-naive if the patient has not previously received migraine prophylactic therapy. For example, in certain embodiments, a treatment-naive patient has not received a prior therapy or has not been administered a therapeutic agent for prophylactically treating episodic migraine. In certain other embodiments, a treatment-naive patient has not received a prior therapy or has not been administered a therapeutic agent for prophylactically treating chronic migraine.

[0068] In some embodiments of the methods described herein, the patient has failed or is intolerant to at least one other migraine prophylactic therapy. For example, in one particular embodiment, the patient does not respond to prior therapy with at least one migraine prophylactic agent. As used herein, "does not respond" or "treatment failure" means a lack of efficacy of the agent in reducing the frequency, duration, and / or severity of the patient's migraines following a standard treatment regimen of the prophylactic agent. For example, in one embodiment, a patient who has failed prior treatment with a migraine prophylactic agent is a patient who experiences the same number of migraine days per month or more migraine days per month after administration of the migraine prophylactic agent as before treatment with the agent. In another embodiment, a patient who has failed prior treatment with a migraine prophylactic agent is a patient who experiences the same number of days of treatment with acute migraine-specific medications per month or more days of treatment with acute migraine-specific medications per month after administration of the migraine prophylactic agent as before treatment with the agent. In another embodiment, a patient who has failed prior treatment with a migraine prophylactic agent is a patient who experiences the same number of migraine attacks or more migraine attacks after administration of the migraine prophylactic agent as before treatment with the agent. In another embodiment, a patient who has failed prior treatment with a migraine prophylactic agent is a patient who experiences the same degree of physical impairment (e.g., average number of days with physical impairment per month) or more severe physical impairment after administration of the migraine prophylactic agent as before treatment with the agent, as measured by MPFID.

[0069] Failure to respond to prior treatment with a migraine prophylactic agent can also include intolerance to the migraine prophylactic agent. For example, in some embodiments, a patient who has failed prior treatment with a migraine prophylactic agent is a patient who cannot tolerate the side effects associated with the agent. In such embodiments, the side effects associated with the agent exacerbate another medical condition the patient has or may be incompatible with another medical condition. For example, a migraine prophylactic agent with teratogenic side effects would be contraindicated in a pregnant patient. In certain embodiments, a patient who has failed prior treatment with a migraine prophylactic agent is a patient who has discontinued the migraine prophylactic agent treatment due to the associated side effects. In these and other embodiments, a patient who has failed prior treatment with a migraine prophylactic agent is a patient who has chosen to terminate treatment, change the treatment regimen, or switch to a different prophylactic agent because the impact of the side effects outweighs the therapeutic benefit of the migraine prophylactic agent.

[0070] Migraine prophylactic agents include (but are not limited to) β-blockers (such as propranolol, timolol, atenolol, metoprolol, and nadolol), anti-epileptic drugs (such as divalproex acid, sodium valproate, valproic acid, topiramate, and gabapentin), tricyclic antidepressants (such as amitriptyline, nortriptyline, doxepin, and fluoxetine), and botulinum toxin type A. Thus, in certain embodiments, patients treated according to the methods of the present invention have failed or are intolerant to one or more of these migraine prophylactic agents. In some embodiments, patients have failed or are intolerant to treatment with at least two migraine prophylactic agents. In other embodiments, patients have failed or are intolerant to treatment with at least three migraine prophylactic agents. In certain embodiments, patients have failed or are intolerant to treatment with one or more agents selected from propranolol, timolol, divalproex acid, valproic acid, topiramate, amitriptyline, or botulinum toxin type A. In one particular embodiment, the patient has failed or is intolerant to treatment with topiramate. In another particular embodiment, the patient has failed or is intolerant to treatment with propranolol. In another particular embodiment, the patient has failed or is intolerant to treatment with amitriptyline.

[0071] In some embodiments, patients have failed or are intolerant to treatment with at least two different classes of migraine prophylactic agents. For example, in one embodiment, the patient may have failed or be intolerant to treatment with an anti-epileptic drug (such as topiramate) and a β-blocker (such as propranolol). In another embodiment, the patient may have failed or be intolerant to treatment with an anti-epileptic drug (such as topiramate) and an antidepressant (such as amitriptyline). In another embodiment, the patient may have failed or be intolerant to treatment with a β-blocker (such as propranolol) and an antidepressant (such as amitriptyline). In certain embodiments, patients have failed or are intolerant to treatment with at least three different classes of migraine prophylactic agents. In such embodiments, the patient has failed or is intolerant to treatment with an anti-epileptic drug (such as topiramate), a β-blocker (such as propranolol), and an antidepressant (such as amitriptyline).

[0072] The methods described herein are also applicable to other types of headache disorders, such as tension-type headache, cluster headache, hemiplegic migraine, and retinal migraine. Thus, the present invention also provides methods of treating (including prophylactic treatment) or preventing any of the foregoing headache disorders by administering to a patient in need thereof an anti-CGRP receptor antibody or a binding fragment thereof according to any of the dosage regimens described herein.

[0073] The methods described herein include administering to a patient an anti-CGRP receptor antibody or a binding fragment thereof. As used herein, the term "antibody" refers to a complete immunoglobulin of any isotype or an antigen-binding fragment thereof that can compete with the complete antibody for specific binding to a target antigen, and includes, for example, chimeric antibodies, humanized antibodies, fully human antibodies, bispecific antibodies, and multivalent antibodies. The structural unit of an antibody typically comprises one or more tetramers, each composed of the same pair of polypeptide chains, although some mammalian species also produce antibodies having only a single heavy chain. In a typical antibody, each pair includes a full-length "light" chain (about 25 kDa in some embodiments) and a full-length "heavy" chain (about 50-70 kDa in some embodiments). Each individual immunoglobulin chain is composed of a number of "immunoglobulin domains", each domain consisting of about 90 to 110 amino acids and expressing a characteristic folding pattern. These domains are the basic units that make up the antibody polypeptide. The amino-terminal portion of each chain typically includes a variable domain responsible for antigen recognition. The carboxyl-terminal portion is more conserved evolutionarily than the other end of the chain and is referred to as the "constant region" or "C region". Human light chains are generally classified as kappa light chains and lambda light chains, and each of these chains contains a variable domain and a constant domain. Heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon chains, and these chains define the isotype of the antibody as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subtypes, including (but not limited to) IgG1, IgG2, IgG3, and IgG4. IgM subtypes include IgM and IgM2. IgA subtypes include IgA1 and IgA2. In humans, the IgA and IgD isotypes contain four heavy chains and four light chains; the IgG and IgE isotypes contain two heavy chains and two light chains; and the IgM isotype contains five heavy chains and five light chains. The heavy chain C region typically contains one or more domains that can be responsible for effector functions. The number of heavy chain constant region domains will depend on the isotype. For example, IgG heavy chains each contain three C region domains, called CH1, CH2, and CH3. Antibodies that can be used in the methods of the present invention can have any of these isotypes and subtypes. In some embodiments, the anti-CGRP receptor antibody belongs to the IgG1, IgG2, or IgG4 subtype. In one particular embodiment, the anti-CGRP receptor antibody is an IgG2 antibody (e.g., comprising a human IgG2 constant domain). In another particular embodiment, the anti-CGRP receptor antibody is an IgG1 antibody (e.g., a human IgG1 constant domain).

[0074] In full-length light and heavy chains, the variable and constant regions are joined by a "J" region of about twelve or more amino acids, and the heavy chain also includes a "D" region of about ten or more amino acids. See, e.g., Fundamental Immunology, 2nd Ed., Chapter 7 (Paul, W. ed.) 1989, New York: Raven Press (incorporated herein by reference in its entirety for all purposes). The variable regions of each light / heavy chain pair generally form the antigen-binding site. The variable regions of immunoglobulin chains generally exhibit the same overall structure, containing relatively conserved framework regions (FRs) joined by three hypervariable regions more commonly referred to as "complementary determining regions" or CDRs. The CDRs in each of the two chains of each heavy and light chain pair are generally aligned by the framework regions to form a structure that specifically binds to a specific epitope on a target protein (e.g., the CGRP receptor). From the N-terminus to the C-terminus, the naturally occurring light and heavy chain variable regions generally follow the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Numbering systems have been devised that assign numbers to the amino acids occupying positions in each of these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, MD) or Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:878-883.

[0075] The term "binding fragment" is used interchangeably herein with the term "antigen-binding fragment" and refers to a portion of an antibody that lacks at least some of the amino acids present in the full-length heavy and / or light chains but is capable of specifically binding to an antigen (regardless of how the portion is obtained or synthesized). Such fragments are biologically active because they specifically bind to the target antigen and can compete with other antigen-binding proteins, including intact antibodies, for specific binding to a designated epitope. In one aspect, such fragments will retain at least one CDR present in the full-length light or heavy chain, and in some embodiments, will comprise a single heavy and / or light chain or a portion thereof. These biologically active fragments can be produced by recombinant DNA techniques or can be produced by enzymatic or chemical cleavage of antigen-binding proteins, including intact antibodies. Immunologically functional immunoglobulin fragments include (but are not limited to) Fab, Fab', F(ab') 2 , Fv, domain antibodies, and single-chain antibodies, and can be derived from any mammalian source, including (but not limited to) human, mouse, rat, camel, or rabbit.

[0076] Antibody binding fragments can be synthetic or genetically engineered proteins. For example, antibody binding fragments include isolated fragments consisting of the variable region of the light chain, "Fv" fragments consisting of the variable regions of the heavy and light chains, and recombinant single-chain polypeptide molecules (scFv proteins) that link the variable regions of the light and heavy chains by a peptide linker. Another form of antibody binding fragment is a peptide containing one or more complementarity determining regions (CDRs) of an antibody. CDRs (also referred to as "minimal recognition units" or "hypervariable regions") are obtained, for example, by constructing a polynucleotide encoding the CDR of interest. Such polynucleotides are prepared, for example, by using polymerase chain reaction to synthesize the variable region using the mRNA of antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, "Genetic Manipulation of Monoclonal Antibodies", Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166, Cambridge University Press (1995); and Ward et al., "Genetic Manipulation and Expression of Antibodies", Monoclonal Antibodies: Principles and Applications, Birch et al. (eds.), page 137, Wiley-Liss, Inc. (1995)).

[0077] An anti-CGRP receptor antibody or a binding fragment thereof used in the methods of the present invention specifically binds to the human CGRP receptor. The human CGRP receptor is a heterodimer that comprises a human calcitonin receptor-like receptor (CRLR) polypeptide and a human receptor activity-modifying protein 1 (RAMP1) polypeptide. In some embodiments, the anti-CGRP receptor antibody or a binding fragment thereof specifically binds to a region of the extracellular domains of CRLR and RAMP1. Amino acid sequences of exemplary extracellular domains and full-length proteins of human CRLR and RAMP1 are provided in the table below.

[0078] Table 1. Sequences of human CRLR and human RAMP1 polypeptides

[0079]

[0080]

[0081] When the dissociation constant (K D ) ≤ 10 -6 M, the antibody or binding fragment is considered to "specifically bind" to its target. When K D ≤ 1 × 10 -8 M, the antibody or binding fragment specifically binds to the target antigen with "high affinity". In one embodiment, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 5 × 10 -7 M. In another embodiment, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 1 × 10 -7 M. In another embodiment, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 5 × 10 -8 M. In another embodiment, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 1 × 10 -8 M. In another embodiment, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 5 × 10 -9 M. In certain embodiments, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 1 × 10 -9 M. In other embodiments, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 5 × 10 -10 M. In yet other embodiments, the antibody or binding fragment binds to the human CGRP receptor with K D ≤ 1 × 10 -10 M. A variety of techniques are used to determine the affinity, examples of which are affinity ELISA assays. In various embodiments, the affinity is determined by BIAcore analysis. In some embodiments, the affinity is determined by kinetic methods. In other embodiments, the affinity is determined by equilibrium / dissolution methods. In certain embodiments, the affinity is determined by FACS binding assays. WO 2010 / 075238 (incorporated herein by reference in its entirety) describes affinity assays suitable for determining the affinity of anti-CGRP receptor antibodies.

[0082] In certain embodiments, the anti-CGRP receptor antibody or binding fragment thereof employed in the methods described herein specifically binds to a residue or sequence or region of residues in the human CRLR and human RAMP1 polypeptides. In a particular embodiment, the anti-CGRP receptor antibody or binding fragment thereof specifically binds to an epitope formed by amino acids in the human CRLR and human RAMP1 polypeptides. An "epitope" is any determinant capable of specifically binding to an antibody or binding fragment thereof or a T cell receptor. Epitopes can be contiguous or non-contiguous (e.g., (i) in a single-chain polypeptide, amino acid residues that are not contiguous to each other in the polypeptide sequence but are bound by an antigen-binding protein within the context of the molecule, or (ii) in a multimeric protein such as one comprising two or more individual components, amino acid residues that are present on two or more of the individual components but are bound by an antibody or binding fragment within the context of the multimeric protein). In some embodiments, the epitope formed by amino acids in the human CRLR and human RAMP1 polypeptides comprises one or more cleavage sites for AspN protease, which cleaves peptides after aspartic acid residues and some glutamic acid residues at the amino terminus.

[0083] In certain embodiments, the anti-CGRP receptor antibody or binding fragment for use in the methods of the invention specifically binds to the extracellular domain of the human CRLR polypeptide comprising the amino acid sequence SEQ ID NO:3. Alternatively or additionally, the anti-CGRP receptor antibody or binding fragment specifically binds to the extracellular domain of the human RAMP1 polypeptide comprising the amino acid sequence SEQ ID NO:4. In some embodiments, the anti-CGRP receptor antibody or binding fragment specifically binds to at least one sequence selected from the following sequences within the human CRLR polypeptide: SEQ ID NO: 5 (DSIQLGVTRNKIMTAQY; corresponding to amino acids 8-24 of SEQ ID NO: 3), SEQ ID NO: 6 (DVAAGTESMQLCP; corresponding to amino acids 55-67 of SEQ ID NO: 3), SEQ ID NO: 7 (DGNWFRHPASNRTWTNYTQCNVNTH; corresponding to amino acids 86-110 of SEQ ID NO: 3), SEQ ID NO: 8 (ECYQKIMQ; corresponding to amino acids 25-32 of SEQ ID NO: 3) or SEQ ID NO: 9 (DGWLCWN; corresponding to amino acids 48-54 of SEQ ID NO: 3). By way of example, in some embodiments, the anti-CGRP receptor antibody binds to a sub-region of the human CRLR polypeptide having SEQ ID NO: 3 (comprising SEQ ID NO:5-9), optionally in its native three-dimensional conformation. Alternatively or additionally, the anti-CGRP receptor antibody or binding fragment specifically binds to at least one sequence selected from the following sequences within the human RAMP1 polypeptide: SEQ ID NO:10 (RELADCTWHMAE; corresponding to amino acids 41-52 of SEQ ID NO: 4), SEQ ID NO:11 (DWGRTIRSYRELA; corresponding to amino acids 32-44 of SEQ ID NO: 4), SEQ ID NO:12 (ELCLTQFQV; corresponding to amino acids 12-20 of SEQ ID NO: 4) or SEQ ID NO:13 (DCTWHMA; corresponding to amino acids 45-51 of SEQ ID NO: 4). In some embodiments, the anti-CGRP receptor antibody binds to a sub-region of the human RAMP1 polypeptide having SEQ ID NO: 4 (comprising SEQ ID NO:10-13), optionally in its native three-dimensional conformation.

[0084] In certain embodiments, an anti-CGRP receptor antibody or binding fragment specifically binds to a human CRLR polypeptide having the amino acid sequences of SEQ ID NO:6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, wherein SEQ ID NOs:6 and 7 are joined by a disulfide bond at amino acid positions 66 and 105 with reference to SEQ ID NO: 3, and SEQ ID NOs:8 and 9 are joined by a disulfide bond at amino acid positions 26 and 52 with reference to SEQ ID NO: 3, optionally wherein the polypeptide maintains the tertiary structure of the corresponding polypeptide region of human CRLR having SEQ ID NO: 3. In some embodiments, an anti-CGRP receptor antibody or binding fragment specifically binds to a human RAMP1 polypeptide having the amino acid sequences of SEQ ID NO:12 and SEQ ID NO:13, wherein the sequences are joined by a disulfide bond at amino acid positions 14 and 46 with reference to SEQ ID NO: 4, optionally wherein the polypeptide maintains the tertiary structure of the corresponding polypeptide region of human RAMP1 having SEQ ID NO: 4. In certain embodiments, an anti-CGRP receptor antibody or binding fragment specifically binds to a human CRLR polypeptide and a human RAMP1 polypeptide, wherein the human CRLR polypeptide has the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, wherein SEQ ID NOs:6 and 7 are joined by a disulfide bond at amino acid positions 66 and 105 with reference to SEQ ID NO: 3, and SEQ ID NOs:8 and 9 are joined by a disulfide bond at amino acid positions 26 and 52 with reference to SEQ ID NO: 3, and wherein the human RAMP1 polypeptide has the amino acid sequences of SEQ ID NO:12 and SEQ ID NO:13, wherein SEQ ID NOs:12 and 13 are joined by a disulfide bond at amino acid positions 14 and 46 with reference to SEQ ID NO: 4. In such embodiments, the human CRLR and human RAMP1 polypeptides each maintain the tertiary structure of the corresponding polypeptide regions of human CRLR and human RAMP1 having SEQ ID NOs:3 and 4, respectively. In related embodiments, the human CRLR and human RAMP1 polypeptides form a heterodimer.

[0085] The anti-CGRP receptor antibody or binding fragment in the method applicable to the present invention preferably inhibits, interferes with, or modulates one or more biological activities of the human CGRP receptor. The biological activities of the human CGRP receptor include (but are not limited to) inducing the CGRP receptor signal transduction pathway, inducing vasodilation, inhibiting vasoconstriction, and inducing inflammation (such as neurogenic inflammation). In some embodiments, the anti-CGRP receptor or its antigen-binding fragment substantially inhibits the binding of the human CGRP receptor to the CGRP ligand. When measuring binding, for example, in an in vitro competitive binding assay, an excess of the antibody or its binding fragment reduces the amount of binding of the human CGRP receptor to CGRP or the binding of CGRP to the human CGRP receptor by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99% or more, "substantial binding inhibition" occurs.

[0086] In certain embodiments, the anti-CGRP receptor antibody or binding fragment used in the methods described herein selectively inhibits the human CGRP receptor as compared to human adrenomedullin 1 (AM1), adrenomedullin 2 (AM2), or amylin receptor (such as the human AMY1 receptor). The human AM1 receptor comprises the human CRLR polypeptide and the RAMP2 polypeptide, while the human AM2 receptor comprises the human CRLR polypeptide and the RAMP3 polypeptide. Thus, it is expected that an antibody or other binding protein that binds only CRLR (and not RAMP1) will not selective inhibit the CGRP receptor because the CRLR polypeptide is also a component of the AM1 and AM2 receptors. The human amylin (AMY) receptor comprises the human calcitonin receptor (CT) polypeptide and one of the RAMP1, RAMP2, or RAMP3 subunits. Specifically, the human AMY1 receptor is composed of the CT polypeptide and the RAMP1 polypeptide, the human AMY2 receptor is composed of the CT polypeptide and the RAMP2 polypeptide, and the human AMY3 receptor is composed of the CT polypeptide and the RAMP3 polypeptide. Thus, it is expected that an antibody or other binding protein that binds only RAMP1 (and not CRLR) will not selective inhibit the CGRP receptor because the RAMP1 polypeptide is also a component of the human AMY1 receptor.

[0087] An antibody or antigen-binding fragment thereof "selectively inhibits" a specific receptor relative to other receptors when the IC50 value of the antibody or antigen-binding fragment thereof in an inhibition assay of the specific receptor is at least 50-fold lower than the IC50 value in an inhibition assay of another "reference" receptor. "IC50" is the amount of a drug or substance required to inhibit a specified biological process by half. The IC50 value of any particular substance or antagonist can be determined by constructing a dose-response curve and examining the effect of different concentrations of the drug or antagonist in a specific functional assay to reverse agonist activity. The IC50 value of a specified antagonist or drug can be calculated by determining the concentration required to inhibit half of the maximal biological response of an agonist. Thus, the IC50 value of any anti-CGRP antibody or binding fragment can be calculated by determining the concentration of the antibody or binding fragment required to inhibit half of the maximal biological response of CGRP ligand activation of the CGRP receptor in any functional assay.

[0088] "Selectivity ratio" is the ratio of the IC50 value of a reference receptor divided by the IC50 value of a specific receptor. If, in a functional CGRP receptor assay such as a cyclic AMP (cAMP) assay, the IC50 value of an anti-CGRP receptor antibody or an antigen-binding fragment thereof is at least 50-fold lower than the IC50 value of the antibody or antigen-binding fragment in an assay for inhibiting a human AM1, AM2, or amylin receptor (such as AMY1), then the antibody or antigen-binding fragment selectively inhibits the human CGRP receptor. As a non-limiting example, if the IC50 value of a specific anti-CGRP receptor antibody in a cAMP assay for the human CGRP receptor is, for example, between 0.1 nM and 20 nM, and the IC50 value of the antibody in a cAMP assay for the human AM1, human AM2, or human AMY1 receptor is 1000 nM or higher, then the antibody is considered to selectively inhibit the human CGRP receptor. Any suitable CGRP receptor functional assay, such as the cAMP assay described in Example 4 of WO 2010 / 075238 (incorporated herein by reference in its entirety), can be used to determine the degree of selective inhibition. An antibody or antigen-binding fragment that selectively inhibits a specific receptor should also be understood to be a neutralizing antibody or antigen-binding fragment against the receptor. In certain embodiments, an anti-CGRP receptor antibody or binding fragment thereof can selectively inhibit the human CGRP receptor relative to the human AM1, AM2, and / or AMY1 receptors, for example, with a selectivity ratio of 100 or higher, 250 or higher, 500 or higher, 750 or higher, 1,000 or higher, 2,500 or higher, 5,000 or higher, or 10,000 or higher. In one embodiment, an anti-CGRP receptor antibody or binding fragment thereof selectively inhibits the human CGRP receptor relative to the human AM1, AM2, and / or AMY1 receptors, with a selectivity ratio of 100 or higher. In another embodiment, an anti-CGRP receptor antibody or binding fragment thereof selectively inhibits the human CGRP receptor relative to the human AM1, AM2, and / or AMY1 receptors, with a selectivity ratio of 500 or higher.

[0089] In some embodiments, an anti-CGRP receptor antibody or binding fragment thereof specifically binds to the human CRLR and human RAMP1 polypeptides and does not specifically bind to the human AM1, human AM2, and / or human amylin receptors (such as AMY1 or AMY2). For example, an anti-CGRP receptor antibody or binding fragment thereof can specifically bind to the human CGRP receptor, and K D ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, or ≤ 5 nM. In some embodiments, as determined using a FACS binding assay and, for example, using Rathanaswami et al. , Biochemical and Biophysical Research CommunicationsAnalyzed by the method described in 334(2005)1004 - 1013, the anti - CGRP receptor antibody or its binding fragment specifically binds to the human CGRP receptor, and K D ≤ 100 nM, ≤ 10 nM or ≤ 5 nM. In certain embodiments, the anti - CGRP receptor antibody or its binding fragment specifically binds to the human CGRP receptor, and K D ≤ 100 nM. In other embodiments, the anti - CGRP receptor antibody or its binding fragment specifically binds to the human CGRP receptor, and K D ≤ 10 nM.

[0090] In certain embodiments, in a CGRP - binding competition assay, the Ki of the anti - CGRP receptor antibody or its binding fragment is ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.5 nM or ≤ 0.1 nM. "Ki" refers to the equilibrium dissociation constant of a ligand measured in an inhibition study. Typically, in a competitive radiolabeled ligand - binding study, the Ki of a specified ligand is determined by measuring the inhibition of the binding of a reference radiolabeled ligand by the competing substance of interest under equilibrium conditions. Binding competition assays for inhibitors to evaluate ligand / receptor interactions are known to those skilled in the art and can include assays using radiolabeled ligands (such as radiolabeled CGRP) and cells expressing the receptor (such as the human CGRP receptor). In some embodiments, a radiolabeled 125 125I - CGRP - binding competition assay is used to determine the Ki of the anti - CGRP receptor antibody or its binding fragment, wherein the binding of the radiolabeled ligand to the membrane of cells expressing the human CGRP receptor is evaluated. Example 5 of WO 2010 / 075238, which is incorporated herein by reference in its entirety, describes an exemplary protocol for conducting such an assay. In one embodiment, the Ki of the anti - CGRP receptor antibody or its binding fragment in a CGRP - binding competition assay is less than 10 nM. In another embodiment, the Ki of the anti - CGRP receptor antibody or its binding fragment in a CGRP - binding competition assay is less than 1 nM.

[0091] Examples of anti-CGRP receptor antibodies or binding fragments thereof suitable for use in the methods of the present invention are described in WO 2010 / 075238, which is incorporated herein by reference in its entirety. In one embodiment, the anti-CGRP receptor antibody or binding fragment thereof employed in the methods described herein cross-blocks the binding of at least one of antibodies 1E11, 1H7, 2E7, 3B6, 3C8, 4E4, 4H6, 5F5, 9D4, 9F5, 10E4, 11D11, 11H9, 12E8, 12G8, 13H2, and 32H7 (all of these antibodies are described herein and in WO 2010 / 075238) to the human CGRP receptor. Alternatively or additionally, at least one of antibodies 1E11, 1H7, 2E7, 3B6, 3C8, 4E4, 4H6, 5F5, 9D4, 9F5, 10E4, 11D11, 11H9, 12E8, 12G8, 13H2, and 32H7 (all of these antibodies are described herein) cross-blocks the binding of an anti-CGRP receptor antibody or binding fragment thereof to the human CGRP receptor. All of these antibodies have been determined to be neutralizing antibodies to the human CGRP receptor and bind to substantially the same region of the human CGRP receptor, which region is different from the region to which non-neutralizing antibodies to the receptor bind. See Example 7 of WO 2010 / 075238. The terms "cross-block," "cross-blocked," and "cross-blocking" are used interchangeably herein and mean the ability of an antibody to interfere with the binding of another antibody or binding fragment to the human CGRP receptor. A competitive binding assay can be used to determine the extent to which an antibody or binding fragment is able to interfere with the binding of another antibody to the human CGRP receptor and thus determine whether it can be said to cross-block. In some embodiments, the cross-blocking antibody or binding fragment thereof reduces the binding of the human CGRP receptor to a reference antibody by between about 40% and 100%, such as between about 60% and about 100%, specifically between about 70% and 100%, and more specifically between about 80% and 100%. A quantitative assay particularly suitable for detecting cross-blocking is the use of a Biacore machine, which uses surface plasmon resonance technology to measure the extent of interaction. Another suitable quantitative cross-blocking assay is the use of a FACS-based method to measure the competition between antibodies based on their binding to the human CGRP receptor.

[0092] The anti-CGRP receptor antibodies and binding fragments thereof for use in the methods disclosed herein can comprise a heavy chain CDR1 ("CDRH1") and / or a heavy chain CDR2 ("CDRH2") and / or a heavy chain CDR3 ("CDRH3"), and / or a light chain CDR1 ("CDRL1") and / or a light chain CDR2 ("CDRL2") and / or a light chain CDR3 ("CDRL3"). In some embodiments, the anti-CGRP receptor antibody or binding fragment comprises at least one heavy chain variable region comprising CDRH1, CDRH2, and CDRH3 and at least one light chain variable region comprising CDRL1, CDRL2, and CDRL3. Specific heavy and light chain CDRs are listed in Tables 2 and 3, respectively.

[0093] The complementarity determining regions (CDRs) and framework regions (FRs) of a designated antibody can be identified using the system described by Kabat et al. in Sequences of Proteins of Immunological Interest, 5th ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication No. 91-3242, 1991. Certain antibodies and binding fragments disclosed herein comprise one or more amino acid sequences that are the same as or have substantial sequence identity to one or more of the amino acid sequences of the CDRs presented in Table 2 (heavy chain CDRs, i.e., CDRH) and Table 3 (light chain CDRs, i.e., CDRL).

[0094] Table 2. Exemplary Heavy Chain CDR Amino Acid Sequences

[0095]

[0096]

[0097] Table 3. Exemplary Light Chain CDR Amino Acid Sequences

[0098]

[0099]

[0100] In some embodiments, the anti-CGRP receptor antibody or a binding fragment thereof comprises one or more heavy chain CDRs selected from the following: (i) CDRH1 selected from the group consisting of SEQ ID NOs: 14 to 22; (ii) CDRH2 selected from the group consisting of SEQ ID NOs: 23 to 33; (iii) CDRH3 selected from the group consisting of SEQ ID NOs: 34 to 43; and (iv) CDRHs in (i), (ii), and (iii) that contain one or more, such as one, two, three, four, or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions, or insertions of no more than five, four, three, two, or one amino acid. In these and other embodiments, the anti-CGRP receptor antibody or a binding fragment thereof comprises one or more light chain CDRs selected from the following: (i) CDRL1 selected from the group consisting of SEQ ID NOs: 44 to 54; (ii) CDRL2 selected from the group consisting of SEQ ID NOs: 55 to 64; (iii) CDRL3 selected from the group consisting of SEQ ID NOs: 65 to 74; and (iv) CDRLs in (i), (ii), and (iii) that contain one or more, such as one, two, three, four, or more amino acid substitutions (e.g., conservative amino acid substitutions), deletions, or insertions of no more than five, four, three, two, or one amino acid.

[0101] In certain embodiments, the anti-CGRP receptor antibody or a binding fragment thereof may comprise 1, 2, 3, 4, 5, or 6 variant forms of the CDRs listed in Tables 2 and 3, each of which has at least 80%, 85%, 90%, or 95% sequence identity with the CDR sequences listed in Tables 2 and 3. Some anti-CGRP receptor antibodies or a binding fragment thereof include 1, 2, 3, 4, 5, or 6 of the CDRs listed in Tables 2 and 3, each of which has no more than 1, 2, 3, 4, or 5 amino acids different from the CDRs listed in the tables.

[0102] In some embodiments, the anti-CGRP receptor antibody or binding fragment includes a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein:

[0103] (a) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 14, 23, and 34, respectively;

[0104] (b) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 15, 24, and 35, respectively;

[0105] (c) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 16, 25, and 36, respectively;

[0106] (d) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:17, 26, and 37, respectively;

[0107] (e) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:18, 27, and 38, respectively;

[0108] (f) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:15, 29, and 35, respectively;

[0109] (g) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:20, 30, and 40, respectively;

[0110] (h) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:15, 31, and 35, respectively;

[0111] (i) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:14, 23, and 41, respectively;

[0112] (j) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:21, 32, and 42, respectively;

[0113] (k) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:22, 33, and 43, respectively; or

[0114] (l) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:19, 28, and 39, respectively.

[0115] In some embodiments, the anti-CGRP receptor antibody or binding fragment comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, wherein:

[0116] (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:44, 55, and 65, respectively;

[0117] (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:45, 56, and 66, respectively;

[0118] (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:46, 57, and 67, respectively;

[0119] (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:47, 58, and 68, respectively;

[0120] (e) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:48, 59, and 69, respectively;

[0121] (f) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:49, 60, and 70, respectively;

[0122] (g) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:50, 59, and 69, respectively;

[0123] (h) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:45, 61, and 66, respectively;

[0124] (i) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:51, 62, and 71, respectively;

[0125] (j) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:52, 59, and 69, respectively;

[0126] (k) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:53, 63, and 72, respectively;

[0127] (l) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:54, 64, and 73, respectively; or

[0128] (m) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:54, 64, and 74, respectively.

[0129] In certain embodiments, the anti-CGRP receptor antibody or binding fragment comprises a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3 and a light chain variable region comprising CDRL1, CDRL2, and CDRL3, wherein:

[0130] (a) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:14, 23, and 34, respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:44, 55, and 65, respectively;

[0131] (b) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:14, 23, and 41 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:44, 55, and 65 respectively;

[0132] (c) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:15, 24, and 35 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:45, 56, and 66 respectively;

[0133] (d) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:15, 29, and 35 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:45, 61, and 66 respectively;

[0134] (e) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:15, 31, and 35 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:45, 61, and 66 respectively;

[0135] (f) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:16, 25, and 36 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:46, 57, and 67 respectively;

[0136] (g) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:17, 26, and 37 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:47, 58, and 68 respectively;

[0137] (h) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:18, 27, and 38 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:48, 59, and 69 respectively;

[0138] (i) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:18, 27, and 38 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:50, 59, and 69 respectively;

[0139] (j) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:19, 28, and 39 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:49, 60, and 70 respectively;

[0140] (k) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:20, 30, and 40 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:51, 62, and 71 respectively;

[0141] (l) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:21, 32, and 42 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:53, 63, and 72 respectively;

[0142] (m) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:22, 33, and 43 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:54, 64, and 73 respectively; or

[0143] (n) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:22, 33, and 43 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:54, 64, and 74 respectively; or

[0144] (o) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NO:18, 27, and 38 respectively, and CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NO:52, 59, and 69 respectively.

[0145] In some embodiments, the anti-CGRP receptor antibody or binding fragment thereof for use in the methods of the present invention comprises a CDRH1 having the sequence of SEQ ID NO:14, a CDRH2 having the sequence of SEQ ID NO:23, a CDRH3 having the sequence of SEQ ID NO:34, a CDRL1 having the sequence of SEQ ID NO:44, a CDRL2 having the sequence of SEQ ID NO:55, and a CDRL3 having the sequence of SEQ ID NO:65. In other embodiments, the anti-CGRP receptor antibody or binding fragment thereof for use in the methods of the present invention comprises a CDRH1 having the sequence of SEQ ID NO:15, a CDRH2 having the sequence of SEQ ID NO:29, a CDRH3 having the sequence of SEQ ID NO:35, a CDRL1 having the sequence of SEQ ID NO:45, a CDRL2 having the sequence of SEQ ID NO:61, and a CDRL3 having the sequence of SEQ ID NO:66.

[0146] In certain embodiments of the methods described herein, the anti-CGRP receptor antibody or binding fragment thereof comprises a heavy chain variable region selected from the group consisting of V H 1, V H 2, V H 3, V H 4, V H 5, V H 6, V H 7, V H 8, V H 9, V H 10, V H 11, V H 12 and V H 13, and / or a light chain variable region selected from the group consisting of V L 1, V L 2, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 and V L 17 (as shown in Table 4 below), and immunologically functional fragments, derivatives, mutant proteins, and variants of these light and heavy chain variable regions.

[0147] Table 4. Exemplary V L and V H chain amino acid sequences

[0148]

[0149]

[0150]

[0151] Each of the heavy chain variable regions listed in Table 4 can be combined with any one of the light chain variable regions shown in Table 4 to form an anti-CGRP receptor antibody or binding fragment suitable for use in the methods of the present invention. Examples of such combinations include V H 1 with V L 1, V L 2, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L 17; V H 2 with V L 1, V L 2, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L 17; V H 3 with V L 1, V L 2, V L 3, V L 4, V L 5, V L 6, VL 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L Any one combination of 17; and so on.

[0152] In some embodiments, the anti-CGRP receptor antibody or a binding fragment thereof comprises at least one heavy chain variable region and / or at least one light chain variable region from those variable regions listed in Table 4. In certain embodiments, the anti-CGRP receptor antibody or binding fragment comprises at least two different heavy chain variable regions and / or light chain variable regions from those variable regions listed in Table 4. Examples of such anti-CGRP receptor antibodies or binding fragments include (a) one V H 1, and (b) V H 2, V H 3, V H 4, V H 5, V H 6, V H 7, V H 8, V H 9, V H 10, V H 11, V H 12 or V H 13. Another example includes (a) one V H 2, and (b) V H 1, V H 3, V H 4, V H 5, V H 6, V H 7, V H 8, V H 9, V H 10, V H 11, V H 12 or V H 13. Another example includes (a) one V H 3, and (b) V H 1, V H 2, V H 4, V H 5, V H 6, V H 7, V H 8, V H 9, V H 10, VH 11, V H 12 or V H One of 13, etc. Another example of such an anti-CGRP receptor antibody or binding fragment comprises (a) a V L 1, and (b) V L 2, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L 17, V L 18, V L 19, V L 20 or V L One of 21. Another example of such an anti-CGRP receptor antibody or binding fragment comprises (a) a V L 2, and (b) V L 1, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L 17, V L 18, V L 19, V L 20 or V L One of 21. Another example of such an anti-CGRP receptor antibody or binding fragment comprises (a) a V L 3, and (b) V L 1, V L 2, V L 4, V L 5, V L 6, V L 7, V L 8, V L9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L 17, V L 18, V L 19, V L 20 or V L One of 21, etc. It will be apparent to those skilled in the art that various combinations of heavy chain variable regions can be combined with any one of the various combinations of light chain variable regions.

[0153] In other embodiments, the anti-CGRP receptor antibody or binding fragment contains two identical light chain variable regions and / or two identical heavy chain variable regions. For example, the anti-CGRP receptor antibody or binding fragment includes two light chain variable regions and two heavy chain variable regions in the form of a combination of light chain variable region pairs and heavy chain variable region pairs listed in Table 4.

[0154] In certain embodiments of the methods described herein, the anti-CGRP receptor antibody or its binding fragment includes an amino acid sequence that differs from a heavy chain variable domain selected from V H 1, V H 2, V H 3, V H 4, V H 5, V H 6, V H 7, V H 8, V H 9, V H 10, V H 11, V H 12 and V H 13 at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues, where each such sequence difference is independently a deletion, insertion or substitution of one amino acid, and the deletion, insertion and / or substitution results in no more than 15 amino acid changes relative to the foregoing variable domain sequence. The heavy chain variable region in some anti-CGRP receptor antibodies or their binding fragments contains an amino acid sequence that is identical to V H 1, V H 2, V H 3, V H 4, V H 5, V H 6, V H 7, V H 8, V H 9, V H10, V H 11, V H 12 and V H The amino acid sequences of the heavy chain variable regions of 13 have at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity.

[0155] In some embodiments of the methods described herein, the anti-CGRP receptor antibody or its binding fragment comprises an amino acid sequence that differs from a light chain variable domain selected from V L 1, V L 2, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L 17 at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues, wherein each such sequence difference is independently a deletion, insertion or substitution of one amino acid, and the deletion, insertion and / or substitution results in no more than 15 amino acid changes relative to the foregoing variable domain sequence. The light chain variable region in some anti-CGRP receptor antibodies or their binding fragments comprises an amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity with the light chain variable region of V L 1, V L 2, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 or V L 17.

[0156] In certain embodiments, the anti-CGRP receptor antibody or antigen-binding fragment thereof applicable in the methods of the present invention comprises a light chain variable region (V L ) and a heavy chain variable region (V H ), wherein:

[0157] (a) V L comprises the sequence of SEQ ID NO:75 and V H comprises the sequence of SEQ ID NO:92;

[0158] (b) V L comprises the sequence of SEQ ID NO:76 and V H comprises the sequence of SEQ ID NO:93;

[0159] (c) V L comprises the sequence of SEQ ID NO:77 and V H comprises the sequence of SEQ ID NO:94;

[0160] (d) V L comprises the sequence of SEQ ID NO:78 and V H comprises the sequence of SEQ ID NO:95;

[0161] (e) V L comprises the sequence of SEQ ID NO:79 and V H comprises the sequence of SEQ ID NO:96;

[0162] (f) V L comprises the sequence of SEQ ID NO:80 and V H comprises the sequence of SEQ ID NO:92;

[0163] (g) V L comprises the sequence of SEQ ID NO:81 and V H comprises the sequence of SEQ ID NO:97;

[0164] (h) V L comprises the sequence of SEQ ID NO:82 and V H comprises the sequence of SEQ ID NO:96;

[0165] (i) V L comprises the sequence of SEQ ID NO:83 and V H comprises the sequence of SEQ ID NO:92;

[0166] (j) V LThe sequence containing SEQ ID NO:84 and V H The sequence containing SEQ ID NO:98;

[0167] (k) V L The sequence containing SEQ ID NO:85 and V H The sequence containing SEQ ID NO:99;

[0168] (l) V L The sequence containing SEQ ID NO:86 and V H The sequence containing SEQ ID NO:100;

[0169] (m) V L The sequence containing SEQ ID NO:86 and V H The sequence containing SEQ ID NO:101;

[0170] (n) V L The sequence containing SEQ ID NO:87 and V H The sequence containing SEQ ID NO:96;

[0171] (o) V L The sequence containing SEQ ID NO:88 and V H The sequence containing SEQ ID NO:102;

[0172] (p) V L The sequence containing SEQ ID NO:89 and V H The sequence containing SEQ ID NO:103;

[0173] (q) V L The sequence containing SEQ ID NO:90 and V H The sequence containing SEQ ID NO:104; or

[0174] (r) V L The sequence containing SEQ ID NO:91 and V H The sequence containing SEQ ID NO:104.

[0175] In some embodiments, the anti-CGRP receptor antibody binding fragment may comprise an amino acid sequence having 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% sequence identity to the variable domains described in the pairings above. In a particular embodiment, the anti-CGRP receptor antibody or its binding fragment for use in the methods described herein comprises a heavy chain variable region comprising the sequence of SEQ ID NO:92 and a light chain variable region comprising the sequence of SEQ ID NO:80. In another particular embodiment, the anti-CGRP receptor antibody or its binding fragment for use in the methods described herein comprises a heavy chain variable region comprising the sequence of SEQ ID NO:98 and a light chain variable region comprising the sequence of SEQ ID NO:84.

[0176] Some full-length light and heavy chains of anti-CGRP receptor antibodies and specific examples of their corresponding amino acid sequences that can be used in the methods of the present invention are outlined in Tables 5 and 6. Table 5 shows exemplary heavy chain sequences, while Table 6 shows exemplary light chain sequences.

[0177] Table 5. Exemplary Antibody Heavy Chain Amino Acid Sequences

[0178]

[0179]

[0180]

[0181]

[0182] Table 6. Exemplary Antibody Light Chain Amino Acid Sequences

[0183]

[0184]

[0185]

[0186] For example, to promote the expression of heavy and light chain sequences in certain types of host cells, a signal peptide sequence can be attached / fused to the amino terminus of any of the heavy and light chain sequences listed in Tables 5 and 6. By way of example, in some embodiments, a signal peptide having the amino acid sequence MDMRVPAQLLGLLLLWLRGARC (SEQ ID NO:135) is fused to the amino terminus of any of the heavy and light chain sequences in Tables 5 and 6. In other embodiments, a signal peptide having the amino acid sequence METPAQLLFLLLLWLPDTTG (SEQ ID NO:136) is fused to the amino terminus of any of the heavy and light chain sequences in Tables 5 and 6. Other signal peptides are known to those of skill in the art and can be fused to any of the heavy and / or light chains listed in Tables 5 and 6, for example to promote or optimize expression in a particular host cell.

[0187] Each of the exemplary heavy chains (H1, H2, H3, etc.) listed in Table 5 can be combined with any of the exemplary light chains shown in Table 6 to form an anti-CGRP receptor antibody suitable for use in the methods described herein. Examples of such combinations include the combination of H1 with any of L1 to L17; the combination of H2 with any of L1 to L17; the combination of H3 with any of L1 to L17, and so on. In some embodiments, the anti-CGRP receptor antibody comprises at least one heavy chain and one light chain of those listed in Tables 5 and 6. In some embodiments, the anti-CGRP receptor antibody comprises two different heavy chains and two different light chains listed in Tables 5 and 6. In other embodiments, the anti-CGRP receptor antibody contains two identical light chains and two identical heavy chains. By way of example, the anti-CGRP receptor antibody or a binding fragment thereof can include two H1 heavy chains and two L1 light chains as listed in Tables 5 and 6, or two H2 heavy chains and two L2 light chains, or two H3 heavy chains and two L3 light chains, and similar combinations of other light chain and heavy chain pairs.

[0188] The anti-CGRP receptor antibody employed in the methods of the present invention can be an antibody variant formed by the combination of the heavy and light chains shown in Tables 5 and 6, and the light chain and / or heavy chain contained therein each has at least 70%, 75%, 80%, 85%, 90%, 95%, 97% or 99% identity to the amino acid sequence of these chains. In some cases, such antibodies include at least one heavy chain and one light chain, while in other cases, the variant form contains two identical light chains and two identical heavy chains.

[0189] In some embodiments of the methods described herein, the anti-CGRP receptor antibody comprises:

[0190] (a) a heavy chain comprising the sequence of SEQ ID NO:105 and a light chain comprising the sequence of SEQ ID NO:118;

[0191] (b) A heavy chain comprising the sequence of SEQ ID NO: 106 and a light chain comprising the sequence of SEQ ID NO: 119;

[0192] (c) A heavy chain comprising the sequence of SEQ ID NO: 107 and a light chain comprising the sequence of SEQ ID NO: 120;

[0193] (d) A heavy chain comprising the sequence of SEQ ID NO: 108 and a light chain comprising the sequence of SEQ ID NO: 121;

[0194] (e) A heavy chain comprising the sequence of SEQ ID NO: 109 and a light chain comprising the sequence of SEQ ID NO: 122;

[0195] (f) A heavy chain comprising the sequence of SEQ ID NO: 105 and a light chain comprising the sequence of SEQ ID NO: 123;

[0196] (g) A heavy chain comprising the sequence of SEQ ID NO: 110 and a light chain comprising the sequence of SEQ ID NO: 124;

[0197] (h) A heavy chain comprising the sequence of SEQ ID NO: 109 and a light chain comprising the sequence of SEQ ID NO: 125;

[0198] (i) A heavy chain comprising the sequence of SEQ ID NO: 105 and a light chain comprising the sequence of SEQ ID NO: 126;

[0199] (j) A heavy chain comprising the sequence of SEQ ID NO: 111 and a light chain comprising the sequence of SEQ ID NO: 127;

[0200] (k) A heavy chain comprising the sequence of SEQ ID NO: 112 and a light chain comprising the sequence of SEQ ID NO: 128;

[0201] (l) A heavy chain comprising the sequence of SEQ ID NO: 113 and a light chain comprising the sequence of SEQ ID NO: 129;

[0202] (m) A heavy chain comprising the sequence of SEQ ID NO: 114 and a light chain comprising the sequence of SEQ ID NO: 129;

[0203] (n) A heavy chain comprising the sequence of SEQ ID NO: 109 and a light chain comprising the sequence of SEQ ID NO: 130;

[0204] (o) A heavy chain comprising the sequence of SEQ ID NO: 115 and a light chain comprising the sequence of SEQ ID NO: 131;

[0205] (p) A heavy chain comprising the sequence of SEQ ID NO: 116 and a light chain comprising the sequence of SEQ ID NO: 132;

[0206] (q) A heavy chain comprising the sequence of SEQ ID NO: 117 and a light chain comprising the sequence of SEQ ID NO: 133; or

[0207] (r) A heavy chain comprising the sequence of SEQ ID NO: 117 and a light chain comprising the sequence of SEQ ID NO: 134.

[0208] In a particular embodiment, the anti-CGRP receptor antibody for use in the methods of the invention comprises a heavy chain comprising the sequence of SEQ ID NO: 105 and a light chain comprising the sequence of SEQ ID NO: 123. In another particular embodiment, the anti-CGRP receptor antibody for use in the methods of the invention comprises a heavy chain comprising the sequence of SEQ ID NO: 111 and a light chain comprising the sequence of SEQ ID NO: 127.

[0209] Exemplary anti-CGRP receptor antibodies for use in the methods of the invention include (but are not limited to) antibodies 1E11, 1H7, 2E7, 3B6, 3C8, 4E4, 4H6, 5F5, 9D4, 9F5, 10E4, 11D11, 11H9, 12E8, 12G8, 13H2, and 32H7. Table 7 outlines the structural characteristics of each of these antibodies.

[0210] Table 7. Exemplary anti-CGRP receptor antibodies

[0211]

[0212]

[0213]

[0214]

[0215] The anti-CGRP receptor antibodies for use in the methods described herein can be monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, chimeric antibodies, multispecific antibodies, or antigen-binding fragments thereof. In certain embodiments, the anti-CGRP receptor antibody is a monoclonal antibody. In such embodiments, the anti-CGRP receptor antibody can be a human monoclonal antibody. In some embodiments, the anti-CGRP receptor antibody is a human antibody and can be of the IgG1, IgG2, IgG3, or IgG4 isotype. Thus, in some embodiments, the anti-CGRP receptor antibody can have a human IgG1 or human IgG2 constant domain. In one embodiment, the anti-CGRP receptor antibody is a monoclonal IgG1 antibody. In another embodiment, the anti-CGRP receptor antibody is a monoclonal IgG2 antibody.

[0216] After completion of the immunization protocol, monoclonal antibodies can be generated using any technique known in the art, such as immortalizing splenocytes collected from transgenic animals. Any technique known in the art can be used to immortalize splenocytes, such as by fusing the splenocytes with myeloma cells to generate hybridomas. The myeloma cells used in the fusion procedure to generate hybridomas preferably do not produce antibodies, have a high fusion efficiency, and have an enzymatic defect that renders them unable to grow in a specific selective medium that supports the growth of only the desired fused cells (hybridomas). Examples of suitable cell lines for use in mouse fusions include Sp-20, P3-X63 / Ag8, P3-X63-Ag8.653, NS1 / 1.Ag 4 1, Sp210-Ag14, FO, NSO / U, MPC-11, MPC11-X45-GTG 1.7, and S194 / 5XXO Bul; examples of cell lines for use in rat fusions include R210.RCY3, Y3-Ag 1.2.3, IR983F, and 4B210. Other cell lines suitable for cell fusion are U-266, GM1500-GRG2, LICR-LON-HMy2, and UC729-6.

[0217] In some cases, hybridoma cell lines are generated by immunizing an animal (e.g., a transgenic animal having human immunoglobulin sequences) with a CGRP receptor immunogen; collecting splenocytes from the immunized animal; fusing the collected splenocytes with a myeloma cell line, thereby generating hybridoma cells; establishing a hybridoma cell line from the hybridoma cells, and identifying hybridoma cell lines that produce antibodies that bind to the CGRP receptor.

[0218] Any technique known in the art can be used to purify monoclonal antibodies secreted by hybridoma cell lines. For example, cAMP assays can be used to further screen the hybridomas or mAbs, as described herein, to identify mAbs with specific properties, such as the ability to bind to cells expressing the CGRP receptor, the ability to block or interfere with the binding of the CGRP ligand or CGRP 8-37 peptide, or the ability to functionally block the receptor.

[0219] In some embodiments, the anti-CGRP receptor antibodies used in the methods of the invention are chimeric or humanized antibodies based on the foregoing sequences. A chimeric antibody is an antibody composed of protein segments from different antibodies covalently joined to produce a functional immunoglobulin light or heavy chain or an immunologically functional portion thereof. A portion of the heavy and / or light chain is generally identical or homologous to the corresponding sequence in an antibody from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in an antibody from another species or belonging to another antibody class or subclass. For methods related to chimeric antibodies, see, for example, U.S. Patent No. 4,816,567; and Morrison et al., 1985, Proc. Natl. Acad. Sci. USA 81:6851-6855, which references are incorporated herein by reference. CDR grafting is described, for example, in U.S. Patent Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101.

[0220] Generally, the purpose of making chimeric antibodies is to produce chimeras in which the number of amino acids from a predetermined species is maximized. An example is a "CDR-grafted" antibody, in which the antibody contains one or more CDRs from a particular species or belonging to a particular antibody class or subclass, while the remainder of the antibody chain is identical or homologous to the corresponding sequence in an antibody from another species or belonging to another antibody class or subclass. When used in humans, the variable region or selected CDRs from a rodent antibody are typically grafted into a human antibody, replacing the naturally occurring variable region or CDRs of the human antibody.

[0221] A useful type of chimeric antibody is a "humanized" antibody. Humanized antibodies are generally made from monoclonal antibodies originally produced in non-human animals. Certain amino acid residues in such monoclonal antibodies (usually from the non-antigen-recognition portion of the antibody) are typically modified to be homologous to the corresponding residues in the corresponding isotype of a human antibody. Humanization can be carried out, for example, by replacing at least a portion of the rodent variable region with the corresponding region of a human antibody (see, for example, U.S. Patent Nos. 5,585,089 and 5,693,762; Jones et al., 1986, Nature321: 522-525; Riechmann et al., 1988, Nature 332 :323-27; Verhoeyen et al., 1988, Science 239: 1534-1536).

[0222] In one aspect, the CDRs (see Tables 2 and 3) of the light and heavy chain variable regions of the antibodies provided herein are grafted onto the framework regions (FRs) of antibodies from the same or different phylogenetic species. For example, the CDRs of the heavy and light chain variable regions V H 1, V H 2, V H 3, V H 4, V H 5, V H 6, V H 7, V H 8, V H 9, V H 10, V H 11, V H 12 and V H 13 and / or V L 1, V L 2, V L 3, V L 4, V L 5, V L 6, V L 7, V L 8, V L 9, V L 10, V L 11, V L 12, V L 13, V L 14, V L 15, V L 16 and V L 17 are grafted onto a common human FR. To generate a common human FR, the FRs from several human heavy or light chain amino acid sequences can be aligned to identify the common amino acid sequences. In other embodiments, the FRs of the heavy or light chains disclosed herein are replaced with FRs from different heavy or light chains. In one aspect, the rare amino acids in the FRs of the heavy and light chains of the anti-CGRP receptor antibody are not replaced, but the remaining FR amino acids are replaced. A "rare amino acid" is a specific amino acid located at a position where this specific amino acid is not normally found in the FR. Alternatively, the variable region transplanted from one heavy or light chain can be used with a constant region different from the specific heavy or light chain constant region as disclosed herein. In other embodiments, the transplanted variable region is part of a single-chain Fv antibody.

[0223] In certain embodiments, the anti-CGRP receptor antibody or antigen-binding fragment thereof used in the methods of the invention is a fully human antibody. Methods are available for producing fully human antibodies ("fully human antibodies") that are specific for a designated antigen without exposing humans to the antigen. One particular method provided for practicing the production of fully human antibodies is the "humanization" of the murine humoral immune system. Introduction of the human immunoglobulin (Ig) locus into mice in which the endogenous Ig genes have been inactivated is a means of generating fully human monoclonal antibodies (mAbs) in mice, an animal that can be immunized with any desired antigen. The use of fully human antibodies can minimize the immunogenic and allergic responses that can sometimes occur upon administration of murine or murine-derived mAbs to humans as therapeutic agents.

[0224] Fully human antibodies can be produced by immunizing transgenic animals (commonly mice) that are capable of generating a human antibody repertoire without producing endogenous immunoglobulins. For this purpose, the antigen typically has six or more contiguous amino acids and is optionally conjugated to a carrier such as a hapten. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA 90 :2551-2555; Jakobovits et al., 1993, Nature 362 :255-258; and Bruggermann et al., 1993, Year in Immunol. 7:33. In one example of such methods, transgenic animals are generated by disabling the endogenous murine immunoglobulin heavy and light chain genes in which they are encoded, and inserting large fragments of human genomic DNA containing the loci encoding the human heavy and light chain proteins into the mouse genome. The partially modified animals having less than a full set of human immunoglobulin loci are then crossbred to obtain animals having all the desired immune system modifications. When immunogen is administered, these transgenic animals produce antibodies that are immunospecific for the immunogen but have human rather than murine amino acid sequences, including the variable regions. For additional details of such methods, see, e.g., WO96 / 33735 and WO94 / 02602. Additional methods for producing transgenic mice for the production of human antibodies are described in the following patents: U.S. Patent Nos. 5,545,807, 6,713,610, 6,673,986, 6,162,963, 5,545,807, 6,300,129, 6,255,458, 5,877,397, 5,874,299, and 5,545,806; PCT Publication Nos. WO91 / 10741, WO90 / 04036; and EP 546073B1 and EP 546073A1.

[0225] The transgenic mice described above (referred to herein as "HuMab" mice) contain a human immunoglobulin gene minilocus encoding unrearranged human heavy ([μ] and [γ]) and [κ] light chain immunoglobulin sequences, as well as targeted mutations that inactivate the endogenous [μ] and [κ] chain loci (Lonberg et al., 1994, Nature 368 :856-859). Thus, the mice exhibit reduced mouse IgM or [κ] expression and responsiveness to immunization, and the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to produce high-affinity human IgG[κ] monoclonal antibodies (Lonberg et al., loc. cit.; Lonberg and Huszar, 1995, Intern. Rev. Immunol. 13 : 65-93; Harding and Lonberg, 1995, Ann. N. Y Acad. Sci. 764 :536-546). The preparation of HuMab mice is described in detail in the following references: Taylor et al., 1992, Nucleic Acids Research 20 :6287-6295; Chen et al., 1993, International Immunology 5 :647-656; Tuaillon et al., 1994, J. Immunol. 152 :2912-2920; Lonberg et al., 1994, Nature 368 :856-859; Lonberg, 1994, Handbook of Exp. Pharmacology 113 :49-101; Taylor et al., 1994, International Immunology 6 :579-591; Lonberg and Huszar, 1995, Intern. Rev. Immunol. 13 :65-93; Harding and Lonberg, 1995, Ann. N.Y Acad. Sci. 764 :536-546; Fishwild et al., 1996, Nature Biotechnology 14: 845-851; the foregoing references are incorporated herein by reference in their entirety for all purposes. See also U.S. Patent Nos. 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,789,650, 5,877,397, 5,661,016, 5,814,318, 5,874,299, and 5,770,429, and U.S. Patent No. 5,545,807; International Publication Nos. WO 93 / 1227, WO92 / 22646, and WO 92 / 03918, the disclosures of all of these patents are incorporated herein by reference in their entirety for all purposes. WO 98 / 24893 and Mendez et al., 1997, Nature Genetics 15 : 146-156 also disclose techniques for making human antibodies in these transgenic mice, and these methods are incorporated herein by reference. For example, the HCo7 and HCo12 transgenic mouse lines can be used to generate anti-CGRP receptor antibodies.

[0226] Some of the anti-CGRP receptor antibodies or binding fragments that can be used in the methods described herein are variant forms of the anti-CGRP receptor antibodies disclosed above (e.g., those antibodies having the sequences listed in Tables 2-7). For example, the anti-CGRP receptor antibody or binding fragment can have one or more conservative amino acid substitutions in one or more of the heavy or light chains, variable regions, or CDRs listed in Tables 2-7. Conservative amino acid substitutions can involve the exchange of an amino acid with another amino acid having common side chain properties (e.g., hydrophobicity, neutral hydrophilicity, acidity, basicity, and aromaticity). For example, conservative substitutions include the replacement of a hydrophobic amino acid (e.g., norleucine, methionine, alanine, valine, leucine, or isoleucine) with another hydrophobic amino acid. Conservative amino acid substitutions can encompass non-naturally occurring amino acid residues that are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These materials include peptidomimetics and other inverted or reversed forms of amino acid moieties.

[0227] In making such changes, according to certain embodiments, the hydrophilicity index of the amino acids can be considered. The hydrophilic profile of a protein is calculated by assigning a numerical value ("hydrophilicity index") to each amino acid and then repeatedly calculating the average of these values along the peptide chain. Hydrophilicity indices have been assigned to each amino acid based on hydrophobic and charge characteristics. They are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

[0228] In the art, the importance of hydrophilic profiles in conferring biological functions on protein interactions has been appreciated (see, e.g., Kyte et al., 1982, J. Mol. Biol. 157:105-131). It is known that certain amino acids can substitute for other amino acids having similar hydrophilicity indices or scores and still retain similar biological activity. When making changes based on the hydrophilicity index, in certain embodiments, substitutions of amino acids with hydrophilicity indices within ±2 are incorporated. In some aspects, those amino acids within ±1 are incorporated, while in other aspects, those amino acids within ±0.5 are incorporated.

[0229] It should also be appreciated in the art that substitutions of similar amino acids can be effectively made based on hydrophilicity, particularly as in the case of the present invention when the resulting biologically functional protein or peptide is to be used in immunological embodiments. In certain embodiments, the maximum local average hydrophilicity of a protein (depending on the hydrophilicity of its neighboring amino acids) is related to its immunogenicity and antigen binding or immunogenicity (i.e., the biological properties of the protein).

[0230] The following hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0); aspartic acid (+3.0 ± 1); glutamic acid (+3.0 ± 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ± 1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); and tryptophan (-3.4). When making changes based on similar hydrophilicity values, in certain embodiments, substitutions of amino acids with hydrophilicity values within ±2 are incorporated, in other embodiments, those amino acids within ±1 are incorporated, and in other embodiments, those amino acids within ±0.5 are incorporated. In some cases, epitopes can also be identified from the primary amino acid sequence based on hydrophilicity. These regions are also referred to as "epitope core regions".

[0231] Exemplary conservative amino acid substitutions are set forth in Table 8.

[0232] Table 8: Conservative Amino Acid Substitutions

[0233] original residue exemplary substitution Ala Ser Arg Lys Asn Gln, His Asp Glu Cys Ser Gln Asn Glu Asp Gly Pro His Asn, Gln Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe Met, Leu, Tyr Ser Thr Thr Ser Trp Tyr Tyr Trp, Phe Val Ile, Leu

[0234] Those skilled in the art will be able to determine suitable variants of the anti-CGRP receptor antibodies as described herein using well-known techniques. Those skilled in the art can identify suitable regions in the molecule that can be altered without disrupting activity by targeting regions believed to be unimportant for activity. Those skilled in the art will also be able to identify residues and portions in the molecule that are conserved in similar polypeptides. In other embodiments, even regions that may be important for biological activity or for structure can be subjected to conservative amino acid substitutions without disrupting biological activity or adversely affecting polypeptide structure.

[0235] In addition, those skilled in the art can review structure-function studies that identify residues important for activity or structure in similar polypeptides. In view of such comparisons, the importance of amino acid residues in a protein corresponding to amino acid residues important for activity or structure in a similar protein can be predicted. Those skilled in the art can select chemically similar amino acids to substitute such predicted important amino acid residues.

[0236] Those skilled in the art can also analyze the three-dimensional structure and amino acid sequence in connection with the structure of similar polypeptides. Given such information, those skilled in the art can predict the arrangement of amino acid residues for the three-dimensional structure of the antibody. Those skilled in the art may choose not to make radical changes to the amino acid residues predicted to be located on the surface of the protein, as such residues may be involved in important interactions with other molecules. In addition, those skilled in the art can generate test variants containing a single amino acid substitution at each desired amino acid residue. Then, assays for CGRP receptor neutralizing activity can be used to screen these variants, thereby obtaining information on which amino acids can be altered and which cannot. In other words, based on the information collected from such routine experiments, those skilled in the art can readily determine the amino acid positions at which further substitutions should be avoided, either alone or in combination with other mutations.

[0237] Other preferred antibody variants include cysteine variants in which one or more cysteine residues in the parental or native amino acid sequence are deleted or replaced with another amino acid (e.g., serine). Cysteine variants are applicable, especially when the antibody must refold into a biologically active conformation. Compared to native antibodies, cysteine variants may have fewer cysteine residues and typically an even number to minimize interactions resulting from unpaired cysteines.

[0238] The subclass exchange method can be used to convert an anti-CGRP receptor antibody or its binding fragment belonging to one subclass into an antibody or binding fragment from a different subclass. Thus, an IgG antibody can be derived, for example, from an IgM antibody, and vice versa. Such techniques allow the preparation of new antibodies that have the antigen-binding properties of a designated antibody (the parental antibody) and also exhibit biological properties associated with an antibody isotype or subclass different from the parental antibody. Recombinant DNA techniques can be employed. Cloned DNA encoding a specific antibody polypeptide, such as DNA encoding the constant domain of an antibody of the desired isotype, can be used in such procedures. See, for example, Lantto et al., 2002, Methods Mol. Biol. 178:303-316.

[0239] Thus, the anti-CGRP receptor antibodies described herein include those antibodies comprising, for example, the combinations of variable domains described above having a desired isotype (e.g., IgA, IgG1, IgG2, IgG3, IgG4, IgE, and IgD) and their Fab or F(ab')2 fragments. In addition, if IgG4 is desired, it may also be necessary, as described by Bloom et al., 1997, Protein Science 6:407 (incorporated herein by reference), to introduce a point mutation (CPSCP->CPPCP) in the hinge region to alleviate the tendency to form inter-H chain disulfide bonds, which can cause heterogeneity in IgG4 antibodies.

[0240] In addition, techniques are also known for generating antibodies having different properties (i.e., different affinities for the antigen to which they bind). One such technique is called chain shuffling and involves displaying a repertoire of immunoglobulin variable domain genes on the surface of filamentous phage, commonly referred to as phage display. As described by Marks et al., 1992, BioTechnology, 10:779, chain shuffling has been used to prepare high-affinity antibodies against the hapten 2-phenyloxazol-5-one.

[0241] Conservative modifications can be made to the heavy and light chain variable regions described in Table 4 or the CDRs described in Tables 2 and 3 (and the corresponding nucleic acids encoding them) to produce CGRP receptor antibodies or binding fragments thereof having certain desired functions and biochemical characteristics. Methods for achieving such modifications are described above.

[0242] Anti-CGRP receptor antibodies or binding fragments thereof for use in the methods of the invention can be prepared by any of a variety of conventional techniques. For example, the anti-CGRP receptor antibodies described herein can be made using any technique known in the art through a recombinant expression system. See, e.g., Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Kennet et al. (eds) Plenum Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow and Lane (eds), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988).

[0243] An anti-CGRP receptor antibody or a binding fragment thereof can be expressed in a hybridoma cell line (e.g., specifically, the antibody can be expressed in a hybridoma) or in a cell line other than a hybridoma. An expression construct encoding the antibody can be used to transform mammalian, insect, or microbial host cells. Transformation can be carried out using any known method for introducing a polynucleotide into a host cell, including, for example, as exemplified by U.S. Patent Nos. 4,399,216; 4,912,040; 4,740,461; 4,959,455, packaging the polynucleotide in a virus or phage and transducing the host cell with the construct by transfection procedures known in the art. The optimal transformation procedure used will depend on the type of host cell being transformed. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include (but are not limited to) dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, native protoplast fusion, electroporation, encapsulation of polynucleotides in liposomes, mixing of nucleic acids with positively charged lipids, and direct microinjection of DNA into the nucleus.

[0244] A recombinant expression construct typically contains a nucleic acid molecule encoding a polypeptide that comprises one or more of the following: one or more CDRs provided herein; a light chain constant region; a light chain variable region; a heavy chain constant region (e.g., CH1, CH2, and / or CH3); a heavy chain variable region; and / or another scaffold portion of an anti-CGRP receptor antibody. These nucleic acid sequences are inserted into an appropriate expression vector using standard ligation techniques. In one embodiment, a heavy chain or light chain constant region is attached to the C-terminus of an anti-CGRP receptor-specific heavy chain or light chain variable region and ligated to the expression vector. A vector that is functional in the particular host cell used is typically selected (i.e., the vector is compatible with the host cell machinery to allow amplification and / or expression of the gene). In some embodiments, the vector used employs a protein reporter (such as dihydrofolate reductase) and uses protein fragment complementation analysis (see, for example, U.S. Patent No. 6,270,964, which is incorporated herein by reference). Suitable expression vectors can be purchased, for example, from Invitrogen Life Technologies or BD Biosciences (formerly known as "Clontech"). Other suitable vectors for cloning and expressing antibodies and fragments include those described in Bianchi and McGrew, 2003, Biotech. Biotechnol. Bioeng. 84:439-44, which is incorporated herein by reference. Other suitable expression vectors are discussed, for example, in Methods Enzymol., Vol. 185 (D. V. Goeddel, ed.), 1990, New York: Academic Press.

[0245] Typically, an expression vector for use in any host cell will contain sequences for plasmid maintenance and for cloning and expressing exogenous nucleotide sequences. In certain embodiments, such sequences (collectively referred to as "flanking sequences") will generally include one or more of the following nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcription termination sequence, a complete intron sequence containing donor and acceptor splice sites, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for insertion of nucleic acid encoding the polypeptide to be expressed, and selectable marker elements. Each of these sequences is discussed below.

[0246] Optionally, the vector may contain a "tag" coding sequence, i.e., an oligonucleotide molecule located at the 5' or 3' end of the anti-CGRP receptor antibody coding sequence; the oligonucleotide sequence encodes polyhistidine (such as hexahistidine) or another "tag", such as FLAG®, HA (hemagglutinin influenza virus), or myc, for which commercially available antibodies exist. This tag typically fuses with the polypeptide after polypeptide expression and can serve as a means for affinity purification or detection of the anti-CGRP receptor antibody from the host cell. Affinity purification can be achieved, for example, by column chromatography using an antibody against the tag as the affinity matrix. Optionally, the tag can subsequently be removed from the purified anti-CGRP receptor antibody by various means, such as using certain peptidases for cleavage.

[0247] The flanking sequences can be homologous (i.e., from the same species and / or strain as the host cell), heterologous (i.e., from a species different from the host cell species or strain), chimeric (i.e., a combination of flanking sequences from more than one source), synthetic, or natural. Thus, the source of the flanking sequences can be any prokaryotic or eukaryotic organism, any vertebrate or invertebrate organism, or any plant, provided that the flanking sequences are functional in the host cell machinery and can be activated by the host cell machinery.

[0248] The flanking sequences useful for the vector can be obtained by any of several methods well known in the art. Generally, the flanking sequences suitable for use herein will be pre-identified by mapping and / or by restriction endonuclease digestion and can thus be isolated from appropriate tissue sources using appropriate restriction endonucleases. In some cases, the complete nucleotide sequence of the flanking sequences may be known. Herein, the flanking sequences can be synthesized using the methods for nucleic acid synthesis or cloning described herein.

[0249] Whether all or only a part of the flanking sequences are known, they can be obtained using polymerase chain reaction (PCR) and / or by screening a genomic library with suitable probes such as oligonucleotides and / or flanking sequence fragments from the same or another species. When the flanking sequences are unknown, DNA fragments containing the flanking sequences can be isolated from larger DNA fragments that may contain, for example, coding sequences or even other genes. Isolation can be achieved by restriction endonuclease digestion to produce appropriate DNA fragments, followed by separation using agarose gel purification, Qiagen® column chromatography (Chatsworth, CA), or other methods known to those skilled in the art. Selecting a suitable enzyme to achieve this purpose will be obvious to one of ordinary skill in the art.

[0250] Origins of replication are usually part of those prokaryotic expression vectors that are commercially available, and the origin helps the vector to amplify in the host cell. If the selected vector does not contain an origin of replication site, then the origin of replication can be chemically synthesized based on known sequences and ligated into the vector. For example, the origin of replication from plasmid pBR322 (New England Biolabs, Beverly, MA) is suitable for most gram-negative bacteria, while various viral origins (such as SV40, polyomavirus, adenovirus, vesicular stomatitis virus (VSV), or papillomaviruses such as HPV or BPV) are suitable for cloning vectors in mammalian cells. Mammalian expression vectors generally do not require an origin of replication component (for example, usually only the SV40 origin is used because it also contains the viral early promoter).

[0251] Transcription termination sequences are usually located at the 3' end of the polypeptide coding region and are used to terminate transcription. Generally, transcription termination sequences in prokaryotic cells are G-C rich fragments, followed by a poly-T sequence. Although it is easy to clone such sequences from a library or even commercially purchase them as part of a vector, they can also be easily synthesized using methods known for nucleic acid synthesis.

[0252] Selectable marker genes encode proteins that are essential for the survival and growth of host cells growing in selective media. Typical selectable marker genes encode proteins that: (a) confer resistance to antibiotics or other toxins (e.g., ampicillin, tetracycline, or kanamycin for prokaryotic host cells); (b) complement a nutritional deficiency in the cell; or (c) supply a key nutrient not available from complex or defined media. Specific selectable markers are the kanamycin resistance gene, the ampicillin resistance gene, and the tetracycline resistance gene. Advantageously, the neomycin resistance gene can also be used for selection in both prokaryotic and eukaryotic host cells.

[0253] Other selectable genes can be used to amplify the gene to be expressed. Amplification is the process by which genes required to produce proteins vital for growth or cell survival are tandemly repeated in the chromosomes of successive generations of recombinant cells. Examples of selectable markers suitable for mammalian cells include dihydrofolate reductase (DHFR) and the promoterless thymidine kinase gene. Mammalian cell transformants are placed under a selection pressure where only the transformants uniquely adapted to survive due to the presence of the selectable gene in the vector. The selection pressure is imposed by culturing the transformed cells under conditions of continuously increasing concentration of the selection agent in the medium, whereby the selectable gene and the DNA encoding another gene (such as an anti-CGRP receptor antibody) are amplified. Thus, an increased number of polypeptides, such as anti-CGRP receptor antibodies, are synthesized from the amplified DNA.

[0254] Ribosome binding sites are generally required for translation initiation of mRNA and are characterized by the Shine-Dalgarno sequence (for prokaryotes) or the Kozak sequence (for eukaryotes). Such elements are generally located at the 3' end of the promoter and the 5' end of the coding sequence of the polypeptide to be expressed.

[0255] In some cases, such as when glycosylation is required in eukaryotic host cell expression systems, various presequences or prosequences can be manipulated to improve glycosylation or yield. For example, the peptidase cleavage site of a specific signal peptide can be altered, or a prosequence can be added, which may also affect glycosylation. The final protein product may have one or more additional amino acids unexpectedly expressed at the -1 position (relative to the first amino acid of the mature protein), and such additional amino acids may not be completely removed. For example, the final protein product may have one or two amino acid residues present at the peptidase cleavage site attached to the amino terminus. Alternatively, use of some peptidase cleavage sites may produce a slightly truncated form of the desired polypeptide if the enzyme cleaves at that region in the mature polypeptide.

[0256] Expression and cloning generally involve a promoter that is recognized by the host organism and operably linked to a molecule encoding an anti-CGRP receptor antibody or binding fragment. A promoter is a non-transcribed sequence located upstream (i.e., at the 5' end) of the start codon of a structural gene (generally within about 100 to 1000 bp), which controls the transcription of the structural gene. Promoters are typically classified into one of two categories: inducible promoters and constitutive promoters. Inducible promoters initiate an increase in the amount of DNA transcription under their control in response to some change in culture conditions, such as the presence or absence of nutrients or a change in temperature. On the other hand, constitutive promoters transcribe the genes to which they are operably linked uniformly, i.e., with little or no control over gene expression. A large number of promoters recognized by a variety of potential host cells are well known. A suitable promoter is operably linked to the DNA encoding the heavy or light chain of an anti-CGRP receptor antibody or binding fragment by removing the promoter from the source DNA by digestion with a restriction enzyme and inserting the desired promoter sequence into the vector.

[0257] Promoters suitable for yeast hosts are also well known in the art. Yeast enhancers are preferably used in conjunction with yeast promoters. Promoters suitable for mammalian host cells are well known and include (but are not limited to) those obtained from the genomes of viruses such as polyomavirus, fowlpox virus, adenovirus (such as adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, and simian virus 40 (SV40). Other suitable mammalian promoters include heterologous mammalian promoters, such as the heat shock promoter and the actin promoter.

[0258] Other promoters of interest include, but are not limited to: the SV40 early promoter (Benoist and Chambon, 1981, Nature 290:304-310); the CMV promoter (Thornsen et al., 1984, Proc. Natl. Acad. U.S.A. 81:659-663); the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto et al., 1980, Cell 22:787-797); the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:1444-1445); the promoter and regulatory sequences from the metallothionein gene (Prinster et al., 1982, Nature 296:39-42); and prokaryotic promoters such as the β-lactamase promoter (Villa-Kamaroff et al., 1978, Proc. Natl. Acad. Sci. U.S.A. 75:3727-3731); or the tac promoter (DeBoer et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:21-25).Also of interest are the following animal transcriptional control regions that exhibit tissue specificity and have been used in transgenic animals: the elastase I gene control region that is active in pancreatic acinar cells (Swift et al., 1984, Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Quant. Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); the insulin gene control region that is active in pancreatic beta cells (Hanahan, 1985, Nature 315:115-122); the immunoglobulin gene control region that is active in lymphocytes (Grosschedl et al., 1984, Cell 38:647-658; Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, Mol. Cell. Biol. 7: 1436-1444); the mouse mammary tumor virus control region that is active in testis, breast, lymph, and mast cells (Leder et al., 1986, Cell 45:485-495); the albumin gene control region that is active in the liver (Pinkert et al., 1987, Genes and Devel. 1:268-276); the alpha-fetoprotein gene control region that is active in the liver (Krumlauf et al., 1985, Mol. Cell. Biol. 5: 1639-1648; Hammer et al., 1987, Science 253:53-58); the alpha1-antitrypsin gene control region that is active in the liver (Kelsey et al., 1987, Genes and Devel. 1: 161-171); the beta-globin gene control region that is active in myeloid cells (Mogram et al., 1985, Nature 315:338-340; Kollias et al., 1986, Cell 46:89-94); the myelin basic protein gene control region that is active in oligodendrocytes in the brain (Readhead et al., 1987, Cell 48:703-712); the myosin light chain-2 gene control region that is active in skeletal muscle (Sani, 1985, Nature 314:283-286); and the gonadotropin-releasing hormone gene control region that is active in the hypothalamus (Mason et al., 1986, Science 234:1372-1378).

[0259] Enhancer sequences can be inserted into vectors to increase the transcription of DNA encoding the light or heavy chain of an anti-CGRP receptor antibody or a binding fragment thereof in higher eukaryotes. An enhancer is a cis-acting element of DNA, typically about 10 - 300 bp in length, which acts on a promoter to increase transcription. Enhancers are relatively orientation- and position-independent and have been found at positions both 5' and 3' of the transcription unit. A number of enhancer sequences obtainable from mammalian genes are known (e.g., globin, elastase, albumin, alpha-fetoprotein, and insulin). However, enhancers from viruses are commonly used. The SV40 enhancer, cytomegalovirus early promoter enhancer, polyomavirus enhancer, and adenovirus enhancer known in the art are exemplary enhancer elements for activating eukaryotic promoters. Although an enhancer can be located 5' or 3' of the coding sequence in a vector, it is typically located at a site 5' of the promoter. A sequence encoding an appropriate native or heterologous signal sequence (leader sequence or signal peptide) can be incorporated into the expression vector to facilitate the extracellular secretion of the antibody. The choice of signal peptide or leader sequence depends on the type of host cell in which the antibody is to be produced, and a heterologous signal sequence can replace the native signal sequence. Examples of signal peptides functional in mammalian host cells include the signal sequence of interleukin-7 (IL-7) described in U.S. Patent No. 4,965,195; the signal sequence of the interleukin-2 receptor described in Cosman et al., 1984, Nature 312:768; the interleukin-4 receptor signal peptide described in EP Patent No. 0367 566; the type I interleukin-1 receptor signal peptide described in U.S. Patent No. 4,968,607; the type II interleukin-1 receptor signal peptide described in EP Patent No. 0 460 846. Other useful signal peptides for expressing the anti-CGRP receptor antibodies or binding fragments described herein are signal peptides having the sequences set forth in SEQ ID NO:135 or SEQ ID NO:136.

[0260] Expression vectors for the recombinant production of the anti-CGRP receptor antibodies or binding fragments described herein can be constructed from starting vectors such as commercially available vectors. Such vectors may or may not contain all of the required flanking sequences. When one or more of the flanking sequences described herein are not present in the vector, the one or more flanking sequences can be obtained individually and ligated into the vector. Methods for obtaining each flanking sequence are well known to those of skill in the art.

[0261] After a vector has been constructed and nucleic acid molecules encoding the light chain, heavy chain, or light chain and heavy chain that constitute an anti-CGRP receptor antibody or binding fragment have been inserted into appropriate sites of the vector, the completed vector can be inserted into a suitable host cell for amplification and / or polypeptide expression. Transformation of an expression vector for an antigen-binding protein into a selected host cell can be accomplished by well-known methods including the following: transfection, infection, calcium phosphate co-precipitation, electroporation, microinjection, lipofection, DEAE-dextran-mediated transfection, or other known techniques. The method selected will depend in part on the type of host cell to be used. These methods and other suitable methods are well known to those of skill in the art and are described, for example, in Sambrook et al., 2001, supra.

[0262] When cultured under appropriate conditions, the host cell synthesizes an antigen-binding protein (e.g., an antibody or binding fragment), which can then be collected from the culture medium (if the host cell secretes it into the medium) or directly from the host cell that produces it (if it is not secreted). The choice of a suitable host cell will depend on various factors such as the desired level of expression, polypeptide modifications required or necessary for activity (such as glycosylation or phosphorylation), and ease of folding into a bioactive molecule.

[0263] Mammalian cell lines that can be used as expression hosts are well known in the art and include (but are not limited to) immortalized cell lines available from the American Type Culture Collection (ATCC), including (but not limited to) Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and many other cell lines. In certain embodiments, the cell line can be selected by determining which cell lines have high expression levels and constitutively produce an antibody or binding fragment with CGRP receptor-binding properties. In another embodiment, a cell line from the B cell lineage that does not produce antibodies itself but has the ability to manufacture and secrete heterologous antibodies can be selected.

[0264] An anti-CGRP receptor antibody or binding fragment thereof is generally administered to a patient in the form of a pharmaceutical composition, which may include a pharmaceutically acceptable carrier, excipient, or diluent. "Pharmaceutically acceptable" means that the molecule, compound, and composition are non-toxic to the human recipient at the dosages and concentrations employed and / or do not produce allergic or adverse reactions when administered to humans. In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or penetration of the composition. In such embodiments, suitable formulation materials include (but are not limited to) amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrate, phosphate, or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulins); coloring agents, flavoring agents, and diluents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerol, propylene glycol, or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronic, PEG, sorbitan esters, polysorbates (such as polysorbate 20, polysorbate 80), triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancers (such as sucrose or sorbitol); tonicity enhancers (such as alkali metal halides (preferably sodium chloride or potassium chloride), mannitol, sorbitol); delivery vehicles; diluents; excipients; and / or pharmaceutical adjuvants. Methods and suitable materials for formulating molecules for therapeutic use are known in the pharmaceutical art and are described, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition (A.R. Genrmo, ed.), 1990, Mack Publishing Company.

[0265] In some embodiments, the choice of carriers and excipients for incorporation into a pharmaceutical composition affects the physical state, stability, in vivo release rate, and in vivo clearance rate of an anti-CGRP receptor antibody or its binding fragment. In certain embodiments, the primary vehicle or carrier in the pharmaceutical composition can be aqueous or non-aqueous. By way of example, suitable vehicles or carriers can be water for injection, saline solution, or artificial cerebrospinal fluid, which may be supplemented with other materials commonly found in compositions for parenteral administration.

[0266] In certain embodiments of the methods described herein, an anti-CGRP receptor antibody or its binding fragment is administered to a patient parenterally. Parenteral administration includes intraperitoneal, intramuscular, intravenous, intraarterial, intradermal, subcutaneous, intracerebral, intraventricular, and intrathecal administration. In one particular embodiment, a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or its binding fragment is administered subcutaneously to a patient. In these and other embodiments in which the pharmaceutical composition is administered by parenteral injection, the pharmaceutical composition can be administered to the patient using a syringe. In some embodiments, the syringe is prefilled with the pharmaceutical composition. In other embodiments in which the pharmaceutical composition is administered to a patient by parenteral injection, such as subcutaneous injection, the pharmaceutical composition is administered using an injection device, including a device for self-administration. Such devices are commercially available and include, but are not limited to, autoinjectors, dosing pens, microinfusion pumps, and prefilled syringes. Exemplary devices for administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or its binding fragment according to the methods of the present invention include autoinjectors (e.g., SureClick®, EverGentle®, Avanti®, DosePro®, Molly®, and Leva®), pen injection devices (e.g., Madie® pen syringe, DCP TM pen syringe, BD Vystra TM disposable pen syringe, BD TM reusable pen syringe), and prefilled syringes (BD Sterifill TM 、BD Hypak TM 、prefilled syringes from Baxter). In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or binding fragment is administered to a patient using a prefilled syringe. In other embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or binding fragment is administered to a patient using an autoinjector. In certain related embodiments, the injection volume is about 1 mL or less.

[0267] In one embodiment, an anti-CGRP receptor antibody or a binding fragment thereof is administered to a patient at a dose of about 70 mg per month to prevent or reduce the occurrence of migraine in the patient, wherein the dose is delivered by a single subcutaneous injection. In related embodiments, the single subcutaneous injection is delivered using a prefilled syringe. In other related embodiments, the single subcutaneous injection is delivered using an autoinjector. In certain embodiments, the patient may have or be diagnosed with episodic migraine. In other embodiments, the patient may have or be diagnosed with chronic migraine.

[0268] In another embodiment, an anti-CGRP receptor antibody or a binding fragment thereof is administered to a patient at a dose of about 140 mg per month to prevent or reduce the occurrence of migraine in the patient, wherein the dose is delivered by a single subcutaneous injection. In such embodiments, the single injection may be delivered using a prefilled syringe or an autoinjector. In one embodiment, a monthly dose of 140 mg of an anti-CGRP receptor antibody or a binding fragment thereof is administered to the patient by two consecutive injections, each injection comprising a 70 mg dose. In such embodiments, two prefilled syringes or two autoinjectors may be used to deliver the two consecutive injections, each injection containing a 70 mg dose. In some embodiments, the patient may have or be diagnosed with episodic migraine. In other embodiments, the patient may have or be diagnosed with chronic migraine.

[0269] Exemplary pharmaceutical forms suitable for parenteral injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Preferably, the pharmaceutical form is sterile and has sufficient fluidity to allow delivery via a syringe (i.e., the formulation is not overly viscous to prevent passage through the syringe). Sterilization can be achieved by filtration through a sterile filtration membrane. When the composition is in lyophilized form, this method can be used for sterilization before or after lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in solution form. The parenteral composition can be placed in a container having a sterile access port, such as an intravenous solution bag or vial having a stopper that can be pierced by a subcutaneous injection needle. The parenteral composition can also be stored in a syringe, an autoinjector device, or a pen-type injection device or cartridge suitable for use with such injection devices.

[0270] In certain embodiments, the preparation of the pharmaceutical composition to be administered according to the methods of the invention can involve formulating an anti-CGRP receptor antibody or binding fragment thereof with a substance such as injectable microspheres, bioerodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, which can enable controlled or sustained release of the antibody or binding fragment deliverable via depot injection. In certain embodiments, hyaluronic acid can also be used, which has a persistent effect promoting circulation. In certain embodiments, an implantable drug delivery device can be used to deliver the anti-CGRP receptor antibody or binding fragment.

[0271] In some embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or binding fragment thereof to be administered to a patient according to the methods of the invention further comprises a buffer. The buffer is used to maintain the composition at physiological pH or slightly lower pH, typically in the pH range of about 4.5 to about 6.5. Suitable buffers include (but are not limited to) glutamate, acetate, Tris, citrate, histidine, succinate, and phosphate buffers. In certain embodiments, the pharmaceutical composition administered according to the methods described herein comprises an acetate buffer. The acetate buffer can be made from an acetate such as sodium acetate. Other salts can be used, such as the acetate of potassium, ammonium, calcium, or magnesium. The pH of the pharmaceutical composition comprising an acetate buffer is typically from about 4.5 to about 5.5, or about 4.8 to about 5.2, including about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, and about 5.5.

[0272] A pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or a binding fragment thereof may further comprise a surfactant. As used herein, the term "surfactant" refers to a substance that reduces the surface tension of the liquid in which it is dissolved. Surfactants can be included in pharmaceutical compositions for a variety of purposes, including, for example, preventing or controlling aggregation, particle formation, and / or surface adsorption in liquid formulations, or preventing or controlling these phenomena during lyophilization and / or reconstitution of lyophilized formulations. Surfactants include, for example, amphiphilic organic compounds that exhibit partial solubility in organic solvents and aqueous solutions. General characteristics of surfactants include their ability to reduce the surface tension of water, reduce the interfacial tension between oil and water, and form micelles. Surfactants that can be incorporated into the pharmaceutical compositions for use in the methods of the present invention include nonionic and ionic surfactants. Suitable nonionic surfactants include (but are not limited to) alkyl poly(ethylene oxide), alkyl polyglucosides (such as octyl glucoside and decyl maltoside), fatty alcohols (such as cetyl alcohol and oleyl alcohol), coconut amide MEA, coconut amide DEA, and coconut amide TEA. Specific examples of nonionic surfactants include polysorbates, including, for example, polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, etc.; poloxamers, including, for example, poloxamer 188 (also known as poloxalkol or poly(ethylene oxide)-poly(propylene oxide)), poloxamer 407, or polyethylene-polypropylene glycol, etc.; and polyethylene glycol (PEG). Suitable ionic surfactants include, for example, anionic, cationic, and zwitterionic surfactants. Anionic surfactants include (but are not limited to) sulfonate-based or carboxylate-based surfactants, such as soaps, fatty acid salts, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl sulfates. Cationic surfactants include (but are not limited to) quaternary ammonium-based surfactants, such as cetyltrimethylammonium bromide (CTAB), other alkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylated tallow amine (POEA), and benzalkonium chloride. Zwitterionic or amphoteric surfactants include, for example, dodecyl betaine, dodecyldimethylamine oxide, cocamidopropyl betaine, and cocoyl ampho glycinate. In certain embodiments, the pharmaceutical composition administered according to the methods described herein comprises a nonionic surfactant. In one embodiment, the nonionic surfactant is polysorbate 20. In another embodiment, the nonionic surfactant is polysorbate 80.

[0273] In certain embodiments, a pharmaceutical composition comprising a therapeutically effective amount of an anti-CGRP receptor antibody or a binding fragment thereof further comprises a stabilizer. As used herein, the term "stabilizer" is an excipient that stabilizes the native conformation of a polypeptide or antibody and / or prevents or reduces the physical or chemical degradation of the polypeptide or antibody. Suitable stabilizers include, but are not limited to, polyols (e.g., sorbitol, glycerol, mannitol, xylitol, maltitol, lactitol, erythritol, and threitol), sugars (e.g., fructose, glucose, glyceraldehyde, lactose, arabinose, mannose, xylose, ribose, rhamnose, galactose, maltose, sucrose, trehalose, sorbose, sucralose, melezitose, and raffinose), and amino acids (e.g., glycine, methionine, proline, lysine, arginine, histidine, or glutamic acid). In some embodiments, the pharmaceutical composition comprises a sugar as a stabilizer. In these and other embodiments, the sugar is sucrose.

[0274] In certain embodiments, a pharmaceutical composition useful for prophylactically treating migraine according to the methods described herein comprises from about 35 mg / ml to about 210 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, from about 8 mM to about 20 mM of sodium acetate, from about 0.002% to about 0.015% (weight / volume; w / v) of polysorbate, and from about 7% to about 10% w / v of sucrose. In other embodiments, the pharmaceutical composition comprises from about 70 mg / ml to about 140 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, from about 10 mM to about 15 mM of sodium acetate, from about 0.008% to about 0.012% w / v of polysorbate, and from about 8% to about 9% w / v of sucrose. The pH of these compositions ranges from about 4.8 to about 5.5 (e.g., a pH of about 4.8, about 5.0, about 5.2, or about 5.4).

[0275] In one embodiment, the pharmaceutical composition to be administered according to the method of the present invention comprises about 70 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 10 mM sodium acetate, about 0.004% w / v polysorbate 20, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 10 mM sodium acetate, about 0.004% w / v polysorbate 80, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 10 mM sodium acetate, about 0.004% w / v polysorbate 20, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody and its binding fragment, about 10 mM sodium acetate, about 0.004% w / v polysorbate 80, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 10 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 10 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2. In a particular embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 10 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2. In another particular embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 10 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 9% w / v sucrose, with a pH of 5.2 ± 0.2.

[0276] In certain embodiments, the pharmaceutical composition to be administered according to the methods of the invention comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In one particular embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another particular embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In some embodiments, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In other embodiments, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2.

[0277] In some embodiments, the pharmaceutical composition to be administered according to the methods of the invention comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In one embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 70 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprises about 140 mg / ml of an anti-CGRP receptor antibody or binding fragment thereof, about 20 mM sodium acetate, about 0.010% w / v polysorbate 20, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2.

[0278] Any of the anti-CGRP receptor antibodies or binding fragments described herein, including the specific anti-CGRP receptor antibodies described in Table 7, can be incorporated into any of the pharmaceutical compositions described above and administered to a patient according to the methods described herein. In certain embodiments, the anti-CGRP receptor antibody is the 4E4 antibody or a binding fragment thereof described in Table 7. In other specific embodiments, the anti-CGRP receptor antibody is the 9F5 antibody or a binding fragment thereof described in Table 7.

[0279] Any of the pharmaceutical compositions described above can be incorporated into a self-administered injection device. Accordingly, the present invention also encompasses an injection device suitable for prophylactic treatment of migraine in patients in need thereof. In certain embodiments, the present invention provides a pre-filled syringe comprising a pharmaceutical composition comprising an anti-CGRP receptor antibody or a binding fragment thereof, an acetate buffer, sucrose, and polysorbate. In one embodiment, the pharmaceutical composition comprised in the pre-filled syringe comprises about 70 mg / ml of the anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprised in the pre-filled syringe comprises about 140 mg / ml of the anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprised in the pre-filled syringe comprises about 70 mg / ml of the anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprised in the pre-filled syringe comprises about 140 mg / ml of the anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In certain embodiments, the injection volume of the pre-filled syringe is about 1 ml or less (e.g., 0.5 ml).

[0280] In some embodiments, the present invention provides an autoinjector comprising a pharmaceutical composition comprising an anti-CGRP receptor antibody or a binding fragment thereof, an acetate buffer, sucrose, and polysorbate. In one embodiment, the pharmaceutical composition comprised by the autoinjector comprises about 70 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprised by the autoinjector comprises about 140 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.2% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprised by the autoinjector comprises about 70 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In another embodiment, the pharmaceutical composition comprised by the autoinjector comprises about 140 mg / ml of an anti-CGRP receptor antibody or a binding fragment thereof, about 15 mM sodium acetate, about 0.010% w / v polysorbate 80, and about 8.5% w / v sucrose, with a pH of 5.2 ± 0.2. In certain embodiments, the injection volume of the autoinjector is about 1 ml or less (e.g., 0.5 ml).

[0281] The present invention also includes administering to a patient a combination of an anti-CGRP receptor antibody or a binding fragment thereof and one or more agents suitable for the acute or prophylactic treatment of migraine or other headache disorders described herein. As used herein, the term "combination therapy" encompasses the administration of two compounds (e.g., an anti-CGRP receptor antibody or binding fragment and an additional agent) in a sequential manner (i.e., administering each compound in any order at different times) and the administration of the two compounds in a substantially simultaneous manner. Substantially simultaneous administration includes co-administration and can be achieved by administering a single formulation comprising the two compounds (e.g., a single capsule or other formulation containing a fixed ratio of the two compounds, or a prefilled syringe with a fixed ratio of each compound) or by co-administering separate formulations containing each of the compounds.

[0282] In some embodiments, the methods of the invention include administering an anti-CGRP receptor antibody or binding fragment thereof and a second agent that modulates CGRP receptor signaling. For example, the anti-CGRP receptor antibody or binding fragment can be administered in combination with a second CGRP receptor antagonist to prophylactically treat migraine in a patient in need thereof. Other CGRP receptor antagonists include small molecule inhibitors of the CGRP receptor such as those described in U.S. Patent Publication No. 20060142273 and U.S. Patent Nos. 7,842,808, 7,772,244, 7,754,732, 7,569,578, 8,685,965, 8,569,291, 8,377,955, 8,372,859, 8,143,266, 7,947,677, and 7,625,901, which are hereby incorporated by reference in their entirety. CGRP receptor antagonists can also include peptide antagonists of the receptor such as those described in U.S. Patent No. 8,168,592, which is hereby incorporated by reference in its entirety. In some embodiments, the anti-CGRP receptor antibody or binding fragment can be administered in combination with an agent that interferes with the binding of the CGRP ligand to the CGRP receptor to prophylactically treat migraine in a patient in need thereof. The agent that interferes with the binding of the CGRP ligand to the CGRP receptor can be a decoy or soluble CGRP receptor, or another protein that binds to the CGRP ligand such as an anti-CGRP antibody. Anti-CGRP antibodies are known in the art and are described, for example, in WO2007 / 054809; WO 2007 / 076336; WO 2011 / 156324; and WO 2012 / 162243, which are hereby incorporated by reference in their entirety.

[0283] In certain embodiments, the methods of the invention include administering an anti-CGRP receptor antibody or binding fragment thereof and a second anti-migraine agent. The second anti-migraine agent can be an agent for the acute treatment of migraine, such as a triptan (e.g., almotriptan, frovatriptan, rizatriptan, sumatriptan, naratriptan, eletriptan, and zolmitriptan), ergotamine (e.g., dihydroergotamine and ergotamine with caffeine), non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic acid, ibuprofen, naproxen, indomethacin, and diclofenac), and opioid drugs (e.g., codeine, morphine, hydrocodone, fentanyl, pethidine, and oxycodone). In some embodiments, the second anti-migraine agent is an agent for the prophylactic treatment of migraine, such as an anti-epileptic drug (e.g., topiramate), a β-blocker (e.g., propranolol), or an antidepressant (e.g., amitriptyline). In other embodiments, the second anti-migraine agent is an agent that modulates the activity of the pituitary type I adenylyl cyclase activating polypeptide receptor (PAC1 receptor). Agents that modulate the activity of the PAC1 receptor include antibodies or other binding proteins that bind to the PAC1 receptor, such as those described in WO 2014 / 144632, which is incorporated herein by reference in its entirety.

[0284] The invention also includes a kit for the prophylactic treatment of migraine in a patient in need thereof. In one embodiment, the kit comprises a pharmaceutical composition having an anti-CGRP receptor antibody or binding fragment described herein and a packaging material providing instructions regarding the use of the pharmaceutical composition. The pharmaceutical composition in the kit can be present in a container, such as a vial or syringe. The pharmaceutical composition can be provided as a solution, suspension, gel, emulsion, solid, crystal, or in dehydrated or lyophilized powder form. In embodiments where the pharmaceutical composition is provided as a powder, the kit can also comprise a diluent (e.g., water, saline, phosphate-buffered saline) required to reconstitute the pharmaceutical composition and instructions regarding the preparation of the composition for administration. In some embodiments, the kit comprises an injection device for self-administration (e.g., a prefilled syringe or an autoinjector) prefilled with the pharmaceutical composition described herein. Any of the prefilled syringes and autoinjectors described above can be included in the kit.

[0285] The following examples (including the experiments conducted and the results obtained) are provided for illustrative purposes only and should not be construed as limiting the scope of the appended claims. Examples

[0286] Example 1. Establishment of a pharmacokinetic / pharmacodynamic model for monoclonal antibody AMG 334 to characterize the relationship between concentration and capsaicin-induced cutaneous blood flow increase in healthy subjects and migraine patients

[0287] AMG 334 (also known herein as antibody 4E4) is a fully human IgG2 monoclonal antibody that binds to the human CGRP receptor with high in vitro potency. The inhibition of capsaicin (CAP)-induced increase in dermal blood flow (DBF) has been widely used as a translational model to characterize the pharmacological effects of CGRP receptor antagonists. This validated model was used to characterize the pharmacological effects of AMG 334 and to quantify the inhibition of CAP-induced increase in DBF after single and multiple doses of AMG 334 were administered to healthy subjects (HS) and migraine patients (MP).

[0288] The analysis dataset included 52 subjects (40 HS, 12 MP) who received single subcutaneous (SC) doses of AMG 334 (1, 7, 21, 70, 140, or 210 mg) or placebo every 4 weeks, and 40 subjects (24 HS, 16 MP) who received 3 consecutive SC doses of AMG 334 (21, 70, or 140 mg) or placebo. See Table 9 below. At multiple study visits, repeated CAP challenges and DBF measurements were performed within the same subjects using laser Doppler imaging to estimate the inhibition of DBF by AMG 334 before and after CAP administration. Serum AMG 334 concentrations were determined at the corresponding time points of DBF measurement, and additional samples were collected at other time points for pharmacokinetic characterization. A population pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was implemented to evaluate the AMG 334 concentration-DBF relationship. The effects of body weight (44.6 - 104 kg), sex (male and female), age (18 - 53 years), and disease group (MP and HS) on PK and PD parameters were evaluated in the model.

[0289] AMG 334 PK is best characterized by a receptor-mediated drug disposition model that explains the concentration / dose dependency of AMG 334 clearance and distribution. Complete SC absorption occurs at approximately 10 days after dosing. For a typical subject (70 kg) receiving a 70 mg SC dose, the estimated elimination half-life is 21 days, which is characteristic of monoclonal antibodies. When the concentration of AMG334 is approximately <700 ng / mL, the half-life is shortened (i.e., <21 days) and the antibody is rapidly eliminated, presumably because most of AMG 334 is bound to the target receptor, leaving less circulating, unbound AMG 334 available for elimination. AMG 334 significantly inhibits DBF after CAP, but has no significant effect on DBF before CAP. The PK-PD model estimated a mean baseline CAP-induced increase in DBF of 390 AU and a maximum DBF inhibition of 90%. The AMG 334 concentrations required for 50% (EC50) and 99% (EC99) of the maximum inhibition were 218 ng / mL and 1140 ng / mL, respectively. See Figure 1 . Thus, all doses >7 mg produced concentrations exceeding EC99 or maximum DBF inhibition; the duration of maximum inhibition increased with dose and persisted after repeated dosing. See Figure 2 . AMG 334 exposure decreased with increasing body weight, but DBF did not. After adjustment for body weight, no PK and PD differences were observed between HS and MP.

[0290] AMG 334 caused a potent and reproducible inhibition of CAP-induced DBF, indicating complete peripheral CGRP receptor blockade in HS and MP. Body weight was the only covariate affecting PK, but not PD. The long half-life of AMG 334 and the stable concentration-DBF relationship indicate long-term inhibition of the CGRP receptor.

[0291] Table 9. Characteristics of Subjects Included in the Population PK / PD Model

[0292]

[0293] Example 2. Phase 1, randomized, double-blind, placebo-controlled, single-dose, and multiple-dose studies of AMG 334 in healthy subjects and migraine patients

[0294] Migraine is a disabling headache thought to involve calcitonin gene-related peptide (CGRP). AMG 334 (4E4 antibody) is a fully human monoclonal antibody directed against the CGRP receptor. In these Phase 1, randomized, placebo-controlled, single-dose (SD) and multiple-dose (MD) studies, the pharmacokinetics (PK), pharmacodynamics (PD), and safety of AMG 334 were evaluated in healthy subjects and migraineurs.

[0295] In the SD study, subjects received single escalating doses of AMG 334 (n = 42) of 1 to 210 mg SC, 140 mg IV, or matching placebo (n = 18). In the MD study, subjects received multiple doses of AMG 334 (n = 35) of 21 to 280 mg SC or placebo (n = 12) on Days 1, 29, and 57. PK and safety were evaluated in both studies; PK measurements included maximum concentration (C 最大 ), area under the concentration-time curve from time zero to the last quantifiable concentration (AUC 最后 ), and time to reach maximum concentration (t 最大 ). CGRP receptor antagonism was measured using the inhibition of capsaicin-induced dermal blood flow (DBF) by AMG 334 in both studies; E 最大 represents the percent maximum inhibition. In the SD study, an S-shaped E 最大 PK / PD model was applied to analyze the relationship between AMG 334 serum exposure and inhibition of the increase in capsaicin-induced DBF. In the MD study, ambulatory blood pressure monitoring (ABPM) was performed for 24 hours continuously at approximately 7 days after each dose.

[0296] In the SD study, 42 subjects received AMG 334 (36 healthy subjects, 6 migraine subjects); 18 received placebo (12 healthy subjects, 6 migraine subjects). Detectable AMG 334 serum levels were observed from 30 to 160 days after dosing, with 70 mg and higher doses yielding detectable levels 100 days or more after dosing. See Figure 3A . After single SC administration, AMG 334 exhibited non-linear PK; AMG 334 exposure increased more than dose-proportionally from 1 to 70 mg and approximately dose-proportionally from 70 to 210 mg. See Table 10 below. After tripling the dose from 70 to 210 mg, mean AUC 最后 increased 3.8-fold from 171 to 652 μg / mL per day and mean C 最大 increased 2.4-fold from 6.25 to 15.2 μg / mL (Table 10). Across the dose range, median t最大 ranged from 4 to 11 days (Table 10). For the 140-mg AMG 334 dose, the relative exposure, area under the concentration-time curve (AUC) following SC administration, was approximately 54% of that following IV administration. There were no significant differences in PK between healthy subjects and migraine patients.

[0297] Table 10. Estimated pharmacokinetic parameters in the population following single administration of AMG 334

[0298]

[0299] Data are presented as mean (SD or range). AUC 无限 , area under the concentration-time curve from time zero to infinite time; AUC 最后 , area under the concentration-time curve from time zero to the time of the last quantifiable concentration; C 最大 , maximum concentration; IV, intravenous; NR, not reported; SC, subcutaneous; SD, standard deviation; t 最大 , time to reach C 最大 .

[0300] Day 4 was the first time point evaluated for inhibition of capsaicin-induced DNFB in the SD study. On Day 4, for SC doses ≥21 mg, the percent inhibition of the increase in capsaicin-induced DNFB in healthy subjects ranged from 75% to 95% across the dose range (91% in migraine subjects) compared to placebo. See Figure 4A . Application of a sigmoidal E 最大 PK / PD model to analyze the relationship between AMG 334 serum exposure and inhibition of the increase in capsaicin-induced DNFB gave an E 最大 of 94.2% (and standard error of 2.85%) and a serum AMG 334 concentration of 286 ng / mL (and standard error of 37.2 ng / mL) associated with half-maximal effect (EC 50 ).

[0301] In the MD study, 36 subjects (24 healthy subjects, 12 migraine subjects) received a total of 3 doses of AMG 334 (21 to 280 mg); 12 subjects (8 healthy subjects, 4 migraine subjects) received placebo. After SC administration of 3 single doses, the cumulative amount of AMG 334 ranged from 1.42 to 1.69-fold in healthy subjects across the dose range and from 1.50 to 1.78-fold in migraine patients across the dose range. See Figure 3B . For all dose ranges, T 最大The value range is about 3 to 13 days after the first SC dose and about 6 to 14 days after the third dose( Figure 3B ). Similar to the results of the SD study, there were no significant differences in PK parameters between healthy subjects and migraine patients.

[0302] Day 8 was the first time point for evaluating the inhibition of capsaicin-induced DBF in the MD study. On Day 8, in both healthy subjects and migraine patients, significant inhibition relative to placebo was observed in all AMG 334 groups, and there were no significant differences in the drug effects between patient groups. See Figure 4B . In either patient group, there was no obvious dose-dependence in the AMG 334 group. The results at Day 57 and Day 85 (healthy subjects) or at Day 57, Day 86, and Day 169 (migraine patients) were consistent with the findings on Day 8. Subsequent time points (113 days or longer) showed no significant inhibition in the AMG 334 group relative to placebo. The DBF inhibition in the MD study was consistent with the SD DBF results and maintained maximum inhibition during the repeated dosing intervals.

[0303] 24-hour ABPM revealed no change in BP diurnal rhythm and no increase in BP with increasing AMG 334 dose. In healthy subjects, no statistically significant differences were observed between all AMG 334 groups and placebo in terms of least mean square 24-hour and nocturnal BP. In migraine patients, there were also no statistically significant differences between all AMG 334 groups and placebo in terms of least mean square 24-hour diastolic and nocturnal diastolic BP. Treatment-emergent adverse events were similar in type and frequency between treatment groups and between healthy subjects and migraine patients. There was no obvious relationship between AMG 334 dose and the overall incidence of treatment-emergent adverse events. No clinically significant differences in vital signs or laboratory values were observed.

[0304] The AMG 334 PK curve was consistent with the curves of other human IgG2 antibodies. After single administration, PK exposure increased more than proportionally with dose from 1 to 70 mg and increased approximately proportionally with dose from 70 to 210 mg, and there were no obvious differences between healthy subjects and migraine patients. After SC administration of three single doses, similar PK trends were observed in both groups across the dose range. In healthy subjects and migraine patients, administration of AMG 334 caused significant inhibition of the capsaicin-induced increase in DBF relative to placebo, indicating CGRP receptor antagonism. The inhibition of the capsaicin-induced increase in DBF was similar between healthy subjects and migraine patients. Single and multiple doses of AMG 334 were well tolerated and there was no association between serum AMG 334 concentration and blood pressure.

[0305] Example 3. Results of a randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the efficacy and safety of AMG 334 for the prevention of episodic migraine

[0306] In this Phase 2, double-blind, placebo-controlled trial, the effect of AMG 334 (i.e., 4E4 antibody) for the prevention of episodic migraine was evaluated.

[0307] Patients with episodic migraine (migraine days ≥4 days and ≤14 days per month) were randomized at a ratio of 3:2:2:2 to subcutaneous, monthly (QM) placebo or AMG 334 (7 mg, 21 mg, or 70 mg) groups. The primary endpoint was the change in monthly migraine days at Week 12 relative to baseline. Secondary endpoints included the proportion of subjects with a ≥50% reduction in monthly migraine days (i.e., 50% responder rate), reduction in monthly migraine attacks, and safety / tolerability. Key exploratory endpoints included reduction in monthly headache days and days of use of monthly acute migraine-specific medications (e.g., triptans, ergotamine).

[0308] Four hundred and eighty-three subjects were randomized to placebo (n = 160), AMG 334 7 mg (n = 108), 21 mg (n = 108), or 70 mg (n = 107) groups. Subjects were predominantly female (80.5%); mean (SD) age was 41.1 (10.8) years. A statistically significant reduction in mean monthly migraine days was observed with 70 mg AMG 334 (-3.40) relative to placebo (-2.28). See Figure 5 . Post hoc analysis showed a significant treatment effect as early as Week 2. The reduction in monthly migraine days with lower doses of AMG 334 (7 mg: -2.18 and 21 mg: -2.39) was not statistically significant compared to the placebo group (-2.28). See Figure 5 . At Week 12, for 70 mg, the 50% responder rate was 46.5% compared to 29.9% for placebo (P = 0.011). A reduction in monthly headache days (70 mg: -3.54 vs. placebo: -2.39; P = 0.022) and days of use of monthly acute migraine-specific medications (70 mg: -1.64 vs. placebo: -0.69; P = 0.004; Figure 6 ) was also observed to be statistically significant. The change in monthly migraine attacks was not statistically significant. Subgroup analysis confirmed that the efficacy of AMG 334 was similar regardless of gender (data not shown), baseline migraine frequency( Figure 7A ) or prior history of prophylactic medication use( Figure 7B)How. For various endpoints, an overview of the data on 70 mg dose of AMG 334 and placebo is shown in Table 11. No major safety findings were reported. The safety / tolerability profiles of AMG 334 and placebo were similar. No significant differences were observed in the incidence of adverse events between the AMG 334 treatment group and placebo. No dose-dependence of the incidence of adverse events was observed for AMG 334. During the double-blind treatment period, six (1.9%) subjects receiving AMG 334 and two (1.3%) individuals receiving placebo discontinued the investigational product due to adverse events.

[0309] Table 11. Efficacy of AMG 334 in Episodic Migraine a

[0310]

[0311] After the 12-week double-blind (DB) treatment period of the study, patients were eligible to receive monthly (QM) AMG 334 70 mg for up to 256 weeks during the open-label extension (OLE) period. During the OLE period, patients continued to complete daily diaries until week 64. For this interim analysis, patients received AMG 334 70 mg QM until week 76. Safety and tolerability were evaluated monthly. Efficacy endpoints were analyzed for both groups until week 64: Group 1: Patients who switched to AMG 334 70 mg QM after receiving placebo, AMG 334 7 mg, or AMG 334 21 mg (i.e., DB ineffective doses) during the DB phase; Group 2: Patients who continued to receive AMG 334 70 mg QM (i.e., DB effective dose) during the OLE period. Efficacy endpoints were: change in the number of migraine days per month relative to baseline, 50% responder rate, 75% responder rate, 100% responder rate, monthly migraine attacks, monthly days of use of migraine-specific medications (e.g., triptans, ergotamine), and monthly headache days.

[0312] A total of 383 (97%) of the 395 eligible patients entered the OLE and received open-label AMG 334 70 mg QM. The median duration of exposure to AMG 334 70 mg during the OLE period was 239 days (34.1 weeks), and the total exposure of patients over one year was 263.7 days. Figure 8Show the changes in the number of migraine days per month relative to baseline during the DB period and the first ten months of the OLE period. The results showed that monthly administration of 70 mg of AMG 334 reduced the number of migraine days per month in patients who had previously received placebo, 7 mg of AMG 334, or 21 mg of AMG 334. Specifically, compared to week 12 of the DB period (primary endpoint), a further reduction in the mean number of migraine days per month relative to baseline was observed during the OLE period (weeks 16 to 64), regardless of the DB treatment received (Group 1: -2.4 days at week 12 versus -4.0 days at week 16; Group 2: -3.5 days at week 12 versus -3.9 days at week 16). The treatment effect continued during the OLE period (weeks 16 to 64), and the range of change in the number of migraine days per month relative to baseline was from -4.0 to -6.2 days for Group 1 and from -3.7 to -4.9 days for Group 2. Similar results were observed for the 50% responder rate, 75% responder rate, 100% responder rate, monthly migraine attacks, monthly headache days, and migraine-specific medication use. At week 52, 62% of patients experienced a 50% or greater reduction in the number of migraine days, 38% experienced a 75% or greater reduction, and 19% experienced a 100% reduction. Compared to week 12 of the DB period, a further reduction in the number of monthly headache days ( Figure 9A ) and the number of days of migraine-specific medication use ( Figure 9B ) relative to the study baseline was observed during the OLE period.

[0313] Two hundred and forty-three (63%) of the 383 patients reported adverse events (AEs). The most common AEs (≥3%) were nasopharyngitis, upper respiratory tract infection, arthralgia, influenza, back pain, and sinusitis. Most AEs were grade 1 or 2 CTCAE. Thirteen patients (3%) reported serious AEs, and 1 of them (<1%) was considered treatment-related (according to the investigator). Eleven patients (2%) discontinued the OLE period due to AEs. There were no clinically significant findings regarding vital signs or laboratory tests, including liver function tests.

[0314] The results of the Phase 2 study showed that AMG 334 was effective in preventing episodic migraine when administered at a monthly dose of 70 mg, and AMG 334 had a safety / tolerability profile similar to that of placebo. Patients who continued to receive AMG 334 70 mg QM during the OLE period showed a clinically meaningful and sustained reduction in the number of migraine days. The safety and tolerability were consistent with the results observed during the DB period, and no new safety signals were observed.

[0315] Example 4. A randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the efficacy and safety of AMG 334 for the prevention of chronic migraine

[0316] In this Phase 2 study, the effect of AMG 334 (i.e., 4E4 antibody) compared to placebo in the prevention of chronic migraine was evaluated.

[0317] Patients with chronic migraine (≥15 headache days per month and ≥8 migraine days per month) were randomly assigned in a 3:2:2 ratio to receive placebo, 70 mg of AMG 334 subcutaneously (SC) monthly (QM), or 140 mg of AMG 334 SC QM for a 12-week double-blind treatment period. The primary endpoint was the change in the number of migraine days per month at week 12 relative to baseline. Secondary endpoints included the proportion of subjects with a ≥50% reduction in the number of migraine days per month (i.e., 50% responder rate), reduction in the number of migraine attacks per month, and safety / tolerance. Key exploratory endpoints included reduction in the number of headache days per month, change in the cumulative headache hours per month relative to baseline, reduction in the mean migraine severity per month relative to baseline, and the number of days of use of acute migraine-specific medications (e.g., triptans, ergotamines) per month.

[0318] After signing the informed consent form, subjects entered a screening period (up to 3 weeks) during which their eligibility was evaluated. Eligible subjects included adults between 18 and 65 years of age with a history of at least 5 migraine attacks with or without aura, and with a headache history of at least 15 days per month in each of the three months prior to screening, with at least 8 days of headache being migraine days. Subjects with co-medication overuse (MO) of triptans, ergotamine derivatives, analgesics, and combination medications were eligible for the trial.

[0319] All eligible subjects obtained from the screening period were enrolled in a 4-week baseline period. Subjects who met the inclusion criteria during the baseline period were allowed to continue into the treatment period. The inclusion criteria for the baseline period included:

[0320] ● ≥15 headache days, with ≥8 headache days meeting the criteria for migraine days during the baseline period;

[0321] ● ≥4 distinct headache attacks, each lasting ≥4 hours or, if shorter, associated with the use of a triptan or ergotamine derivative on the same calendar day during the baseline period; and

[0322] ● At least 80% consistency with the electronic diary (e.g., at least 23 of 28 days during the baseline period must have completed electronic diary entries).

[0323] At the Day 1 visit, eligible subjects from the baseline period were randomized into a 12-week double-blind treatment period and began receiving the double-blind investigational product QM SC. Eligible and enrolled subjects were randomized into a placebo group, an AMG 334 70 mg group, or an AMG 334 140 mg group at a ratio of 3:2:2, with approximately 210 subjects in the placebo group, approximately 140 subjects in the AMG 334 70 mg group, and approximately 140 subjects in the AMG 334 140 mg group. Randomization was stratified by region at baseline (North America versus others) and medication overuse (MO versus non-MO). Double-blind AMG 334 70 mg, AMG 334 140 mg, or placebo was administered during the 12-week double-blind treatment period (i.e., on Day 1 and at Weeks 4 and 8). During the double-blind treatment period, 2 SC injections were given for each investigational product administration (i.e., on Day 1, Week 4, and Week 8). A safety follow-up visit was conducted 12 weeks after study completion or at early termination (i.e., 16 weeks after the last dose of the investigational product).

[0324] The purpose of the final analysis was to evaluate the efficacy and safety of AMG 334 70 mg and AMG 334 140 mg in subjects with chronic migraine. The final analysis of the study was conducted at the end of the trial. Efficacy and safety data from the entire study period were analyzed and reported by the double-blind treatment groups. The expected results showed that in subjects with chronic migraine, the number of migraine days per month decreased relative to baseline in an AMG 334 dose-dependent manner compared to placebo, and the adverse event profile of AMG 334 was similar to that of placebo.

[0325] After the 12-week double-blind treatment period of the study, an open-label period began. All subjects who completed the 12-week double-blind treatment period were eligible to be enrolled in the open-label period, during which subjects received a monthly dose of 70 mg of AMG 334 SC for 13 months, followed by a 12-week safety follow-up visit. Subjects reported information on their migraine and non-migraine headaches and acute medication use daily using an electronic diary between the Day 1 and Month 3 visits, between the Month 5 and Month 6 visits, between the Month 9 and Month 10 visits, and between the Month 12 and Month 13 visits.

[0326] The purpose of the open-label period was to characterize the safety, tolerability, and efficacy of long-term administration of AMG 334. Key endpoints included:

[0327] ● The change in the number of migraine days per month relative to baseline in subjects with chronic migraine;

[0328] ● The percentage of subjects with at least a 50% reduction in the number of monthly migraine days relative to baseline;

[0329] ● The reduction in monthly migraine attacks relative to baseline in subjects with chronic migraine;

[0330] ● The change over time in physical impairment as measured by the Migraine Physical Function Impact Diary (MPFID); and

[0331] ● The change over time in the impact on daily activities as measured by the MPFID.

[0332] The results of the open-label study are expected to show that chronic migraine subjects were safe and well tolerated with long-term exposure to AMG 334, and that a monthly 70 mg SC dose was effective in reducing migraine days in chronic migraine subjects.

[0333] Example 5. A Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of AMG 334 in the prevention of migraine

[0334] The primary objective of this study was to evaluate the effect of AMG 334 (i.e., the 4E4 antibody) compared to placebo on the change in the mean number of monthly migraine days relative to baseline in subjects with episodic migraine. Secondary objectives of the study included the percentage of subjects with at least a 50% reduction in the mean number of monthly migraine days relative to baseline, the change in the mean number of monthly days of acute migraine-specific medication treatment relative to baseline, the change in physical impairment relative to baseline as measured by the Migraine Physical Function Impact Diary (MPFID), and the change in the impact on daily activities relative to baseline as measured by the MPFID.

[0335] Two doses of AMG 334, 70 mg and 140 mg, were evaluated in this study. Subjects received AMG 334 140 mg, AMG 334 70 mg, or placebo subcutaneously (SC) once monthly (QM) for 24 weeks during the double-blind treatment period, followed by a 28-week active agent treatment period during which they received AMG 334 140 mg or AMG 70 mg QM SC. Approximately 852 subjects with episodic migraine (4 to <15 migraine days per month) were randomized 1:1:1 to the placebo group, the AMG 334 70 mg group, or the AMG 334 140 mg group. Randomization was stratified by region (North America vs. other) and prior treatment with migraine prophylactic medications (prior migraine prophylactic medication treatment vs. no prior migraine prophylactic medication treatment).

[0336] After signing the informed consent form, the subjects enter the screening period. The screening period consists of an initial screening period (up to 3 weeks) followed by a 4-week baseline period. During the screening period and / or the baseline period, the eligibility of the subjects is evaluated. Eligible subjects include adults aged 18 to 65 years with a history of migraine, with or without aura, for ≥ 12 months, and experiencing ≥ 4 to < 15 migraine days per month, where the average number of headache days per month is < 15 in the 3 months prior to screening.

[0337] At the Day 1 visit, eligible subjects are enrolled (i.e., randomized) into a 24-week double-blind treatment period and begin receiving the double-blind investigational product QM SC. At the Week 24 visit, subjects in each treatment group are re-randomized 1:1 to either the AMG 334 70 mg group or the AMG 334 140 mg group for a 28-week active agent treatment period and begin receiving the investigational product QM SC, remaining blinded only to the dose level. Re-randomization is stratified by treatment group assigned during the double-blind period. During the 24-week double-blind treatment period (i.e., on Day 1 and Weeks 4, 8, 12, 16, and 20), double-blind AMG 334 70 mg, AMG 334 140 mg, or placebo is administered, and during the 28-week active agent treatment period (i.e., at Weeks 24, 28, 32, 36, 40, 44, and 48), the active agent AMG 334 70 mg or AMG 334 140 mg is administered. During the entire double-blind treatment period and active agent treatment period, the investigational product is administered as 2 SC injections each time.

[0338] A safety follow-up visit is conducted 16 weeks after the last dose of the investigational product. Subjects use an electronic diary to report information on their migraine and non-migraine headaches and acute headache medication use daily throughout the baseline period, double-blind treatment period, and active agent treatment period. Subjects schedule clinical study visits monthly from Week - 4 until the end of the active agent treatment period.

[0339] The results of the Phase 3 study are expected to show that in subjects with episodic migraine, AMG 334 reduces the average number of migraine days per month by a greater amount relative to baseline compared to placebo. Relative to placebo, the treatment effect of AMG 334 is expected to be an average reduction of 1.12 days and 1.30 days per month in migraine days relative to baseline for 70 mg and 140 mg, respectively.

[0340] All publications, patents, and patent applications discussed and cited herein are hereby incorporated by reference in their entirety. It is to be understood that the disclosed invention is not limited to the specific methods, protocols, and materials described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the appended claims.

[0341] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalent forms to the specific embodiments of the invention described herein. Such equivalent forms are intended to be encompassed by the following claims. <110> Amgen Inc., USA SUN, Hong DUNAYEVICH, Eduardo LENZ, Robert A. VARGAS, Gabriel <120> Method for treating or preventing migraine <130> A-1945-WO-PCT <150> US 62 / 152,708 <151> 2015-04-24 <160> 136 <170> PatentIn version 3.5 <210> 1 <211> 472 <212> PRT <213> Homo sapiens <400> 1 Met Leu Tyr Ser Ile Phe His Phe Gly Leu Met Met Glu Lys Lys Cys 1 5 10 15 Thr Leu Tyr Phe Leu Val Leu Leu Pro Phe Phe Met Ile Leu Val Thr 20 25 30 Ala Glu Leu Glu Glu Ser Pro Glu Asp Ser Ile Gln Leu Gly Val Thr 35 40 45 Arg Asn Lys Ile Met Thr Ala Gln Tyr Glu Cys Tyr Gln Lys Ile Met 50 55 60 Gln Asp Pro Ile Gln Gln Ala Glu Gly Val Tyr Cys Asn Arg Thr Trp 65 70 75 80 Asp Gly Trp Leu Cys Trp Asn Asp Val Ala Ala Gly Thr Glu Ser Met 85 90 95 Gln Leu Cys Pro Asp Tyr Phe Gln Asp Phe Asp Pro Ser Glu Lys Val 100 105 110 Thr Lys Ile Cys Asp Gln Asp Gly Asn Trp Phe Arg His Pro Ala Ser 115 120 125 Asn Arg Thr Trp Thr Asn Tyr Thr Gln Cys Asn Val Asn Thr His Glu 130 135 140 Lys Val Lys Thr Ala Leu Asn Leu Phe Tyr Leu Thr Ile Ile Gly His 145 150 155 160 Gly Leu Ser Ile Ala Ser Leu Leu Ile Ser Leu Gly Ile Phe Phe Tyr 165 170 175 Phe Lys Ser Leu Ser Cys Gln Arg Ile Thr Leu His Lys Asn Leu Phe 180 185 190 Phe Ser Phe Val Cys Asn Ser Val Val Thr Ile Ile His Leu Thr Ala 195 200 205 Val Ala Asn Asn Gln Ala Leu Val Ala Thr Asn Pro Val Ser Cys Lys 210 215 220 Val Ser Gln Phe Ile His Leu Tyr Leu Met Gly Cys Asn Tyr Phe Trp 225 230 235 240 Met Leu Cys Glu Gly Ile Tyr Leu His Thr Leu Ile Val Val Ala Val 245 250 255 Phe Ala Glu Lys Gln His Leu Met Trp Tyr Tyr Phe Leu Gly Trp Gly 260 265 270 Phe Pro Leu Ile Pro Ala Cys Ile His Ala Ile Ala Arg Ser Leu Tyr 275 280 285 Tyr Asn Asp Asn Cys Trp Ile Ser Ser Asp Thr His Leu Leu Tyr Ile 290 295 300 Ile His Gly Pro Ile Cys Ala Ala Leu Leu Val Asn Leu Phe Phe Leu 305 310 315 320 Leu Asn Ile Val Arg Val Leu Ile Thr Lys Leu Lys Val Thr His Gln 325 330 335 Ala Glu Ser Asn Leu Tyr Met Lys Ala Val Arg Ala Thr Leu Ile Leu 340 345 350 Val Pro Leu Leu Gly Ile Glu Phe Val Leu Ile Pro Trp Arg Pro Glu 355 360 365 Gly Lys Ile Ala Glu Glu Val Tyr Asp Tyr Ile Met His Ile Leu Met 370 375 380 His Phe Gln Gly Leu Leu Val Ser Thr Ile Phe Cys Phe Phe Asn Gly 385 390 395 400 Glu Val Gln Ala Ile Leu Arg Arg Asn Trp Asn Gln Tyr Lys Ile Gln 405 410 415 Phe Gly Asn Ser Phe Ser Asn Ser Glu Ala Leu Arg Ser Ala Ser Tyr 420 425 430 Thr Val Ser Thr Ile Ser Asp Gly Pro Gly Tyr Ser His Asp Cys Pro 435 440 445 Ser Glu His Leu Asn Gly Lys Ser Ile His Asp Ile Glu Asn Val Leu 450 455 460 Leu Lys Pro Glu Asn Leu Tyr Asn 465 470 <210> 2 <211> 148 <212> PRT <213> Homo sapiens <400> 2 Met Ala Arg Ala Leu Cys Arg Leu Pro Arg Arg Gly Leu Trp Leu Leu 1 5 10 15 Leu Ala His His Leu Phe Met Thr Thr Ala Cys Gln Glu Ala Asn Tyr 20 25 30 Gly Ala Leu Leu Arg Glu Leu Cys Leu Thr Gln Phe Gln Val Asp Met 35 40 45 Glu Ala Val Gly Glu Thr Leu Trp Cys Asp Trp Gly Arg Thr Ile Arg 50 55 60 Ser Tyr Arg Glu Leu Ala Asp Cys Thr Trp His Met Ala Glu Lys Leu 65 70 75 80 Gly Cys Phe Trp Pro Asn Ala Glu Val Asp Arg Phe Phe Leu Ala Val 85 90 95 His Gly Arg Tyr Phe Arg Ser Cys Pro Ile Ser Gly Arg Ala Val Arg 100 105 110 Asp Pro Pro Gly Ser Ile Leu Tyr Pro Phe Ile Val Val Pro Ile Thr 115 120 125 Val Thr Leu Leu Val Thr Ala Leu Val Val Trp Gln Ser Lys Arg Thr 130 135 140 Glu Gly Ile Val 145 <210> 3 <211> 116 <212> PRT <213> Homo sapiens <400> 3 Glu Leu Glu Glu Ser Pro Glu Asp Ser Ile Gln Leu Gly Val Thr Arg 1 5 10 15 Asn Lys Ile Met Thr Ala Gln Tyr Glu Cys Tyr Gln Lys Ile Met Gln 20 25 30 Asp Pro Ile Gln Gln Ala Glu Gly Val Tyr Cys Asn Arg Thr Trp Asp 35 40 45 Gly Trp Leu Cys Trp Asn Asp Val Ala Ala Gly Thr Glu Ser Met Gln 50 55 60 Leu Cys Pro Asp Tyr Phe Gln Asp Phe Asp Pro Ser Glu Lys Val Thr 65 70 75 80 Lys Ile Cys Asp Gln Asp Gly Asn Trp Phe Arg His Pro Ala Ser Asn 85 90 95 Arg Thr Trp Thr Asn Tyr Thr Gln Cys Asn Val Asn Thr His Glu Lys 100 105 110 Val Lys Thr Ala 115 <210> 4 <211> 137 <212> PRT <213> Homo sapiens <400> 4 Cys Gln Glu Ala Asn Tyr Gly Ala Leu Leu Arg Glu Leu Cys Leu Thr 1 5 10 15 Gln Phe Gln Val Asp Met Glu Ala Val Gly Glu Thr Leu Trp Cys Asp 20 25 30 Trp Gly Arg Thr Ile Arg Ser Tyr Arg Glu Leu Ala Asp Cys Cys Gln 35 40 45 Glu Ala Asn Tyr Gly Ala Leu Leu Arg Glu Leu Cys Leu Thr Gln Phe 50 55 60 Gln Val Asp Met Glu Ala Val Gly Glu Thr Leu Trp Cys Asp Trp Gly 65 70 75 80 Arg Thr Ile Arg Ser Tyr Arg Glu Leu Ala Asp Cys Thr Trp His Met 85 90 95 Ala Glu Lys Leu Gly Cys Phe Trp Pro Asn Ala Glu Val Asp Arg Phe 100 105 110 Phe Leu Ala Val His Gly Arg Tyr Phe Arg Ser Cys Pro Ile Ser Gly 115 120 125 Arg Ala Val Arg Asp Pro Pro Gly Ser 130 135 <210> 5 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 5 Asp Ser Ile Gln Leu Gly Val Thr Arg Asn Lys Ile Met Thr Ala Gln 1 5 10 15 Tyr <210> 6 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 6 Asp Val Ala Ala Gly Thr Glu Ser Met Gln Leu Cys Pro 1 5 10 <210> 7 <211> 25 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 7 Asp Gly Asn Trp Phe Arg His Pro Ala Ser Asn Arg Thr Trp Thr Asn 1 5 10 15 Tyr Thr Gln Cys Asn Val Asn Thr His 20 25 <210> 8 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 8 Glu Cys Tyr Gln Lys Ile Met Gln 1 5 <210> 9 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 9 Asp Gly Trp Leu Cys Trp Asn 1 5 <210> 10 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 10 Arg Glu Leu Ala Asp Cys Thr Trp His Met Ala Glu 1 5 10 <210> 11 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 11 Asp Trp Gly Arg Thr Ile Arg Ser Tyr Arg Glu Leu Ala 1 5 10 <210> 12 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 12 Glu Leu Cys Leu Thr Gln Phe Gln Val 1 5 <210> 13 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 13 Asp Cys Thr Trp His Met Ala 1 5 <210> 14 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 14 Ser Phe Gly Met His 1 5 <210> 15 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 15 Asn Ala Trp Met Ser 1 5 <210> 16 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 16 Ser Tyr Ala Met Ser 1 5 <210> 17 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 17 Gly Tyr Tyr Met His 1 5 <210> 18 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 18 Ser Tyr Gly Met His 1 5 <210> 19 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 19 Asp Tyr Ala Met Ser 1 5 <210> 20 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 20 Asp Tyr Tyr Met Tyr 1 5 <210> 21 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 21 Thr Tyr Ser Met Asn 1 5 <210> 22 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 22 Ser Tyr Gly Met His 1 5 <210> 23 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 23 Val Ile Ser Phe Asp Gly Ser Ile Lys Tyr Ser Val Asp Ser Val Lys 1 5 10 15 Gly <210> 24 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 24 Arg Ile Lys Ser Thr Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala Pro 1 5 10 15 Val Lys Gly <210> 25 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 25 Ala Ile Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 26 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 26 Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 27 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 27 Val Ile Ser Tyr Asp Gly Ser His Glu Ser Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 28 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 28 Phe Ile Arg Ser Arg Ala Tyr Gly Gly Thr Pro Glu Tyr Ala Ala Ser 1 5 10 15 Val Lys Gly <210> 29 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 29 Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Thr Ala Pro 1 5 10 15 Val Lys Gly <210> 30 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 30 Trp Ile Ser Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 31 <211> 19 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 31 Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala Pro 1 5 10 15 Val Lys Gly <210> 32 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 32 Ser Ile Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 33 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 33 Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 34 <211> 21 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 34 Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr Tyr His Tyr Lys Tyr 1 5 10 15 Tyr Gly Met Ala Val 20 <210> 35 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 35 Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr Tyr Tyr Tyr Tyr 1 5 10 15 Gly Met Asp Val 20 <210> 36 <211> 21 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 36 Asp Gln Arg Glu Val Gly Pro Tyr Ser Ser Gly Trp Tyr Asp Tyr Tyr 1 5 10 15 Tyr Gly Met Asp Val 20 <210> 37 <211> 21 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 37 Asp Gln Met Ser Ile Ile Met Leu Arg Gly Val Phe Pro Pro Tyr Tyr 1 5 10 15 Tyr Gly Met Asp Val 20 <210> 38 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 38 Glu Arg Lys Arg Val Thr Met Ser Thr Leu Tyr Tyr Tyr Phe Tyr Tyr 1 5 10 15 Gly Met Asp Val 20 <210> 39 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 39 Gly Arg Gly Ile Ala Ala Arg Trp Asp Tyr 1 5 10 <210> 40 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 40 Gly Gly Tyr Ser Gly Tyr Ala Gly Leu Tyr Ser His Tyr Tyr Gly Met 1 5 10 15 Asp Val <210> 41 <211> 21 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 41 Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr Tyr His Tyr Lys Tyr 1 5 10 15 Tyr Gly Leu Ala Val 20 <210> 42 <211> 22 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 42 Glu Gly Val Ser Gly Ser Ser Pro Tyr Ser Ile Ser Trp Tyr Asp Tyr 1 5 10 15 Tyr Tyr Gly Met Asp Val 20 <210> 43 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 43 Ala Gly Gly Ile Ala Ala Ala Gly Leu Tyr Tyr Tyr Tyr Gly Met Asp 1 5 10 15 Val <210> 44 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 44 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr Val Ser 1 5 10 <210> 45 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 45 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr 1 5 10 <210> 46 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 46 Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly 1 5 10 <210> 47 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 47 Gln Gly Asp Ser Leu Arg Ser Phe Tyr Ala Ser 1 5 10 <210> 48 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 48 Lys Ser Ser Gln Ser Leu Leu His Ser Ala Gly Lys Thr Tyr Leu Tyr 1 5 10 15 <210> 49 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 49 Arg Ser Ser Gln Ser Leu Leu His Ser Phe Gly Tyr Asn Tyr Leu Asp 1 5 10 15 <210> 50 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 50 Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Tyr 1 5 10 15 <210> 51 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 51 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn 1 5 10 <210> 52 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 52 Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Arg Asn Tyr Leu Tyr 1 5 10 15 <210> 53 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 53 Arg Ala Ser Gln Gly Ile Arg Lys Asp Leu Gly 1 5 10 <210> 54 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 54 Arg Ala Ser Gln Ser Val Ser Ser Gly Tyr Leu Thr 1 5 10 <210> 55 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 55 Asp Asn Asn Lys Arg Pro Ser 1 5 <210> 56 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 56 Arg Ser Asn Gln Arg Pro Ser 1 5 <210> 57 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 57 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> 58 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 58 Gly Lys Asn Asn Arg Pro Ser 1 5 <210> 59 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 59 Glu Val Ser Asn Arg Phe Ser 1 5 <210> 60 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Peptide <400> 60 Leu Gly Ser Asn Arg Ala Ser 1 5 <210> 61 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 61 Arg Asn Asn Gln Arg Pro Ser 1 5 <210> 62 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 62 Thr Asn Asn Gln Arg Pro Ser 1 5 <210> 63 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 63 Gly Ala Ser Ser Leu Gln Ser 1 5 <210> 64 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 64 Gly Ala Ser Ser Arg Ala Thr 1 5 <210> 65 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 65 Gly Thr Trp Asp Ser Arg Leu Ser Ala Val Val 1 5 10 <210> 66 <211> 11 <212> PRT <213> Synthetic Sequence <220> <223> Synthetic Peptide <400> 66 Ala Ala Trp Asp Asp Ser Leu Ser Gly Trp Val 1 5 10 <210> 67 <211> 9 <212> PRT <213> Synthetic Sequence <220> <223> Synthetic Peptide <400> 67 Leu Gln Tyr Asn Ile Tyr Pro Trp Thr 1 5 <210> 68 <211> 11 <212> PRT <213> Synthetic Sequence <220> <223> Synthetic Peptide <400> 68 Asn Ser Arg Asp Ser Ser Val Tyr His Leu Val 1 5 10 <210> 69 <211> 9 <212> PRT <213> Synthetic Sequence <220> <223> Synthetic Peptide <400> 69 Met Gln Ser Phe Pro Leu Pro Leu Thr 1 5 <210> 70 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 70 Met Gln Ala Leu Gln Thr Pro Phe Thr 1 5 <210> 71 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 71 Ala Ala Arg Asp Glu Ser Leu Asn Gly Val Val 1 5 10 <210> 72 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 72 Leu Gln Tyr Asn Ser Phe Pro Trp Thr 1 5 <210> 73 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 73 Gln Gln Tyr Gly Asn Ser Leu Cys Arg 1 5 <210> 74 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 74 Gln Gln Tyr Gly Asn Ser Leu Ser Arg 1 5 <210> 75 <211> 110 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 75 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Glu Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Arg Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 76 <211> 110 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 76 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu 35 40 45 Ile Phe Arg Ser Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 77 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 77 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Leu Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ile Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 78 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 78 Ser Ser Glu Leu Thr Gln Asp Pro Thr Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Lys Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Phe Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Phe Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Val Tyr His 85 90 95 Leu Val Leu Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 79 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 79 Asp Ile Ile Leu Ala Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Ala Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Pro 35 40 45 Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ser 85 90 95 Phe Pro Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 80 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 80 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Thr Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Arg Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 81 <211> 112 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 81 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Phe Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 110 <210> 82 <211> 112 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 82 Asp Ile Ile Leu Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Pro 35 40 45 Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe Ser Gly Glu Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Thr Tyr Tyr Cys Met Gln Ser 85 90 95 Phe Pro Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 83 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 83 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Phe Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Arg Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 84 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 84 Gln Ser Val Leu Thr Gln Ser Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu 35 40 45 Ile Leu Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 85 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 85 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Phe Tyr Cys Ala Ala Arg Asp Glu Ser Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 86 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 86 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu 35 40 45 Ile Phe Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 87 <211> 112 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 87 Asp Ile Thr Leu Thr Gln Thr Pro Leu Ser Leu Ser Val Ser Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asp Gly Arg Asn Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Pro 35 40 45 Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe Ser Gly Leu Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ser 85 90 95 Phe Pro Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 88 <211> 110 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 88 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Arg Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 89 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide <400> 89 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Lys Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 90 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 90 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Gly 20 25 30 Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Leu 85 90 95 Cys Arg Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 91 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 91 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Gly 20 25 30 Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Leu 85 90 95 Ser Arg Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 92 <211> 130 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 92 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Ile Lys Tyr Ser Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr Tyr His Tyr 100 105 110 Lys Tyr Tyr Gly Met Ala Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser 130 <210> 93 <211> 131 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 93 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Thr Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser 130 <210> 94 <211> 130 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 94 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gln Arg Glu Val Gly Pro Tyr Ser Ser Gly Trp Tyr Asp 100 105 110 Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser 130 <210> 95 <211> 130 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 95 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gln Met Ser Ile Ile Met Leu Arg Gly Val Phe Pro Pro 100 105 110 Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser 130 <210> 96 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 96 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser His Glu Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Arg Lys Arg Val Thr Met Ser Thr Leu Tyr Tyr Tyr Phe 100 105 110 Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125 Ser <210> 97 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 97 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Gly Asp Tyr 20 25 30 Ala Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Phe Ile Arg Ser Arg Ala Tyr Gly Gly Thr Pro Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Thr Ile 65 70 75 80 Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Phe Cys Ala Arg Gly Arg Gly Ile Ala Ala Arg Trp Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 98 <211> 131 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 98 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Thr Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser 130 <210> 99 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 99 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Gly Tyr Ser Gly Tyr Ala Gly Leu Tyr Ser His Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 100 <211> 131 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 100 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Phe Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser 130 <210> 101 <211> 131 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 101 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser 130 <210> 102 <211> 130 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 102 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Ile Lys Tyr Ser Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr Tyr His Tyr 100 105 110 Lys Tyr Tyr Gly Leu Ala Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser 130 <210> 103 <211> 131 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 103 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Thr Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Val Ser Gly Ser Ser Pro Tyr Ser Ile Ser Trp Tyr 100 105 110 Asp Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser 130 <210> 104 <211> 126 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 104 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ile Ile Ser Arg Asp Lys Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Gly Ile Ala Ala Ala Gly Leu Tyr Tyr Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 105 <211> 456 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 105 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Ile Lys Tyr Ser Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr Tyr His Tyr 100 105 110 Lys Tyr Tyr Gly Met Ala Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr 195 200 205 Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270 Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 275 280 285 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300 Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln 305 310 315 320 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 325 330 335 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro 340 345 350 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 355 360 365 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 385 390 395 400 Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445 Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 106 <211> 457 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 106 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Thr Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 130 135 140 Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 145 150 155 160 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 165 170 175 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 180 185 190 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly 195 200 205 Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 210 215 220 Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 107 <211> 456 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 107 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gln Arg Glu Val Gly Pro Tyr Ser Ser Gly Trp Tyr Asp 100 105 110 Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr 195 200 205 Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270 Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 275 280 285 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300 Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln 305 310 315 320 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 325 330 335 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro 340 345 350 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 355 360 365 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 385 390 395 400 Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445 Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 108 <211> 456 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 108 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gln Met Ser Ile Ile Met Leu Arg Gly Val Phe Pro Pro 100 105 110 Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr 195 200 205 Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270 Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 275 280 285 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300 Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln 305 310 315 320 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 325 330 335 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro 340 345 350 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 355 360 365 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 385 390 395 400 Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445 Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 109 <211> 455 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 109 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser His Glu Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Arg Lys Arg Val Thr Met Ser Thr Leu Tyr Tyr Tyr Phe 100 105 110 Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 125 Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser 130 135 140 Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp 145 150 155 160 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr 165 170 175 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr 180 185 190 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln 195 200 205 Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp 210 215 220 Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala 225 230 235 240 Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 245 250 255 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 260 265 270 Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 275 280 285 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 290 295 300 Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp 305 310 315 320 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 325 330 335 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg 340 345 350 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 355 360 365 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 370 375 380 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 385 390 395 400 Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 405 410 415 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 420 425 430 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 435 440 445 Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 110 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 110 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Gly Asp Tyr 20 25 30 Ala Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Phe Ile Arg Ser Arg Ala Tyr Gly Gly Thr Pro Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Thr Ile 65 70 75 80 Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Phe Cys Ala Arg Gly Arg Gly Ile Ala Ala Arg Trp Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 111 <211> 457 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 111 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Thr Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 130 135 140 Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 145 150 155 160 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 165 170 175 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 180 185 190 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly 195 200 205 Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 210 215 220 Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 112 <211> 453 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 112 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Gly Tyr Ser Gly Tyr Ala Gly Leu Tyr Ser His Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 130 135 140 Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 145 150 155 160 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 180 185 190 Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr 195 200 205 Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr 210 215 220 Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro 225 230 235 240 Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270 Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 275 280 285 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 290 295 300 Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu 305 310 315 320 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala 325 330 335 Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro 340 345 350 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 355 360 365 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 370 375 380 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400 Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 420 425 430 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 435 440 445 Leu Ser Pro Gly Lys 450 <210> 113 <211> 457 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 113 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Phe Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 130 135 140 Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 145 150 155 160 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 165 170 175 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 180 185 190 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly 195 200 205 Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 210 215 220 Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 114 <211> 457 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 114 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asn Ala 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Thr Thr Asp Arg Thr Gly Tyr Ser Ile Ser Trp Ser Ser Tyr 100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 130 135 140 Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 145 150 155 160 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 165 170 175 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 180 185 190 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly 195 200 205 Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 210 215 220 Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 115 <211> 456 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 115 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Ile Lys Tyr Ser Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Leu Asn Tyr Tyr Asp Ser Ser Gly Tyr Tyr His Tyr 100 105 110 Lys Tyr Tyr Gly Leu Ala Val Trp Gly Gln Gly Thr Thr Val Thr Val 115 120 125 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 130 135 140 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 145 150 155 160 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 165 170 175 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 180 185 190 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr 195 200 205 Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 210 215 220 Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270 Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 275 280 285 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300 Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln 305 310 315 320 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 325 330 335 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro 340 345 350 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 355 360 365 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 385 390 395 400 Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445 Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 116 <211> 457 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 116 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Thr Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Ser Ser Tyr Arg Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Val Ser Gly Ser Ser Pro Tyr Ser Ile Ser Trp Tyr 100 105 110 Asp Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr 115 120 125 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 130 135 140 Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 145 150 155 160 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 165 170 175 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 180 185 190 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly 195 200 205 Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 210 215 220 Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 225 230 235 240 Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 117 <211> 452 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 117 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ile Ile Ser Arg Asp Lys Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Gly Ile Ala Ala Ala Gly Leu Tyr Tyr Tyr Tyr Gly 100 105 110 Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser 115 120 125 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr 130 135 140 Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 145 150 155 160 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 165 170 175 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 180 185 190 Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr 195 200 205 Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val 210 215 220 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val 225 230 235 240 Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 290 295 300 Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys 450 <210> 118 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 118 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Glu Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Arg Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 119 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 119 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu 35 40 45 Ile Phe Arg Ser Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 120 <211> 214 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 120 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Leu Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Ile Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 121 <211> 214 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 121 Ser Ser Glu Leu Thr Gln Asp Pro Thr Val Ser Val Ala Leu Gly Gln 1 5 10 15 Thr Val Lys Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Phe Tyr Ala 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Phe Tyr 35 40 45 Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Val Tyr His 85 90 95 Leu Val Leu Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys 100 105 110 Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln 115 120 125 Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly 130 135 140 Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys Ala Gly 145 150 155 160 Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala 165 170 175 Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser 180 185 190 Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val 195 200 205 Ala Pro Thr Glu Cys Ser 210 <210> 122 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 122 Asp Ile Ile Leu Ala Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Ala Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Pro 35 40 45 Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ser 85 90 95 Phe Pro Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 123 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 123 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Thr Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Arg Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 124 <211> 219 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 124 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Phe Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 125 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 125 Asp Ile Ile Leu Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30 Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Pro 35 40 45 Pro Gln Leu Leu Ile Tyr Glu Val Ser Asn Arg Phe Ser Gly Glu Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Thr Tyr Tyr Cys Met Gln Ser 85 90 95 Phe Pro Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 126 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 126 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Phe Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Arg Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 127 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 127 Gln Ser Val Leu Thr Gln Ser Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu 35 40 45 Ile Leu Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Thr Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 128 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 128 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Phe Tyr Cys Ala Ala Arg Asp Glu Ser Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 129 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Polypeptide <400> 129 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Ala Ala Pro Lys Leu Leu 35 40 45 Ile Phe Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <210> 130 <211> 219 <212> PRT <213>...

Claims

1. Use of an anti-CGRP receptor antibody in the preparation of a medicament for preventing or reducing the occurrence of migraine in a patient who has failed or is intolerant to at least two different classes of migraine prophylactic agents, wherein the medicament is formulated for subcutaneous administration at a monthly dose of 70 mg to 140 mg of the anti-CGRP receptor antibody, and wherein the anti-CGRP receptor antibody comprises CDRH1 of the sequence of SEQ ID NO: 14, CDRH2 of the sequence of SEQ ID NO: 23, CDRH3 of the sequence of SEQ ID NO: 34, CDRL1 of the sequence of SEQ ID NO: 44, CDRL2 of the sequence of SEQ ID NO: 55, and CDRL3 of the sequence of SEQ ID NO:

65.

2. The use according to claim 1, wherein the patient has failed or is intolerant to at least three different classes of migraine prophylactic agents.

3. The use according to claim 1 or 2, wherein the classes of migraine prophylactic agents are selected from anti-epileptic drugs, tricyclic antidepressants, or β-blockers.

4. The use according to claim 3, wherein the anti-epileptic drug is selected from divalproex, sodium valproate, valproic acid, topiramate, and gabapentin.

5. The use according to claim 3, wherein the tricyclic antidepressant is selected from amitriptyline, nortriptyline, and doxepin.

6. The use according to claim 3, wherein the β-blocker is selected from propranolol, timolol, atenolol, metoprolol, or nadolol.

7. The use according to claim 1 or 2, wherein the migraine prophylactic agent is selected from propranolol, timolol, divalproex, valproic acid, topiramate, amitriptyline, or botulinum toxin type A.

8. The use according to claim 1 or 2, wherein the patient has failed or is intolerant to at least one anti-epileptic drug and at least one β-blocker.

9. The use according to claim 1 or 2, wherein the patient has failed or is intolerant to at least one anti-epileptic drug and at least one antidepressant.

10. The use according to claim 1 or 2, wherein the patient has failed or is intolerant to at least one β-blocker and at least one antidepressant.

11. The use according to claim 1 or 2, wherein the patient has failed or is intolerant to topiramate, propranolol, and amitriptyline.

12. The use according to claim 1 or 2, wherein the monthly dose is 70 mg.

13. The use according to claim 1 or 2, wherein the monthly dose is 140 mg.

14. The use according to claim 1 or 2, wherein the patient has or is diagnosed with episodic migraine.

15. The use according to claim 1 or 2, wherein the patient has or is diagnosed with chronic migraine.

16. The use according to claim 1 or 2, wherein the anti-CGRP receptor antibody comprises a heavy chain variable region (V H ) containing the sequence of SEQ ID NO: 92 and a light chain variable region (V L ) containing the sequence of SEQ ID NO:

80.

17. The use according to claim 1 or 2, wherein the anti-CGRP receptor antibody comprises a heavy chain containing the sequence of SEQ ID NO: 105 and a light chain containing the sequence of SEQ ID NO:

123.

18. The use according to claim 1 or 2, wherein the medicament is contained in a prefilled device, and wherein the device delivers a subcutaneous injection volume of 1 ml or less.

19. The use according to claim 18, wherein the device is a pre-filled syringe.

20. The use according to claim 18, wherein the device is an auto-injector.

21. The use according to claim 18, wherein the device delivers a subcutaneous injection volume of 1 ml.

22. The use according to claim 18, wherein the device delivers a subcutaneous injection volume of 0.5 ml.

23. The use according to claim 1 or 2, wherein the medicament further comprises an acetate buffer, sucrose, and polysorbate.

24. The use according to claim 23, wherein the polysorbate is polysorbate 20 or polysorbate 80.

25. The use according to claim 1 or 2, wherein the medicament is formulated for once-monthly subcutaneous administration.

26. The use according to claim 1 or 2, wherein the medicament comprises 70 mg of the anti-CGRP receptor antibody.

27. The use according to claim 1 or 2, wherein the medicament comprises 140 mg of the anti-CGRP receptor antibody.

28. The use according to claim 1 or 2, wherein the anti-CGRP receptor antibody is a monoclonal IgG1 or monoclonal IgG2 antibody.

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