US20190071490A1 - Preventing Post-Ictal Headaches - Google Patents

Preventing Post-Ictal Headaches Download PDF

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US20190071490A1
US20190071490A1 US15/909,787 US201815909787A US2019071490A1 US 20190071490 A1 US20190071490 A1 US 20190071490A1 US 201815909787 A US201815909787 A US 201815909787A US 2019071490 A1 US2019071490 A1 US 2019071490A1
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antibody
cgrp
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monoclonal antibody
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Rami Burstein
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Beth Israel Deaconess Medical Center Inc
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/54Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
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    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
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    • C07K2317/51Complete heavy chain or Fd fragment, i.e. VH + CH1
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    • C07K2317/00Immunoglobulins specific features
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    • C07K2317/55Fab or Fab'
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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    • C07ORGANIC CHEMISTRY
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • Ictal headaches are headaches associated with seizure activity. They may occur either before (pre-ictal) or after (post-ictal) a seizure, and in rare circumstances during a seizure. Many cases of ictal headache are misdiagnosed as a migraine with aura, or even a cluster headache. However, while those conditions usually involve only one side of the head (are unilateral), an ictal headache can be centrally situated or cover the entirety of the head.
  • Post-ictal headaches (PIH) can be migrainous or non-migrainous in nature.
  • a migrainous PIH is a PIH that is followed by a headache that fulfill migraine criteria, while a non-migrainous PIH is followed by a headache that does not fulfill migraine criteria.
  • PIHs add an additional significant burden to persons with epilepsy in addition to actual seizures (Schon et al., J. Neurol. Neurosurg. Psychiatry 50:1148-52, 1987; Toldo et al., J. Headache Pain 11:235-40, 2010; Wawrzyniak et al., Epilepsia 50 (Suppl 6):37, 2009).
  • PIHs are very painful, and since they strike repetitively, PIHs cause subjects to endure significant hardship. Nonetheless, PIHs are mentioned only briefly in the latest epilepsy reference literature (see, e.g., Engel et al., Epilepsy: a comprehensive textbook.
  • anti-epilepsy drugs e.g., carbamazepine, clonazepam, lacosamide, nitrazepam, oxcarbazepine, phenobarbital, retigabine, tiagabine, and topiramate, have been reported to be successful in reducing migraine frequency, though they are unsuccessful for preventing PIHs. Accordingly, compositions and methods for preventing PIH are desired.
  • anti-CGRP antibodies e.g., anti-CGRP antagonist antibodies and anti-CGRP receptor antibodies
  • methods of using the same for preventing a PIH e.g., migrainous PIH and non-migrainous PIH.
  • methods of preventing, treating, or reducing incidence of PIH in a subject comprising administering to the subject a therapeutically effective amount of a monoclonal antibody that modulates the CGRP pathway.
  • Methods of preventing, treating, or reducing incidence of at least one secondary symptom associated with migrainous PIH in a subject comprising administering to the subject a therapeutically effective amount of a monoclonal antibody that modulates the CGRP pathway are also provided.
  • the subject who is at risk for a post-ictal headache has a brain infection, traumatic brain injury, personal history of a seizure, family history of epilepsy, stroke, or dementia.
  • the subject is a human.
  • the monoclonal antibody is an anti-CGRP antagonist antibody. In some embodiments, the monoclonal antibody is an anti-CGRP receptor antibody.
  • the monoclonal antibody can be a human or humanized antibody (e.g., a humanized anti-CGRP antagonist antibody or a humanized anti-CGRP receptor antibody).
  • the monoclonal antibody is administered intravenously. In some embodiments, the monoclonal antibody is administered subcutaneously.
  • the monoclonal antibody is an IgG1, an IgG2, an IgG3, or an IgG4 antibody.
  • the monoclonal antibody is administered to the subject from or using a pre-filled syringe, a pre-filled syringe with a needle safety device, an injection device, or an autoinjector comprising a dose of the monoclonal antibody.
  • the methods described herein further comprise administering one or more additional doses of the monoclonal antibody to the subject.
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:3; a CDR H2 as set forth in SEQ ID NO:4; a CDR H3 as set forth in SEQ ID NO:5; a CDR L1 as set forth in SEQ ID NO:6; a CDR L2 as set forth in SEQ ID NO:7; and a CDR L3 as set forth in SEQ ID NO:8.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:1, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:2.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:11, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:12.
  • the monoclonal antibody is fremanezumab.
  • the monoclonal antibody is administered at a dose of from about 225 mg to about 900 mg (e.g., at a dose of about 225 mg, at a dose of about 675 mg, at a dose of about 900 mg). These doses may be administered to the patient monthly or quarterly.
  • any of these doses may be administered intravenously or subcutaneously.
  • the dosing regimen comprises an initial dose (e.g., 675 mg), and further comprises administering to the patient an additional dose of about 225 mg of the monoclonal antibody once per month in each of the two months (or three months, four months, five months, six months, or twelve months) subsequent to the month in which the initial dose is administered to the patient.
  • the monoclonal antibody is administered as a formulation (e.g., a liquid formulation) comprising the antibody at a concentration of at least about 150 mg/mL.
  • the monoclonal antibody is administered in a volume of less than 2 mL (e.g., about 1.8 mL, about 1.7 mL, about 1.6 mL, about 1.5 mL, about 1.4 ml, about 1.3 mL, about 1.2 mL, about 1.1 mL, about 1.0 ml, about 0.9 mL, about 0.8 mL, about 0.7 mL, about 0.6 mL, about 0.5 mL, or less).
  • the monoclonal antibody is preferably administered in a volume of about 1.5 mL.
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:87; a CDR H2 as set forth in SEQ ID NO:88; a CDR H3 as set forth in SEQ ID NO: 89; a CDR L1 as set forth in SEQ ID NO:84; a CDR L2 as set forth in SEQ ID NO:85; and a CDR L3 as set forth in SEQ ID NO:86.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:80.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:83, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:81.
  • the monoclonal antibody is eptinezumab.
  • Eptinezumab may be administered at a dose of about 100 mg, about 300 mg, or about 1000 mg. Any of these doses (e.g., about 100 mg, about 300 mg, or about 1000 mg) may be administered intravenously or subcutaneously.
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:93; a CDR H2 as set forth in SEQ ID NO:94; a CDR H3 as set forth in SEQ ID NO:95; a CDR L1 as set forth in SEQ ID NO:91; a CDR L2 as set forth in SEQ ID NO:92; and a CDR L3 as set forth in SEQ ID NO:90.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:97, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:96.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:99, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:98.
  • the monoclonal antibody is galcanezumab.
  • Galcanezumab may be administered at a dose of about 120 mg or about 240 mg. Further, the 120 mg dose may be administered in a volume of about 1.5 mL and the 240 mg dose may be administered in a volume of about 3 mL. Any of these doses (e.g., about 120 mg or 240 mg) may be administered intravenously or subcutaneously.
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:103; a CDR H2 as set forth in SEQ ID NO:104; a CDR H3 as set forth in SEQ ID NO:105; a CDR L1 as set forth in SEQ ID NO:100; a CDR L2 as set forth in SEQ ID NO:101; and a CDR L3 as set forth in SEQ ID NO:102.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:107, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:106.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:109, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:108.
  • the monoclonal antibody is erenumab.
  • Erenumab may be administered at a dose of about 70 mg or about 140 mg. Further, the 70 mg does may be administered in a volume of about 1 mL. The 140 mg dose may be administered in a volume of about 2 mL. Any of these doses (e.g., about 70 or 140 mg) may be administered intravenously or subcutaneously.
  • the monoclonal antibody is administered prior to a seizure.
  • the monoclonal antibody is administered at least about four hours (e.g., about five, six, seven, eight, nine, ten, eleven, twelve, twenty-four, thirty-six, forty-eight, seventy-two hours, or more) prior to a seizure.
  • the monoclonal antibody e.g., an anti-CGRP antagonist antibody
  • at least about five minutes prior to a seizure e.g., at least about ten minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes
  • the anti-CGRP antagonist antibody may be administered about two hours to about six hours prior to a seizure, e.g., about 2.5 hours to about 5.5 hours, about three hours to about five hours, or about 3.5 hours to about 4.5 hours prior to a seizure.
  • the anti-CGRP antagonist antibody may be administered about four hours prior to a seizure.
  • the anti-CGRP antagonist antibody may be administered about two, three, five, or six hours prior to a seizure.
  • the methods described herein further comprises administering to the subject a second agent simultaneously or sequentially with the monoclonal antibody.
  • the second agent can be non-steroidal anti-inflammatory drugs (NSAIDs) and/or triptans and/or a 5 hydroxytryptamine 1F receptor agonist (i.e., a serotonin receptor agonist).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • triptans i.e., a serotonin receptor agonist
  • a 5 hydroxytryptamine 1F receptor agonist i.e., a serotonin receptor agonist
  • the second agent is an agent taken by the subject prophylactically.
  • monthly use of the second agent by the subject is decreased by at least about 15%, e.g., at least 16%, 17%, 18%, 20%, 22%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least about 95%, after administering the monoclonal antibody.
  • Non-limiting examples of NSAIDs that can be used in combination with an anti-CGRP antibody include aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac, cyclooxygenase-2 (COX-2) inhibitors, celecoxib, rofecoxib, meloxicam, JTE-522, L-745,337, NS398, or a pharmaceutically acceptable salt thereof.
  • COX-2 cyclooxygenase-2
  • Non-limiting examples of triptans that can be used in combination with an anti-CGRP antibody include sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and afrovatriptan.
  • a non-limiting example of a 5 hydroxytryptamine 1F receptor agonist is lasmiditan.
  • CGRP calcitonin gene related peptide
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:3; a CDR H2 as set forth in SEQ ID NO:4; a CDR H3 as set forth in SEQ ID NO:5; a CDR L1 as set forth in SEQ ID NO:6; a CDR L2 as set forth in SEQ ID NO:7; and a CDR L3 as set forth in SEQ ID NO:8.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:1, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:2.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:11, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:12.
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:87; a CDR H2 as set forth in SEQ ID NO:88; a CDR H3 as set forth in SEQ ID NO:89; a CDR L1 as set forth in SEQ ID NO:84; a CDR L2 as set forth in SEQ ID NO:85; and a CDR L3 as set forth in SEQ ID NO:86.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:80.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:83, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:81.
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:93; a CDR H2 as set forth in SEQ ID NO:94; a CDR H3 as set forth in SEQ ID NO:95; a CDR L1 as set forth in SEQ ID NO:91; a CDR L2 as set forth in SEQ ID NO:92; and a CDR L3 as set forth in SEQ ID NO:90.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:97, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:96.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:99, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:98.
  • the monoclonal antibody comprises a CDR H1 as set forth in SEQ ID NO:103; a CDR H2 as set forth in SEQ ID NO:104; a CDR H3 as set forth in SEQ ID NO:105; a CDR L1 as set forth in SEQ ID NO:100; a CDR L2 as set forth in SEQ ID NO:101; and a CDR L3 as set forth in SEQ ID NO:102.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:107, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:106.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:109, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:108.
  • the method comprises administering to the subject an amount of a monoclonal antibody that modulates the CGRP pathway, wherein the monoclonal antibody is in an amount effective to decrease the number of monthly headache or migraine hours by at least 20 (e.g., 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more headache or migraine hours) after a single dose.
  • the number of monthly headache or migraine hours is reduced by at least about 50 hours.
  • the method comprises administering to the subject an amount of a monoclonal antibody that modulates the CGRP pathway, wherein the monoclonal antibody is in an amount effective to decrease the number of monthly headache or migraine hours by at least 15% (e.g., 20%, 25%, 30%, 35%, 40%, or more) after a single dose.
  • the number of monthly headache or migraine hours is reduced by at least about 30%.
  • monthly headache or migraine hours experienced by the subject after said administering is reduced by 40 or more hours (e.g., 45, 50, 55, 60, 65, 70, 75, 80, or more) from a pre-administration level in the subject.
  • Monthly headache or migraine hours may be reduced by more than 60 hours.
  • monthly headache or migraine hours experienced by the subject after said administering are reduced by 25% or more (e.g., 30%, 35%, 40%, 45%, 50%, or more) relative to a pre-administration level in the subject.
  • Monthly headache or migraine hours may be reduced by 40% or more.
  • monthly headache or migraine days experienced by the subject after said administering is reduced by three or more days (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more days) from a pre-administration level in the subject.
  • the number of monthly headache or migraine days can be reduced by at least about 50% from a pre-administration level in the subject.
  • the number of monthly headache or migraine days can be reduced by at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 90%.
  • the method comprises administering to the subject an amount of a monoclonal antibody that modulates the CGRP pathway, wherein the monoclonal antibody is in an amount effective to decrease the number of monthly headache or migraine days by at least 3 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more headache or migraine days) after a single dose.
  • the number of monthly headache or migraine days is reduced by at least about 6 headache or migraine days.
  • the number of monthly headache or migraine days can be reduced by at least about 50% from a pre-administration level in the subject.
  • the number of monthly headache or migraine days can be reduced by at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 90%.
  • the anti-headache medication can be non-steroidal anti-inflammatory drugs (NSAIDs) and/or triptans.
  • the anti-headache medication is a triptan.
  • the invention provides a method of preventing, treating, or reducing incidence of PIH in a subject comprising administering to the subject a single dose of a monoclonal antibody (e.g., monoclonal anti-CGRP-antagonist antibody or an anti-CGRP receptor antibody) in an amount that modulates the CGRP pathway, wherein the amount of the monoclonal antibody is about 225 mg to about 1000 mg, e.g., about 675 mg or about 900 mg.
  • a monoclonal antibody e.g., monoclonal anti-CGRP-antagonist antibody or an anti-CGRP receptor antibody
  • the invention provides methods for preventing, treating, ameliorating, controlling, reducing severity of, reducing incidence of, or delaying the development or progression of PIH in an individual comprising administering to the individual an effective amount of a monoclonal antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) in combination with at least one additional agent useful for treating the PIH.
  • additional agents include analgesic (e.g., NSAIDs) and/or anti-headache medications (e.g., triptans).
  • an antibody that modulates the CGRP pathway can be by any means known in the art, including: orally, intravenously, subcutaneously, intraarterially, intramuscularly, intranasally (e.g., with or without inhalation), intracardially, intraspinally, intrathoracically, intraperitoneally, intraventricularly, sublingually, transdermally, and/or via inhalation.
  • Administration may be systemic, e.g., intravenously, or localized.
  • an initial dose and one or more additional doses are administered via the same route, i.e., subcutaneously or intravenously.
  • the one or more additional doses are administered in a different route than the initial dose, i.e., the initial dose may be administered intravenously and the one or more additional doses may be administered subcutaneously.
  • the antibody that modulates the CGRP pathway may be administered in conjunction with another agent, such as another agent for treating PIH, e.g., NSAIDs and/or triptans.
  • another agent for treating PIH e.g., NSAIDs and/or triptans.
  • the invention provides use of an antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) for the manufacture of a medicament for use in any of the methods described herein, for example, for preventing, treating, or reducing PIH.
  • an antibody that modulates the CGRP pathway e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • CGRP calcitonin gene related peptide
  • the antibody comprises a CDR H1 as set forth in SEQ ID NO:3; a CDR H2 as set forth in SEQ ID NO:4; a CDR H3 as set forth in SEQ ID NO:5; a CDR L1 as set forth in SEQ ID NO:6; a CDR L2 as set forth in SEQ ID NO:7; and a CDR L3 as set forth in SEQ ID NO:8.
  • the antibody comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:2.
  • the antibody comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:11, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:12.
  • the antibody comprises a CDR H1 as set forth in SEQ ID NO: 87; a CDR H2 as set forth in SEQ ID NO:88; a CDR H3 as set forth in SEQ ID NO:89; a CDR L1 as set forth in SEQ ID NO:84; a CDR L2 as set forth in SEQ ID NO:85; and a CDR L3 as set forth in SEQ ID NO:86.
  • the antibody comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:80.
  • the antibody comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:83, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:81.
  • the antibody comprises a CDR H1 as set forth in SEQ ID NO:93; a CDR H2 as set forth in SEQ ID NO:94; a CDR H3 as set forth in SEQ ID NO:95; a CDR L1 as set forth in SEQ ID NO:91; a CDR L2 as set forth in SEQ ID NO:92; and a CDR L3 as set forth in SEQ ID NO:90.
  • the antibody comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:97, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:96.
  • the antibody comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:99, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:98.
  • the antibody comprises a CDR H1 as set forth in SEQ ID NO:103; a CDR H2 as set forth in SEQ ID NO:104; a CDR H3 as set forth in SEQ ID NO:105; a CDR L1 as set forth in SEQ ID NO:100; a CDR L2 as set forth in SEQ ID NO:101; and a CDR L3 as set forth in SEQ ID NO:102.
  • the antibody comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:107, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:106.
  • the antibody comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:109, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:108.
  • the invention provides a pharmaceutical composition for preventing, treating, or reducing PIH comprising an effective amount of a monoclonal antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody), in combination with one or more pharmaceutically acceptable excipients.
  • a monoclonal antibody that modulates the CGRP pathway e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • kits for use in any of the methods described herein comprises a container, a composition comprising an antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody), in combination with a pharmaceutically acceptable carrier, and instructions for using the composition in any of the methods described herein.
  • an antibody that modulates the CGRP pathway e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • the invention provides a monoclonal antibody that modulates the CGRP pathway, or a composition comprising a monoclonal antibody that modulates the CGRP pathway, for use in decreasing a number of monthly headache or migraine hours experienced by a subject.
  • the monoclonal antibody or composition is administered to the subject in an amount effective to decrease the number of monthly headache or migraine hours by at least 20 (e.g., 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more headache or migraine hours) after a single dose.
  • the number of monthly headache or migraine hours is reduced by at least about 50 hours.
  • the monoclonal antibody or composition is administered to the subject in an amount effective to decrease the number of monthly headache or migraine hours by at least 15% (e.g., 20%, 25%, 30%, 35%, 40%, or more) after a single dose. In some embodiments, the number of monthly headache or migraine hours is reduced by at least about 30%.
  • the invention provides a monoclonal antibody that modulates the CGRP pathway, or a composition comprising a monoclonal antibody that modulates the CGRP pathway, for use in decreasing a number of monthly headache or migraine days experienced by a subject.
  • the monoclonal antibody or composition is administered to the subject in an amount effective to decrease the number of monthly headache or migraine days by at least 3 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more headache or migraine days) after a single dose.
  • the number of monthly headache or migraine days is reduced by at least about 6 headache or migraine days.
  • the invention provides a monoclonal antibody that modulates the CGRP pathway, or a composition comprising a monoclonal antibody that modulates the CGRP pathway, for use in decreasing use of any acute headache medication in a subject, comprising administering to the subject a monoclonal antibody (e.g., anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) in an amount effective to decrease monthly use of the acute headache medication by the subject by at least 15% (e.g., 20%, 25%, 30%, 35%, 40%, or more).
  • a monoclonal antibody e.g., anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • the anti-headache medication is selected from the group consisting of NSAIDs and/or triptans.
  • the anti-headache medication is a triptan.
  • compositions for use according to any of the methods described herein are also provided.
  • the invention provides a monoclonal antibody that modulates the CGRP pathway, or a composition comprising a monoclonal antibody that modulates the CGRP pathway, for use in preventing, treating, or reducing incidence of PIH in a subject, comprising administering to the subject a single dose of the monoclonal antibody (e.g., monoclonal anti-CGRP-antagonist antibody) in an amount that modulates the CGRP pathway, wherein the amount of the monoclonal antibody administered to the subject is about 675 mg to about 1000 mg.
  • the monoclonal antibody e.g., monoclonal anti-CGRP-antagonist antibody
  • FIG. 1 is a table showing binding affinities of 12 murine antibodies for different alanine substituted human ⁇ -CGRP fragments. Binding affinities were measured at 25° C. using Biacore by flowing Fabs across CGRPs on the chip. The boxed values represent the loss in affinity of alanine mutants relative to parental fragment, 25-37 (italic), except K35A, which was derived from a 19-37 parent. “ a ” indicates affinities for 19-37 and 25-37 fragments are the mean average ⁇ standard deviation of two independent measurements on different sensor chips.
  • “ b ” indicates these interactions deviated from a simple bimolecular interaction model due to a biphasic off rate, so their affinities were determined using a conformational change model.
  • Grey-scale key white (1.0) indicates parental affinity; light grey (less than 0.5) indicates higher affinity than parent; dark grey (more than 2) indicates lower affinity than parent; and black indicates that no binding was detected.
  • FIGS. 2A and 2B show the effect of administering CGRP 8-37 (400 nmol/kg), antibody 4901 (25 mg/kg), and antibody 7D11 (25 mg/kg) on skin blood flow measured as blood cell flux after electrical pulse stimulation for 30 seconds.
  • CGRP 8-37 was administered intravenously (iv) 3-5 min before electrical pulse stimulation.
  • Antibodies were administered intraperitoneal (IP) 72 hours before electrical pulse stimulation.
  • Each point in the graphs represents AUC of one rat treated under the conditions as indicated.
  • Each line in the graphs represents average AUC of rats treated under the condition as indicated.
  • AUC area under the curve
  • “ ⁇ flux” represents the change of flux units after the electrical pulse stimulation; and “ ⁇ time” represents the time period taken for the blood cell flux level to return to the level before the electrical pulse stimulation.
  • FIG. 3 shows the effect of administering different dosage of antibody 4901 (25 mg/kg, 5 mg/kg, 2.5 mg/kg, or 1 mg/kg) on skin blood flow measured as blood cell flux after electrical pulse stimulation for 30 seconds.
  • Antibodies were administered intravenously (IV) 24 hours before electrical pulse stimulation.
  • Each point in the graph represents AUC of one rat treated under the conditions as indicated.
  • the line in the graph represents average AUC of rats treated under the condition as indicated.
  • FIGS. 4A and 4B show the effect of administering antibody 4901 (1 mg/kg or 10 mg/kg, i.v.), antibody 7E9 (10 mg/kg, i.v.), and antibody 8B6 (10 mg/kg, i.v.) on skin blood flow measured as blood cell flux after electrical pulse stimulation for 30 seconds.
  • Antibodies were administered intravenously (i.v.) followed by electrical pulse stimulation at 30 min, 60 min, 90 min, and 120 min after antibody administration.
  • Y axis represents percent of AUC as compared to level of AUC when no antibody was administered (time 0).
  • X axis represents time (minutes) period between the administration of antibodies and electrical pulse stimulation. “*” indicates P ⁇ 0.05, and “**” indicates P ⁇ 0.01, as compared to time 0. Data were analyzed using one-way ANOVA with a Dunnett's Multiple comparison test.
  • FIG. 5 shows the amino acid sequence of the heavy chain variable region (SEQ ID NO:1) and light chain variable region (SEQ ID NO:2) of antibody G1.
  • the Kabat CDRs are in bold text, and the Chothia CDRs are underlined.
  • the amino acid residues for the heavy chain and light chain variable region are numbered sequentially.
  • FIG. 6 shows epitope mapping of antibody G1 by peptide competition using Biacore.
  • N-biotinylated human ⁇ -CGRP was captured on SA sensor chip.
  • G1 Fab 50 nM
  • G1 Fab 50 nM
  • Binding of G1 Fab to the human ⁇ -CGRP on the chip was measured.
  • Y axis represents percentage of binding blocked by the presence of the competing peptide compared with the binding in the absence of the competing peptide.
  • FIG. 7A shows how single-unit recordings were obtained from dural primary afferent nociceptors in the trigeminal ganglion while recording electrocorticogram activity from the caudal cortex.
  • Triangle shows site of picrotoxin administration.
  • FIG. 7B shows dural afferents were identified by their response to single-shock stimulation applied to the dura overlying the transverse sinus, and were further characterized as mechanosensitive by their response to von Frey (VFH) stimulation of the dura.
  • VH von Frey
  • FIG. 7C is a bar graph that shows location of dural receptive field.
  • FIG. 7D is an electrocorticogram (upper trace) and firing rate of a dural afferent (lower trace) before and after induction of seizure by picrotoxin. Triangle shows time of picrotoxin administration.
  • FIG. 8A shows an experimental setup showing locations of ECG recording in the parietal cortex, neuronal recording in lamina I of the upper cervical dorsal horn, and the neuron's dural and facial receptive fields.
  • FIG. 8B is a graph showing electrical stimulation on dura.
  • FIG. 8C is a bar graph that shows mechanical stimulation on dura.
  • FIG. 8D shows an ECG recording of a neuron characterized as wide dynamic range (WDR) by its responses to graded mechanical stimulation of the facial skin.
  • WDR wide dynamic range
  • FIG. 8E shows that topical application of picrotoxin to the parietal cortex induced cortical seizure (upper trace) and transient suppression of neuronal firing, which was followed by a prolonged increase above baseline that persisted after the cessation of seizure activity.
  • FIG. 9 shows that an anti-CGRP antagonist antibody prevents activation of central trigeminovascular neuron by seizure.
  • TEV-48125 prevented the activation of a central trigeminovascular neuron but not the occurrence of a seizure.
  • Top panel shows the seizure activity in the cortex.
  • Bottom panel shows lack of activity in the central neuron.
  • FIGS. 10A and 10F show recording sites plotted on a representative transverse section through the first cervical segment.
  • the circles represent HT and WDR neurons, as indicated.
  • FIGS. 10B, 10D, 10G, and 10I show the most sensitive regions of cutaneous (i.e., where brush, pressure and pinch were applied) and corneal receptive fields.
  • FIGS. 10C, 10E, 10H, and 10J show the mechanically sensitive receptive fields on the dura, which were all on or around the transverse sinus.
  • the portion of the dura shown in the receptive field drawings is outlined by the dashed line in the inset in FIG. 10H . All dural and facial receptive fields were ipsilateral to the recorded neuron.
  • FIGS. 11A, 11B, 11C, 11D, 11E, 11F, and 11G show the effect of CGRP-mAb ( FIGS. 11A, 11B, 11C, and 11D ) and isotype-conAb ( FIGS. 11E, 11F, and 11G ) on the spontaneous activity of trigeminovascular neurons in male and female rats.
  • FIGS. 11A, 11B, 11C, 11D, 11E, 11F, and 11G show the effect of CGRP-mAb ( FIGS. 11A, 11B, 11C, and 11D ) and isotype-conAb ( FIGS. 11E
  • FIGS. 11B and 11C are histograms showing mean ( ⁇ S.E.) spontaneous discharge of HT and WDR neurons recorded at baseline and 1-4 hours following CGRP-mAb administration in male ( FIG. 11B ) and female ( FIG. 11C ) rats.
  • FIGS. 11F and 11G are histograms showing mean ( ⁇ S.E.) spontaneous discharge of HT and WDR neurons recorded at baseline and 1-4 hours following isotype-conAb administration in male ( FIG. 11F ) and female ( FIG. 11G ) rats. * p ⁇ 0.05 compared to baseline. Numbers in parentheses in FIGS. 11B, 11C, 11F, and 11G depict the number of neurons in each group.
  • FIGS. 12A, 12B, 12C, 12D, 12E, and 12F are graphs showing the effect of CGRP-mAb ( FIGS. 12A, 12B, and 12C ) and isotype-conAb ( FIGS. 12D, 12E, and 12F ) on the response of trigeminovascular neurons to dural indentation in male and female rats.
  • FIGS. 12A and 12D are graphs showing the responses to indentation of the dura with a von Frey hair (VFH, 4.19 g) at baseline (BL) and at 1-4 hours following CGRP-mAb ( FIG. 12A ) or isotype control antibody (isotype-conAb) ( FIG. 12D ) administration to HT neurons.
  • VFH von Frey hair
  • FIGS. 12B and 12C are graphs showing the mean ( ⁇ S.E.) discharge rates in response to dural stimulation at baseline and 1-4 hours following drug administration for the entire sample of neurons that received CGRP-mAb in male ( FIG. 12B ) and female ( FIG. 12C ) rats.
  • FIGS. 12E and 12F are graphs showing the mean ( ⁇ S.E.) discharge rates in response to dural stimulation at baseline and 1-4 hours following drug administration for the entire sample of neurons that received isotype-conAb in male ( FIG. 12E ) and female ( FIG. 12F ) rats. * p ⁇ 0.05 compared to baseline. Numbers in parentheses in FIGS. 12B, 12C, 12E, and 12F depict number of neurons in each group.
  • FIGS. 13A, 13B, 13C, 13D, 13E, 13F, 13G, and 13H are graphs showing the effect of CGRP-mAb ( FIGS. 13A, 13B, 13C, 13D ) and isotype-conAb ( FIGS. 13E, 13F, 13G, and 13H ) on the response of central trigeminovascular neurons to innocuous and noxious mechanical stimulation of cutaneous receptive fields of male and female rats.
  • FIGS. 13A, 13B, 13E, and 13F are graphs showing the responses to mechanical stimulation of the cutaneous receptive fields of HT ( FIGS. 13A and 13E ) and WDR ( FIGS.
  • FIGS. 13B and 13F are graphs showing the mean ( ⁇ S.E.) discharge rates in response to cutaneous stimulation at baseline and 1-4 hours following drug administration for the entire sample of neurons that received CGRP-mAb in male ( FIG. 13C ) and female ( FIG. 13D ) rats.
  • FIGS. 13G and 13H are graphs showing the mean ( ⁇ S.E.) discharge rates in response to cutaneous stimulation at baseline and 1-4 hours following drug administration for the entire sample of neurons that received isotype-conAb in male ( FIG. 13G ) and female ( FIG. 13H ) rats.
  • Numbers in parentheses in FIGS. 13C, 13D, 13G, and 13H depict number of neurons in each group.
  • FIGS. 14A, 14B, 14C, 14D, 14E, and 14F are graphs showing the effect of CGRP-mAb ( FIGS. 14A, 14B, and 14C ) and isotype-conAb ( FIGS. 14D, 14E, and 14F ) on the response of central trigeminovascular neurons to mechanical stimulation of the cornea in male and female rats.
  • FIGS. 14B and 14C are graphs showing the mean ( ⁇ S.E.) discharge rates in response to cornea stimulation at baseline and 1-4 hours following drug administration for the entire sample of neurons that received CGRP-mAb in male ( FIG. 14B ) and female ( FIG. 14C ) rats.
  • FIGS. 14E and 14F are graphs showing the mean ( ⁇ S.E.) discharge rates in response to cornea stimulation at baseline and 1-4 hours following drug administration for the entire sample of neurons that received isotype-conAb in male ( FIG. 14E ) and female ( FIG. 14F ) rats. Numbers in parentheses in FIGS. 14B, 14C, 14E, and 14F depict number of neurons in each group.
  • FIGS. 15A, 15B, 15C, 15D, 15E, and 15F are graphs showing the effect of CGRP-mAb ( FIGS. 15A, 15B, and 15C ) and isotype-conAb ( FIGS. 15D, 15E, and 15F ) on the activation of trigeminovascular neurons by cortical spreading depression (CSD) induced 4 hours post-drug treatment.
  • FIGS. 15A and 15D are graphs show the discharge of trigeminovascular neurons prior to CSD induction (top), during CSD induction (middle), and 2 hours post-CSD (bottom), in two HT neurons that received CGRP-mAb ( FIG. 15A ) or isotype-conAb ( FIG.
  • FIGS. 15B and 15C are graphs showing the mean ( ⁇ S.E.) discharge rates for the entire sample of HT and WDR trigeminovascular neurons tested for CSD responses after isotype-conAb administration in male ( FIG. 15B ) and female ( FIG. 15C ) rats.
  • FIGS. 15E and 15F are graphs showing the mean ( ⁇ S.E.) discharge rates for the entire sample of HT and WDR trigeminovascular neurons tested for CSD responses after CGRP-mAb administration in male ( FIG. 15E ) and female ( FIG. 15F ) rats. Discharge is shown at baseline (4 hours post-drug treatment, prior to CSD induction) and 2 hours post-CSD. * p ⁇ 0.05 compared to baseline. Numbers in parentheses in FIGS. 15B, 15C, 15E, and 15F depict number of neurons in each group.
  • FIGS. 16A and 16B depict the expansion of dural and cutaneous receptive fields following occurrence of CSD in male and female rats.
  • Blue upper left to lower right diagonal lines
  • pink upper right to lower left diagonal lines
  • FIGS. 16A and 16B depict the expansion of dural and cutaneous receptive fields following occurrence of CSD in male and female rats.
  • Blue upper left to lower right diagonal lines
  • pink upper right to lower left diagonal lines
  • FIGS. 16A and 16B depict the expansion of dural and cutaneous receptive fields following occurrence of CSD in male and female rats.
  • Blue upper left to lower right diagonal lines
  • pink upper right to lower left diagonal lines
  • FIGS. 17A, 17B, 17C, 17D, 17E, and 17F are graphs showing that the enhanced responses to mechanical stimulation of the dura following CSD are prevented by the CGRP-mAb.
  • FIGS. 17B, 17C, 17E, and 17F are graphs showing the mean ( ⁇ S.E.) discharge in response to dural indentation prior to CSD induction (Baseline) and 2 hours post-CSD, in neurons that received treatment with isotype-conAb ( FIGS. 17B and 17C ) or CGRP-mAb ( FIGS. 17E and 17F ).
  • Neurons recorded in males are shown in FIGS. 17B and 17E ; neurons recorded in females are shown in FIGS. 17C and 17F .
  • Numbers in parentheses in FIGS. 17B, 17C, 17E, and 17F depict number of neurons in each group.
  • FIGS. 18A, 18B, 18C, 18D, 18E, and 18F are graphs showing the enhanced responses to cutaneous stimulation following CSD are prevented by the CGRP-mAb.
  • 18B, 18C, 18E, and 18F are graphs showing the mean ( ⁇ S.E.) discharge in response to cutaneous stimulation prior to (Baseline) and 2 hours post-CSD induction, in HT neurons that received treatment with isotype-conAb or CGRP-mAb 4 hours prior to CSD induction.
  • Neurons recorded in males are shown in FIGS. 18B and 18E ; neurons recorded in females are shown in FIGS. 18C and 18F .
  • FIGS. 19A, 19B, 19C, 19D, 19E, and 19F are graphs showing the enhanced responses to mechanical stimulation of the cornea following CSD are prevented by CGRP-mAb (female only).
  • FIGS. 19A, 19B, 19C, 19D, 19E, and 19F are graphs showing the enhanced responses to mechanical stimulation of the cornea following CSD are prevented by CGRP-mAb (female only).
  • FIGS. 19A and 19D are graphs showing the responses to corneal stimulation (gentle brush) prior to CSD induction (BL) and 2 hours post-CSD, in two HT neurons that received treatment with isotype-
  • FIGS. 19B, 19C, 19E, and 19F are graphs showing the mean ( ⁇ S.E.) discharge in response to corneal stimulation prior to CSD induction (Baseline) and 2 hours post-CSD, in neurons that received treatment with isotype-conAb ( FIGS. 19B and 19C ) or CGRP-mAb ( FIGS. 19E and 19F ) 4 hours prior to CSD induction.
  • Neurons recorded in males are shown in FIGS. 19B and 19E ; neurons recorded in females are shown in FIGS. 19C and 19F .
  • FIG. 20 are tables showing the results of the studies (as described in Example 6) of spontaneous activity of the HT and WDR neurons in male and female rats in a na ⁇ ve state and post-CSD state upon application of the indicated stimuli.
  • FIGS. 21A, 21B and 21C are graphs showing the activation of a-delta meningeal nociceptors by CSD.
  • FIG. 21A are graphs showing an exemplary individual a-delta fiber response to CSD. The baseline spontaneous activity of the neuron is shown from 0 to 60 min whereas the firing rate of the neuron after CSD is shown from 60 to 120 min.
  • FIG. 21B is a bar graph showing the mean ( ⁇ SE) response magnitude of the six a-delta fibers that were activated by CSD (p ⁇ 0.05).
  • FIG. 21C is a graph showing the changes in response frequency of all six a-delta neurons.
  • FIGS. 22A, 22B, and 22C are graphs showing the activation of C-type meningeal nociceptors by CSD.
  • FIG. 22A are graphs showing an exemplary individual C-type fiber response to CSD. The baseline spontaneous activity of the neuron is shown from 0 to 60 min whereas the firing rate of the neuron after CSD is shown from 60 to 120 min.
  • FIG. 22B shows the mean ( ⁇ SE) response magnitude of the six C-type fibers that were activated by CSD (p ⁇ 0.05).
  • FIG. 22C shows the changes in response frequency of all six C-type neurons.
  • FIGS. 23A and 23B show that fremanezumab prevents the activation of most a-delta and some C-type meningeal nociceptors.
  • FIG. 23A shows an individual example of fremanezumab treated a-delta fiber showing no change in spontaneous activity after CSD.
  • FIG. 23B shows examples of responses of two C-type meningeal nociceptors to CSD after treatment with fremanezumab. Note that the upper neuron was not activated by CSD whereas the lower neuron was activated by CSD.
  • FIGS. 24A and 24B are tables showing the incidence of activation of A-delta or C-type meningeal nociceptors by CSD.
  • the invention disclosed herein provides methods for preventing, treating, and/or reducing PIH in an individual by administering to the individual a therapeutically effective amount of a monoclonal antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody).
  • a monoclonal antibody that modulates the CGRP pathway e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody.
  • an “antibody” is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
  • a target such as a carbohydrate, polynucleotide, lipid, polypeptide, etc.
  • the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab′, F(ab′) 2 , Fv), single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion (such as domain antibodies), and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.
  • An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class.
  • immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.
  • the heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • “monoclonal antibody” or “mAb” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature, 256:495, or may be made by recombinant DNA methods such as described in U.S. Pat. No. 4,816,567.
  • the monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCafferty et al., 1990, Nature, 348:552-554, for example.
  • humanized antibodies refer to forms of non-human (e.g., murine) antibodies that are specific chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab′, F(ab′) 2 or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and, biological activity.
  • CDR complementarity determining region
  • Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • the humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin.
  • Antibodies may have Fc regions modified as described in WO 99/58572.
  • Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, six) which are altered with respect to the original antibody, which are also termed one or more CDRs “derived from” one or more CDRs from the original antibody.
  • human antibody means an antibody having an amino acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies known in the art or disclosed herein.
  • This definition of a human antibody includes antibodies comprising at least one human heavy chain polypeptide or at least one human light chain polypeptide.
  • One such example is an antibody comprising murine light chain and human heavy chain polypeptides.
  • Human antibodies can be produced using various techniques known in the art.
  • the human antibody is selected from a phage library, where that phage library expresses human antibodies (Vaughan et al., 1996 , Nature Biotechnology, 14:309-314; Sheets et al., 1998 , PNAS , (USA) 95:6157-6162; Hoogenboom and Winter, 1991 , J. Mol. Biol., 227:381; Marks et al., 1991 , J. Mol. Biol., 222:581).
  • Human antibodies can also be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. This approach is described in U.S. Pat. Nos.
  • the human antibody may be prepared by immortalizing human B lymphocytes that produce an antibody directed against a target antigen (such B lymphocytes may be recovered from an individual or may have been immunized in vitro). See, e.g., Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., 1991, J. Immunol., 147 (1):86-95; and U.S. Pat. No. 5,750,373.
  • calcitonin gene-related peptide and “CGRP” refers to any form of calcitonin gene-related peptide and variants thereof that retain at least part of the activity of CGRP.
  • CGRP may be ⁇ -CGRP or ⁇ -CGRP.
  • CGRP includes all mammalian species of native sequence CGRP, e.g., human, canine, feline, equine, and bovine.
  • an “anti-CGRP antibody” refers to an antibody that modulates CGRP biological activity, or the CGRP pathway, including downstream pathways mediated by CGRP signaling, such as receptor binding and/or elicitation of a cellular response to CGRP.
  • an anti-CGRP antibody may block, inhibit, suppress or reduce the calcitonin gene related peptide (CGRP) pathway.
  • the term anti-CGRP antibody encompasses both “anti-CGRP antagonist antibodies” and “anti-CGRP receptor antibodies.”
  • the anti-CGRP antibody is a monoclonal antibody (i.e., an anti-CGRP monoclonal antibody).
  • an “anti-CGRP antagonist antibody” refers to an antibody that is able to bind to CGRP and inhibit CGRP biological activity and/or downstream pathway(s) mediated by CGRP signaling.
  • An anti-CGRP antagonist antibody encompasses antibodies that modulate, block, antagonize, suppress or reduce (including significantly) CGRP biological activity, or otherwise antagonize the CGRP pathway, including downstream pathways mediated by CGRP signaling, such as receptor binding and/or elicitation of a cellular response to CGRP.
  • an anti-CGRP antagonist antibody encompasses all the previously identified terms, titles, and functional states and characteristics whereby CGRP itself, CGRP biological activity (including but not limited to its ability to mediate any aspect of headache), or the consequences of the biological activity, are substantially nullified, decreased, or neutralized in any meaningful degree.
  • an anti-CGRP antagonist antibody binds CGRP and prevents CGRP binding to a CGRP receptor.
  • an anti-CGRP antagonist antibody binds CGRP and prevents activation of a CGRP receptor. Examples of anti-CGRP antagonist antibodies are provided herein.
  • an “anti-CGRP receptor antibody” refers to an antibody that is able to bind to a CGRP receptor and thereby modulate the CGRP pathway. Examples of anti-CGRP receptor antibodies are provided herein (e.g., erenumab).
  • G1 As used herein, the terms “G1,” “antibody G1,” “TEV-48125” and “fremanezumab” are used interchangeably to refer to an anti-CGRP antagonist antibody produced by expression vectors having deposit numbers of ATCC PTA-6867 and ATCC PTA-6866.
  • the amino acid sequence of the heavy chain and light chain variable regions are shown in FIG. 5 .
  • the CDR portions of antibody G1 (including Chothia and Kabat CDRs) are diagrammatically depicted in FIG. 5 .
  • the polynucleotides encoding the heavy and light chain variable regions are shown in SEQ ID NO:9 and SEQ ID NO:10.
  • the G1 heavy chain full length amino acid sequence is shown in SEQ ID NO:11.
  • G1 light chain full length amino acid sequence is shown in SEQ ID NO:12.
  • the characterization of G1 is described in the Examples, as well as PCT Publication No. WO 2007/054809 and WHO Drug Information 30(2): 280-1 (2016), which are hereby incorporated by reference in its entirety.
  • eptinezumab refers to an anti-CGRP antagonist antibody, which is a humanized IgG1 monoclonal antibody from a rabbit precursor. Characterization and processes for making eptinezumab can be found in U.S. Publication No. US 2012/0294797 and WHO Drug Information 30(2): 274-5 (2016), which are incorporated by reference in its entirety.
  • galcanezumab refers to an anti-CGRP antagonist antibody, which is a humanized IgG4 monoclonal antibody from a murine precursor. Characterization and processes for making galcanezumab can be found in U.S. Publication No. US 2011/0305711 and WHO Drug Information 29(4): 526-7 (2015), which is incorporated by reference in its entirety. Dosing and formulations associated with galcanezumab can be found in PCT Publication No. WO 2016/205037, which is also incorporated by reference in its entirety.
  • AMG334 refers to an anti-CGRP receptor antibody, which is a fully humanized IgG2 antibody. Characterization and processes for making erenumab can be found in U.S. Publication No. US 2010/0172895 and U.S. Pat. No. 9,102,731, and WHO Drug Information 30(2): 275-6 (2016), each of which are incorporated by reference in their entireties. Dosing and formulations associated with erenumab can be found in PCT Publication No. WO 2016/171742, which is also incorporated by reference in its entirety.
  • polypeptide oligopeptide
  • peptide and “protein” are used interchangeably herein to refer to polymers of amino acids of any length.
  • the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • the terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component.
  • polypeptides containing one or more analogs of an amino acid including, for example, unnatural amino acids, etc.
  • the polypeptides of this invention are based upon an antibody, the polypeptides can occur as single chains or associated chains.
  • Polynucleotide or “nucleic acid,” as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA.
  • the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer.
  • the sequence of nucleotides may be interrupted by non-nucleotide components.
  • a polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • modifications include, for example, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alky
  • any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports.
  • the 5′ and 3′ terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms.
  • Other hydroxyls may also be derivatized to standard protecting groups.
  • Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2′-O-methyl-, 2′-O-allyl, 2′-fluoro- or 2′-azido-ribose, carbocyclic sugar analogs, ⁇ -anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside.
  • One or more phosphodiester linkages may be replaced by alternative linking groups.
  • linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S (“thioate”), P(S)S (“dithioate”), (O)NR 2 (“amidate”), P(O)R, P(O)OR′, CO or CH 2 (“formacetal”), in which each R or R′ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (—O—) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.
  • a “post-ictal headache” can be a headache that is attributed to a non-vascular intracranial disorder and can be caused by and occurring within three hours after an epileptic seizure, and remitting spontaneously within 72 hours after seizure termination, as further described in The International Classification of Headache Disorders, 3rd edition (beta version), Cephalalgia, 33(9): 629-808 (2013).
  • PIH occurs in over 40% of subjects with either temporal lobe epilepsy or frontal lobe epilepsy and in up to 60% of subjects with occipital lobe epilepsy. It occurs more frequently after generalized tonic-clonic seizures than other seizure types.
  • diagnostic criteria for a PIH can include:
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement in any aspect of a PIH, including lessening severity, alleviation of pain intensity, and other associated symptoms, increasing the quality of life of those suffering from the PIH, and decreasing dose of other medications required to treat the PIH.
  • patient and “subject” are used interchangeably herein. In some embodiments, the patient is a human.
  • “Reducing incidence” of PIH means any of reducing severity (which can include reducing need for and/or amount of (e.g., exposure to) other drugs and/or therapies generally used for this condition, including, for example, NSAIDS and/or triptans) and/or duration.
  • individuals may vary in terms of their response to treatment, and, as such, for example, a “method of reducing incidence of PIH in an individual” reflects administering an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody based on a reasonable expectation that such administration may likely cause such a reduction in incidence in that particular individual.
  • “Ameliorating” PIH or one or more symptoms of PIH means a lessening or improvement of one or more symptoms of PIH as compared to not administering an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody. “Ameliorating” also includes shortening or reduction in duration of a symptom.
  • controlling PIH refers to maintaining or reducing severity or duration of one or more symptoms of PIH in an individual (as compared to the level before treatment). For example, the duration or severity of head pain is reduced by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more, in the individual as compared to the level before treatment.
  • the relevant endpoint is a reduction in headache hours after a seizure.
  • a reduction in headache hours, headache days, migraine hours, migraine days (per day or per month) can be relevant. Therefore, “migraine hours” and “migraine days” are used herein only in the context of PIHs that are migrainous.
  • a “headache hour” and a “migraine hour” refers to an hour during which a subject experiences headache or migraine, respectively.
  • Headache or migraine hours can be expressed in terms of whole hours (e.g., one headache or migraine hour, two headache or migraine hours, three headache or migraine hours, etc.) or in terms of whole and partial hours (e.g., 0.5 headache or migraine hours, 1.2 headache or migraine hours, 2.67 headache or migraine hours, etc.).
  • One or more headache or migraine hours may be described with respect to a particular time interval.
  • “daily headache or migraine hours” may refer to the number of headache or migraine hours a subject experiences within a day interval (e.g., a 24-hour period).
  • weekly headache or migraine hours may refer to the number of headache or migraine hours a subject experiences within a week interval (e.g., a 7-day period). As can be appreciated, a week interval may or may not correspond to a calendar week. In another example, “monthly headache or migraine hours” may refer to the number of headache or migraine hours a subject experiences within a month interval. As can be appreciated, a month interval (e.g., a period of 28, 29, 30, or 31 days) may vary in terms of number of days depending upon the particular month and may or may not correspond to a calendar month.
  • a “headache day” and a “migraine day” refers to a day during which a subject experiences headache or migraine, respectively.
  • Headache or migraine days can be expressed in terms of whole days (e.g., one headache or migraine day, two headache or migraine days, three headache or migraine days, etc.) or in terms of whole and partial days (e.g., 0.5 headache or migraine days, 1.2 headache or migraine days, 2.67 headache or migraine days, etc.).
  • One or more headache or migraine days may be described with respect to a particular time interval.
  • “weekly headache or migraine days” may refer to the number of headache or migraine days a subject experiences within a week interval (e.g., a 7-day period).
  • a week interval may or may not correspond to a calendar week.
  • “monthly headache or migraine days” may refer to the number of headache or migraine days a subject experiences within a month interval.
  • a month interval e.g., a period of 28, 29, 30, or 31 days
  • “delaying” the development of PIH means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop PIH.
  • a method that “delays” development of the symptom is a method that reduces probability of developing the symptom in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • “Development” or “progression” of PIH means initial manifestations and/or ensuing progression of the disorder. Development of PIH can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development or progression refers to the biological course of the symptoms. “Development” includes occurrence and onset. As used herein “onset” or “occurrence” of PIH includes initial onset.
  • an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as reducing pain intensity or duration, and decreasing one or more symptoms resulting from PIH (biochemical, histological and/or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication, and/or delaying the progression of the disease of patients.
  • An effective dosage can be administered in one or more administrations.
  • an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • mammals are a mammal, more preferably a human. Mammals also include, but are not limited to, farm animals, sport animals, pets, primates, horses, dogs, cats, mice and rats.
  • a “subject who is at risk for a PIH” may have a brain infection, traumatic brain injury, personal history of a seizure, family history of epilepsy, stroke, and/or dementia. Skilled practitioners will be able to ascertain subjects who are at risk for a PIH.
  • the invention provides methods of preventing, treating, or reducing incidence of PIH, e.g., migrainous PIH and non-migrainous PIH, in a subject.
  • the invention provides a method of preventing, treating, or reducing incidence of at least one secondary symptom associated with migrainous PIH in a subject.
  • the method comprises administering to the individual an effective amount of an antibody or polypeptides derived from the antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody).
  • the invention provides methods for preventing, ameliorating, controlling, reducing severity of, reducing incidence of, or delaying the development or progression of PIH in an individual or symptoms associated with PIH comprising administering to the individual an effective amount of an antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) in combination with at least one additional agent useful for preventing, treating, or reducing PIH.
  • the at least one additional agent can be administered simultaneously or sequentially with the antibody.
  • a therapeutic effect may be greater as compared to use of an antibody or one or more additional agent(s) alone. Accordingly, a synergistic effect between an antibody and the one or more additional agents may be achieved.
  • the one or more additional agent(s) may be taken by a subject prophylactically.
  • Such additional agents include, but are not limited to, NSAIDs and triptans.
  • the antibody and the at least one additional agent can be concomitantly administered, i.e., they can be given in close enough temporal proximity to allow their individual therapeutic effects to overlap.
  • the amount of NSAID administered in combination with an antibody that modulates the CGRP pathway e.g., an anti-CGRP antibody
  • Additional non-limiting examples of additional agents that may be administered in combination with an antibody that modulates the CGRP pathway include triptans and/or a 5 hydroxytryptamine 1F receptor agonist (i.e., a serotonin receptor agonist) and/or a nonsteroidal anti-inflammatory drug (NSAID), e.g., aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac, cyclooxygenase-2 (CO) e.g., aspirin, diclofenac, diflusinal
  • Non-limiting examples of triptans that can be used in combination with an antibody that modulates the CGRP pathway include sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, and afrovatriptan.
  • a non-limiting example of a 5 hydroxytryptamine 1F receptor agonist is lasmiditan.
  • sumatriptan may be administered in a dosage from about 0.01 to about 300 mg.
  • sumatriptan may be administered in a dosage from about 2 mg to about 300 mg, e.g., about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, or about 5 mg to about 25 mg.
  • the typical dosage of sumatriptan is from about 25 to about 100 mg with about 50 mg being generally preferred, e.g., about 45 mg, about 55 mg, or about 60 mg.
  • the preferred dosage is about 6 mg, e.g., about 5 mg, about 7 mg, or about 8 mg.
  • these dosages may be varied according to methods standard in the art so that they are optimized for a particular patient or for a particular combination therapy.
  • celecoxib may be administered in an amount of between 50 and 500 mg, e.g., about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, about 100 mg to about 400 mg, or about 200 mg to about 300 mg.
  • the disclosure provides a method of preventing, treating, or reducing incidence of PIH in a subject comprising administering to the subject a monoclonal antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody).
  • a monoclonal antibody that modulates the CGRP pathway e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody.
  • the disclosure provides a method of preventing, treating, or reducing incidence of PIH in a subject comprising administering to the subject a single dose of a monoclonal antibody (e.g., a monoclonal, anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) in an amount that modulates the CGRP pathway.
  • a monoclonal antibody e.g., a monoclonal, anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • the disclosure provides a method of preventing, treating, or reducing incidence of PIH in a subject comprising administering to the subject a monthly dose of a monoclonal antibody (e.g., a monoclonal, anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) in an amount that modulates the CGRP pathway.
  • a monoclonal antibody e.g., a monoclonal, anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • the disclosure provides a method of decreasing a number of monthly headache or migraine hours experienced by a subject, comprising administering to the subject an amount of a monoclonal antibody (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) that modulates the CGRP pathway.
  • a monoclonal antibody e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody
  • the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine hours by at least 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more headache or migraine hours after a single dose, monthly dose, or quarterly dose.
  • the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine hours by at least 20 headache or migraine hours after a single dose, monthly dose, or quarterly dose. In some embodiments, the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine hours by at least 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, or more headache or migraine hours.
  • the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine hours by at least 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more after a single dose.
  • the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine hours by at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more after a single dose, monthly dose, or quarterly dose.
  • the disclosure provides a method of decreasing a number of monthly headache or migraine days experienced by a subject, comprising administering to the subject an amount of a monoclonal antibody (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) that modulates the CGRP pathway.
  • a monoclonal antibody e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody
  • the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine days by at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more headache or migraine days after a single dose.
  • the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine days by at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more headache or migraine days after a monthly dose or quarterly dose. In some embodiments, the monoclonal antibody can be in an amount effective to decrease the number of monthly headache or migraine days by at least 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more after a single dose, monthly dose, or quarterly dose.
  • the disclosure provides a method of decreasing use of an anti-headache medication in a subject, comprising administering to the subject a monoclonal antibody (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) that modulates the CGRP pathway.
  • a monoclonal antibody e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody
  • the monoclonal antibody can be in an amount effective to decrease daily, monthly, quarterly, and/or yearly use of the anti-headache medication by the subject by at least 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more.
  • the monoclonal antibody can be in an amount effective to decrease monthly use of the anti-headache medication by the subject by at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more.
  • the anti-headache medication can be any type of anti-headache medication described herein.
  • Non-limiting examples of anti-headache medications include, for example, triptans (e.g., sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan, afrovatriptan), and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac, cyclooxygenase-2 (COX-2) inhibitors, celecoxib, rof
  • anti-CGRP antibodies that include a) a CDR H1 as set forth in SEQ ID NO:3; a CDR H2 as set forth in SEQ ID NO:4; a CDR H3 as set forth in SEQ ID NO:5; a CDR L1 as set forth in SEQ ID NO:6; a CDR L2 as set forth in SEQ ID NO:7; and a CDR L3 as set forth in SEQ ID NO:8 or b) a variant of an antibody according to (a) as shown in Table 5.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:1, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:2. In some embodiments, the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:11, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:12.
  • An exemplary monoclonal antibody is fremanezumab (also referred to herein as “G1”).
  • Monoclonal antibodies including these amino acid sequences can be administered at a dose of from about 225 mg to about 900 mg, e.g., a dose of about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 500 mg, about 525 mg, about 550 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg.
  • the dosing regimen can include an initial dose (e.g., 675 mg), and further include administering to the subject an additional 225 mg dose of the monoclonal antibody once per month in each of the two months (or three months, four months, five months, six months, or twelve months) subsequent to the month in which the subject receives the initial dose.
  • an initial dose e.g. 675 mg
  • an additional 225 mg dose of the monoclonal antibody once per month in each of the two months (or three months, four months, five months, six months, or twelve months) subsequent to the month in which the subject receives the initial dose.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:80.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:83, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:81.
  • a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:83
  • a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:81.
  • Exemplary of such an antibody would be eptinezumab.
  • Monoclonal antibodies having these amino acid sequences may be administered at a dose of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.
  • Any of the doses provided herein e.g., about 100 mg, about 300 mg, or about 1000 mg
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:97, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:96.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:99, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:98.
  • exemplary of such an antibody would be galcanezumab.
  • Monoclonal antibodies having these amino acid sequences may be administered at a dose of about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 450 mg, about 480 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.
  • the 120 mg dose may be administered in a volume of about 1.5 mL and the 240 mg dose may be administered in a volume of about 3 mL.
  • Any of the doses provided herein e.g., about 120 mg or about 240 mg may be administered intravenously or subcutaneously.
  • the monoclonal antibody comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:107, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:106.
  • the monoclonal antibody comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:109, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:108.
  • a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:109
  • a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:108.
  • Exemplary of such an antibody would be erenumab.
  • Monoclonal antibodies having these amino acid sequences may be administered at a dose of 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, or about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg.
  • the 70 mg does may be administered in a volume of about 1 mL.
  • the 140 mg dose may be administered in a volume of about 2 mL. Any of the doses provided herein (e.g., about 70 mg or about 140 mg) may be administered intravenously or subcutaneously.
  • a monoclonal antibody to be used in the methods described herein may be selected from the group consisting of fremanezumab, eptinezumab, galcanezumab, erenumab, and bioequivalents thereof.
  • a single dose of a monoclonal antibody that modulates the CGRP pathway may be an amount of antibody between 0.1 mg-5000 mg, 1 mg-5000 mg, 10 mg-5000 mg, 100 mg-5000 mg, 1000 mg-5000 mg, 0.1 mg-4000 mg, 1 mg-4000 mg, 10 mg-4000 mg, 100 mg-4000 mg, 1000 mg 4000 mg, 0.1 mg-3000 mg, 1 mg-3000 mg, 10 mg-3000 mg, 100 mg-3000 mg, 1000 mg 3000 mg, 0.1 mg-2000 mg, 1 mg-2000 mg, 10 mg-2000 mg, 100 mg-2000 mg, 1000 mg 2000 mg, 0.1 mg-1000 mg, 1 mg-1000 mg, 10 mg-1000 mg or 100 mg-1000 mg, 10 mg-3000 mg, 10 mg-2000 mg, 100 mg-2000 mg, 150 mg-2000 mg, 200 mg-2000 mg, 250 mg-2000 mg, 300 mg-2000 mg, 350 mg-2000 mg, 400 mg-2000 mg, 450 mg-2000 mg, 500 mg-2000 mg,
  • the monthly dose may be an amount of antibody between about 225 mg and about 1000 mg (e.g., a dose of about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 500 mg, about 525 mg, about 550 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg).
  • An exemplary dosing regimen comprises administering an initial antibody dose of about 675 mg subcutaneously, followed by a monthly antibody dose of about 225 mg subcutaneously for about two months, e.g., about three months, four months, five months, six months, or 12 months.
  • One dosing regimen comprises administering an initial antibody dose of about 675 mg intravenously in an infusion over about 60 minutes, followed by doses of about 675 mg administered intravenously in an infusion over about 60 minutes every quarter for one year, two years, three years, four years, or five years.
  • Yet another dosing regimen comprises administering an initial antibody dose of about 900 mg intravenously in an infusion over about 60 minutes, followed by doses of about 900 mg administered intravenously in an infusion over about 60 minutes every quarter for one year, two years, three years, four years, or five years.
  • the initial dose and one or more of the additional doses are administered via the same route, e.g., subcutaneously or intravenously.
  • the one or more additional doses are administered in a different way than the initial dose, e.g., the initial dose may be administered intravenously and the one or more additional doses may be administered subcutaneously.
  • an antibody described herein may be administered to a subject based on a body weight-based dosing (e.g., an initial candidate dosage can be about 2 mg/kg).
  • the dose or amount of an antibody (e.g., monoclonal antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody)) described herein and administered to a subject may range from about 0.1 to 500, 0.1 to 100, 0.1 to 50, 0.1 to 20, 0.1 to 10, 1 to 10, 1 to 7, 1 to 5 or 0.1 to 3 mg/kg of body weight.
  • the dose or amount of an antibody described herein and administered to a subject may be, may be at most, may be less than, or may be at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180
  • a daily dosage might range from about any of 3 ⁇ g/kg to 30 ⁇ g/kg to 300 ⁇ g/kg to 3 mg/kg, to 30 mg/kg to 100 mg/kg or more.
  • dosage of about 1 mg/kg, about 2.5 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, and about 30 mg/kg may be used.
  • the monoclonal antibody that modulates the CGRP pathway can be administered as part of any useful formulation and in any formulation volume.
  • Particularly useful is a formulation comprising the antibody at a concentration of at least about 150 mg/mL (e.g., about 175 mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, about 300 mg/mL, about 325 mg/mL, about 350 mg/mL, about 375 mg/mL, about 400 mg/mL, about 425 mg/mL, about 450 mg/mL or more).
  • 150 mg/mL e.g., about 175 mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, about 300 mg/mL, about 325 mg/mL, about 350 mg/mL, about 375 mg/mL, about 400 mg/mL, about 425 mg/mL, about 450 mg
  • a dose (or sub-dose) or amount of an antibody described herein may be formulated in a liquid formulation and administered (e.g., via subcutaneous injection, or via intravenous injection) to a subject.
  • the volume of liquid formulation comprising antibody may vary depending upon, for example, the concentration of antibody in the liquid formulation, the desired dose of antibody, and/or the route of administration used.
  • formulations wherein the monoclonal antibody can be administered in a volume of less than 2 mL (e.g., about 1.8 mL, about 1.7 mL, about 1.6 mL, about 1.5 mL, about 1.4 ml, about 1.3 mL, about 1.2 mL, about 1.1 mL, about 1.0 ml, about 0.9 mL, about 0.8 mL, about 0.7 mL, about 0.6 mL, about 0.5 mL, or less).
  • Any of the doses provided herein e.g., about 225 mg, about 675 mg, or about 900 mg
  • fremanezumab may be administered at a dose of about 225 mg monthly or quarterly, and be administered subcutaneously.
  • An antibody formulation may comprise one or more components including the antibody and other species described elsewhere herein.
  • the antibody and other components may be in any suitable amount and/or any suitable concentration for therapeutic efficacy of the antibody, safety and storage.
  • a liquid formulation comprising an antibody e.g., monoclonal antibody that modulates the CGRP pathway described herein (e.g., anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) may be prepared for any suitable route of administration with an antibody concentration ranging from about 0.1 mg/mL to about 500 mg/mL, about 0.1 mg/mL to about 375 mg/mL, about 0.1 mg/mL to about 250 mg/mL, about 0.1 to about 175 mg/mL, about 0.1 to 100 mg/mL, about 1 mg/mL to about 500 mg/mL, about 1 mg/mL to about 375 mg/mL, about 1 mg/mL to about 300 mg/mL, about 1 mg/mL to 250 mg/mL, about 1 mg/mL to 200 mg
  • a liquid formulation may comprise an antibody described herein at a concentration of, of at most, of at least, or less than about 0.1, 0.5, 1, 5, 10, 15 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or about 500 mg/mL.
  • Suitable administration schedules include, but are not limited to, monthly, quarterly, or a single dose.
  • the monoclonal antibody can be administered monthly.
  • the monoclonal antibody can be administered monthly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months.
  • the monoclonal antibody can be administered monthly for three or more months.
  • the number of doses of antibody administered to a subject over the course of treatment may vary depending upon, for example, achieving reduced incidence of a PIH, e.g., migrainous PIH and non-migrainous PIH, and/or secondary symptom associated with a migrainous PIH in the subject.
  • the number of doses administered over the course of treatment may be, may be at least, or may be at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or treatment may be given indefinitely.
  • treatment may be acute such that at most 1, 2, 3, 4, 5, or 6 doses are administered to a subject for treatment.
  • the frequency at which a dose or amount of an antibody described herein is administered to a subject may vary. In some embodiments, a single dose of antibody may be given to a subject during therapy. In some embodiments, the frequency at which a dose or amount of an antibody is administered to a subject is constant (e.g., administered about once per month or about once per quarter). In some embodiments, the frequency at which a dose or amount of an antibody is administered to a subject is about every quarter for about one year, two years, three years, four years, or five years.
  • the frequency at which a dose or amount of an antibody described herein is administered to a subject is variable (e.g., an initial dose followed by a dose at once per month, followed by additional doses at about three months and about seven months). In some embodiments, the frequency at which an antibody is administered to a subject is, is at least, is less than, or is at most about one, two, three, four, five, or six time(s) per day. In some embodiments, the frequency at which an antibody described herein is administered to a subject is, is at least, is less than, or is at most about one, two, three, four, five, or six dose(s) per day.
  • the frequency at which a dose or amount of an antibody described herein is administered to a subject is is at least, is less than, or is at most one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty time(s) per every one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two, forty-three, forty-four, forty-five, forty-six, forty-seven, forty-eight, forty-nine, forty,
  • the frequency at which a dose or amount of an antibody (e.g., monoclonal antibody that modulates the CGRP pathway described herein (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) is administered to a subject is at least, is less than, or is at most one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty time(s) per every one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, thirty, thirty-
  • the frequency at which a dose or amount of an antibody described herein is administered to a subject is is at least, is less than, or is at most about one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty time(s) per every month, every two months, every three months, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, every twelve months, every thirteen months, every fourteen months, every fifteen months, every sixteen months, every seventeen months, or every eighteen month(s).
  • the frequency at which a dose or amount of an antibody described herein is administered to a subject is about one time per every one month. In some embodiments, the frequency at which a dose or amount of an antibody described herein is administered to a subject is about one time per every three months. In some embodiments, the frequency at which an antibody described herein is administered to a subject is less than about one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen dose(s) per month. In some embodiments, a dose or amount of an antibody described herein may be administered to a subject one time, two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times or more per month.
  • an antibody described herein may depend on the antibody (or compositions thereof) employed, the type and severity of the secondary symptom associated with a migrainous PIH, the type and severity of the PIH or other condition to be treated, whether the agent is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the agent, and the discretion of the attending physician. Typically, the clinician will administer an antibody, until a dosage is reached that achieves the desired result. Dose and/or frequency can vary over course of treatment. In one embodiment, dosages for an antibody described herein may be determined empirically in individuals who have been given one or more administration(s) of the antibody. Individuals are given incremental dosages of an antibody. To assess efficacy of an antibody, an indicator of the disease can be followed.
  • Empirical considerations such as the half-life, generally will contribute to the determination of the dosage.
  • antibodies that are compatible with the human immune system such as humanized antibodies or fully human antibodies, may be used to prolong half-life of the antibody and to prevent the antibody being attacked by the host's immune system.
  • Frequency of administration may be determined and adjusted over the course of therapy, and is generally, but not necessarily, based on treatment and/or suppression and/or amelioration and/or delay of PIH or other condition.
  • sustained continuous release formulations of antibodies may be appropriate.
  • formulations and devices for achieving sustained release are known in the art.
  • references to antibodies also include compositions comprising one or more of these agents. Accordingly, such a composition may be used according to a method referring to an antibody described herein. These compositions may further comprise suitable excipients, such as pharmaceutically acceptable excipients as described elsewhere herein.
  • the present invention can be used alone or in combination with other conventional methods of treatment.
  • an antibody described herein e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • an antibody described herein can be administered to an individual or subject in any therapeutic dose, via any suitable route and in any suitable formulation. It should be apparent to a person skilled in the art that the examples described herein are not intended to be limiting but to be illustrative of the techniques available.
  • an antibody described herein can be administered to a subject in accord with known methods, such as intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, e.g., about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 120 minutes, about 180 minutes, or about 240 minutes.
  • intravenous administration e.g., as a bolus or by continuous infusion over a period of time, e.g., about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 120 minutes, about 180 minutes, or about 240 minutes.
  • the antibody described herein can also be administered to the subject by subcutaneous, intramuscular, intraperitoneal, intracerebrospinal, intra-articular, sublingually, intra-arterial, intrasynovial, via insufflation, intrathecal, oral, inhalation, intranasal (e.g., with or without inhalation), buccal, rectal, transdermal, intracardiac, intraosseous, intradermal, transmucosal, vaginal, intravitreal, peri-articular, local, epicutaneous, or topical routes.
  • Administration can be systemic, e.g., intravenous administration, or localized.
  • nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers are useful for administration.
  • Liquid formulations can be directly nebulized and lyophilized powder can be nebulized after reconstitution.
  • an antibody described herein can be aerosolized using a fluorocarbon formulation and a metered dose inhaler, or inhaled as a lyophilized and milled powder.
  • an antibody described herein can be administered via site-specific or targeted local delivery techniques.
  • site-specific or targeted local delivery techniques include various implantable depot sources of the antibody or local delivery catheters, such as infusion catheters, an indwelling catheter, or a needle catheter, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site specific carriers, direct injection, or direct application. See e.g., PCT Publication No. WO 00/53211 and U.S. Pat. No. 5,981,568, which are hereby incorporated by reference in their entireties.
  • an antibody may be administered neat.
  • antibody and a pharmaceutically acceptable excipient may be in various formulations.
  • Pharmaceutically acceptable excipients are known in the art, and are relatively inert substances that facilitate administration of a pharmacologically effective substance.
  • an excipient can give form or consistency, or act as a diluent.
  • Suitable excipients include but are not limited to stabilizing agents, wetting and emulsifying agents, salts for varying osmolarity, encapsulating agents, buffers, and skin penetration enhancers. Excipients as well as formulations for parenteral and nonparenteral drug delivery are set forth in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000).
  • the antibody(ies) can be administered to the patient using any method known in the art.
  • the antibody(ies) can be administered to the patient using a pre-filled syringe, a pre-filled syringe with a needle safety device, an injection pen, an auto-injector, or any combination thereof.
  • an antibody e.g., monoclonal antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) in accordance with the methods of the present invention can be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
  • the administration of an antibody may be essentially continuous over a preselected period of time or may be in a series of spaced dose, e.g., either before, during, or after developing a seizure; before; during; before and after; during and after; before and during; or before, during, and after developing a seizure.
  • Administration can be before, during, and/or after any event likely to give rise to a seizure, e.g., at least about five minutes prior to a seizure, e.g., at least about ten minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, at least about one hour, at least about two hours, at least about three hours, at least about four hours, at least about five hours, at least about six hours, at least about seven hours, at least about eight hours, at least about nine hours, at least about ten hours, at least about 12 hours, at least about 18 hours, at least about 24 hours, at least about 48 hours, or at least about 72 hours prior to a seizure.
  • at least about five minutes prior to a seizure e.g., at least about ten minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, at least about one hour, at least about two hours, at least about three hours, at least about four hours,
  • more than one antibody may be present. At least one, at least two, at least three, at least four, at least five different, or more antibodies can be present. Generally, those antibodies may have complementary activities that do not adversely affect each other.
  • An antibody e.g., a monoclonal antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody)) described herein can also be used in conjunction with other CGRP antagonists or CGRP receptor antagonists.
  • one or more of the following CGRP antagonists may be used: an anti-sense molecule directed to a CGRP (including an anti-sense molecule directed to a nucleic acid encoding CGRP), a CGRP inhibitory compound, a CGRP structural analog, a dominant-negative mutation of a CGRP receptor that binds a CGRP, and an anti-CGRP receptor antibody.
  • An antibody can also be used in conjunction with other agents that serve to enhance and/or complement the effectiveness of the agents.
  • Diagnosis or assessment of PIH is well-established in the art. Assessment may be performed based on subjective measures, such as patient characterization of symptoms. In some embodiments, assessment of PIH may be via headache or migraine hours, as described elsewhere herein. For example, assessment of PIH may be in terms of daily headache or migraine hours, weekly headache or migraine hours, and/or monthly headache or migraine hours. In some cases, headache or migraine hours may be as reported by the subject.
  • Treatment efficacy can be assessed by methods well-known in the art. For example, pain relief may be assessed. Accordingly, in some embodiments, pain relief is subjectively observed after 1, 2, or a few hours after administering an anti-CGRP antibody.
  • a method for preventing, treating, or reducing incidence of PIH in a subject as described herein may reduce incidence of PIH after a single administration of an antibody (e.g., monoclonal antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) described herein for an extended period of time.
  • an antibody e.g., monoclonal antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) described herein for an extended period of time.
  • incidence of PIH may be reduced for at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more days after a single administration.
  • PIHs can be short, lasting only several hours, or they can progress to a typical migraine attack.
  • the relevant endpoint is a reduction in headache hours after a seizure.
  • a reduction in headache hours, headache days, migraine hours, migraine days (per day or per month) can be relevant.
  • the preventing, treating, or reducing can comprise reducing the number of headache hours of any severity, reducing the number of migraine hours of any severity, reducing the number of monthly headache days of any severity, reducing the number of monthly migraine days of any severity, reducing the use of any acute headache medications, reducing a 6-item Headache Impact Test (HIT-6) disability score, improving 12-Item Short Form Health Survey (SF-12) score (Ware et al., Med Care 4:220-233, 1996), reducing Patient Global Impression of Change (PGIC) score (Hurst et al., J. Manipulative. Physiol. Ther. 27:26-35, 2004), improving Sport ConCuSSion ASSeSment tool 3 (SCAT-3) score (McCrory et al. British Journal of Sports Medicine 47:263-266, 2013), or any combination thereof.
  • HIT-6 6-item Headache Impact Test
  • SF-12 12-Item Short Form Health Survey
  • PGIC Patient Global Impression of Change
  • SCAT-3
  • a method for preventing, treating, or reducing incidence of PIH in a subject as described herein may reduce the number of headache or migraine hours experienced by a subject from a pre-administration level after administration of one or more doses of an antibody (e.g., a monoclonal antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) described herein to the subject.
  • an antibody e.g., a monoclonal antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) described herein to the subject.
  • daily headache or migraine hours experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 headache or migraine hours from a pre-administration level in the subject.
  • daily headache or migraine hours experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more relative to a pre-administration level in the subject.
  • weekly headache or migraine hours experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more headache or migraine hours from a pre-administration level in the subject.
  • weekly headache or migraine hours experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more relative to a pre-administration level in the subject.
  • monthly headache or migraine hours experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, or more headache or migraine hours from a pre-administration level.
  • weekly headache or migraine hours experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more relative to a pre-administration level in the subject.
  • the number of monthly headache or migraine days can be reduced for at least seven days after a single administration.
  • a method for preventing, treating, or reducing incidence of PIH in a subject as described herein may reduce the number of headache or migraine days experienced by a subject from a pre-administration level after administration of one or more doses of an antibody (e.g., a monoclonal antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) described herein to the subject.
  • an antibody e.g., a monoclonal antibody that modulates the CGRP pathway (e.g., a monoclonal anti-CGRP antagonist antibody or a monoclonal anti-CGRP receptor antibody) described herein to the subject.
  • weekly headache or migraine days experienced by the subject after administering one or more doses of an antibody to the subject may be reduced by 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 headache or migraine days from a pre-administration level in the subject.
  • weekly headache or migraine days experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more relative to a pre-administration level in the subject.
  • monthly headache or migraine days experienced by the subject after administering one or more doses of an antibody described herein to the subject may be reduced by 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or more headache or migraine days from a pre-administration level.
  • an antibody which can be an anti-CGRP antagonist antibody.
  • An anti-CGRP antagonist antibody can refer to any antibody molecule that blocks, suppresses or reduces (including significantly) CGRP biological activity, including downstream pathways mediated by CGRP signaling, such as receptor binding and/or elicitation of a cellular response to CGRP.
  • An anti-CGRP antagonist antibody can exhibit any one or more of the following characteristics: (a) bind to CGRP; (b) block CGRP from binding to its receptor(s); (c) block or decrease CGRP receptor activation (including, but not limited to, cAMP activation); (d) inhibit CGRP biological activity or downstream pathways mediated by CGRP signaling function; (e) prevent, ameliorate, reduce severity of, or treat any aspect of PIH; (f) increase clearance of CGRP; and (g) inhibit (reduce) CGRP synthesis, production or release.
  • Anti-CGRP antagonist antibodies are known in the art. See e.g., Tan et al., Clin. Sci. (Lond). 89:565-73, 1995; Sigma (Missouri, US), product number C7113 (clone #4901); Plourde et al., Peptides 14:1225-1229, 1993.
  • the antibody reacts with CGRP in a manner that inhibits CGRP, and/or the CGRP pathway, including downstream pathways mediated by the CGRP signaling function.
  • the anti-CGRP antagonist antibody recognizes human CGRP.
  • the anti-CGRP antagonist antibody binds to both human ⁇ -CGRP and ⁇ -CGRP.
  • the anti-CGRP antagonist antibody binds human and rat CGRP.
  • the anti-CGRP antagonist antibody binds the C-terminal fragment having amino acids 25-37 of CGRP.
  • the anti-CGRP antagonist antibody binds a C-terminal epitope within amino acids 25-37 of CGRP.
  • the anti-CGRP antibodies useful in the present invention can encompass monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab′, F(ab′)2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion (e.g., a domain antibody), humanized antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies.
  • the antibodies may be murine, rat, human, or any other origin (including chimeric or humanized antibodies).
  • the anti-CGRP antagonist antibody is a monoclonal antibody. In some embodiments, the anti-CGRP antagonist antibody is humanized. In some embodiments, the antibody is human. In some embodiments, the anti-CGRP antagonist antibody is antibody G1 (as described herein). In some embodiments, the anti-CGRP antagonist antibody comprises one or more CDR(s) (such as one, two, three, four, five, or, in some embodiments, all six CDRs) of antibody G1 or variants of G1 shown in Table 5. In still other embodiments, the anti-CGRP antagonist antibody comprises the amino acid sequence of the heavy chain variable region shown in FIG. 5 (SEQ ID NO:1) and the amino acid sequence of the light chain variable region shown in FIG. 5 (SEQ ID NO:2). In still other embodiments, the anti-CGRP antagonist antibody comprises a heavy chain full length amino acid sequence shown in SEQ ID NO:11, and a light chain full length amino acid sequence shown if SEQ ID NO:12.
  • the antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR) selected from the groups consisting of: (a) LCVR17 (SEQ ID NO:58) and HCVR22 (SEQ ID NO:59); (b) LCVR18 (SEQ ID NO:60) and HCVR23 (SEQ ID NO:61); (c) LCVR19 (SEQ ID NO:62) and HCVR24 (SEQ ID NO:63); (d) LCVR20 (SEQ ID NO:64) and HCVR25 (SEQ ID NO:65); (e) LCVR21 (SEQ ID NO:66) and HCVR26 (SEQ ID NO:67); (f) LCVR27 (SEQ ID NO:68) and HCVR28 (SEQ ID NO:69); (g) LCVR29 (SEQ ID NO:70) and HCVR30 (SEQ ID NO:71); (h) LCVR31 (SEQ ID NO:72) and HCVR32 (S
  • the antibody comprises a modified constant region, such as a constant region that is immunologically inert described herein.
  • the binding affinity (K D ) of an anti-CGRP antagonist antibody to CGRP can be about 0.02 to about 200 nM.
  • the binding affinity is any of about 200 nM, about 100 nM, about 50 nM, about 10 nM, about 1 nM, about 500 pM, about 100 pM, about 60 pM, about 50 pM, about 20 pM, about 15 pM, about 10 pM, about 5 pM, or about 2 pM.
  • the binding affinity is less than any of about 250 nM, about 200 nM, about 100 nM, about 50 nM, about 10 nM, about 1 nM, about 500 pM, about 100 pM, or about 50 pM.
  • an anti-CGRP receptor antibody can be used in any of the methods described herein.
  • anti-CGRP receptor antibodies as described in U.S. Patent Publication No. US 2010/0172895 and U.S. Pat. No. 9,102,731, which are hereby incorporated by reference in their entireties, may be used. Therefore, antibodies with any of the following sequences may be used.
  • Light chain variable region protein sequence CDR1 (U.S. Pat. No. 9,102,731) (SEQ ID NO: 100) SGSSSNIGNNYVS Light chain variable region protein sequence CDR2 (U.S. Pat. No. 9,102,731) (SEQ ID NO: 101) DNNKRPS Light chain variable region protein sequence CDR3 (U.S. Pat. No. 9,102,731) (SEQ ID NO: 102) GTWDSRLSAVV Heavy chain variable region protein sequence CDR1 (U.S. Pat. No. 9,102,731) (SEQ ID NO: 103) SFGMH Heavy chain variable region protein sequence CDR2 (U.S. Pat. No.
  • compositions e.g., pharmaceutical compositions
  • the compositions used in the methods provided herein comprise one or more antibodies or polypeptides (which may or may not be an antibody) that bind to CGRP, and/or one or more polynucleotides comprising sequences encoding one or more antibodies or polypeptides that bind to CGRP.
  • suitable excipients such as pharmaceutically acceptable excipients including buffers, which are well known in the art.
  • Anti-CGRP antagonist antibodies and polypeptides useful in the methods described herein may be characterized by any (one or more) of the following characteristics: (a) bind to CGRP; (b) block CGRP from binding to its receptor(s); (c) block or decrease CGRP receptor activation (including cAMP activation); (d) inhibit CGRP biological activity or downstream pathways mediated by CGRP signaling function; (e) prevent, ameliorate, reduce severity of, or treat any aspect of PIH; (f) increase clearance of CGRP; and (g) inhibit (reduce) CGRP synthesis, production or release.
  • compositions comprising any of the following: (a) antibody G1 or its variants shown in Table 5 (b) a fragment or a region of antibody G1 or its variants shown in Table 5; (c) a light chain of antibody G1 or its variants shown in Table 5; (d) a heavy chain of antibody G1 or its variants shown in Table 5; (e) one or more variable region(s) from a light chain and/or a heavy chain of antibody G1 or its variants shown in Table 5; (f) one or more CDR(s) (one, two, three, four, five or six CDRs) of antibody G1 or its variants shown in Table 5; (g) CDR H3 from the heavy chain of antibody G1; (h) CDR L3 from the light chain of antibody G1 or its variants shown in Table 5; (i) three CDRs from the light chain of antibody G1 or its variants shown in Table 5; (j) three CDRs from
  • CDR portions of antibody G1 are diagrammatically depicted in FIG. 5 . Determination of CDR regions is well within the skill of the art. Skilled practitioners will appreciate that CDRs can be a combination of the Kabat and Chothia CDR (also termed “combined CDRs” or “extended CDRs”). In some instances, the CDRs are the Kabat CDRs and in others the CDRs are the Chothia CDRs. In other words, in some instances where more than one CDR are useful, the CDRs may be any of Kabat, Chothia, combination CDRs, or combinations thereof.
  • Methods described herein can employ a polypeptide (which may or may not be an antibody) which comprises at least one CDR, at least two, at least three, or at least four, at least five, or all six CDRs that are substantially identical to at least one CDR, at least two, at least three, at least four, at least five or all six CDRs of G1 or its variants shown in Table 5.
  • the methods include using antibodies which have at least two, three, four, five, or six CDR(s) that are substantially identical to at least two, three, four, five or six CDRs of G1 or derived from G1.
  • the at least one, two, three, four, five, or six CDR(s) are at least about 85%, 86%, 87%, 88%, 89%, 90%, 95%, 96%, 97%, 98%, or 99% identical to at least one, two, three, four, five or six CDRs of G1 or its variants shown in Table 5.
  • Methods provided herein can utilize a polypeptide (which may or may not be an antibody) which comprises an amino acid sequence of G1 or its variants shown in Table 5 that has any of the following: at least 5 contiguous amino acids, at least 8 contiguous amino acids, at least about 10 contiguous amino acids, at least about 15 contiguous amino acids, at least about 20 contiguous amino acids, at least about 25 contiguous amino acids, at least about 30 contiguous amino acids of a sequence of G1 or its variants shown in Table 5, wherein at least 3 of the amino acids are from a variable region of G1 ( FIG. 5 ) or its variants shown in Table 5.
  • the variable region can be from a light chain or from a heavy chain of G1.
  • An exemplary polypeptide has contiguous amino acid (lengths described above) from both the heavy and light chain variable regions of G1.
  • the 5 (or more) contiguous amino acids are from a complementarity determining region (CDR) of G1 shown in FIG. 5 .
  • the contiguous amino acids are from a variable region of G1.
  • the binding affinity (K D ) of an anti-CGRP antagonist antibody and polypeptide to CGRP can be about 0.06 to about 200 nM.
  • the binding affinity can be any of about 200 nM, 100 nM, about 50 nM, about 10 nM, about 1 nM, about 500 pM, about 100 pM, about 60 pM, about 50 pM, about 20 pM, about 15 pM, about 10 pM, about 5 pM, or about 2 pM.
  • the binding affinity is less than any of about 250 nM, about 200 nM, about 100 nM, about 50 nM, about 10 nM, about 1 nM, about 500 pM, about 100 pM, or about 50 pM.
  • the methods provided herein may use single chain variable region fragments (“scFv”) of antibodies described herein, such as G1.
  • Single chain variable region fragments are made by linking light and/or heavy chain variable regions by using a short linking peptide. Bird et al. (1988) Science 242:423-426.
  • Humanized antibody comprising one or more CDRs of antibody G1 or its variants shown in Table 5, or one or more CDRs derived from antibody G1 or its variants shown in Table 5 can be made using any methods known in the art.
  • methods described herein can employ using antibody G1 comprising modifications such as those shown in Table 5, including functionally equivalent antibodies which do not significantly affect their properties and variants which have enhanced or decreased activity and/or affinity.
  • the amino acid sequence of antibody G1 or its variants shown in Table 5 may be mutated to obtain an antibody with the desired binding affinity to CGRP.
  • modified polypeptides include polypeptides with conservative substitutions of amino acid residues, one or more deletions or additions of amino acids which do not significantly deleteriously change the functional activity, or use of chemical analogs.
  • Modifications also include glycosylated and nonglycosylated polypeptides, as well as polypeptides with other post-translational modifications, such as, for example, glycosylation with different sugars, acetylation, and phosphorylation. Techniques to achieve this type of modification are well known in the art.
  • compositions comprising any of the polynucleotides encoding polypeptides described herein can be used in the presently described methods.
  • the composition comprises an expression vector comprising a polynucleotide encoding the G1 antibody and/or any of the antibodies or polypeptides described herein.
  • the composition can include either or both of the polynucleotides shown in SEQ ID NO:9 and SEQ ID NO:10.
  • Useful expression vectors, and methods of administering polynucleotide compositions are known in the art and further described herein.
  • compositions used in a method described herein comprise an effective amount of an antibody that modulates the CGRP pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody) or an antibody-derived polypeptide described herein.
  • a composition e.g., a medicament or therapeutic formulation
  • an antibody e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody
  • compositions thereof provided herein can also be used in conjunction with other agents that serve to enhance and/or complement the effectiveness of the antibody.
  • Kits can include one or more containers comprising an antibody described herein (e.g., an anti-CGRP antagonist antibody (such as a humanized antibody)) or polypeptide described herein and instructions for use in accordance with any of the methods described herein.
  • these instructions comprise a description of administration of the antibody to treat, ameliorate, reduce severity of, or prevent PIH according to any of the methods described herein.
  • the kit may comprise a description of how to select an individual suitable for treatment based on identifying whether that individual has a seizure or whether the individual is at risk of having PIH.
  • the instructions include a description of how to administer an antibody (e.g., anti-CGRP antagonist antibody) to an individual at risk of having PIH.
  • kits can include, e.g., a pre-filled syringe, a pre-filled syringe with a needle safety device, an injection pen, or an auto-injector comprising a dose of a monoclonal antibody that modulates the CGRP pathway; and instructions for use in accordance with any of the methods described herein.
  • the kit may further comprise instructions relating to the use of the antibody (e.g., for treating, ameliorating, reducing severity of, and/or preventing PIH) including information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the kit may be include unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in the kits are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • a monoclonal antibody provided in the kit can include a CDR H1 as set forth in SEQ ID NO:3; a CDR H2 as set forth in SEQ ID NO:4; a CDR H3 as set forth in SEQ ID NO:5; a CDR L1 as set forth in SEQ ID NO:6; a CDR L2 as set forth in SEQ ID NO:7; and a CDR L3 as set forth in SEQ ID NO:8.
  • a monoclonal antibody provided in a kit comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:1, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:2.
  • a monoclonal antibody provided in a kit comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:11, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:12.
  • a monoclonal antibody provided in a kit can include a CDR H1 as set forth in SEQ ID NO:87; a CDR H2 as set forth in SEQ ID NO:88; a CDR H3 as set forth in SEQ ID NO:89; a CDR L1 as set forth in SEQ ID NO:84; a CDR L2 as set forth in SEQ ID NO:85; and a CDR L3 as set forth in SEQ ID NO:86.
  • a monoclonal antibody provided in a kit comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:82, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:80.
  • a monoclonal antibody provided in a kit comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:83, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:81.
  • a monoclonal antibody provided in a kit can include a CDR H1 as set forth in SEQ ID NO:93; a CDR H2 as set forth in SEQ ID NO:94; a CDR H3 as set forth in SEQ ID NO:95; a CDR L1 as set forth in SEQ ID NO:91; a CDR L2 as set forth in SEQ ID NO:92; and a CDR L3 as set forth in SEQ ID NO:90.
  • a monoclonal antibody provided in a kit comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:97, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:96.
  • a monoclonal antibody provided in a kit comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:99, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:98.
  • a monoclonal antibody provided in a kit can include a CDR H1 as set forth in SEQ ID NO:103; a CDR H2 as set forth in SEQ ID NO:104; a CDR H3 as set forth in SEQ ID NO:105; a CDR L1 as set forth in SEQ ID NO:100; a CDR L2 as set forth in SEQ ID NO:101; and a CDR L3 as set forth in SEQ ID NO:102.
  • a monoclonal antibody provided in a kit comprises a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:107, and a light chain variable region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:106.
  • a monoclonal antibody provided in a kit comprises a heavy chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:109, and a light chain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:108.
  • a monoclonal antibody provided in a kit can be fremanezumab, eptinezumab, galcanezumab, erenumab, or any bioequivalent thereof. Skilled practitioners will appreciate that a kit can include a combination of any of the foregoing antibodies
  • kits can be provided in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
  • packages for use in combination with a specific device such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump.
  • a kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • At least one active agent in the composition is an antibody that modulates the CGRP receptor pathway (e.g., an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody).
  • the container may further comprise a second pharmaceutically active agent.
  • Kits may optionally provide additional components such as buffers and interpretive information.
  • the kit comprises a container and a label or package insert(s) on or associated with the container.
  • mice were immunized with 25-100 ⁇ g of human ⁇ -CGRP or ⁇ -CGRP conjugated to KLH in adjuvant (50 ⁇ l per footpad, 100 ⁇ l total per mouse) at various intervals. Immunization was generally performed as described in Geerligs H J et al., 1989, J. Immunol. Methods 124:95-102; Kenney J S et al., 1989, J. Immunol. Methods 121:157-166; and Wicher K et al., 1989, Int. Arch. Allergy Appl. Immunol. 89:128-135.
  • mice were first immunized with 50 ⁇ g of human ⁇ -CGRP or ⁇ -CGRP conjugated to KLH in CFA (complete Freund's adjuvant). After 21 days, mice were secondly immunized with 25 ⁇ g of human ⁇ -CGRP (for mice first immunized with human ⁇ -CGRP) or ⁇ -CGRP (for mice first immunized with human ⁇ -CGRP) conjugated to KLH in IFA (incomplete Freund's adjuvant). Twenty-three days later after the second immunization, third immunization was performed with 25 ⁇ g of rat ⁇ -CGRP conjugated to KLH in IFA. Ten days later, antibody titers were tested using ELISA.
  • Forth immunization was performed with 25 ⁇ g of the peptide (rat ⁇ -CGRP-KLH) in IFA 34 days after the third immunization.
  • Final booster was performed with 100 ⁇ g soluble peptide (rat ⁇ -CGRP) 32 days after the forth immunization.
  • Splenocytes were obtained from the immunized mouse and fused with NSO myeloma cells at a ratio of 10:1, with polyethylene glycol 1500.
  • the hybrids were plated out into 96-well plates in DMEM containing 20% horse serum and 2-oxaloacetate/pyruvate/insulin (Sigma), and hypoxanthine/aminopterin/thymidine selection was begun. On day 8, 100 ⁇ l of DMEM containing 20% horse serum was added to all the wells. Supernatants of the hybrids were screened by using antibody capture immunoassay. Determination of antibody class was done with class-specific second antibodies.
  • a panel of monoclonal antibody-producing cell lines was selected based on their binding to human and rat CGRP for further characterization. These antibodies and characteristics are shown below in Tables 2 and 3.
  • Monoclonal antibodies selected for further characterization were purified from supernatants of hybridoma cultures using protein A affinity chromatography. The supernatants were equilibrated to pH 8. The supernatants were then loaded to the protein A column MabSelect (Amersham Biosciences #17-5199-02) equilibrated with PBS to pH 8. The column was washed with 5 column volumes of PBS, pH 8. The antibodies were eluted with 50 mM citrate-phosphate buffer, pH 3. The eluted antibodies were neutralized with 1 M Phosphate Buffer, pH 8. The purified antibodies were dialyzed with PBS, pH 7.4. The antibody concentrations were determined by SDS-PAGE, using a murine monoclonal antibody standard curve.
  • Affinity determination of the Fabs Affinities of the anti-CGRP monoclonal antibodies were determined at either 25° C. or 37° C. using the BIACORE3000TM surface plasmon resonance (SPR) system (Biacore, INC, Piscataway N.J.) with the manufacture's own running buffer, HBS-EP (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% v/v polysorbate P20).
  • SPR surface plasmon resonance
  • Affinity was determined by capturing N-terminally biotinylated CGRP peptides (custom ordered from GenScript Corporation, New Jersey or Global Peptide Services, Colorado) via pre-immobilized streptavidin on SA chip and measuring binding kinetics of antibody Fab titrated across the CGRP surface. Biotinylated CGRP was diluted into HBS-EP and injected over the chip at a concentration of less than 0.001 mg/ml. Using variable flow time across the individual chip channels, two ranges of antigen density were achieved: ⁇ 50 response units (RU) for detailed kinetic studies and about 800 RU for concentration studies and screening.
  • RU response units
  • FIG. 1 shows their binding affinities measured at 25° C. As shown in FIG. 1 , all antibodies, except antibody 4901, bind to human ⁇ -CGRP fragments 19-37 and 25-37 with affinity similar to their binding affinity to full length human ⁇ -CGRP (1-37).
  • Antibody 4901 binds to human ⁇ -CGRP fragment 25-37 with six-fold lower affinity than binding to full length human ⁇ -CGRP fragment, due mainly to a loss in off-rate.
  • the data indicate that these anti-CGRP antibodies generally bind to the C-terminal end of CGRP.
  • amino acid residue S34 also plays a significant, but lesser, role in the binding of these four high affinity antibodies.
  • Murine anti-CGRP antibodies were further screened for antagonist activity in vitro using cell based cAMP activation assay and binding assay.
  • Antagonist activity measured by cAMP assay Five microliters of human or rat ⁇ -CGRP (final concentration 50 nM) in the presence or absence of an anti-CGRP antibody (final concentration 1-3000 nM), or rat ⁇ -CGRP or human ⁇ -CGRP (final concentration 0.1 nM-10 ⁇ M; as a positive control for c-AMP activation) was dispensed into a 384-well plate (Nunc, Cat. No. 264657).
  • cAMP activation was performed using HitHunterTM Enzyme Fragment Complementation Assay (Applied Biosystems) following manufacture's instruction.
  • the assay is based on a genetically engineered ⁇ -galactosidase enzyme that consists of two fragments—termed Enzyme Acceptor (EA) and Enzyme Donor (ED). When the two fragments are separated, the enzyme is inactive. When the fragments are together they can recombine spontaneously to form active enzyme by a process called complementation.
  • EFC assay platform utilizes an ED-cAMP peptide conjugate in which cAMP is recognized by anti-cAMP. This ED fragment is capable of reassociation with EA to form active enzyme.
  • anti-cAMP antibody is optimally titrated to bind ED-cAMP conjugate and inhibit enzyme formation.
  • Levels of cAMP in cell lysate samples compete with ED-cAMP conjugate for binding to the anti-cAMP antibody.
  • the amount of free ED conjugate in the assay is proportional to the concentration of cAMP. Therefore, cAMP is measured by the formation of active enzyme that is quantified by the turnover of ⁇ -galactosidase luminescent substrate.
  • the cAMP activation assay was performed by adding 10 ⁇ l of lysis buffer and anti-cAMP antibody (1:1 ratio) following by incubation at room temperature for 60 min.
  • antibodies having K D (determined at 25° C.) of about 80 nM or less to human ⁇ -CGRP or having K D (determined at 37° C.) of about 47 nM or less to rat ⁇ -CGRP showed antagonist activity in this assay.
  • Radioligand binding assay was performed to measure the IC 50 of anti-CGRP antibody in blocking the CGRP from binding to the receptor as described previously.
  • Membranes (25 Kg) from SK-N-MC cells were incubated for 90 min at room temperature in incubation buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl 2 , 0.1% BSA) containing 10 pM 125 I-human ⁇ -CGRP in a total volume of 1 mL.
  • IC 50 inhibition concentrations (IC 50 )
  • antibodies or unlabeled CGRP (as a control) from a about 100 fold higher stock solution were dissolved at varying concentrations in the incubation buffer and incubated at the same time with membranes and 10 pM 125 I-human ⁇ -CGRP. Incubation was terminated by filtration through a glass microfiber filter (GF/B, 1 ⁇ m) which had been blocked with 0.5% polyethylemimine.
  • GF/B glass microfiber filter
  • the reported IC 50 value (in terms of IgG molecules) was converted to binding sites (by multiplying it by 2) so that it could be compared with the affinities (K D ) determined by Biacore (see Table 1).
  • Table 1 shows the IC 50 of murine antibodies 7E9, 8B6, 6H2 and 4901. Data indicate that antibody affinity generally correlates with IC 50 : antibodies with higher affinity (lower K D values) have lower IC 50 in the radioligand binding assay.
  • Bretylium tosylate (30 mg/kg, administered i.v.) was given at the beginning of the experiment to minimize vasoconstriction due to the concomitant stimulation of sympathetic fibers of the saphenous nerve.
  • Body temperature was maintained at 37° C. by the use of a rectal probe thermostatically connected to a temperature controlled heating pad.
  • Compounds including antibodies, positive control (CGRP 8-37), and vehicle (PBS, 0.01% Tween 20) were given intravenously through the right femoral vein, except for the experiment shown in FIG. 3 , the test compound and the control were injected through tail vein, and for experiments shown in FIGS. 2A and 2B , antibodies 4901 and 7D11 were injected intraperitoneally (IP).
  • Positive control compound CGRP 8-37 (vasodilatation antagonist), due to its short half-life, was given 3-5 min before nerve stimulation at 400 nmol/kg (200 ⁇ l). Tan et al., Clin. Sci. 89:656-73, 1995. The antibodies were given in different doses (1 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, and 25 mg/kg).
  • antibody 4901 25 mg/kg
  • antibody 7D11 25 mg/kg
  • vehicle control PBS with 0.01% Tween 20
  • IP intraperitoneally
  • FIG. 3 antibody 4901 (1 mg/kg, 2.5 mg/kg, 5 mg/kg, or 25 mg/kg) or vehicle control (PBS with 0.01% Tween 20) was administered intravenously 24 hours before the electrical pulse stimulation.
  • saphenous nerve of the right hindlimb was exposed surgically, cut proximally and covered with plastic wrap to prevent drying.
  • a laser Doppler probe was placed over the medio-dorsal side of the hindpaw skin, which is the region innervated by the saphenous nerve.
  • Skin blood flow measured as blood cell flux, was monitored with a laser Doppler flow meter.
  • a stable base-line flux (less than 5% variation) was established for at least 5 minutes, the nerve was placed over platinum bipolar electrodes and electrically stimulated with 60 pulses (2 Hz, 10 V, 1 ms, for 30 seconds) and then again 20 minutes later.
  • Cumulative change in skin blood flow was estimated by the area under the flux-time curve (AUC, which is equal to change in flux multiplied by change in time) for each flux response to electrical pulse stimulation. The average of the blood flow response to the two stimulations was taken. Animals were kept under anesthesia for a period of one to three hours.
  • CGRP 8-37 400 nmol/kg, administered i.v.
  • antibody 4901 25 mg/kg, administered ip
  • antibody 7D11 25 mg/kg, administered ip
  • blood flow increase stimulated by applying electronic pulses on saphenous nerve was inhibited by the presence of antibody 4901 at different doses (1 mg/kg, 2.5 mg/kg, 5 mg/kg, and 25 mg/kg) administered intravenously at 24 hours before the saphenous nerve stimulation.
  • saphenous nerve was exposed surgically before antibody administration.
  • the saphenous nerve of the right hindlimb was exposed surgically, cut proximally and covered with plastic wrap to prevent drying.
  • a laser Doppler probe was placed over the medio-dorsal side of the hindpaw skin, which is the region innervated by the saphenous nerve. Skin blood flow, measured as blood cell flux, was monitored with a laser Doppler flow meter.
  • the nerve was subsequently stimulated (2 Hz, 10V, 1 ms, for 30 sec) at 30 minutes, 60 minutes, 90 minutes, and 120 minutes after antibody or vehicle administration. Animals were kept under anesthesia for a period of approximately three hours. Cumulative change in skin blood flow was estimated by the area under the flux-time curve (AUC, which is equal to change in flux multiplied by change in time) for each flux response to electrical pulse stimulations.
  • AUC area under the flux-time curve
  • blood flow increase stimulated by applying electronic pulses on saphenous nerve was significantly inhibited by the presence of antibody 4901 1 mg/kg administered i.v., when electronic pulse stimulation was applied at 60 minutes, 90 minutes, and 120 minutes after the antibody administration
  • blood flow increase stimulated by applying electronic pulses on saphenous nerve was significantly inhibited by the presence of antibody 4901 10 mg/kg administered i.v., when electronic pulse stimulation was applied at 30 minutes, 60 minutes, 90 minutes, and 120 minutes after the antibody administration.
  • 4B shows that blood flow increase stimulated by applying electronic pulses on saphenous nerve was significantly inhibited by the presence of antibody 7E9 (10 mg/kg, administered i.v.) when electronic pulse stimulation was applied at 30 min, 60 min, 90 min, and 120 min after antibody administration, and by the presence of antibody 8B6 (10 mg/kg, administered i.v.) when electronic pulse stimulation was applied at 30 min after antibody administration.
  • antibodies 4901, 7E9, 7D11, and 8B6 are effective in blocking CGRP activity as measured by skin vasodilatation induced by stimulation of rat saphenous nerve.
  • Amino acid sequences for the heavy chain variable region and light chain variable region of anti-CGRP antibody G1 are shown in FIG. 5 . The following methods were used for expression and characterization of antibody G1 and its variants.
  • Small scale Fab preparation From E. coli transformed (either using electroporation-competent TG1 cells or chemically-competent Top 10 cells) with a Fab library, single colonies were used to inoculate both a master plate (agar LB+carbenicillin (50 ⁇ g/mL)+2% glucose) and a working plate (2 mL/well, 96-well/plate) where each well contained 1.5 mL LB+carbenicillin (50 ⁇ g/mL)+2% glucose. A gas permeable adhesive seal (ABgene, Surrey, UK) was applied to the plate. Both plates were incubated at 30° C. for 12-16 hours; the working plate was shaken vigorously. The master plate was stored at 4° C.
  • Lysis of HB-SEP resuspended cells was accomplished by freezing ( ⁇ 80° C.) and then thawing at 37° C. Cell lysates were centrifuged at 4000 rpm, 4° C. for 1 hour to separate the debris from the Fab-containing supernatants, which were subsequently filtered (0.2 ⁇ m) using a Millipore MultiScreen Assay System 96-Well Filtration Plate and vacuum manifold. Biacore was used to analyze filtered supernatants by injecting them across CGRPs on the sensor chip. Affinity-selected clones expressing Fabs were rescued from the master plate, which provided template DNA for PCR, sequencing, and plasmid preparation.
  • Fabs were expressed on a larger scale as follows. Erlenmeyer flasks containing 150 mL LB+carbenicillin (50 ⁇ g/mL)+2% glucose were inoculated with 1 mL of a “starter” overnight culture from an affinity-selected Fab-expressing E. coli clone. The remainder of the starter culture ( ⁇ 3 mL) was used to prepare plasmid DNA (QIAprep mini-prep, Qiagen kit) for sequencing and further manipulation. The large culture was incubated at 30° C. with vigorous shaking until an OD 600 nm of 1.0 was attained (typically 12-16 h).
  • the cells were pelleted by centrifuging at 4000 rpm, 4° C. for 20 minutes, and resuspended in 150 mL LB+carbenicillin (50 ⁇ g/mL)+0.5 mM IPTG. After 5 hours expression at 30° C., cells were pelleted by centrifuging at 4000 rpm, 4° C. for 20 minutes, resuspended in 10 mL Biacore HBS-EP buffer, and lysed using a single freeze ( ⁇ 80° C.)/thaw (37° C.) cycle. Cell lysates were pelleted by centrifuging at 4000 rpm, 4° C. for one hour, and the supernatant was collected and filtered (0.2 um).
  • Full antibody preparation For expression of full antibodies, heavy and light chain variable regions were cloned in mammalian expression vectors and transfected using lipofectamine into HEK 293 cells for transient expression. Antibodies were purified using protein A using standard methods.
  • Vector pDb.CGRP.hFcGI is an expression vector comprising the heavy chain of the G1 antibody, and is suitable for transient or stable expression of the heavy chain.
  • Vector pDb.CGRP.hFcGI has nucleotide sequences corresponding to the following regions: the murine cytomegalovirus promoter region (nucleotides 7-612); a synthetic intron (nucleotides 613-1679); the DHFR coding region (nucleotides 688-1253); human growth hormone signal peptide (nucleotides 1899-1976); heavy chain variable region of G1 (nucleotides 1977-2621); human heavy chain IgG2 constant region containing the following mutations: A330P331 to S330S331 (amino acid numbering with reference to the wildtype IgG2 sequence; see Eur. J. Immunol. (1999) 29:2613-2624).
  • Vector pDb.CGRP.hFcGI was deposited
  • Vector pEb.CGRP.hKGI is an expression vector comprising the light chain of the G1 antibody, and is suitable for transient expression of the light chain.
  • Vector pEb.CGRP.hKGI has nucleotide sequences corresponding to the following regions: the murine cytomegalovirus promoter region (nucleotides 2-613); human EF-1 intron (nucleotides 614-1149); human growth hormone signal peptide (nucleotides 1160-1237); antibody G1 light chain variable region (nucleotides 1238-1558); human kappa chain constant region (nucleotides 1559-1882).
  • Vector pEb.CGRP.hKGI was deposited at the ATCC on Jul. 15, 2005, and was assigned ATCC Accession No. PTA-6866.
  • Biacore assay for affinity determination Affinities of G1 monoclonal antibody and its variants were determined at either 25° C. or 37° C. using the BIACORE3000TM surface plasmon resonance (SPR) system (Biacore, INC, Piscataway N.J.). Affinity was determined by capturing N-terminally biotinylated CGRP or fragments via pre-immobilized streptavidin (SA sensor chip) and measuring the binding kinetics of antibody G1 Fab fragments or variants titrated across the CGRP or fragment on the chip.
  • SPR surface plasmon resonance
  • HBS-EP running buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% v/v polysorbate P20).
  • CGRP surfaces were prepared by diluting the N-biotinylated CGRP to a concentration of less than 0.001 mg/mL into HBS-EP buffer and injecting it across the SA sensor chip using variable contact times.
  • Low capacity surfaces, corresponding to capture levels ⁇ 50 response units (RU) were used for high-resolution kinetic studies, whereas high capacity surfaces (about 800 RU of captured CGRP) were used for concentration studies, screening, and solution affinity determinations.
  • Kinetic data were obtained by diluting antibody G1 Fab serially in two- or three-fold increments to concentrations spanning 1 uM-0.1 nM (aimed at 0.1-10 ⁇ estimated K D ). Samples were typically injected for 1 minute at 100 ⁇ L/min and dissociation times of at least 10 minutes were allowed. After each binding cycle, surfaces were regenerated with 25 mM NaOH in 25% v/v ethanol, which was tolerated over hundreds of cycles. An entire titration series (typically generated in duplicate) was fit globally to a 1:1 Langmuir binding model using the BIAevaluation program.
  • affinities were obtained in a two-part experiment.
  • the protocol described above was used with the following modifications.
  • the association rate constant (k on ) was determined by injecting a 2-fold titration series (in duplicate) spanning 550 nM-1 nM for 30 seconds at 100 ⁇ L/min and allowing only a 30 second dissociation phase.
  • the dissociation rate constant (k off ) was determined by injecting three concentrations (high, medium, and low) of the same titration series in duplicate for 30 seconds and allowing a 2-hour dissociation phase.
  • the affinity (K D ) of each interaction was obtained by combining the k on and k off values obtained in both types of experiments, as shown in Table 4.
  • Antibody G1 Fab solutions in the absence or presence of solution-based competing peptide were injected across CGRP on the chip and the depletion of binding responses detected at the chip surface as a result of solution competition was monitored. These binding responses were converted to “free Fab concentrations” using a calibration curve, which was constructed by titrating antibody G1 Fab alone (5, 2.5, 1.25, 0.625, 0.325 and 0 nM) across the CGRP on the chip. “Free Fab concentrations” were plotted against the concentration of competing solution-based peptide used to generate each data point and fit to a solution affinity model using the BIAevaluation software.
  • the solution affinities determined (indirectly) in this way are shown in Tables 4 and 6 and were used to validate the affinities obtained when Fabs are injected directly across N-biotinylated CGRPs on a SA chip.
  • the close agreement between the affinities determined by these two methods confirms that tethering an N-biotinylated version of the CGRP to the chip does not alter its native solution binding activity.
  • Table 4 shows the binding affinities of antibody G1 to human ⁇ -CGRP, human ⁇ -CGRP, rat ⁇ -CGRP, and rat ⁇ -CGRP determined by Biacore, by flowing Fab fragments across N-biotinylated CGRPs on a SA chip.
  • affinities were also determined in a two-part experiment to complement this assay orientation, the solution affinity of the rat ⁇ -CGRP interaction was also determined (as described above). The close agreement of the affinities measured in both assay orientations confirms that the binding affinity of the native rat ⁇ -CGRP in solution is not altered when it is N-biotinylated and tethered to a SA chip.
  • Affinities for ⁇ -CGRPs were determined by global analysis using only a 20-min dissociation phase, which was not accurate enough to quantify their extremely off-rates (their off-rates are likely slower than stated here and therefore their affinities are likely even higher).
  • Antibody G1 Fab dissociated extremely slowly from all CGRPs (except ⁇ -rat CGRP) with off-rates that approached the resolution limit of the Biacore assay (especially at 25° C.). **Solution affinity determined by measuring the depletion of binding responses detected at CGRP on the chip for antibody G1 Fab pre-incubated with solution-based rat ⁇ -CGRP competitor.
  • Table 5 shows antibodies having the amino acid sequence variation as compared to antibody G1 and their affinities to both rat ⁇ -CGRP and human ⁇ -CGRP. All amino acid substitutions of the variants shown in Table 5 are described relative to the sequence of G1. The binding affinities of Fab fragments were determined by Biacore by flowing them across CGRPs on a SA chip.
  • Human ⁇ -CGRP was purchased as an N-biotinylated version to enable its high-affinity capture via SA sensor chips.
  • the binding of G1 Fab fragment to the human ⁇ -CGRP on the chip in the absence or presence of a CGRP peptide was determined.
  • a 2000:1 mol peptide/Fab solution e.g., 10 ⁇ M peptide in 50 nM G1 Fab was injected across human ⁇ -CGRP on the chip.
  • FIG. 6 shows the percentage of binding blocked by competing peptide. Data shown in FIG.
  • peptides that block 100% binding of G1 Fab to human ⁇ -CGRP are 1-37 (WT), 8-37, 26-37, P29A (19-37), K35A (19-37), K35E (19-37), and K35M (19-37) of human ⁇ -CGRP; 1-37 of ⁇ -CGRP (WT); 1-37 of rat ⁇ -CGRP (WT); and 1-37 of rat ⁇ -CGRP (WT). All these peptides are amidated at the C-terminus.
  • Peptides F37A (19-37) and 19-37 (the latter not amidated at the C-terminus) of human ⁇ -CGRP also blocked about 80% to 90% of binding of G1 Fab to human ⁇ -CGRP.
  • Peptide 1-36 (not amidated at the C-terminus) of human ⁇ -CGRP blocked about 40% of binding of G1 Fab to human ⁇ -CGRP.
  • Peptide fragment 19-36 (amidated at the C-terminus) of human ⁇ -CGRP; peptide fragments 1-13 and 1-19 of human ⁇ -CGRP (neither of which are amidated at the C-terminus); and human amylin, calcitonin, and adrenomedullin (all amidated at the C-terminus) did not compete with binding of G1 Fab to human ⁇ -CGRP on the chip.
  • Binding affinities of G1 Fab to variants of human ⁇ -CGRP was also determined. Table 6 below shows the affinities as measured directly by titrating G1 Fab across N-biotinylated human ⁇ -CGRP and variants on the chip. Data in Table 6 indicate that antibody G1 binds to a C-terminal epitope with F37 and G33 being the most important residues. G1 does not bind to CGRP when an extra amino acid residue (alanine) is added at the C-terminal (which is amidated).
  • Single-unit electrophysiological techniques were used to study the response profile of peripheral and central trigeminovascular neurons in the spinal trigeminal nucleus in response to occurrence of seizure in rats treated with fremanezumab (TEV-48125) as compared to untreated rats.
  • Cortical electrodes were used to trace the magnitude, extent and progression of epileptiform seizures.
  • the same craniotomies were made over the ipsilateral cortex and the ipsilateral transverse sinus, but no contralateral craniotomy was made. Instead, a laminectomy was made to expose the upper cervical spinal cord (C1-2) for microelectrode recording.
  • the search stimulus for finding dura-sensitive neurons is single-shock electrical stimulation applied to the dura covering the transverse sinus.
  • Seizure was induced by application of picrotoxin to the surface of the cerebral cortex (10 ⁇ l, applied on a small piece of gelfoam, at a concentration of either 5 mM or 100 mM, for focal or generalized seizure, respectively).
  • cortical activity was recorded with a glass micropipette (0.9% saline, ⁇ 1 megohm, 7 ⁇ m tip) placed just below the surface of the cerebral cortex, at the parietal and the occipital site.
  • TEV-48125 (TEVA Pharmaceutical Industries Ltd., Israel) is a humanized monoclonal anti-CGRP antibody (CGRP-mAb). It was diluted in saline to a final dose of 30 mg/kg and administered intravenously (total volume 0.8 ml) four hours before induction of seizure.
  • CGRP-mAb humanized monoclonal anti-CGRP antibody
  • This example shows activation of the trigeminovascular pathway by seizure and prevention of such activation by TEV-48125. Since the trigeminovascular pathway mediates PIH, the findings demonstrate that TEV-48125 can prevent PIH if given prophylactically. Critically, the results show that in untreated animals, the induction of seizure triggered prolonged activation in 28/30 (93%) neurons whereas in the TEV-48125 treated animals, only 2/13 (15%) neurons were activated by the seizure.
  • fremanezumab inhibited na ⁇ ve high-threshold (HT) but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. Additionally, when given sufficient time, fremanezumab prevents activation and sensitization of HT neurons by cortical spreading depression.
  • HT high-threshold
  • mice Male and female Sprague-Dawley rats (250-350 g) were anesthetized with urethane (0.9-1.2 g/kg i.p.). They were fitted with an intra-tracheal tube to allow artificial ventilation (0.1 L/min of O 2 ), and an intra-femoral-vein cannula for later infusion of drugs. Rats were placed in a stereotaxic apparatus, and core temperature was kept at 37° C. using a heating blanket.
  • End-tidal CO 2 was continuously monitored and kept within physiological range (3.5-4.5 pCO 2 ).
  • rats were paralyzed with rocuronium bromide (10 mg/ml, 1 ml/hr continuous intravenous infusion) and ventilated.
  • rocuronium bromide (10 mg/ml, 1 ml/hr continuous intravenous infusion)
  • a 5 ⁇ 5-mm opening was carefully carved in the parietal and occipital bones in front and behind the lambda suture, directly above the left transverse sinus.
  • the exposed dura was kept moist using a modified synthetic interstitial fluid (135 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 5 mM CaCl 2 ), 10 mM glucose and 10 mM Hepes, pH 7.2).
  • a segment of the spinal cord between the obex and C2 was uncovered from overlying tissues, stripped of the dura mater, and kept moist with mineral oil.
  • Trigeminovascular neurons were first identified based on their responses to electrical stimulation of the dura. They were selected for the study if they exhibited discrete firing bouts in response to ipsilateral electrical (0.1-3.0 mA, 0.5 msec, 0.5 Hz pulses) and mechanical (with a calibrated von Frey monofilaments) stimulation of the exposed cranial dura and to mechanical stimulation of the facial skin and cornea.
  • Dural receptive fields were mapped by indenting the dura (with the 4.19 g VFH monofilament) at points separated by 1 mm mediolaterally and rostrocaudally. Points at which dural indentation produced a response in ⁇ 50% of the trials were considered inside the neurons receptive field. Cutaneous receptive fields were mapped by applying innocuous and noxious mechanical stimulation to all facial skin areas and the cornea. An area was considered outside the receptive field if no stimulus produced a response in ⁇ 50% of the trials. Responses to mechanical stimulation of the skin were determined by applying brief (10 s) innocuous and noxious stimuli to the most sensitive portion of the cutaneous receptive field.
  • Innocuous stimuli consisted of slowly passing a soft bristled brush across the cutaneous receptive field (one 5-s brush stroke from caudal to rostral and one 5-s brush stroke from rostral to caudal) and pressure applied with a loose arterial clip.
  • Noxious stimuli consisted of pinch with a strong arterial clip (Palecek et al., 1992 , J. Neurophysiol. 67:1562-1573; Dado et al., 1994, J. Neurophysiol. 71:981-1002; Burstein et al., 1998, J. Neurophysiol. 79:964-982). More intense or prolonged stimuli were not used to avoid inducing prolonged changes in spontaneous neuronal discharge or response properties.
  • WDR wide-dynamic-range
  • HT high-threshold
  • Real-time waveform discriminator was used to create and store a template for the action potential evoked in the neuron under study by electrical pulses on the dura; spikes of activity matching the template waveform were acquired and analyzed online and offline using Spike 2 software (CED, Cambridge, UK).
  • Cortical spreading depression was induced mechanically by inserting a glass micropipette (tip diameter 25 ⁇ m) about 1 mm into the visual cortex for 10 sec. At a propagation rate of 3-5 mm/min, a single wave of CSD was expected to enter the neuronal receptive field within 1-2 min of cortical stimulation.
  • cortical activity was recorded (electrocorticogram) with a glass micropipette (0.9% saline, ⁇ 1 megohm, 7 um tip) placed just below the surface of the cerebral cortex (approximately 100 ⁇ m). The electrocorticogram electrode was positioned about 6 mm anterior to the visual cortex.
  • Fremanezumab (also known as TEV-48125/LBR-101/RN-307) (TEVA Pharmaceutical Industries Ltd., Israel) is a humanized monoclonal anti-CGRP antibody (CGRP-mAb). It was diluted in saline to a final dose of 30 mg/kg and administered intravenously (bolus injection, total volume 0.6-0.7 ml). A corresponding human IgG2 isotype control antibody (isotype-conAb) was also diluted in saline to a final dose of 30 mg/kg and administered intravenously (bolus injection, total volume 1.6-2.0 ml).
  • CGRP-mAb humanized monoclonal anti-CGRP antibody
  • the experimental protocol included two parts. The first part was designed to compare CGRP-mAb vs isotype-conAb effects on spontaneous and induced activity of na ⁇ ve trigeminovascular neurons, and the second part was designed to test CGRP-mAb vs isotype-conAb effects on the activation and sensitization of trigeminovascular neurons by CSD. Both parts included sampling of WDR and HT neurons in male and female rats.
  • the baseline neuronal profile was established by (a) mapping the dural, cutaneous and corneal receptive field; (b) measuring responses (mean spikes/sec) to mechanical stimulation of the dura (with a fixed force), skin (brush, pressure, pinch) and cornea (brush), and (c) measuring spontaneous firing rate (recorded over 30 min prior to treatment).
  • CGRP-mAb or isotype-conAb were administered and receptive fields were remapped, neuronal responses to stimulation of the dura, skin and cornea were re-examined, and the spontaneous activity rate was re-sampled at 1, 2, 3, and 4 hours post-treatment. The resulting values for each measure were then compared with the respective baseline values obtained before treatment.
  • CSD was induced 4 hours after administration of CGRP-mAb or isotype-conAb and 2 hours later (i.e., 6 hours after treatment) receptive field size, spontaneous activity rate, and response magnitude to stimulation of the dura, skin and cornea were measured again.
  • the resulting post-CSD values for each measure were then compared with the respective pre-CSD values obtained at the 4-hour post-treatment time.
  • This part was initiated only in cases in which the physiological condition of the rats (heart rate, blood pressure, respiration, end tidal CO2) and the neuronal isolation signal (signal-to-noise ratio ⁇ 1:3) were stable at the 4-hour post-treatment time point.
  • the mean firing frequency occurring before the onset of the first stimulus (30 min for spontaneous activity, 10 sec for mechanical stimulation of the dura, skin and cornea) was subtracted from the mean firing frequency that occurred throughout the duration of each stimulus.
  • corresponding values for each measure (determined at 1, 2, 3, 4 hrs after treatment) were compared with the respective baseline values obtained before fremanezumab or isotype-conAb administration.
  • resulting values for each measure (determined 2 hours after CSD induction) were compared with the respective values obtained before CSD induction in the 2 treatment groups (fremanezumab and isotype-conAb).
  • a neuron was considered activated when its mean firing rate after CSD exceeded its mean baseline activity by 2 standard deviations of that mean for a period >10 min, which translated to ⁇ 33% increase in activity.
  • a neuron was considered sensitized if 2 hours after occurrence of CSD it exhibited enhanced responses to at least 3 of the following 5 stimuli: dural indentation, brushing, pressuring or pinching the skin, and brushing the cornea.
  • Mean firing rates of respective values were compared using nonparametric statistics (Wilcoxon signed-ranks test). Two-tailed level of significance was set at 0.05.
  • the database for testing CGRP-mAb vs isotype-conAb effects on spontaneous and induced activity of na ⁇ ve trigeminovascular neurons consisted of 63 neurons. Of these, 31 were classified as WDR and 32 as HT. Of the 31 WDR neurons, 18 (11 in males, 7 in females) were tested before and after administration of the CGRP-mAb, and 13 (7 in males, 6 in females) were tested before and after administration of the isotype-conAb. Of the 32 HT neurons, 18 (11 in males, 7 in female) were tested before and after administration of the CGRP-mAb, and 14 (8 in males, 6 in females) were tested before and after administration of the isotype-conAb.
  • the database for testing CGRP-mAb vs. isotype-conAb effects on the activation and sensitization of the neurons by CSD consisted of 50 neurons. Of these, 23 were classified as WDR and 27 as HT. Of the 23 WDR neurons, 13 (7 in males, 6 in females) were tested in the CGRP-mAb treated animals and 10 (5 in males, 5 in females) in the isotype-conAb treated animals. Of the 27 HT neurons, 14 (8 in males, 6 in female) were tested in the CGRP-mAb treated animals, and 13 (7 in males, 6 in females) in the isotype-conAb treated animals.
  • FIGS. 10A-10J Recording Sites, Receptive Fields and Neuronal Classes Recording site, maps of dural and cutaneous receptive fields, and cell types did not differ between neurons tested for CGRP-mAb and those tested for the isotype-conAb ( FIGS. 10A-10J ). All identified recording sites were localized in laminae I-II and IV-V of the first cervical segment of the spinal cord and the caudal part of nucleus caudalis. In all cases, the most sensitive area of the dural receptive field was along the transverse sinus and the most sensitive area of the cutaneous receptive field was around the eye, involving the cornea in more than 90% of the cases.
  • intravenous administration of the CGRP-mAb reduced the sensitivity to mechanical stimulation of the dura in the HT but not the WDR neurons ( FIGS. 12A-12C ).
  • intravenous administration of the isotype-conAb did not alter the sensitivity to dural stimulation in either group of neurons ( FIGS. 12D-12F ).
  • Intravenous administration of the CGRP-mAb did not alter the responses of HT or WDR neurons to innocuous (brush, pressure) or noxious (pinch) mechanical stimulation of the skin or the cornea FIGS. 14A-14F in male or female rats.
  • dural receptive fields expanded in 5/7 HT neurons in males and 6/6 HT neurons in females ( FIG. 16A ).
  • the study demonstrates that the humanized monoclonal anti-CGRP antibody fremanezumab inhibits activation and sensitization of HT but not WDR trigeminovascular neurons ( FIG. 20 ).
  • the CGRP-mAb inhibited the spontaneous activity of naive HT neurons and their responses to stimulation of the intracranial dura but not facial skin or cornea, whereas in females it only inhibited their responses to stimulation of the intracranial dura.
  • the CGRP-mAb prevented in both sexes the activation and consequential sensitization of the HT neurons by CSD, but not the partial activation of WDR neurons.
  • CGRP-mAb When given intravenously, CGRP-mAb reduced baseline spontaneous activity in HT but not WDR neurons.
  • WDR trigeminovascular neurons are activated by a variety of dural stimulation used to study the pathophysiology of migraine (Davis and Dostrovsky, 1988, J. Neurophysiol. 59:648-666; Burstein et al., 1998, J. Neurophysiol. 79:964-982; Storer et al., 2004 , Brit. J. Pharmacol. 142:1171-1181; Zhang et al., 2011 , Ann. Neurol.
  • HT and WDR neurons have been thought to play different roles in the processing of noxious stimuli and the perception of pain (Craig A D, 2002 , Nat. Rev. Neurosci. 3:655-666; Craig A D, 2003 , Trends Neurosci. 26:303-307; Craig A D, 2003 , Annu. Rev. Neurosci. 26:1-30). While most HT neurons exhibit small receptive fields and respond exclusively to noxious mechanical stimuli, most WDR neurons exhibit large receptive fields and respond to both mechanical and thermal noxious stimuli (Price et al., 1976, J. Neurophysiol. 39:936-953; Price et al., 1978, J. Neurophysiol.
  • Fremanezumab reduced responsiveness to mechanical stimulation of the dura (both in males and females) but not to innocuous or noxious stimulation of the skin or cornea. This finding, together with the fact that the CGRP-mAb also prevented the activation of HT trigeminovascular neurons by CSD, provides a scientific basis for fremanezumab's effectiveness in preventing headaches of intracranial origin. Conversely, lack of effects on modulating the processing of sensory and nociceptive signals that arise in the facial skin and cornea predicts that this class of drugs will have little therapeutic effect on treating prolonged trigeminal pain conditions such as dry eye and herpes-induced trigeminal neuralgia.
  • migraine is more common in women than men
  • hyperalgesia (rather than allodynia) is more likely to develop in women than in men during migraine with aura, and that attempts to reduce neuronal excitability by CGRP-mAb in the interictal state (i.e., as a preventative), may also be more challenging in women than men.
  • the three observed differences could be attributed to greater excitability of female HT neurons, either due to these neurons' internal properties or due to differences in the strength of inputs they receive from peripheral nociceptors.
  • the effect of fremanezumab was selective for A-delta neurons: the percentage of A-delta neurons that responded to CSD was reduced significantly (p ⁇ 0.05) from 54% (isotype) to 14% (felanezumab) ( FIG. 24A ), whereas the percentage of C-fibers neurons that responded to CSD showed no significant change (31% vs. 23%, isotype vs. fremanezumab) ( FIG. 24B ).
  • CSD induces brief constriction, brief dilatation, and prolonged constriction of pial arteries, as well as immediate and delayed activation of C-fiber meningeal nociceptors containing CGRP.
  • C-fiber meningeal C-fibers Upon their CGRP-independent activation, meningeal C-fibers release CGRP in the dura and by doing so, mediate a CGRP-dependent activation of the nearby A ⁇ -fibers.
  • C-fiber meningeal nociceptors converge on and activate WDR neurons in the spinal trigeminal nucleus
  • a ⁇ -fibers converge on and activate both WDR and HT neurons that eventually transmit the nociceptive signals from the dura to the thalamus.
  • the absence of CGRP receptors from the meningeal C-fibers renders the activation of the C-WDR pathway CGRP-independent, and thus, unresponsive to the anti-CGRP monoclonal antibodies.
  • the presence of CGRP receptors on the meningeal A ⁇ -fibers renders the activation of the A ⁇ -HT pathway CGRP-dependent, and thus, responsive to the anti-CGRP monoclonal antibodies.
  • Vector pEb.CGRP.hKGI is a polynucleotide encoding the G1 light chain variable region and the light chain kappa constant region; and vector pDb.CGRP.hFcGI is a polynucleotide encoding the G1 heavy chain variable region and the heavy chain IgG2 constant region containing the following mutations: A330P331 to S330S331 (amino acid numbering with reference to the wildtype IgG2 sequence; see Eur. J. Immunol. (1999) 29:2613-2624).
  • G1 heavy chain variable region amino acid sequence (SEQ ID NO: 1) EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWISWVRQAPGKGLEWVAEIRSESDASATHYAEAVKGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCLAYFDYGLAIQNYWGQGTLVTVSS
  • G1 light chain variable region amino acid sequence (SEQ ID NO: 2) EIVLTQSPATLSLSPGERATLSCKASKRVTTYVSWYQQKPGQAPRLLIYGASNRYLGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCSQSYNYPYTFGQGTKLEIK
  • CDR H1 (extended CDR) (SEQ ID NO: 3) GFTFSNYWIS G1 CDR H2 (extended CDR) (SEQ ID NO: 4)
  • EIRSESDASATHYAEAVKG G1 CDR H3 (SEQ ID NO: 5) YFDYGLAIQNY G1 CDR L1 (

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US20200385449A1 (en) 2020-12-10
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MX2019010397A (es) 2020-08-20
AU2018226811A1 (en) 2019-09-26
WO2018160897A1 (fr) 2018-09-07
JP7195262B2 (ja) 2022-12-23
CA3055195A1 (fr) 2018-09-07
RU2019130867A (ru) 2021-04-02
WO2018160896A8 (fr) 2019-09-26
US11718664B2 (en) 2023-08-08
JP2020510667A (ja) 2020-04-09
CN110621343A (zh) 2019-12-27
KR20190133174A (ko) 2019-12-02
EP3589317A1 (fr) 2020-01-08
US10766952B2 (en) 2020-09-08
RU2019130867A3 (fr) 2021-07-02
US20190085061A1 (en) 2019-03-21

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