+

WO2018140510A1 - Composition et méthodes de traitement d'un accident vasculaire cérébral et d'autres troubles du snc - Google Patents

Composition et méthodes de traitement d'un accident vasculaire cérébral et d'autres troubles du snc Download PDF

Info

Publication number
WO2018140510A1
WO2018140510A1 PCT/US2018/015068 US2018015068W WO2018140510A1 WO 2018140510 A1 WO2018140510 A1 WO 2018140510A1 US 2018015068 W US2018015068 W US 2018015068W WO 2018140510 A1 WO2018140510 A1 WO 2018140510A1
Authority
WO
WIPO (PCT)
Prior art keywords
hours
inclusive
vla
subject
antagonist
Prior art date
Application number
PCT/US2018/015068
Other languages
English (en)
Inventor
Lahar R. MEHTA
Bharath Kumar KANDADI MURALIDHARAN
Jacob Elkins
Ivan Nestorov
Original Assignee
Biogen Ma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biogen Ma Inc. filed Critical Biogen Ma Inc.
Publication of WO2018140510A1 publication Critical patent/WO2018140510A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the invention relates to compositions and methods for treating stroke and/or other neurological deficits associated with stroke or traumatic brain injury.
  • Stroke is the second leading cause of death worldwide (fourth in the U.S., first in Japan). Nearly one-third of patients are left permanently disabled, with speech, movement, coordination, and cognition often affected. The annual stroke recurrence rate among survivors is 5%. The overall incidence of stroke is rising with the aging population (about 2% compound annual growth rate). Stroke places a heavy economic burden on patients, families, and the healthcare system.
  • Acute ischemic stroke occurs when the brain does not receive adequate blood flow, typically due to occlusion of a blood vessel. Brain ischemia rapidly results in neuronal dysfunction and cell death. Over 1.7 million first-time AIS incidents occur each year in the seven major markets. AIS accounts for about 85% of all strokes (another type of stroke is hemorrhagic, which occurs when a weakened blood vessel ruptures causing bleeding into the surrounding brain tissue). Current AIS therapies include intravenous (IV) thrombolysis and endovascular intervention.
  • IV intravenous
  • IV tissue plasminogen activator (for thrombolysis) is the only approved agent for AIS and is effective in a limited time window (up to 3 hours in the U.S., 4.5 hours in Europe) after the last known normal (LKN).
  • Functional measures such as modified Rankin Scale (mRS) indicate a 15% relative improvement by tPA versus placebo.
  • mRS modified Rankin Scale
  • a risk of intracerebral hemorrhage and contra-indications e.g., anti-coagulant use or uncontrolled hypertension
  • tPA use about 5% of AIS patients are given tPA.
  • Endovascular intervention includes surgical clot removal of a large vessel occlusion and has demonstrated modest efficacy. Eligibility criteria and restriction to hospitals with expertise and surgical capabilities limits use broadly. Less than 2% of AIS patients undergo endovascular intervention. Thus, current AIS therapies are limited and suboptimal.
  • ischemic stroke e.g., AIS, or hemorrhagic stroke
  • therapies that are available and useful to a larger percentage of stroke patients.
  • therapies for subarachnoid hemorrhage and traumatic brain injury are also a need for therapies for subarachnoid hemorrhage and traumatic brain injury.
  • the present invention provides, at least in part, methods and compositions for treating stroke, e.g. , ischemic stroke (e.g. , acute ischemic stroke (AIS)), hemorrhagic stroke (e.g. , intracerebral hemorrhage or subarachnoid hemorrhage (SAH)), or traumatic brain injury (TBI).
  • ischemic stroke e.g. , acute ischemic stroke (AIS)
  • hemorrhagic stroke e.g. , intracerebral hemorrhage or subarachnoid hemorrhage (SAH)
  • TBI traumatic brain injury
  • a VLA-4 antagonist e.g., an anti-alpha4 antibody molecule
  • administration of a VLA-4 antagonist to a subject, e.g., a patient with acute ischemic stroke, up to 5 days (e.g., within 24 hours or less) after last known normal (LKN)
  • beneficial effects e.g., an improvement in a clinical outcome, such as functional independence, activities of daily living, and/or cognitive ability.
  • LNN last known normal
  • therapies targeting lymphocyte infiltration after ischemia such as by administration of a VLA-4 antagonist, can still have beneficial effects even when administration of the therapy is initiated at a later time point than previously determined.
  • the treatment window can be tailored, at least in part, based on the severity of the stroke. For example, a subject with a moderate or mild stroke, e.g., having an NIHSS score of 5 to 15 points at baseline can have a longer treatment window, e.g., initiated within 24 hours or less after LKN, compared to a subject with a severe stroke, e.g. , having an NIHSS score of 15 points or higher at baseline, e.g., having a treatment window initiated within 9 hours or less.
  • a method of treating a human subject having a stroke e.g., an ischemic stroke, e.g., an acute ischemic stroke, a hemorrhagic stroke, e.g., an intracerebral hemorrhage or a subarachnoid hemorrhage, or a traumatic brain injury
  • ischemic stroke e.g., an acute ischemic stroke
  • hemorrhagic stroke e.g., an intracerebral hemorrhage or a subarachnoid hemorrhage
  • traumatic brain injury e.g., traumatic brain injury
  • the method comprises administering a VLA-4 antagonist, e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, to the subject, during a treatment window chosen from:
  • LKN up to and including 24 hours, e.g., 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13 hours or less, after LKN, e.g., wherein administration of the VLA-4 antagonist is not initiated within a period of 12 hours or less after LKN (e.g., administration does not occur within 12, 11, 10, 9, 8, 6, 5 or fewer hours after LKN);
  • administration e.g., at baseline; (vi) within and including 9 hours or less, e.g., 9, 8, 7, 6 hours or less, after LKN in the subject, e.g., wherein the subject has, or is determined to have, an NIHSS score greater than 15 points, e.g., 16 to 23 points, at the time of initial administration, e.g., at baseline; or
  • the VLA-4 antagonist e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g., natalizumab
  • a dosage e.g., as a single administration of:
  • a dosage that results in an AUC e.g., over a period of time of 0-10 days, 0-20 days, 0- 30 days, 0-60 days, 0-90 days, or 0- 120 days
  • AUC e.g., over a period of time of 0-10 days, 0-20 days, 0- 30 days, 0-60 days, 0-90 days, or 0- 120 days
  • the method comprises administering the VLA-4 antagonist, e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab at a dosage of about 300 mg, e.g. , intravenously (IV), e.g. , at a single dosage of 300 mg IV.
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab) is administered at a dosage of about 450 mg to about 600 mg, e.g. , IV.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab) is administered at a dosage of about 600 mg, e.g. , IV, e.g. , at a single dosage of 600 mg IV.
  • the method comprises administering the VLA-4 antagonist at a dosage of about 300 mg IV. In embodiments, the method comprises administering the VLA-4 antagonist at a dosage of about 450 mg IV. In embodiments, the method comprises administering the VLA- 4 antagonist at a dosage of about 600 mg IV.
  • the method comprises administering the VLA-4 antagonist at a dosage of about 300 mg IV during a treatment window greater than 12 hours to and including 24 hours after LKN. In embodiments, the method comprises administering the VLA-4 antagonist at a dosage of about 450 mg IV during a treatment window greater than 12 hours to and including 24 hours after LKN. In embodiments, the method comprises administering the VLA-4 antagonist at a dosage of about 600 mg IV during a treatment window greater than 12 hours to and including 24 hours after LKN.
  • VLA-4 antagonist is natalizumab
  • the treatment window is greater than 12 hours to and including 24 hours after LKN;
  • the VLA-4 antagonist is administered at a dosage of about 300 mg (e.g., 300+/- 5% mg), e.g., intravenously (IV), e.g., at a single dosage of 300 mg IV.
  • a dosage of about 300 mg e.g., 300+/- 5% mg
  • IV intravenously
  • VLA-4 antagonist is natalizumab
  • the treatment window is greater than 12 hours to and including 24 hours after LKN;
  • the VLA-4 antagonist is administered at a dosage of about 450 mg to about 600 mg, e.g., IV.
  • VLA-4 antagonist is natalizumab
  • the treatment window is greater than 12 hours to and including 24 hours after LKN; and (iii) the VLA-4 antagonist is administered at a dosage of about 450 mg (e.g., 450+/-
  • VLA-4 antagonist is natalizumab
  • the treatment window is greater than 12 hours to and including 24 hours after LKN;
  • the VLA-4 antagonist is administered at a dosage of about 600 mg (e.g., 600+/- 5% mg), e.g., IV, e.g., at a single dosage of 600 mg IV.
  • the subject has, or is determined to have, an NIHSS score from 5 to 23 points (e.g., an NIHSS score from 5 to 15 points or 16 to 23 points) at baseline. In embodiments, the subject has, or is determined to have, an NIHSS score greater than 15 points, e.g., 16 to 23 points, at baseline. In embodiments, the subject has, or is determined to have, an NIHSS score of 15 points or less, e.g., from 5 to 15 points, at baseline.
  • VLA-4 antagonist is natalizumab
  • the treatment window is within and including 9 hours after LKN;
  • the VLA-4 antagonist is administered at a dosage of about 300 mg (e.g., 300+/- 5% mg), e.g., intravenously (IV), e.g., at a single dosage of 300 mg IV.
  • VLA-4 antagonist is natalizumab
  • the treatment window is within and including 9 hours after LKN;
  • the VLA-4 antagonist is administered at a dosage of about 450 mg to about 600 mg, e.g., IV.
  • VLA-4 antagonist is natalizumab
  • the treatment window is within and including 9 hours after LKN;
  • the VLA-4 antagonist is administered at a dosage of about 450 mg (e.g., 450+/- 5% mg), e.g., IV, e.g., at a single dosage of 450 mg IV.
  • 450 mg e.g., 450+/- 5% mg
  • IV e.g., at a single dosage of 450 mg IV.
  • VLA-4 antagonist is natalizumab
  • the treatment window is within and including 9 hours after LKN;
  • the VLA-4 antagonist is administered at a dosage of about 600 mg (e.g., 600+/- 5% mg), e.g., IV, e.g., at a single dosage of 600 mg IV.
  • the subject has, or is determined to have, an NIHSS score from 5 to 23 points (e.g., an NIHSS score from 5 to 15 points or 16 to 23 points) at baseline. In embodiments, the subject has, or is determined to have, an NIHSS score greater than 15 points, e.g., 16 to 23 points, at baseline. In embodiments, the subject has, or is determined to have, an NIHSS score of 15 points or less, e.g., from 5 to 15 points, at baseline.
  • the method comprises administering the VLA-4 antagonist, e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g.,
  • natalizumab to the subject within more than 12 hours up to and including 5 days, e.g. , more than 12 hours up to and including 4 days or less, more than 12 hours up to and including 3 days or less, more than 12 hours up to and including 2 days or less, more than 12 hours up to and including 1 day or less, after LKN in the subject.
  • the method comprises administering the VLA-4 antagonist, e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g.,
  • natalizumab within more than 12 hours up to and including 24 hours, e.g. , more than 12 hours up to and including 23 hours or less, more than 12 hours up to and including 22 hours or less, more than 12 hours up to and including 21 hours or less, more than 12 hours up to and including 20 hours or less, more than 12 hours up to and including 19 hours or less, more than 12 hours up to and including 18 hours or less, more than 12 hours up to and including 17 hours or less, more than 12 hours up to and including 16 hours or less, more than 12 hours up to and including 15 hours or less, more than 12 hours up to and including 14 hours or less, more than 12 hours up to and including 13 hours or less, after LKN in the subject.
  • the method comprises administering the VLA-4 antagonist, e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g.,
  • natalizumab within more than 12 hours, e.g., 12.5 hours or more, 13 hours or more, 14 hours or more, 15 hours or more, 16 hours or more, 17 hours or more, 18 hours or more, 19 hours or more, 20 hours or more, 21 hours or more, 22 hours or more, 23 hours or more, 24 hours or more, after LKN in the subject.
  • the method comprises administering the VLA-4 antagonist, e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g.,
  • natalizumab within about 13 hours (e.g., 13 hours + 5%), about 14 hours (e.g., 14 hours + 10%), about 15 hours (e.g., 15 hour + 10%), about 16 hours (e.g., 16 hours + 10%), about 17 hours (e.g., 17 hours + 10%), about 18 hours (e.g., 18 hours + 10%), about 19 hours (e.g., 19 hours + 10%), about 20 hours (e.g., 20 hours + 10%), about 21 hours (e.g., 21 hours + 10%), about 22 hours (e.g., 22 hours + 10%), about 23 hours (e.g., 23 hours + 10%), or about 24 hours (e.g., 24 hours + 10%), after LKN in the subject.
  • about 14 hours e.g., 14 hours + 10%
  • about 15 hours e.g., 15 hour + 10%
  • about 16 hours e.g., 16 hours + 10%
  • about 17 hours e.g., 17 hours + 10%
  • about 18 hours e.g
  • the method comprises administering the VLA-4 antagonist, e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g.,
  • natalizumab within more than 13 hours up to and including 24 hours, e.g. , more than 13 hours up to and including 23 hours or less, more than 13 hours up to and including 22 hours or less, more than 13 hours up to and including 21 hours or less, more than 13 hours up to and including 20 hours or less, more than 13 hours up to and including 19 hours or less, more than 13 hours up to and including 18 hours or less, more than 13 hours up to and including 17 hours or less, more than 13 hours up to and including 16 hours or less, more than 13 hours up to and including 15 hours or less, more than 13 hours up to and including 14 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 14 hours to 24 hours (24 inclusive), within more than 14 hours to 23 hours (23 inclusive), within more than 14 hours to 22 hours (22 inclusive), within more than 14 hours to 21 hours (21 inclusive), within more than 14 hours to 20 hours (20 inclusive), within more than 14 hours to 19 hours (19 inclusive), within more than 14 hours to 18 hours (18 inclusive), within more than 14 hours to 17 hours (17 inclusive), within more than 14 hours to 16 hours (16 inclusive), within more than 14 hours to 15 hours (15 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 15 hours to 24 hours (24 inclusive), within more than 15 hours to 23 hours (23 inclusive), within more than 15 hours to 22 hours (22 inclusive), within more than 15 hours to 21 hours (21 inclusive), within more than 15 hours to 20 hours (20 inclusive), within more than 15 hours to 19 hours (19 inclusive), within more than 15 hours to 18 hours (18 inclusive), within more than 15 hours to 17 hours (17 inclusive), within more than 15 hours to 16 hours (16 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 16 hours to 24 hours (24 inclusive), within more than 16 hours to 23 hours (23 inclusive), within more than 16 hours to 22 hours (22 inclusive), within more than 16 hours to 21 hours (21 inclusive), within more than 16 hours to 20 hours (20 inclusive), within more than 16 hours to 19 hours (19 inclusive), within more than 16 hours to 18 hours (18 inclusive), within more than 16 hours to 17 hours (17 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 17 hours to 24 hours (24 inclusive), within more than 17 hours to 23 hours (23 inclusive), within more than 17 hours to 22 hours (22 inclusive), within more than 17 hours to 21 hours (21 inclusive), within more than 17 hours to 20 hours (20 inclusive), within more than 17 hours to 19 hours (19 inclusive), within more than 17 hours to 18 hours (18 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 18 hours to 24 hours (24 inclusive), within more than 18 hours to 23 hours (23 inclusive), within more than 18 hours to 22 hours (22 inclusive), within more than 18 hours to 21 hours (21 inclusive), within more than 18 hours to 20 hours (20 inclusive), within more than 18 hours to 19 hours (19 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 19 hours to 24 hours (24 inclusive), within more than 19 hours to 23 hours (23 inclusive), within more than 19 hours to 22 hours (22 inclusive), within more than 19 hours to 21 hours (21 inclusive), within more than 19 hours to 20 hours (20 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 20 hours to 24 hours (24 inclusive), within more than 20 hours to 23 hours (23 inclusive), within more than 20 hours to 22 hours (22 inclusive), within more than 20 hours to 21 hours (21 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 21 hours to 24 hours (24 inclusive), within more than 21 hours to 23 hours (23 inclusive), within more than 21 hours to 22 hours (22 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 22 hours to 24 hours (24 inclusive), within more than 22 hours to 23 hours (23 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 23 hours to 24 hours (24 inclusive), after LKN in the subject.
  • the method comprises administering the VLA-4 antagonist to the subject within and including 5 days or less, e.g. , 5, 4, 3, 2, 1 day or less, or a range defined by any two of the preceding values, after LKN in the subject.
  • the VLA-4 antagonist is administered within and including 24 hours or less, e.g. , 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 hours or less, or a range defined by any two of the preceding values, after LKN in the subject.
  • administration of the VLA-4 antagonist is not within a period of 12 hours or less after LKN (e.g., administration does not occur within 12, 11, 10, 9, 8, 6, 5 or fewer hours after LKN, or a range defined by any two of the preceding values).
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g.
  • the VLA-4 binding antibody e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist is administered at a dosage of about 450 mg, e.g. , IV, e.g. , at a single dosage of 450 mg IV.
  • the VLA-4 antagonist e.g.
  • the VLA-4 binding antibody e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the method comprises administering a VLA-4 antagonist to the subject within and including 9 hours or less, e.g., within and including 8 hours or less, within and including 7 hours or less, within and including 6 hours or less, within and including 5 hours or less, within and including 4 hours or less, within and including 3 hours or less, within and including 2 hours or less, within and including 1 hour or less, or a range defined by any two of the preceding values, after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g.
  • natalizumab has, or is identified as having, a NIHSS score of, e.g. , 5 to 23, inclusive; 5 to 22, inclusive; 5 to 21, inclusive; 5 to 20, inclusive; 5 to 19, inclusive; 5 to 18, inclusive; 5 to 17, inclusive; 5 to 16, inclusive; 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; 5 to 6, inclusive, or 5.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist is administered at a dosage of about 450 mg to about 600 mg, e.g. , IV.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g.
  • natalizumab is administered at a dosage of about 450 mg, e.g. , IV, e.g. , at a single dosage of 450 mg IV.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the method comprises administering a VLA-4 antagonist to the subject within and including 9 hours or less after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 5 to 23, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within and including 9 hours or less after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 5 to 15, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within and including 9 hours or less, e.g.
  • LKN in the subject and the subject e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of, e.g. , 16 to 23, inclusive; 16 to 22, inclusive; 16 to 21, inclusive; 16 to 20, inclusive; 16 to 19, inclusive; 16 to 18, inclusive; or 16 to 17, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within 9 hours or less after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 16 to 23, inclusive.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab- like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab- like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody e.g. , a natalizumab- like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g.
  • a natalizumab-like antibody molecule (e.g. , natalizumab), is administered, e.g. , at a dosage of about 600 mg, e.g. , IV, e.g. , at a single dosage of 600 mg IV.
  • the method comprises administering a VLA-4 antagonist to the subject, e.g. , within more than 9 hours to 24 hours (24 inclusive), within more than 9 hours to 23 hours (23 inclusive), within more than 9 hours to 22 hours (22 inclusive), within more than 9 hours to 21 hours (21 inclusive), within more than 9 hours to 20 hours (20 inclusive), within more than 9 hours to 19 hours (19 inclusive), within more than 9 hours to 18 hours (18 inclusive), within more than 9 hours to 17 hours (17 inclusive), within more than 9 hours to 16 hours (16 inclusive), within more than 9 hours to 15 hours (15 inclusive), within more than 9 hours to 14 hours (14 inclusive), within more than 9 hours to 13 hours (13 inclusive), within more than 9 hours to 12 hours (12 inclusive), within more than 9 hours to 11 hours (11 inclusive), or within more than 9 hours to 10 hours (10 inclusive), after LKN in the subject and the subject, e.g.
  • a natalizumab-like antibody molecule e.g. , natalizumab
  • a NIHSS score of 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 9 hours to 24 hours (24 inclusive) after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 5 to 15, inclusive.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody e.g. , a natalizumab-like antibody molecule
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g.
  • a natalizumab-like antibody molecule (e.g. , natalizumab), is administered, e.g. , at a dosage of about 600 mg, e.g. , IV, e.g. , at a single dosage of 600 mg IV.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 9 hours to 5 days, e.g. , more than 9 hours to 4 days or less, more than 9 hours to 3 days or less, more than 9 hours to 2 days or less, more than 9 hours to 1 day or less, after LKN in the subject.
  • the subject e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g.
  • natalizumab has a NIHSS score of 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • the VLA-4 antagonist is administered within more than 9 hours to 24 hours (24 inclusive), e.g. , within more than 9 hours to 23 hours (23 inclusive), within more than 9 hours to 22 hours (22 inclusive), within more than 9 hours to 21 hours (21 inclusive), within more than 9 hours to 20 hours (20 inclusive), within more than 9 hours to 19 hours (19 inclusive), within more than 9 hours to 18 hours (18 inclusive), within more than 9 hours to 17 hours (17 inclusive), within more than 9 hours to 16 hours (16 inclusive), within more than 9 hours to 15 hours (15 inclusive), within more than 9 hours to 14 hours (14 inclusive), within more than 9 hours to 13 hours (13 inclusive), within more than 9 hours to 12 hours (12 inclusive), within more than 9 hours to 11 hours (11 inclusive), or within more than 9 hours to 10 hours (10 inclusive), after LKN in the subject.
  • the subject e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • a NIHSS score of 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 6 hours to 5 days, e.g. , more than 6 hours to 4 days or less, more than 6 hours to 3 days or less, more than 6 hours to 2 days or less, more than 6 hours to 1 day or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within more than 6 hours to 24 hours, e.g.
  • the method comprises administering a VLA-4 antagonist to the subject within 12 hours or less, e.g., 11, 10, 9, 8, 7, 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within 9 hours or less after LKN, e.g., within 9, 8, 7, or 6 hours or less after LKN, or between 6 and 9 hours after LKN, or within 6 hours after LKN.
  • the VLA-4 antagonist is administered within 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 and 6 hours, 5 and 6 hours, after LKN.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 2 hours to 12 hours, e.g., more than 2 hours to 10 hours or less, more than 2 hours to 9 hours or less, more than 2 hours to 8 hours or less, more than 2 hours to 7 hours or less, more than 2 hours to 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within more than 2 hours to 9 hours or less after LKN, e.g., between 6 and 9 hours after LKN.
  • the VLA-4 antagonist is administered within more than 2 hours to 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 and 6 hours, 5 and 6 hours, after LKN.
  • administration of the dosage is initiated within 6 hours of last known normal. In embodiments, administration of the dosage is initiated within 9 hours, e.g., 6 to 9 hours, of last known normal. In embodiments, administration of the dosage is initiated within 12 hours, e.g., 6 to 12 hours, or 9 to 12 hours, of last known normal.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab) is administered, e.g.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab- like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist is administered, e.g. , at a dosage of about 450 mg, e.g. , IV, e.g. , at a single dosage of 450 mg IV.
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule e.g.
  • natalizumab is administered, e.g. , at a dosage of about 600 mg, e.g. , IV, e.g. , at a single dosage of 600 mg IV. Additional features or embodiments of any of the methods or compositions described herein include one or more of the following:
  • the subject has a stroke.
  • the stroke is an embolism-, thrombus- or hypoperfusion-associated stroke.
  • the subject having the stroke does not have an intracranial hemorrhage.
  • the subject has not received a previous treatment with a VLA-4 antagonist, e.g., natalizumab.
  • a VLA-4 antagonist e.g., natalizumab.
  • the subject does not have or is not at risk for developing progressive multifocal leukoencephalopathy (PML).
  • PML progressive multifocal leukoencephalopathy
  • the subject has a severe stroke, e.g., a stroke having a NIHSS score equal to or greater than 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 or higher, e.g., 16 to 23.
  • the subject has a stroke having a NIHSS score equal to or greater than 15.
  • the subject has a stroke having a NIHSS score equal to or greater than 21.
  • the subject has a less than severe stroke, e.g., a stroke having a NIHSS score of equal to or less than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or less e.g., 5 to 15.
  • the subject has a mild stroke.
  • the subject has a mild to moderate stroke.
  • the subject at baseline, has an infarct size equal to or greater than 4.6 cm in diameter.
  • the subject at baseline, has an infarct size less than 4.6 cm in diameter.
  • the method comprises determining, e.g., determining prior to
  • determining comprises determining a NIHSS score, e.g., determining if the NIHSS score is equal to or greater than 15 or 21, e.g., 16 to 23.
  • determining comprises determining if the NIHSS score is equal to or greater than 15. In embodiments, determining comprises determining if the NIHSS score is equal to or greater than 21. In embodiments, determining comprises determining if the NIHSS score is equal to or between 16 to 23. In embodiments, determining comprises determining a NIHSS score, e.g., determining if the NIHSS score is equal to or less than 15, e.g., 5 to 15. In embodiments, determining comprises determining if the NIHSS score is equal to or between 5 to 15. In yet other embodiments, determining comprises determining if the NIHSS score is equal to or between 5 to 23. In embodiments, responsive to the determination of severity, a dosage of anti- VLA4 antagonist is selected.
  • the dosage is 250 to 350 mg. In embodiments, the dosage is 300+/-5% mg. In embodiments, the dosage is about 300 mg. In embodiments, the dosage is 300 mg. In embodiments, the dosage is 350 to 500 mg. In embodiments, the dosage is 390 to 450 mg. In embodiments, the dosage is 450+/- 5% mg. In embodiments, the dosage is about 450 mg. In embodiments, the dosage is 450 mg. In embodiments, the dosage is 550 to 650 mg. In embodiments, the dosage is 575 to 625 mg. In embodiments, the dosage is 600+/- 5% mg. In embodiments, the dosage is about 600 mg. In embodiments, the dosage is 600 mg.
  • the method further comprises administering a subsequent dosage of the VLA-4 antagonist.
  • the subsequent dosage is 125 to 175, 150+/-5%, about 150, or 150, mg.
  • the subsequent dosage is 150 mg.
  • the subsequent dosage is 250 to 350, or 300+/-5%, e.g., about 300, e.g., 300, mg.
  • the subsequent dosage is 300 mg.
  • the subsequent dosage is 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg.
  • the subsequent dosage is 450 mg.
  • the subsequent dosage is 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg. In embodiments, the subsequent dosage is 600 mg.
  • the subsequent dosage is administered on day 3 after the dosage (e.g., if the dosage is administered on the first day of the month the subsequent dosage is administered on the third day of the month. In embodiments, the subsequent dosage is administered on day 5 after the dosage. In embodiments, the subsequent dosage is administered on day 7 after the dosage. In embodiments, the subsequent dosage is administered four to six weeks after the dosage.
  • VLA-4 antagonists e.g., if the dosage is administered on the first day of the month the subsequent dosage is administered on the third day of the month. In embodiments, the subsequent dosage is administered on day 5 after the dosage. In embodiments, the subsequent dosage is administered on day 7 after the dosage. In embodiments, the subsequent dosage is administered four to six weeks after the dosage.
  • the VLA-4 antagonist comprises an antibody molecule that comprises CDRl, CDR2 and CDR3 from the light chain and CDRl, CDR2 and CDR3 from the heavy chain of natalizumab.
  • the VLA-4 antagonist comprises an antibody molecule that comprises the light chain variable region and the heavy chain variable region of natalizumab.
  • the VLA-4 antagonist comprises natalizumab.
  • the VLA-4 antagonist is an anti-VLA-4 antibody molecule, e.g., an anti- VLA-4 antibody molecule described herein.
  • the anti-VLA-4 antibody molecule is a monoclonal, a humanized, a human, or a chimeric anti-VLA-4 antibody molecule.
  • the VLA-4 antagonist is an a4-binding fragment of an anti-VLA-4 antibody.
  • the a4 binding fragment is an Fab, Fab', F(ab')2, or Fv fragment.
  • the anti-VLA-4 antibody molecule comprises one or more, preferably all, of HC CDRl, HC CDR2, HC CDR3, LC CDRl, LC CDR2 and LC CDR3 of natalizumab.
  • the VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, is administered by intravenous administration, e.g., over a period of less than 90 minutes, e.g., 30 to 60 minutes.
  • the VLA-4 antagonist is administered in combination with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered simultaneously with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered sequentially with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, after the additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, before the additional agent or procedure.
  • the additional agent ameliorates one or more side effects associated with the administration of the VLA-4 antagonist, e.g., an agent which reduces or inhibits one or more symptoms of hypersensitivity.
  • the agent which reduces or inhibits one or more symptoms of hypersensitivity can be one or more of a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), an HI antagonist and an H2 antagonist (e.g., ranitidine or famotidine).
  • a corticosteroid e.g., dexamethasone
  • an antihistamine e.g., diphenhydramine
  • an H2 antagonist e.g., ranitidine or famotidine
  • the additional agent is an agent which reduces one or more symptoms of stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or TBI.
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • TBI ischemic stroke
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the VLA-4 antagonist is administered at a dosage and/or dosing schedule described herein. In embodiments, the VLA-4 antagonist is administered intravenously.
  • the VLA-4 antagonist is administered in combination with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered simultaneously with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered sequentially with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, after the additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, before the additional agent or procedure.
  • the additional agent ameliorates one or more side effects associated with the administration of the VLA-4 antagonist, e.g., an agent which reduces or inhibits one or more symptoms of hypersensitivity.
  • the agent which reduces or inhibits one or more symptoms of hypersensitivity can be one or more of a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), an HI antagonist and an H2 antagonist (e.g., ranitidine or famotidine).
  • a corticosteroid e.g., dexamethasone
  • an antihistamine e.g., diphenhydramine
  • an H2 antagonist e.g., ranitidine or famotidine
  • the additional agent is an agent which reduces one or more symptoms of stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or TBI.
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • TBI ischemic stroke
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • a severe stroke e.g., a severe ischemic stroke, e.g., a severe acute ischemic stroke, a severe hemorrhagic stroke, e.g., a severe acute intracerebral hemorrhage or a severe subarachnoid hemorrhage, or severe TBI, comprising:
  • VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, to the subject,
  • the method comprises determining, e.g., determining prior to administration of the VLA-4 antagonist, if the patient has a severe stroke.
  • determining comprises determining a NIHSS score, e.g., determining if the NIHSS score is equal to or greater than 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or higher.
  • determining comprises determining if the NIHSS score is equal to or greater than 15, e.g., 16 to 26 (e.g., 16 to 23).
  • determining comprises determining if the NIHSS score is equal to or greater than 21.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has, or is determined to have a NIHSS score of equal to or greater than 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or higher, e.g., 21 to 26.
  • the NIHSS score is equal to or greater than 15.
  • the NIHSS score is equal to or greater than 21.
  • administration is initiated within 6 hours of last known normal. In embodiments, administration is initiated within 9 hours, e.g., 6 to 9 hours, of last known normal. In embodiments, administration is initiated within 12 hours, e.g., 6 to 12 hours, or 9 to 12 hours, of last known normal.
  • the method comprises administering a VLA-4 antagonist to the subject within and including 9 hours or less, e.g., within and including 8 hours or less, within and including 7 hours or less, within and including 6 hours or less, within and including 5 hours or less, within and including 4 hours or less, within and including 3 hours or less, within and including 2 hours or less, within and including 1 hour or less, or a range defined by any two of the preceding values, after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g.
  • natalizumab has, or is identified as having, a NIHSS score of, at least 15, e.g. , 15 to 26, inclusive; 15 to 25, inclusive; 15 to 24, inclusive; 15 to 23, inclusive; 15 to 22, inclusive; 15 to 21, inclusive; 15 to 20, inclusive; 15 to 19, inclusive; 15 to 18, inclusive; 15 to 17, inclusive; 15 to 16, inclusive; or 15.
  • the method comprises administering a VLA-4 antagonist to the subject within and including 9 hours or less after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 15 to 25, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within and including 9 hours or less, e.g. , within and including 8 hours or less, within and including 7 hours or less, within and including 6 hours or less, within and including 5 hours or less, within and including 4 hours or less, within and including 3 hours or less, within and including 2 hours or less, within and including 1 hour or less, after LKN in the subject and the subject has a NIHSS score of, e.g. , 16 to 23, inclusive; 16 to 22, inclusive; 16 to 21, inclusive; 16 to 20, inclusive; 16 to 19, inclusive; 16 to 18, inclusive; 16 to 17, inclusive; or 16.
  • the method comprises administering a VLA-4 antagonist to the subject within 9 hours or less after LKN in the subject and the subject has a NIHSS score of 16 to 23, inclusive.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab- like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab- like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody e.g. , a natalizumab- like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g.
  • a natalizumab-like antibody molecule (e.g. , natalizumab), is administered, e.g. , at a dosage of about 600 mg, e.g. , IV, e.g. , at a single dosage of 600 mg IV.
  • the method further comprises providing a subsequent administration of the VLA-4 antagonist to the subject.
  • the VLA-4 antagonist comprises an antibody molecule that comprises CDRl, CDR2 and CDR3 from the light chain and CDRl, CDR2 and CDR3 from the heavy chain of natalizumab. In embodiments, the VLA-4 antagonist comprises an antibody molecule that comprises the light chain variable region and the heavy chain variable region of natalizumab.
  • the VLA-4 antagonist comprises natalizumab.
  • the method comprises administering a VLA-4 antagonist to the subject within 12 hours or less, e.g., 10, 9, 8, 7, 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within 9 hours or less after LKN, e.g., within 9, 8, 7, or 6 hours or less after LKN, or between 6 and 9 hours after LKN, or within 6 hours after LKN. In embodiments, the VLA-4 antagonist is administered within 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 2 hours to 12 hours, e.g., more than 2 hours to 10 hours or less, more than 2 hours to 9 hours or less, more than 2 hours to 8 hours or less, more than 2 hours to 7 hours or less, more than 2 hours to 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within more than 2 to 9 hours or less after LKN, e.g., between 6 and 9 hours after LKN.
  • the VLA-4 antagonist is administered within more than 2 hours to 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the VLA-4 antagonist is an anti- VLA-4 antibody molecule, e.g., an anti- VLA-4 antibody molecule described herein.
  • the anti- VLA-4 antibody molecule is a monoclonal, a humanized, a human, or a chimeric anti- VLA-4 antibody molecule.
  • the VLA-4 antagonist is an a4-binding fragment of an anti- VLA-4 antibody.
  • the a4 binding fragment is an Fab, Fab', F(ab')2, or Fv fragment.
  • the anti- VLA-4 antibody molecule comprises one or more, preferably all, of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 of natalizumab.
  • the VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, is administered by intravenous
  • administration e.g., over a period of less than 90 minutes, e.g., 30 to 60 minutes.
  • the stroke is a embolism-, thrombus- or hypoperfusion-associated stroke.
  • the subject having the stroke does not have an intracranial hemorrhage.
  • the subject has not received a previous treatment with a VLA-4 antagonist, e.g., natalizumab.
  • the subject does not have or is not at risk for developing progressive multifocal leukoencephalopathy (PML).
  • PML progressive multifocal leukoencephalopathy
  • the VLA-4 antagonist is administered in combination with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered simultaneously with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered sequentially with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, after the additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, before the additional agent or procedure.
  • the additional agent ameliorates one or more side effects associated with the administration of the VLA-4 antagonist, e.g., an agent which reduces or inhibits one or more symptoms of hypersensitivity.
  • the agent which reduces or inhibits one or more symptoms of hypersensitivity can be one or more of a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), an HI antagonist and an H2 antagonist (e.g., ranitidine or famotidine).
  • a corticosteroid e.g., dexamethasone
  • an antihistamine e.g., diphenhydramine
  • an H2 antagonist e.g., ranitidine or famotidine
  • the additional agent is an agent which reduces one or more symptoms of stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), or hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or TBI.
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • TBI ischemic stroke
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the VLA-4 antagonist is administered at a dosage and/or dosing schedule described herein. In embodiments, the VLA-4 antagonist is administered intravenously.
  • a method of treating a human subject having a less severe stroke e.g., a mild or moderate ischemic stroke, e.g., a mild or moderate acute ischemic stroke, or a mild or moderate hemorrhagic stroke, e.g., a mild or moderate acute intracerebral hemorrhage, or a mild or moderate subarachnoid hemorrhage.
  • the method comprises:
  • a VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab
  • administering within more than 12 hours to 24 hours (24 inclusive), within more than 12 hours to 23 hours (23 inclusive), within more than 12 hours to 22 hours (22 inclusive), within more than 12 hours to 21 hours (21 inclusive), within more than 12 hours to 20 hours (20 inclusive), within more than 12 hours to 19 hours (19 inclusive), within more than 12 hours to 18 hours (18 inclusive), within more than 12 hours to 17 hours (17 inclusive), within more than 12 hours to 16 hours (16 inclusive), within more than 12 hours to 15 hours (15 inclusive), within more than 12 hours to 14 hours (14 inclusive), within more than 12 hours to 13 hours (13 inclusive), after LKN in the subject, thereby treating the human subject.
  • a VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule
  • the subject has, or is identified as having, a NIHSS score of 15 or less, e.g., 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • a NIHSS score of 15 or less, e.g., 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • the method comprises administering the VLA-4 antagonist, e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g.,
  • natalizumab within more than 12 hours, e.g., 12.5 hours or more, 13 hours or more, 14 hours or more, 15 hours or more, 16 hours or more, 17 hours or more, 18 hours or more, 19 hours or more, 20 hours or more, 21 hours or more, 22 hours or more, 23 hours or more, 24 hours or more, after LKN in the subject.
  • the method comprises administering the VLA-4 antagonist, e.g., the anti-alpha4 antibody molecule, e.g., the natalizumab-like antibody molecule, e.g.,
  • natalizumab within about 13 hours (e.g., 13 hours + 5%), about 14 hours (e.g., 14 hours + 10%), about 15 hours (e.g., 15 hour + 10%), about 16 hours (e.g., 16 hours + 10%), about 17 hours (e.g., 17 hours + 10%), about 18 hours (e.g., 18 hours + 10%), about 19 hours (e.g., 19 hours + 10%), about 20 hours (e.g., 20 hours + 10%), about 21 hours (e.g., 21 hours + 10%), about 22 hours (e.g., 22 hours + 10%), about 23 hours (e.g., 23 hours + 10%), or about 24 hours (e.g., 24 hours + 10%), after LKN in the subject.
  • about 14 hours e.g., 14 hours + 10%
  • about 15 hours e.g., 15 hour + 10%
  • about 16 hours e.g., 16 hours + 10%
  • about 17 hours e.g., 17 hours + 10%
  • about 18 hours e.g
  • the VLA-4 antagonist is administered to the subject within more than 13 hours to 24 hours (24 inclusive), within more than 13 hours to 23 hours (23 inclusive), within more than 13 hours to 22 hours (22 inclusive), within more than 13 hours to 21 hours (21 inclusive), within more than 13 hours to 20 hours (20 inclusive), within more than 13 hours to 19 hours (19 inclusive), within more than 13 hours to 18 hours (18 inclusive), within more than 13 hours to 17 hours (17 inclusive), within more than 13 hours to 16 hours (16 inclusive), within more than 13 hours to 15 hours (15 inclusive), within more than 13 hours to 14 hours (14 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 14 hours to 24 hours (24 inclusive), within more than 14 hours to 23 hours (23 inclusive), within more than 14 hours to 22 hours (22 inclusive), within more than 14 hours to 21 hours (21 inclusive), within more than 14 hours to 20 hours (20 inclusive), within more than 14 hours to 19 hours (19 inclusive), within more than 14 hours to 18 hours (18 inclusive), within more than 14 hours to 17 hours (17 inclusive), within more than 14 hours to 16 hours (16 inclusive), within more than 14 hours to 15 hours (15 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 15 hours to 24 hours (24 inclusive), within more than 15 hours to 23 hours (23 inclusive), within more than 15 hours to 22 hours (22 inclusive), within more than 15 hours to 21 hours (21 inclusive), within more than 15 hours to 20 hours (20 inclusive), within more than 15 hours to 19 hours (19 inclusive), within more than 15 hours to 18 hours (18 inclusive), within more than 15 hours to 17 hours (17 inclusive), within more than 15 hours to 16 hours (16 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 16 hours to 24 hours (24 inclusive), within more than 16 hours to 23 hours (23 inclusive), within more than 16 hours to 22 hours (22 inclusive), within more than 16 hours to 21 hours (21 inclusive), within more than 16 hours to 20 hours (20 inclusive), within more than 16 hours to 19 hours (19 inclusive), within more than 16 hours to 18 hours (18 inclusive), within more than 16 hours to 17 hours (17 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 17 hours to 24 hours (24 inclusive), within more than 17 hours to 23 hours (23 inclusive), within more than 17 hours to 22 hours (22 inclusive), within more than 17 hours to 21 hours (21 inclusive), within more than 17 hours to 20 hours (20 inclusive), within more than 17 hours to 19 hours (19 inclusive), within more than 17 hours to 18 hours (18 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 18 hours to 24 hours (24 inclusive), within more than 18 hours to 23 hours (23 inclusive), within more than 18 hours to 22 hours (22 inclusive), within more than 18 hours to 21 hours (21 inclusive), within more than 18 hours to 20 hours (20 inclusive), within more than 18 hours to 19 hours (19 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 19 hours to 24 hours (24 inclusive), within more than 19 hours to 23 hours (23 inclusive), within more than 19 hours to 22 hours (22 inclusive), within more than 19 hours to 21 hours (21 inclusive), within more than 19 hours to 20 hours (20 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 20 hours to 24 hours (24 inclusive), within more than 20 hours to 23 hours (23 inclusive), within more than 20 hours to 22 hours (22 inclusive), within more than 20 hours to 21 hours (21 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 21 hours to 24 hours (24 inclusive), within more than 21 hours to 23 hours (23 inclusive), within more than 21 hours to 22 hours (22 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 22 hours to 24 hours (24 inclusive), within more than 22 hours to 23 hours (23 inclusive), after LKN in the subject.
  • the VLA-4 antagonist is administered to the subject within more than 23 hours to 24 hours (24 inclusive), after LKN in the subject.
  • a method of treating a human subject having a stroke comprising: administering a VLA-4 antagonist, e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab like antibody molecule, e.g., natalizumab, to the subject, at a dosage of
  • a VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab like antibody molecule, e.g., natalizumab
  • a dosage that results in an AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • an AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • a dosage that results in an AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • the method comprises determining, e.g., determining prior to
  • determining comprises determining NIHSS score, e.g., determining if the NIHSS score is equal to or less than 15, e.g., 5 to 15 points, e.g., less than 14, 13 12, 11, 10, 9, 8, 7, 6, 5, 4, or less.
  • the subject has a less than severe stroke.
  • the subject has a mild stroke.
  • the subject has a mild to moderate stroke.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 3 to 7.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 8 to 10.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 11 to 14.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 15 to 14.
  • administration is initiated within 6 hours of last known normal. In embodiments, administration is initiated within 9 hours, e.g., 6 to 9 hours, of last known normal. In embodiments, administration is initiated within 12 hours, e.g., 6 to 12 hours, or 9 to 12 hours, of last known normal.
  • the dosage is about 300 mg.
  • the method comprises administering a VLA-4 antagonist to the subject, e.g. , within more than 9 hours to 24 hours (24 inclusive), within more than 9 hours to 23 hours (23 inclusive), within more than 9 hours to 22 hours (22 inclusive), within more than 9 hours to 21 hours (21 inclusive), within more than 9 hours to 20 hours (20 inclusive), within more than 9 hours to 19 hours (19 inclusive), within more than 9 hours to 18 hours (18 inclusive), within more than 9 hours to 17 hours (17 inclusive), within more than 9 hours to 16 hours (16 inclusive), within more than 9 hours to 15 hours (15 inclusive), within more than 9 hours to 14 hours (14 inclusive), within more than 9 hours to 13 hours (13 inclusive), within more than 9 hours to 12 hours (12 inclusive), within more than 9 hours to 11 hours (11 inclusive), or within more than 9 hours to 10 hours (10 inclusive), after LKN in the subject and the subject, e.g.
  • a natalizumab-like antibody molecule e.g. , natalizumab
  • a NIHSS score of 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 9 hours to 24 hours (24 inclusive) after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 5 to 15, inclusive.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody e.g. , a natalizumab-like antibody molecule
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g.
  • a natalizumab-like antibody molecule (e.g. , natalizumab), is administered, e.g. , at a dosage of about 600 mg, e.g. , IV, e.g. , at a single dosage of 600 mg IV.
  • the VLA-4 antagonist comprises an antibody molecule that comprises CDRl, CDR2 and CDR3 from the light chain and CDRl, CDR2 and CDR3 from the heavy chain of natalizumab. In embodiments, the VLA-4 antagonist comprises an antibody molecule that comprises the light chain variable region and the heavy chain variable region of natalizumab. In embodiments, the VLA-4 antagonist comprises natalizumab.
  • the method comprises administering a VLA-4 antagonist to the subject within 12 hours or less, e.g., 10, 9, 8, 7, 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within 9 hours or less after LKN, e.g., within 9, 8, 7, or 6 hours or less after LKN, or between 6 and 9 hours after LKN, or within 6 hours after LKN. In embodiments, the VLA-4 antagonist is administered within 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 2 hours to 12 hours, e.g., more than 2 hours to 10 hours or less, more than 2 hours to 9 hours or less, more than 2 hours to 8 hours or less, more than 2 hours to 7 hours or less, more than 2 hours to 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within more than 2 to 9 hours or less after LKN, e.g., between 6 and 9 hours after LKN.
  • the VLA-4 antagonist is administered within more than 2 hours to 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the VLA-4 antagonist is an anti- VLA-4 antibody molecule, e.g., an anti- VLA-4 antibody molecule described herein.
  • the anti- VLA-4 antibody molecule is a monoclonal, a humanized, a human, or a chimeric anti- VLA-4 antibody molecule.
  • the VLA-4 antagonist is an a4-binding fragment of an anti- VLA-4 antibody.
  • the a4 binding fragment is an Fab, Fab', F(ab') 2 , or Fv fragment.
  • the anti- VLA-4 antibody molecule comprises one or more, preferably all, of HC CDRl, HC CDR2, HC CDR3, LC CDRl, LC CDR2 and LC CDR3 of natalizumab.
  • the VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, is administered by intravenous
  • administration e.g., over a period of less than 90 minutes, e.g., 30 to 60 minutes.
  • the stroke is a embolism-, thrombus- or hypoperfusion-associated stroke.
  • the subject having the stroke does not have an intracranial hemorrhage.
  • the subject has not received a previous treatment with a VLA-4 antagonist, e.g., natalizumab.
  • a VLA-4 antagonist e.g., natalizumab.
  • the subject does not have or is not at risk for developing progressive multifocal leukoencephalopathy (PML).
  • PML progressive multifocal leukoencephalopathy
  • the VLA-4 antagonist is administered in combination with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered simultaneously with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered sequentially with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, after the additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, before the additional agent or procedure.
  • the additional agent ameliorates one or more side effects associated with the administration of the VLA-4 antagonist, e.g., an agent which reduces or inhibits one or more symptoms of hypersensitivity.
  • the agent which reduces or inhibits one or more symptoms of hypersensitivity can be one or more of a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), an HI antagonist and an H2 antagonist (e.g., ranitidine or famotidine).
  • a corticosteroid e.g., dexamethasone
  • an antihistamine e.g., diphenhydramine
  • an H2 antagonist e.g., ranitidine or famotidine
  • the additional agent is an agent which reduces one or more symptoms of stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), or hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or TBI.
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • TBI ischemic stroke
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the VLA-4 antagonist is administered at a dosage and/or dosing schedule described herein. In embodiments, the VLA-4 antagonist is administered intravenously.
  • a method of treating a human subject having a less than severe stroke e.g., a less than severe ischemic stroke, e.g., a less than severe acute ischemic stroke, or a less than severe hemorrhagic stroke, e.g., a less than severe intracerebral hemorrhage or a less than severe subarachnoid hemorrhage, or a less than severe TBI, comprising:
  • VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, to the subject.
  • a VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab
  • the subject has a mild stroke. In embodiments, the subject has a mild to moderate stroke.
  • the method comprises determining, e.g., determining prior to
  • determining comprises determining NIHSS score, e.g., determining if the NIHSS score is less than 15.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with the VLA-4 antagonist has a NIHSS score of 3 to 7. In embodiments, the subject, e.g., at baseline, e.g., after stroke onset but prior to treatment with the VLA-4 antagonist has a NIHSS score of 8 to 10. In embodiments, the subject, e.g., at baseline, e.g., after stroke onset but prior to treatment with the VLA-4 antagonist has a NIHSS score of 11 to 14.
  • administration is initiated within 6 hours of last known normal. In embodiments, administration is initiated within 9 hours, e.g., 6 to 9 hours, of last known normal. In embodiments, administration is initiated within 12 hours, e.g., 6 to 12 hours, or 9 to 12 hours, of last known normal.
  • the method further comprises providing a subsequent administration of the VLA-4 antagonist to the subject.
  • the method comprises administering a VLA-4 antagonist to the subject, e.g. , within more than 9 hours to 24 hours (24 inclusive), within more than 9 hours to 23 hours (23 inclusive), within more than 9 hours to 22 hours (22 inclusive), within more than 9 hours to 21 hours (21 inclusive), within more than 9 hours to 20 hours (20 inclusive), within more than 9 hours to 19 hours (19 inclusive), within more than 9 hours to 18 hours (18 inclusive), within more than 9 hours to 17 hours (17 inclusive), within more than 9 hours to 16 hours (16 inclusive), within more than 9 hours to 15 hours (15 inclusive), within more than 9 hours to 14 hours (14 inclusive), within more than 9 hours to 13 hours (13 inclusive), within more than 9 hours to 12 hours (12 inclusive), within more than 9 hours to 11 hours (11 inclusive), or within more than 9 hours to 10 hours (10 inclusive), after LKN in the subject and the subject, e.g.
  • a natalizumab-like antibody molecule e.g. , natalizumab
  • a NIHSS score of 5 to 15, inclusive; 5 to 14, inclusive; 5 to 13, inclusive; 5 to 12, inclusive; 5 to 11, inclusive; 5 to 10, inclusive; 5 to 9, inclusive; 5 to 8, inclusive; 5 to 7, inclusive; or 5 to 6, inclusive.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 9 hours to 24 hours (24 inclusive) after LKN in the subject and the subject, e.g. , at baseline, e.g. , after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g. , natalizumab, has a NIHSS score of 5 to 15, inclusive.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g.
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g. , a natalizumab-like antibody molecule (e.g. , natalizumab)
  • the VLA-4 antagonist, e.g. , the VLA-4 binding antibody e.g. , a natalizumab-like antibody molecule
  • the VLA-4 antagonist e.g. , the VLA-4 binding antibody, e.g.
  • a natalizumab-like antibody molecule (e.g. , natalizumab), is administered, e.g. , at a dosage of about 600 mg, e.g. , IV, e.g. , at a single dosage of 600 mg IV.
  • the VLA-4 antagonist comprises an antibody molecule that comprises CDRl, CDR2 and CDR3 from the light chain and CDRl, CDR2 and CDR3 from the heavy chain of natalizumab. In embodiments, the VLA-4 antagonist comprises an antibody molecule that comprises the light chain variable region and the heavy chain variable region of natalizumab. In embodiments, the VLA-4 antagonist comprises natalizumab. In embodiments, the method comprises administering a VLA-4 antagonist to the subject within 12 hours or less, e.g., 10, 9, 8, 7, 6 hours or less, after LKN in the subject. In
  • the VLA-4 antagonist is administered within 9 hours or less after LKN, e.g., within 9, 8, 7, or 6 hours or less after LKN, or between 6 and 9 hours after LKN, or within 6 hours after LKN. In embodiments, the VLA-4 antagonist is administered within 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 2 hours to 12 hours, e.g., more than 2 hours to 10 hours or less, more than 2 hours to 9 hours or less, more than 2 hours to 8 hours or less, more than 2 hours to 7 hours or less, more than 2 hours to 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within more than 2 to 9 hours or less after LKN, e.g., between 6 and 9 hours after LKN.
  • the VLA-4 antagonist is administered within more than 2 hours to 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the VLA-4 antagonist is an anti- VLA-4 antibody molecule, e.g., an anti- VLA-4 antibody molecule described herein.
  • the anti- VLA-4 antibody molecule is a monoclonal, a humanized, a human, or a chimeric anti- VLA-4 antibody molecule.
  • the VLA-4 antagonist is an a4-binding fragment of an anti- VLA-4 antibody.
  • the a4 binding fragment is an Fab, Fab', F(ab') 2 , or Fv fragment.
  • the anti- VLA-4 antibody molecule comprises one or more, preferably all, of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 of natalizumab.
  • the VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, is administered by intravenous
  • administration e.g., over a period of less than 90 minutes, e.g., 30 to 60 minutes.
  • the stroke is a embolism-, thrombus- or hypoperfusion-associated stroke.
  • the subject having the stroke does not have an intracranial hemorrhage.
  • the subject has not received a previous treatment with a VLA-4 antagonist, e.g., natalizumab.
  • a VLA-4 antagonist e.g., natalizumab.
  • the subject does not have or is not at risk for developing progressive multifocal leukoencephalopathy (PML).
  • the VLA-4 antagonist is administered in combination with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered simultaneously with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered sequentially with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, after the additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, before the additional agent or procedure.
  • the additional agent ameliorates one or more side effects associated with the administration of the VLA-4 antagonist, e.g., an agent which reduces or inhibits one or more symptoms of hypersensitivity.
  • the agent which reduces or inhibits one or more symptoms of hypersensitivity can be one or more of a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), an HI antagonist and an H2 antagonist (e.g., ranitidine or famotidine).
  • a corticosteroid e.g., dexamethasone
  • an antihistamine e.g., diphenhydramine
  • an H2 antagonist e.g., ranitidine or famotidine
  • the additional agent is an agent which reduces one or more symptoms of stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), or hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or TBI.
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • TBI ischemic stroke
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the VLA-4 antagonist is administered at a dosage and/or dosing schedule described herein. In embodiments, the VLA-4 antagonist is administered intravenously.
  • a stroke e.g., an ischemic stroke, e.g., an acute ischemic stroke, a hemorrhagic stroke, e.g., an intracerebral hemorrhage or a subarachnoid hemorrhage, or a traumatic brain injury (TBI)
  • ischemic stroke e.g., an acute ischemic stroke
  • hemorrhagic stroke e.g., an intracerebral hemorrhage or a subarachnoid hemorrhage
  • TBI traumatic brain injury
  • determining the severity of a stroke e.g., by receiving information, e.g., from a third party, on the severity of the stroke (or TBI), and responsive to that determination, selecting a dosage of a VLA-4 antagonist, e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab,
  • a VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab
  • the method further comprises administering the selected dosage to the subject.
  • the method comprises, if the stroke is determined to be a severe stroke, selecting and/or administering a dosage-A of the VLA-4 antagonist and if the stroke is determined to be a less than severe stroke, selecting and or administering a dosage-B, e.g., wherein the dosage-A is higher than dosage-B, e.g., is at least 10, 20 or 30% higher.
  • dosage-A is 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg; or 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg.
  • dosage-A is 350 to 500 mg.
  • dosage-A is 390 to 450 mg.
  • dosage-A is 450 +/- 5% mg.
  • dosage-A is about 450 mg.
  • dosage-A is 450 mg.
  • dosage-A is 550 to 650 mg.
  • dosage-A is 575 to 625 mg. In embodiments, dosage-A is 600 +/- 5% mg. In embodiments, dosage-A is about 600 mg. In embodiments, dosage-A is 600 mg. In embodiments, dosage-A results in an AUC (e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days) of at least about 20,000 to 30,000, e.g., at least about 20,000, 25,000, or 30,000 mg*hr/L; or wherein dosage-A is results in an AUC that is comparable or higher than (e.g., within 5-10% of) the median exposure observed in lower body weight (e.g., body weight of ⁇ 80 kg) or less severe stroke patients.
  • AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • AUC e.g
  • dosage-B is 250 to 390, e.g., 275 to 325, e.g., 300 +/- 5%, or about 300, e.g., 300, mgs. In embodiments, dosage-B is 250 to 390 mg. In embodiments, dosage-B is 275 to 325 mg. In embodiments, dosage-B is 300 +/- 5% mg. In embodiments, dosage-B is about 300 mg. In embodiments, dosage-B is 300 mg.
  • dosage-B results in an AUC (e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days) of at least about 20,000 to 30,000, e.g., at least about 20,000, 25,000, or 30,000, mg*hr/L; or wherein dosage-B is results in an AUC thatis comparable or higher than (e.g., within 5-10% of) the median exposure observed in lower body weight (e.g., body weight of ⁇ 80 kg) or less severe stroke patients.
  • AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • dosage-B is results in an AUC thatis comparable
  • determining comprises determining a NIHSS score, e.g., determining if the NIHSS score is equal to or greater than 15 or 21. In embodiments, determining comprises determining if the NIHSS score is equal to or greater than 15. In embodiments, determining comprises determining if the NIHSS score is equal to or greater than 21.
  • the method comprises determining that the stroke is a severe stroke.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 21 or greater, e.g., 21 to 26.
  • the NIHSS score is equal to or greater than 15.
  • the NIHSS score is equal to or greater than 21.
  • determining comprises determining NIHSS score, e.g., determining if the NIHSS score is less than 15.
  • the stroke is determined to be less than severe. In embodiments, the stroke is mild stroke. In embodiments, the stroke is a mild to moderate stroke.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 3 to 7.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 8 to 10.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 11 to 14.
  • the subject e.g., at baseline, e.g., after stroke onset but prior to treatment with a natalizumab-like antibody molecule, e.g., natalizumab, has a NIHSS score of 5 to 14.
  • administration is initiated within 6 hours of last known normal. In embodiments, administration is initiated within 9 hours, e.g., 6 to 9 hours, of last known normal. In embodiments, administration is initiated within 12 hours, e.g., 6 to 12 hours, or 9 to 12 hours, of last known normal.
  • the VLA-4 antagonist comprises an antibody molecule that comprises CDRl, CDR2 and CDR3 from the light chain and CDRl, CDR2 and CDR3 from the heavy chain of natalizumab. In embodiments, he VLA-4 antagonist comprises an antibody molecule that comprises the light chain variable region and the heavy chain variable region of natalizumab. In embodiments, the VLA-4 antagonist comprises natalizumab. In embodiments, the method comprises administering a VLA-4 antagonist to the subject within 12 hours or less, e.g., 10, 9, 8, 7, 6 hours or less, after LKN in the subject. In
  • the VLA-4 antagonist is administered within 9 hours or less after LKN, e.g., within 9, 8, 7, or 6 hours or less after LKN, or between 6 and 9 hours after LKN, or within 6 hours after LKN. In embodiments, the VLA-4 antagonist is administered within 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 2 hours to 12 hours, e.g., more than 2 hours to 10 hours or less, more than 2 hours to 9 hours or less, more than 2 hours to 8 hours or less, more than 2 hours to 7 hours or less, more than 2 hours to 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within more than 2 to 9 hours or less after LKN, e.g., between 6 and 9 hours after LKN.
  • the VLA-4 antagonist is administered within more than 2 hours to 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the VLA-4 antagonist is an anti- VLA-4 antibody molecule, e.g., an anti- VLA-4 antibody molecule described herein.
  • the anti- VLA-4 antibody molecule is a monoclonal, a humanized, a human, or a chimeric anti- VLA-4 antibody molecule.
  • the VLA-4 antagonist is an a4-binding fragment of an anti- VLA-4 antibody.
  • the a4 binding fragment is an Fab, Fab', F(ab')2, or Fv fragment.
  • the anti- VLA-4 antibody molecule comprises one or more, preferably all, of HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 of natalizumab.
  • the VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, is administered by intravenous
  • administration e.g., over a period of less than 90 minutes, e.g., 30 to 60 minutes.
  • the stroke is a embolism-, thrombus- or hypoperfusion-associated stroke.
  • the subject having the stroke does not have an intracranial hemorrhage.
  • the subject has not received a previous treatment with a VLA-4 antagonist, e.g., natalizumab.
  • a VLA-4 antagonist e.g., natalizumab.
  • the subject does not have or is not at risk for developing progressive multifocal leukoencephalopathy (PML).
  • PML progressive multifocal leukoencephalopathy
  • the VLA-4 antagonist is administered in combination with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered simultaneously with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered sequentially with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, after the additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, before the additional agent or procedure.
  • the additional agent ameliorates one or more side effects associated with the administration of the VLA-4 antagonist, e.g., an agent which reduces or inhibits one or more symptoms of hypersensitivity.
  • the agent which reduces or inhibits one or more symptoms of hypersensitivity can be one or more of a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), an HI antagonist and an H2 antagonist (e.g., ranitidine or famotidine).
  • a corticosteroid e.g., dexamethasone
  • an antihistamine e.g., diphenhydramine
  • an H2 antagonist e.g., ranitidine or famotidine
  • the additional agent is an agent which reduces one or more symptoms of stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or TBI.
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • TBI ischemic stroke
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the VLA-4 antagonist is administered at a dosage and/or dosing schedule described herein. In embodiments, the VLA-4 antagonist is administered intravenously.
  • a stroke e.g., an ischemic stroke, e.g., an acute ischemic stroke, a hemorrhagic stroke, e.g., an intracerebral hemorrhage or a subarachnoid hemorrhage, or a traumatic brain injury (TBI)
  • ischemic stroke e.g., an acute ischemic stroke
  • hemorrhagic stroke e.g., an intracerebral hemorrhage or a subarachnoid hemorrhage
  • TBI traumatic brain injury
  • the method comprises administering a third dosage of a VLA-4 antagonist to the subject at a time t3.
  • the three dosages result in an AUC (e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days) of at least about 20,000 to 30,000, e.g., at least about 20,000, 25,000, or 30,000 mg*hr/L.
  • the three dosages result in an AUC that is comparable to or higher than (e.g., within 5-10% of) the median AUC of a less than severe stroke patient or a patient having a lower body weight (e.g., of ⁇ 80 kg).
  • the first dosage is greater than one or both of the second and third dosages. In embodiments, the first dosage is the same as one or both of the second and third dosages, e.g., wherein all three dosages are the same.
  • tl is the day (i.e., within 24 hours) of diagnosis.
  • At least one or more days are interposed between tl and t2.
  • about 2 days e.g., 36-60 hours, e.g., 40-56 hours, e.g., 44-52 hours, e.g., about 48 hours
  • at least one or more days are interposed between t2 and t3.
  • about 2 days are interposed between t2 and t3.
  • tl is the day on which the first dosage is administered; g2 is the third day after tl, (e.g., if tl is a Monday, then t2 is the first following Wednesday); and t3 is the fifth day after tl.
  • the first dosage is 250 to 350 mg
  • the second dosage is 100 to 200 mg
  • the third dosage is 100 to 200 mg.
  • the first dosage is 275 to 325 mg
  • the second dosage is 125 mg to 175 mg
  • the third dosage is 125 to 175 mg.
  • the first dosage is 300+/- 5% mg
  • the second dosage is 150+/- 5% mg
  • the third dosage is 150+/- 5% mg.
  • the first dosage is about 300 mg
  • the second dosage is about 150 mg
  • the third dosage is about 150 mg.
  • the first dosage is 300 mg
  • the second dosage is 150 mg
  • the third dosage is 150 mg.
  • the first, second and third dosage each is 100 to 200 mg.
  • the first, second and third dosage each is 125 to 175 mg.
  • the first, second and third dosage each is 150+/- 5% mg.
  • the first, second and third dosage each is about 150 mg. In embodiments, the first, second and third dosage, each is 150 mg.
  • the subject has a severe stroke, e.g., a stroke having a NIHSS score equal to or greater than 15 or 21.
  • the NIHSS score is equal to or greater than 15.
  • the NIHSS score is equal to or greater than 21.
  • the subject has a less than severe stroke, e.g., a stroke having a NIHSS score of less than 15.
  • the subject has a mild stroke.
  • the subject has a mild to moderate stroke.
  • the method comprises determining, e.g., determining prior to
  • the severity of the stroke e.g., determining if the patient has a severe stroke.
  • determining comprises determining a NIHSS score, e.g., determining if the NIHSS score is equal to or greater than 15 or 21. In embodiments, determining comprises determining if the NIHSS score is equal to or greater than 15. In embodiments, determining comprises determining if the NIHSS score is equal to or greater than 21.
  • the method comprises determining, e.g., determining prior to
  • the severity of the stroke e.g., determining if the patient has less than severe stroke.
  • determining comprises determining a NIHSS score, e.g., determining if the NIHSS score is less than 15.
  • a dosage of anti-VLA4 antagonist is selected.
  • administration of the first dosage is initiated within 6 hours of last known normal. In embodiments, administration of the first dosage is initiated within 9 hours, e.g., 6 to 9 hours, of last known normal. In embodiments, administration of the first dosage is initiated within 12 hours, e.g., 6 to 12 hours, or 9 to 12 hours, of last known normal.
  • the VLA-4 antagonist comprises an antibody molecule that comprises CDRl, CDR2 and CDR3 from the light chain and CDRl, CDR2 and CDR3 from the heavy chain of natalizumab. In embodiments, the VLA-4 antagonist comprises an antibody molecule that comprises the light chain variable region and the heavy chain variable region of natalizumab. In embodiments, the VLA-4 antagonist comprises natalizumab.
  • the method comprises administering a VLA-4 antagonist to the subject within 12 hours or less, e.g., 10, 9, 8, 7, 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within 9 hours or less after LKN, e.g., within 9, 8, 7, or 6 hours or less after LKN, or between 6 and 9 hours after LKN, or within 6 hours after LKN. In embodiments, the VLA-4 antagonist is administered within 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the method comprises administering a VLA-4 antagonist to the subject within more than 2 hours to 12 hours, e.g., more than 2 hours to 10 hours or less, more than 2 hours to 9 hours or less, more than 2 hours to 8 hours or less, more than 2 hours to 7 hours or less, more than 2 hours to 6 hours or less, after LKN in the subject.
  • the VLA-4 antagonist is administered within more than 2 to 9 hours or less after LKN, e.g., between 6 and 9 hours after LKN.
  • the VLA-4 antagonist is administered within more than 2 hours to 6 hours or less after LKN, e.g., between 3 and 6 hours, 4.5 to 6 hours, 5 to 6 hours, after LKN.
  • the VLA-4 antagonist is an anti- VLA-4 antibody molecule, e.g., an anti- VLA-4 antibody molecule described herein.
  • the anti- VLA-4 antibody molecule is a monoclonal, a humanized, a human, or a chimeric anti- VLA-4 antibody molecule.
  • the VLA-4 antagonist is an a4-binding fragment of an anti- VLA-4 antibody.
  • the a4 binding fragment is an Fab, Fab', F(ab') 2 , or Fv fragment.
  • the anti- VLA-4 antibody molecule comprises one or more, preferably all, of HC CDRl, HC CDR2, HC CDR3, LC CDRl, LC CDR2 and LC CDR3 of natalizumab.
  • the VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule, e.g., natalizumab, is administered by intravenous
  • administration e.g., over a period of less than 90 minutes, e.g., 30 to 60 minutes.
  • the stroke is a embolism-, thrombus- or hypoperfusion-associated stroke.
  • the subject having the stroke does not have an intracranial hemorrhage.
  • the subject has not received a previous treatment with a VLA-4 antagonist, e.g., natalizumab.
  • a VLA-4 antagonist e.g., natalizumab.
  • the subject does not have or is not at risk for developing progressive multifocal leukoencephalopathy (PML).
  • PML progressive multifocal leukoencephalopathy
  • the VLA-4 antagonist is administered in combination with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered simultaneously with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered sequentially with an additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, after the additional agent or procedure. In embodiments, the VLA-4 antagonist is administered, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, before the additional agent or procedure.
  • the additional agent ameliorates one or more side effects associated with the administration of the VLA-4 antagonist, e.g., an agent which reduces or inhibits one or more symptoms of hypersensitivity.
  • the agent which reduces or inhibits one or more symptoms of hypersensitivity can be one or more of a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), an HI antagonist and an H2 antagonist (e.g., ranitidine or famotidine).
  • a corticosteroid e.g., dexamethasone
  • an antihistamine e.g., diphenhydramine
  • an H2 antagonist e.g., ranitidine or famotidine
  • the additional agent is an agent which reduces one or more symptoms of stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or TBI.
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • TBI ischemic stroke
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the VLA-4 antagonist is administered at a dosage and/or dosing schedule described herein. In embodiments, the VLA-4 antagonist is administered intravenously.
  • the subject is evaluated using one or more of the modified Rankin Scale (mRS), Barthel Index (BI), Stroke Impact Scale-16 (SIS-16), Montreal Cognitive Assessment (MoCA), safety, the National Institutes of Health Stroke Scale (NIHSS), Functional Independent Measure (FIM), Symbol-Digits Modalities Test (SDMT), Fatigue Severity Scale (FSS), Beck Depression Inventory 2 (BDI-2) score, Glasgow Outcome Scale, pharmacokinetic assessments (e.g., serum concentration of natalizumab, e.g., at selected times after dosing), pharmacodynamics assessments (e.g., serum cytokines, inflammatory markers of stroke, or blood biomarkers of natalizumab, e.g., blood biomarkers of natalizuma
  • the subject is evaluated by determining mRS score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • a positive outcome is defined as an mRS score of 0 or 1, e.g., at day 90.
  • the subject is evaluated by determining BI score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • a positive outcome is defined as a BI score of at least 95, e.g., at day 90.
  • a positive outcome is defined as an mRS score of 0 or 1 and a BI score of at least 95, e.g., at day 90.
  • the subject is evaluated by determining SIS-16 score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining MoCA score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • a severe cognitive impairment is defined as a MoCA score below 10.
  • a moderate cognitive impairment is defined as a MoCA score of 10 to 17 inclusive.
  • a mild cognitive impairment is defined as a MoCA score greater than or equal to 18.
  • the subject is evaluated by determining a safety score, e.g., incidence and/or proportion of adverse events and serious adverse events, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • a safety score e.g., incidence and/or proportion of adverse events and serious adverse events, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55
  • the subject is evaluated by determining FIM score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • predetermined time periods e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining SDMT score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • predetermined time periods e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining FSS score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • predetermined time periods e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining BDI-2 score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining serum
  • concentration of natalizumab e.g., at selected times after dosing, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining blood biomarkers of natalizumab, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • a blood biomarkers of natalizumab e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining subject direct resource use, e.g., assessed using a health resource utilization questionnaire, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first
  • the subject is evaluated by determining EuroQoL EQ-5D-3L score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • predetermined time periods e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the subject is evaluated by determining NIHSS score, e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • NIHSS score e.g., at one or more predetermined time periods, e.g., 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein (e.g, after first administration of a VLA-4 antagonist).
  • the NIHSS classifies the severity of a stroke based on a subject's ability to answer questions and perform activities relating to level of consciousness, language, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, sensory loss and extinction and inattention. Generally, there are 15 items and ratings for each item are scored with 3 to 5 grades with 0 as normal and a maximum severity score of 42 for all items. In some embodiments, NIHSS of 1-4 is indicative of a minor stroke; a score of 5-15 is indicative of a moderate stroke, a score of 16-20 is indicative of a moderate to severe stroke; and a score of 21-42 is indicative of a severe stroke.
  • a treatment described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the method further comprises monitoring the subject after administration of the VLA-4 antagonist using one or more of the modified Rankin Scale (mRS), Barthel Index (BI), Stroke Impact Scale-16 (SIS-16), Montreal Cognitive Assessment (MoCA), safety, the National Institutes of Health Stroke Scale (NIHSS), Functional Independence Measure (FEVI), Symbol-Digits Modalities Test (SDMT), Fatigue Severity Scale (FSS), Beck Depression Inventory 2 (BDI-2) score, Glasgow Outcome Scale, pharmacokinetic assessments (e.g., serum concentration of natalizumab, e.g., at selected times after dosing), pharmacodynamics assessments (e.g., serum cytokines, inflammatory markers of stroke, or blood biomarkers of natalizumab, e.g., blood biomarkers of natalizumab target engagement), infarct volume, subject direct resource use, or EuroQoL EQ-5D-3L.
  • mRS modified Rankin Scale
  • FIG. 1 is a schematic showing the Phase II trial protocol described in the Examples section.
  • FIG. 2 is a graph showing the median infarct volume over time in patients treated with natalizumab or placebo.
  • FIG. 3 is a set of schematics showing the functional outcomes (modified Rankin Scale scores) of patients treated with natalizumab or placebo at 30 or 90 days.
  • FIG. 4 is a graph showing the median Barthel's index (BI) scores over time in patients treated with natalizumab or placebo.
  • FIG. 5 is a graph showing the median NIHSS scores over time of patients treated with natalizumab or placebo.
  • FIG. 6 is a graph showing the median SIS-16 scores over time of patients treated with natalizumab or placebo.
  • FIG. 7 is a graph showing the median Montreal Cognitive Assessment (MoCA) scores over time of patients treated with natalizumab or placebo.
  • MoCA Montreal Cognitive Assessment
  • FIG. 8 is a set of graphs showing the PK profile of natalizumab in stroke and multiple sclerosis (MS) patients.
  • Studies 1801, 1802, 1803, 102, and 1805 refer to MS studies;
  • study 201 refers to the ACTION study on acute ischemic stroke, as described herein.
  • the data points indicate the mean +/- standard deviation of serum natalizumab concentration.
  • FIG. 9 is a table illustrating the scoring methodology for the Bartel Index.
  • FIG. 10 is a table illustrating the scoring methodology for NIHSS.
  • FIG. 11A, 1 IB, and 11C are plots showing the relationship between AUC and weight (11 A), baseline infarct volume (11B), and baseline NIHSS score (11C).
  • FIG. 12A and 12B are graphs showing the relationship between Cmax and baseline NIHSS score (FIG. 12A) or between AUC and baseline NIHSS score (FIG. 12B).
  • FIG. 13 is a set of plots and table showing the Cmax and AUC (0-672 hours) of
  • FIG. 14 is a graph showing the functional outcomes (modified Rankin Scale (mRS) ⁇ 1) of patients treated with natalizumab or placebo at day 30 or day 90. Highlighted in the box are data for patients who received study treatment at ⁇ 6 hours from last known normal (LKN) or received study treatment within the >6 to ⁇ 9 hour window.
  • mRS modified Rankin Scale
  • FIG 15 is a graph showing the study design of 101SK202.
  • VLA-4 antagonists such as natalizumab can effectively improve clinical outcomes for victims of stroke, e.g., an ischemic stroke, e.g., an acute ischemic stroke, e.g., when administered within a specified time period after the last known normal (LKN).
  • administration of a VLA-4 antagonist e.g., an anti- alpha4 antibody molecule, e.g.
  • natalizumab to a subject, e.g., a patient with acute ischemic stroke, during a treatment window, e.g., initiated up to 5 days (e.g., within 24 hours or less) after last known normal (LKN) can have beneficial effects, e.g., an improvement in a clinical outcome, such as functional independence, activities of daily living, and/or cognitive ability.
  • a treatment window e.g., initiated up to 5 days (e.g., within 24 hours or less) after last known normal (LKN)
  • beneficial effects e.g., an improvement in a clinical outcome, such as functional independence, activities of daily living, and/or cognitive ability.
  • therapies targeting lymphocyte infiltration after ischemia can still have beneficial effects when administration of the therapy is initiated at a later time point than previously
  • the treatment window can be tailored, at least in part, based on the severity of the stroke.
  • a subject with a moderate or mild stroke e.g., having an NIHSS score of 5 to 15 points at baseline can have a longer treatment window, e.g., within 24 hours or less after LKN, compared to a subject with a severe stroke, e.g., having an NIHSS score of 15 points or higher at baseline, e.g., having a treatment window of 9 hours or less.
  • the administration of a VLA-4 antagonist e.g., natalizumab to a subject within a period of nine hours or less, e.g., 8, 7, 6 hours or less, after LKN, e.g., an ischemic stroke, e.g., acute ischemic stroke, provides an improvement in clinical outcomes, such as functional independence, activities of daily living, and/or cognitive ability.
  • LKN e.g., an ischemic stroke, e.g., acute ischemic stroke
  • the administration of a VLA-4 antagonist e.g., natalizumab to a subject within a period of 12 hours or less (e.g., 12, 11, 10, 9 hours or less) after LKN may provide an improvement in clinical outcomes.
  • a VLA-4 antagonist e.g., natalizumab
  • treatment of stroke e.g., acute ischemic stroke
  • a VLA-4 antagonist e.g., natalizumab, e.g., at a dosage of 250 to 650 mg
  • a dosage of 250 to 650 mg provides an extended time period for treating subjects having a stroke as compared to other approved treatments such as rtPA.
  • Embodiments of the invention are also based, at least in part, on the discovery that when administered a dosage of a VLA-4 antagonist, e.g., natalizumab, stroke patients vary in the exposure that they have to the drug. Results described herein show that patients having a higher exposure to the VLA-4 antagonist, e.g., natalizumab, tended to exhibit better clinical outcomes than those having a lower exposure to the drug. As described in the Example, exposure (e.g., as measured by area under the curve (AUC)) correlated with a number of factors including weight, baseline infarct volume, and baseline severity of stroke.
  • AUC area under the curve
  • compositions and methods that provide a dosage of VLA-4 antagonist, e.g., natalizumab-like antibody molecule (e.g., natalizumab), that ensures that a majority of stroke patients (e.g., patients with various weights; patients who have large infarct volumes at baseline; patients who have small infarct volumes at baseline; patients who have suffered a less than severe stroke (e.g., mild, or mild to moderate); as well as patients who have suffered a severe stroke) receive adequate coverage/exposure of the drug.
  • VLA-4 antagonist e.g., natalizumab-like antibody molecule
  • a majority of stroke patients e.g., patients with various weights; patients who have large infarct volumes at baseline; patients who have small infarct volumes at baseline; patients who have suffered a less than severe stroke (e.g., mild, or mild to moderate); as well as patients who have suffered a severe stroke) receive adequate coverage/exposure of the drug.
  • An exemplary dosage range of a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab), includes 250 to 350, e.g., about 300, e.g., 300, mg; 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg; or 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg.
  • the dosage of VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab) is sufficient to achieve an AUC (e.g., over a period of time of 0- 10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0- 120 days) at least about 20,000 to 30,000, e.g., at least about 20,000, 25,000, or 30,000 mg*hr/L.
  • AUC e.g., over a period of time of 0- 10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0- 120 days
  • the dosage of VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab) is sufficient to result in an AUC that is comparable to or higher than (e.g., within 5-10% of) the median AUC of a less than severe stroke patient or a patient having a lower body weight (e.g., of ⁇ 80 kg).
  • the dosage can be tailored to the patient characteristics, e.g., severity of stroke, at baseline. For example, a patient having a more severe stroke is administered a higher dosage of the VLA-4 antagonist, e.g. a natalizumab-like antibody molecule (e.g., natalizumab), compared to a patient having a less severe stroke.
  • An exemplary dosage range is 350 to 500 mg, e.g., 390-450 mg, e.g., about 450 mg, e.g., for a patient having a severe stroke.
  • the invention is also based, at least in part, on the finding that a subgroup of stroke (e.g., ischemic stroke, e.g., acute ischemic stroke), patients that had a small to medium sized infarct at baseline (e.g., after stroke and before treatment) responded with a greater improvement in one or more clinical outcomes, e.g., a clinical outcome described herein, compared to patients having large infarcts at baseline.
  • ischemic stroke e.g., acute ischemic stroke
  • patients that had a small to medium sized infarct at baseline e.g., after stroke and before treatment
  • a clinical outcomes e.g., a clinical outcome described herein
  • the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.
  • the term “or” is used herein to mean, and is used interchangeably with, the term “and/or”, unless context clearly indicates otherwise.
  • “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
  • proteins and “polypeptides” are used interchangeably herein.
  • Baseline refers to a value or measurement prior to administration of a therapy, e.g., a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy e.g., a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • VLA very late antigen
  • glycoproteins consisting of heterodimeric (alpha and beta), transmembrane receptor molecules found in various combinations on almost every mammalian cell type.
  • Integrins of the VLA family include (at present) VLA-1, -2, -3, - 4, -5, -6, -9, and - 11 in which each of the molecules comprise a ⁇ ⁇ chain non-covalently bound to an a chain, (al, a2, a3, a4, a5, a6 and the like), respectively.
  • the integrin alpha 4 beta 1 ( ⁇ 4 ⁇ 1) is a cell-surface receptor for fibronectin, VCAM-1, and possibly other ligands (the latter ligands individually and collectively referred to as "alpha4 ligand(s)").
  • ⁇ 4 ⁇ 1 integrin refers to polypeptides which are capable of binding to VCAM-1 and members of the extracellular matrix proteins, most particularly fibronectin, or fragments thereof, although it will be appreciated by persons of ordinary skill in the art that other ligands for VLA-4 may exist and can be analyzed using conventional methods.
  • alpha 4 integrin or "alpha 4 subunit-containing integrin", as used herein, refers to those integrins whose a4 subunit associates with one or another of the beta subunits.
  • alpha4beta7 alpha4beta7 ( ⁇ 4 ⁇ 7) (See Lobb and Adams, supra).
  • molecules that antagonize the action of more than one a4 subunit-containing integrin e.g., small molecules or antibody molecules that antagonize both VLA-4 and ⁇ 4 ⁇ 7 or other combinations of a4 subunit- containing integrins.
  • methods using a combination of molecules such that the combination antagonizes the action of more than one integrin such as methods using several small molecules or antibody molecules that in combination antagonize both VLA-4 and ⁇ 4 ⁇ 7 ⁇ other combinations of a4 subunit-containing integrins.
  • Covalently coupled means that the specified moieties ⁇ e.g., PEGylated VLA-4 antagonist, immunoglobulin fragment/VLA-4 antagonist) are either directly covalently bonded to one another, or else are indirectly covalently joined to one another through an intervening moiety or moieties, such as a spacer moiety or moieties.
  • the intervening moiety or moieties are called a "coupling group”.
  • conjugated is used interchangeably with “covalently coupled”.
  • a "spacer” refers to a moiety that may be inserted between an amino acid or other component of a VLA-4 antagonist and the remainder of the molecule. A spacer may provide separation between the amino acid or other component and the rest of the molecule so as to prevent the modification from interfering with protein function and/or make it easier for the amino acid or other component to link with another moiety.
  • “Expression vector,” as used herein refers to a polynucleotide, such as a DNA plasmid or phage (among other common examples) which allows expression of at least one gene when the expression vector is introduced into a host cell.
  • the vector may, or may not, be able to replicate in a cell.
  • “Functional equivalent” of an amino acid residue is (i) an amino acid having similar reactive properties as the amino acid residue that was replaced by the functional equivalent; (ii) an amino acid of an antagonist of the invention, the amino acid having similar properties as the amino acid residue that was replaced by the functional equivalent; (iii) a non-amino acid molecule having similar properties as the amino acid residue that was replaced by the functional equivalent.
  • a first polynucleotide encoding a proteinaceous antagonist of the invention is
  • the "functional equivalent” is a first polynucleotide that hybridizes to the second polynucleotide under standard hybridization conditions and/or is degenerate to the first polynucleotide sequence. Most preferably, it encodes a mutant protein having the activity of a VLA-4 antagonist protein;
  • the "functional equivalent” is a first polynucleotide that codes on expression for an amino acid sequence encoded by the second polynucleotide.
  • the VLA-4 antagonists include, but are not limited to, the agents listed herein as well as their functional equivalents.
  • the term "functional equivalent” therefore refers to a VLA-4 antagonist or a polynucleotide encoding the VLA-4 antagonist that has the same or an improved beneficial effect on the recipient as the VLA-4 antagonist of which it is deemed a functional equivalent.
  • a functionally equivalent protein can be produced by recombinant techniques, e.g., by expressing a "functionally equivalent DNA”.
  • the disclosure embraces integrin proteins encoded by naturally- occurring DNAs, as well as by non-naturally-occurring DNAs which encode the same protein as encoded by the naturally-occurring DNA. Due to the degeneracy of the nucleotide coding sequences, other polynucleotides may be used to encode integrin protein. These include all, or portions of the above sequences which are altered by the substitution of different codons that encode the same amino acid residue within the sequence, thus producing a silent change. Such altered sequences are regarded as equivalents of these sequences.
  • Trp (F) is coded for by two codons, TTC or TTT
  • Tyr (Y) is coded for by TAC or TAT
  • His (H) is coded for by CAC or CAT.
  • Trp (W) is coded for by a single codon, TGG.
  • chimeric when referring to an antagonist, means that the antagonist is comprised of a linkage (chemical cross-linkage or covalent or other type) of two or more proteins having disparate structures and/or having disparate sources of origin.
  • a chimeric VLA-4 antagonist may include one moiety that is a VLA-4 antagonist or fragment and another moiety that is not a VLA-4 antagonist.
  • a species of "chimeric” protein is a “fusion” or “fusion protein” which refers to a co- linear, covalent linkage of two or more proteins or fragments thereof via their individual peptide backbones, most preferably through genetic expression of a polynucleotide molecule encoding those proteins.
  • preferred fusion proteins are chimeric proteins that include a VLA-4 antagonist or fragment covalently linked to a second moiety that is not a VLA-4 antagonist.
  • Preferred fusion proteins include portions of intact antibodies that retain antigen-binding specificity, for example, Fab fragments, Fab' fragments, F(ab')2 fragments, F(v) fragments, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy and one light chain, and the like.
  • the other preferred fusion proteins are chimeric and comprise a VLA-4 antagonist moiety fused or otherwise linked to all or part of the hinge and constant regions of an immunoglobulin light chain, heavy chain, or both.
  • the methods described herein can utilize a molecule that include: (1) an VLA-4 antagonist moiety, (2) a second peptide, e.g., one which increases solubility or in vivo life time of the VLA-4 antagonist moiety, e.g., a member of the immunoglobulin super family or fragment or portion thereof, e.g., a portion or a fragment of IgG, e.g., the human IgGl heavy chain constant region, e.g., CH2, CH3, and hinge regions.
  • VLA-4 antagonist/lg fusion is a protein comprising a biologically active VLA-4 antagonist (e.g. a soluble VLA-4 ligand), or a biologically active fragment thereof linked to an N-terminus of an immunoglobulin chain wherein a portion of the N-terminus of the immunoglobulin is replaced with the VLA-4 antagonist.
  • a species of VLA-4 antagonist/lg fusion is a "VLA-4/Fc fusion" which is a protein comprising a VLA-4 antagonist, e.g., described herein, linked to at least a part of the constant domain of an immunoglobulin.
  • a preferred Fc fusion comprises a VLA-4 antagonist, e.g., described herein, linked to a fragment of an antibody containing the C terminal domain of the heavy immunoglobulin chains.
  • fusion protein also means a VLA-4 antagonist chemically linked via a mono- or hetero-functional molecule to a second moiety that is not a VLA-4 antagonist (resulting in a "chimeric" molecule).
  • VLA-4 subunit targeting moiety e.g., a VCAM- 1 moiety capable of binding to VLA-4
  • a second molecule which increases solubility or in vivo life time of the targeting moiety e.g., a polyalkylene glycol polymer such as polyethylene glycol (PEG).
  • the VLA-4 targeting moiety can be any naturally occurring VLA-4 ligand or fragment thereof, e.g., a VCAM-1 peptide or a similar conservatively substituted amino acid sequence.
  • sequence identity is calculated as follows.
  • the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes).
  • the optimal alignment is determined as the best score using the GAP program in the GCG software package with a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
  • the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared.
  • amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences.
  • hybridizes under high stringency conditions describes conditions for hybridization and washing.
  • Guidance for performing hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which is incorporated by reference. Aqueous and nonaqueous methods are described in that reference and either can be used.
  • High stringency hybridization conditions include hybridization in 6.times.SSC at about 45 C, followed by one or more washes in 0.2 x SSC, 0.1% SDS at 65 C, or substantially similar conditions.
  • isolated when applied to nucleic acid i.e., polynucleotide sequences that encode VLA antagonists, means an RNA or DNA
  • polynucleotide portion of genomic polynucleotide, cDNA or synthetic polynucleotide which, by virtue of its origin or manipulation: (i) is not associated with all of a polynucleotide with which it is associated in nature (e.g., is present in a host cell as an expression vector, or a portion thereof); or (ii) is linked to a nucleic acid or other chemical moiety other than that to which it is linked in nature; or (iii) does not occur in nature.
  • isolated it is further meant a polynucleotide sequence that is: (i) amplified in vitro by, for example, polymerase chain reaction (PCR); (ii) synthesized chemically; (iii) produced recombinantly by cloning; or (iv) purified, as by cleavage and gel separation.
  • substantially pure nucleic acid is a nucleic acid which is not immediately contiguous with one or both of the coding sequences with which it is normally contiguous in the naturally occurring genome of the organism from which the nucleic acid is derived.
  • Substantially pure DNA also includes a recombinant DNA which is part of a hybrid gene encoding additional integrin sequences.
  • isolated when applied to polypeptides means a polypeptide or a portion thereof which, by virtue of its origin or manipulation: (i) is present in a host cell as the expression product of a portion of an expression vector; or (ii) is linked to a protein or other chemical moiety other than that to which it is linked in nature; or (iii) does not occur in nature, for example, a protein that is chemically manipulated by appending, or adding at least one hydrophobic moiety to the protein so that the protein is in a form not found in nature.
  • isolated it is further meant a protein that is: (i) synthesized chemically; or (ii) expressed in a host cell and purified away from associated and contaminating proteins.
  • the term generally means a polypeptide that has been separated from other proteins and nucleic acids with which it naturally occurs.
  • the polypeptide is also separated from substances such as antibodies or gel matrices (polyacrylamide) which are used to purify it.
  • a “pharmacological agent” is defined as one or more compounds or molecules or other chemical entities administered to a subject (in addition to the VLA-4 antagonists) that affects the action of the antagonist.
  • pharmacological agent refers to such an agent(s) that are administered during “combination therapy” where the VLA-4 antagonist is administered either prior to, after, or simultaneously with, administration of one or more pharmacological agents.
  • Protein refers to any polymer consisting essentially of any of the 20 amino acids. Although “polypeptide” is often used in reference to relatively large polypeptides, and “peptide” is often used in reference to small polypeptides, usage of these terms in the art overlaps and is varied.
  • protein refers to peptides, proteins and polypeptides, unless otherwise noted.
  • Recombinant means that a protein is derived from recombinant, mammalian expression systems. Since integrin is not glycosylated nor contains disulfide bonds, it can be expressed in most prokaryotic and eukaryotic expression systems.
  • VLA-4 antagonist refers to chemical agents (i.e., organic molecules) capable of disrupting the integrin/integrin ligand interaction by, for instance, blocking VLA- 4/VCAM interactions by binding VLA-4 on the surface of cells or binding VC AM- 1 on the surface of cells. Such small molecules may also bind respective VLA-4 and VCAM-1 receptors. VLA-4 and VCAM-1 small molecule inhibitors may themselves be peptides, semi-peptidic compounds or non-peptidic compounds, such as small organic molecules that are antagonists of the VCAM- l/VLA-4 interaction.
  • a VLA-4 antagonist (and a therapeutic composition comprising the same) is said to have "therapeutic efficacy,” and an amount of the agent is said to be “therapeutically effective,” if administration of that amount of the agent is sufficient to cause a clinically significant improvement in neurological recovery in a standard neurological test (see below, Methods of Treatment) when administered to a subject (e.g., an animal model or human patient) after brain damage (e.g., stroke, e.g., ischemic stroke, e.g., acute ischemic stroke).
  • a subject e.g., an animal model or human patient
  • brain damage e.g., stroke, e.g., ischemic stroke, e.g., acute ischemic stroke.
  • treating refers to administering a therapy in an amount, manner (e.g., schedule of administration), and/or mode (e.g., route of administration), effective to improve a disorder or a symptom thereof, or to prevent or slow the progression of a disorder or a symptom thereof. This can be evidenced by, e.g., an improvement in a parameter associated with a disorder or a symptom thereof, e.g., to a statistically significant degree or to a degree detectable to one skilled in the art.
  • An effective amount, manner, or mode can vary depending on the subject and may be tailored to the subject. By preventing or slowing progression of a disorder or a symptom thereof, a treatment can prevent or slow deterioration resulting from a disorder or a symptom thereof in an affected or diagnosed subject.
  • biological refers to a protein-based therapeutic agent.
  • the biologic is at least 10, 20, 130, 40, 50 or 100 amino acid residues in length.
  • VLA-4 binding agent refers to any compound that binds to VLA-4 integrin with a K d of less than 10 "6 M.
  • An example of a VLA-4 binding agent is a VLA-4 binding protein, e.g., a VLA-4 binding antibody such as a natalizumab-like antibody molecule (e.g., natalizumab).
  • VLA-4 antagonist refers to any compound that at least partially inhibits an activity of a VLA-4 integrin, particularly a binding activity of a VLA-4 integrin or a signaling activity, e.g., ability to transduce a VLA-4 mediated signal.
  • a VLA-4 antagonist may inhibit binding of VLA-4 to a cognate ligand of VLA-4, e.g., a cell surface protein such as VCAM-1, or to an extracellular matrix component, such as fibronectin or osteopontin.
  • a typical VLA-4 antagonist can bind to VLA-4 or to a VLA-4 ligand, e.g., VCAM-1 or an extracellular matrix component, such as fibronectin or osteopontin.
  • a VLA-4 antagonist that binds to VLA-4 may bind to either the a4 subunit or the ⁇ ⁇ subunit, or to both.
  • a VLA-4 antagonist may also interact with other a4 subunit containing integrins (e.g., ⁇ 4 ⁇ 7) or with other ⁇ containing integrins.
  • a VLA-4 antagonist may bind to VLA-4 or to a VLA-4 ligand with a K d of less than 10 ⁇ 6 , 10 ⁇ 7 , 10 s , 10 ⁇ 9 , or 10 "10 M.
  • antibody molecule refers to an antibody or antigen binding fragment thereof.
  • antibody refers to a protein that includes at least one immunoglobulin variable region, e.g., an amino acid sequence that provides an immunoglobulin variable domain or immunoglobulin variable domain sequence.
  • an antibody can include a heavy (H) chain variable region (abbreviated herein as VH), and a light (L) chain variable region
  • an antibody in another example, includes two heavy (H) chain variable regions and two light (L) chain variable regions.
  • the term "antibody” encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab fragments, F(ab') 2 fragments, Fd fragments, Fv fragments, and dAb fragments) as well as complete antibodies, e.g., intact immunoglobulins of types IgA, IgG, IgE, IgD, IgM (as well as subtypes thereof).
  • the light chains of the immunoglobulin may be of types kappa or lambda.
  • the antibody is glycosylated.
  • An antibody can be functional for antibody-dependent cytotoxicity and/or complement-mediated cytotoxicity, or may be non-functional for one or both of these activities.
  • VH and VL regions can be further subdivided into regions of hypervariability, termed “complementarity determining regions” ("CDR"), interspersed with regions that are more conserved, termed “framework regions” (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • the extent of the FR's and CDR's has been precisely defined (see, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91- 3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). Kabat definitions are used herein.
  • Each VH and VL is typically composed of three CDR's and four FR's, arranged from amino- terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • Immunoglobulin domain refers to a domain from the variable or constant domain of immunoglobulin molecules. Immunoglobulin domains typically contain two ⁇ -sheets formed of about seven ⁇ -strands, and a conserved disulphide bond (see, e.g., A. F. Williams and A. N. Barclay 1988 Ann. Rev Immunol. 6:381-405).
  • an "immunoglobulin variable domain sequence” refers to an amino acid sequence that can form the structure of an immunoglobulin variable domain.
  • the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain.
  • the sequence may omit one, two or more N- or C-terminal amino acids, internal amino acids, may include one or more insertions or additional terminal amino acids, or may include other alterations.
  • the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain.
  • the sequence may omit one, two or more N- or C-terminal amino acids, internal amino acids, may include one or more insertions or additional terminal amino acids, or may include other alterations.
  • a polypeptide that includes an amino acid sequence of a naturally-occurring variable domain may omit one, two or more N- or C-terminal amino acids, internal amino acids, may include
  • immunoglobulin variable domain sequence can associate with another immunoglobulin variable domain sequence to form a target binding structure (or "antigen binding site"), e.g., a structure that interacts with VLA-4.
  • a target binding structure e.g., a structure that interacts with VLA-4.
  • the VH or VL chain of the antibody can further include all or part of a heavy or light chain constant region, to thereby form a heavy or light immunoglobulin chain, respectively.
  • the antibody is a tetramer of two heavy immunoglobulin chains and two light immunoglobulin chains.
  • the heavy and light immunoglobulin chains can be connected by disulfide bonds.
  • the heavy chain constant region typically includes three constant domains, CHi, CH 2 and CH 3 .
  • the light chain constant region typically includes a CL domain.
  • the variable region of the heavy and light chains contains a binding domain that interacts with an antigen.
  • the constant regions of the antibodies typically mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • one or more regions of an antibody can be human, effectively human, or humanized, in some examples, one or more of the variable regions can be human or effectively human.
  • one or more of the CDRs e.g., HC CDRl, HC CDR2, HC CDR3, LC CDRl, LC CDR2, and LC CDR3, can be human.
  • Each of the light chain CDRs can be human.
  • HC CDR3 can be human.
  • One or more of the framework regions can be human, e.g., FR1, FR2, FR3, and FR4 of the HC or LC.
  • all the framework regions are human, e.g., derived from a human somatic cell, e.g., a hematopoietic cell that produces immunoglobulins or a non-hematopoietic cell.
  • the human sequences are germline sequences, e.g., encoded by a germline nucleic acid.
  • One or more of the constant regions can be human, effectively human, or humanized.
  • At least 70, 75, 80, 85, 90, 92, 95, or 98% of the framework regions (e.g., FRl, FR2, and FR3, collectively, or FRl, FR2, FR3, and FR4, collectively) or the entire antibody can be human, effectively human, or humanized.
  • FRl, FR2, and FR3 collectively can be at least 70, 75, 80, 85, 90, 92, 95, 98, or 99% identical to a human sequence encoded by a human germline segment.
  • an “effectively human” immunoglobulin variable region is an immunoglobulin variable region that includes a sufficient number of human framework amino acid positions such that the immunoglobulin variable region does not elicit an immunogenic response in a normal human.
  • An “effectively human” antibody is an antibody that includes a sufficient number of human amino acid positions such that the antibody does not elicit an immunogenic response in a normal human.
  • a "humanized" immunoglobulin variable region is an immunoglobulin variable region that is modified such that the modified form elicits less of an immune response in a human than does the non-modified form, e.g., is modified to include a sufficient number of human framework amino acid positions such that the immunoglobulin variable region does not elicit an
  • humanized immunoglobulins include, for example, U.S. Patent No.: 6,407,213 and U.S. Patent No.: 5,693,762.
  • humanized immunoglobulins can include a non-human amino acid at one or more framework amino acid positions.
  • an antibody can be encoded by an immunoglobulin gene or a segment thereof.
  • exemplary human immunoglobulin genes include the kappa, lambda, alpha (IgAl and IgA2), gamma (IgGl, IgG2, IgG3, IgG4), delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
  • Full-length immunoglobulin "light chains" (about 25 Kd or 214 amino acids) are encoded by a variable region gene at the NH2-terminus (about 110 amino acids) and a kappa or lambda constant region gene at the COOH-terminus.
  • Full-length immunoglobulin "heavy chains” (about 50 Kd or 446 amino acids), are similarly encoded by a variable region gene (about 116 amino acids) and one of the other aforementioned constant region genes, e.g., gamma (encoding about 330 amino acids).
  • the term "antigen-binding fragment" of a full length antibody refers to one or more fragments of a full-length antibody that retain the ability to specifically bind to a target of interest, e.g., VLA-4.
  • binding fragments encompassed within the term "antigen- binding fragment" of a full length antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab').sub.2 fragment, a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:54-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) that retains functionality.
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CHI domains
  • F(ab').sub.2 fragment a bivalent fragment including two
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules known as single chain Fv (scFv).
  • scFv single chain Fv
  • a "fixed dose” or dosage unit form refers to physically discrete units suited as unitary doses for a subject to be treated. Each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • a “dosage” as used herein refers to a quantity or amount of a therapeutic agent.
  • a dosage is the amount administered to the subject in a single administration, e.g., in a single injection, a single infusion, or single administration of one or more oral fixed doses.
  • an exemplary dosage is 450+/-5% mgs.
  • an exemplary dosage is 600+/-5% mgs.
  • terapéuticaally effective dosage and “therapeutically effective amount” refer to that amount of an agent (e.g., an agent described herein, e.g., VLA-4 antagonist, e.g., a nataiizumab-like antibody molecule (e.g., natalizumab)) which results in at least one of prevention or delay of onse or amelioration of symptoms of a neurological disorder, e.g., stroke (e.g., ischemic stroke, e.g., acute ischemic stroke, hemorrhagic stroke, e.g., intracerebral hemorrhage or subarachnoid hemorrhage), or traumatic brain injury, in a subject or an attainment of a desired biological outcome, such as reduced size of infarct or reduced disability/increased functional independence.
  • an agent e.g., an agent described herein, e.g., VLA-4 antagonist, e.g., a nataii
  • a therapeutically effective amount of an agent can vary according to factors such as disease state, age, sex, weight of the subject, as well as the ability of the agent to elicit a desired responses in the subject.
  • a therapeutically effective amount is one in which the therapeutically beneficial effects of the agent outweight its toxic or adverse effects.
  • Cmax refers to the maximum plasma concentration of a drug (e.g., a drug described herein) achieved after a single administration of a dosage form of the drug as described herein.
  • AUC Absolute under the curve
  • a biological fluid e.g., plasma and blood
  • AUC a function of time (e.g., 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0- 90 days, or 0-120 days) following administration of the compound/molecule to the patient.
  • Suitable methods for calculating the AUC from a drug concentration-versus-time curve are known in the art.
  • Neatalizumab is an exemplary VLA-4 antagonist that is described in greater detail below.
  • a "natalizumab-like antibody molecule” as used herein is natalizumab or an antibody molecule that differs from the amino acid sequence of natalizumab at least one amino acid residue, but which has similar biological properties to natalizumab. In an embodiment it comprises:
  • the natalizumab-like antibody molecule comprises a)i) and b)i).
  • natalizumab-like antibody molecule comprises a)ii) and b)ii).
  • natalizumab-like antibody molecule comprises a)iii) and b)iii).
  • the natalizumab-like antibody molecule comprises a)iv) and b)iv).
  • the natalizumab-like antibody molecule comprises a)v) and b)v).
  • the natalizumab-like antibody molecule is an antibody molecule i) comprising one or more CDRs, e.g., all three HC CDRs and/or all three LC CDRs of
  • natalizumab ii) comprising one or more CDRs that are, in sum, at least 80, 85, 90, 92, 94, 95, 96, 97, 98, 99%, or 100% identical to natalizumab or iii) comprising a HC and/or LC variable domain amino acid sequence having at least 70, 80, 85, 90, 92, 95, 97, 98, 99, or 100% identity to the amino acid sequence of the HC and/or LC variable domain of natalizumab.
  • Severity of a stroke can be determined by evaluating a patient who has suffered a stroke, e.g., at baseline, e.g., after stroke onset and prior to treatment, by using one or more of the evaluations described herein, e.g., NIHSS score. For example, a "severe stroke” or a “less than severe stroke” can be indicated by a number of ways.
  • “Severe stroke” as used herein refers to a stroke having a NIHSS score equal to or greater than 15, e.g., equal to or greater than 21, e.g., in the range of 15 to 24 or 21 to 42.
  • the NIHSS (or other) evaluation is made at baseline, e.g., after stroke onset and prior to treatment with natalizumab or a natalizumab-like antibody molecule.
  • Other forms of evaluation can be used to determine that a stroke is a severe stroke and if it is equivalent in severity of a stroke having a NIHSS score equal to or greater than 15, e.g., equal to or greater than 21, e.g., in the range of 15 to 24 or 21 to 42.
  • a severe stroke can include a very severe stroke (e.g., having a NIHSS score greater than 25). See, e.g., Brott et al. Stroke. 20(1989):864-70.
  • Less than severe stroke refers to a stroke having a NIHSS score of less than 15.
  • the NIHSS (or other) evaluation is made at baseline, e.g., after stroke onset and prior to treatment with natalizumab or a natalizumab-like antibody molecule.
  • Less than severe strokes can be further divided into several categories. Other forms of evaluation can be used to determine that a stroke is a less than severe stroke and if it is equivalent in severity of a stroke having a NIHSS score of less than 15. For example, a NIHSS of 1-5 is indicative of mild stroke; and a score of 5-14 is indicative of mild to moderate stroke. See, e.g., Brott et al.
  • LNN Last known normal
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., an ischemic stroke
  • the LKN time can be determined by the subject or by another individual (e.g., family member, e.g., father, mother, child, spouse, relative; or neighbor) who has observed the subject prior to (e.g., within 6 hours, e.g., 6, 5, 4, 3, 2, 1 hour or less, and/or during the beginning of a symptom of the disease.
  • the LKN can be self -reported by the subject, reported by a witness, or both.
  • Treatment window refers to a dosage regimen, including dose and/or timing of administration (e.g., initiation of administration), of a compound or therapy, e.g., a VLA-4 antagonist as described herein, that results in the amelioration of one or more symptoms associated with a disorder or condition, e.g., stroke.
  • the treatment window can result in at least one beneficial or desired clinical result including, but are not limited to, alleviation of a symptom, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, whether detectable or undetectable.
  • Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the treatment window can be a function of disease severity in a subject, e.g., subject with a stroke as described herein.
  • a subject with a moderate or mild stroke e.g., having an NIHSS score of less than 15 points, e.g., 5 to 15 points, at baseline can have a later initiation of a treatment window, e.g., within 24 hours or less after LKN, compared to a subject with a severe stroke, e.g., having an NIHSS score of 15 points or higher at baseline, e.g., having a treatment window initiated within 9 hours or less.
  • a VLA-4 antagonist is an antagonist of interactions of a4 integrins with their ligands, such as the VCAM- l/VLA-4 interaction.
  • This is an agent, e.g., a polypeptide or other molecule, which can inhibit or block VC AM- 1 and/or VLA-4-mediated binding or which can otherwise modulate VCAM- 1 and/or VLA-4 function, e.g., by inhibiting or blocking VLA-4-ligand mediated VLA-4 signal transduction or VCAM-1 -ligand mediated VCAM- 1 signal transduction and which is effective in the treatment of acute brain injury, preferably in the same manner as anti- VLA-4 binding agents such as anti- VLA-4 antibodies.
  • a VLA-4 antagonist can have one or more of the following properties: (1) it coats, or binds to, VLA-4 on the surface of a VLA-4 bearing cell (e.g., an endothelial cell) with sufficient specificity to inhibit a VLA-4-ligand/VLA-4 interaction, e.g., the VCAM- l/VLA-4 interaction; (2) it coats, or binds to, VLA-4 on the surface of a VLA-4 bearing cell (i.e., a lymphocyte) with sufficient specificity to modify, and preferably to inhibit, transduction of a VLA-4-mediated signal e.g., VLA-4/VCAM- 1 -mediated signaling; (3) it coats, or binds to, a VLA-4-ligand, (e.g., VCAM-1) on endothelial cells with sufficient specificity to inhibit the VLA-4/VCAM- 1 interaction; (4) it coats, or binds to, a VLA-4-ligand (e.g., VCAM
  • the antagonist has one or both of properties 1 and 2. In other preferred embodiments the antagonist has one or both of properties 3 and 4. Moreover, more than one antagonist can be administered to a patient, e.g., an agent which binds to VLA-4 can be combined with an agent which binds to VC AM- 1.
  • antibody molecules as well as soluble forms of the natural binding proteins for VLA-4 and VCAM-1 are useful.
  • Natalizumab an a4 integrin binding antibody, inhibits the migration of leukocytes from the blood to the central nervous system.
  • Natalizumab binds to VLA-4 on the surface of activated T-cells and other mononuclear leukocytes. It can disrupt adhesion between the T-cell and endothelial cells, and thus prevent migration of mononuclear leukocytes across the endothelium and into the parenchyma. As a result, the levels of proinflammatory cytokines can also be reduced.
  • Natalizumab and related VLA-4 binding antibodies are described, e.g., in U.S. Patent No.: 5,840,299.
  • Monoclonal antibodies 21.6 and HP1/2 are exemplary murine monoclonal antibodies that bind VLA-4.
  • Natalizumab is a humanized version of murine monoclonal antibody 21.6 (see, e.g., U.S. Patent No.: 5,840,299).
  • a humanized version of HP1/2 has also been described (see, e.g., U.S. Patent No.: 6,602,503).
  • VLA-4 binding monoclonal antibodies such as HP2/1, HP2/4, L25 and P4C2, are described, e.g., in U.S.
  • the VLA-4 antagonist comprises an antibody molecule that comprises CDRl, CDR2 and CDR3 from the light chain and CDRl, CDR2 and CDR3 from the heavy chain of natalizumab. In embodiments, the VLA-4 antagonist comprises an antibody molecule that comprises the light chain variable region and the heavy chain variable region of natalizumab.
  • a natalizumab-like antibody molecule e.g., natalizumab
  • natalizumab comprises a light chain amino acid sequence, variable light chain amino acid sequence, and/or one or more (e.g., one or more, two or more, or all three) light chain CDR sequences described herein, e.g., of natalizumab.
  • a natalizumab-like antibody molecule comprises a light chain comprising a CDRl (SEQ ID NO: 3), CDR2 (SEQ ID NO: 4) and CDR3 (SEQ ID NO: 5) and a heavy chain comprising a CDRl (SEQ ID NO: 8), CDR2 (SEQ ID NO: 9) and CDR3 (SEQ ID NO: 10).
  • a natalizumab-like antibody molecule e.g., natalizumab, comprises a light chain variable region sequence of SEQ ID NO: 2 and a heavy chain variable region sequence of SEQ ID NO: 7.
  • a natalizumab-like antibody molecule e.g., natalizumab, comprises one or more (e.g., one or more, two or more, or all three) CDRs (e.g., according to a numbering scheme described herein, e.g., Kabat and/or Chothia) from a variable light chain sequence of SEQ ID NO: 2.
  • a natalizumab-like antibody molecule e.g., natalizumab, comprises one or more (e.g., one or more, two or more, or all three) CDRs (e.g., according to a numbering scheme described herein, e.g., Kabat and/or Chothia) from a variable heavy chain sequence of SEQ ID NO: 7.
  • Natalizumab light chain amino acid sequence (SEQ ID NO: 1) (the CDRs (according to the Kabat numbering scheme) are boxed and the variable light (VL) chain sequence is underlined):
  • Natalizumab VL sequence (SEQ ID NO: 2) (the CDRs (according to the Kabat numbering scheme) are boxed):
  • LCDR light chain CDRs
  • Kabat numbering scheme Kabat numbering scheme (Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD) are as follows: LCDR1 : KTSQDINKYMA (SEQ ID NO: 3)
  • LCDR2 YTSALQP (SEQ ID NO: 4)
  • LCDR3 LQYDNLWT (SEQ ID NO: 5)
  • a natalizumab-like antibody molecule e.g., natalizumab, comprises a heavy chain amino acid sequence, variable heavy chain amino acid sequence, and/or one or more (e.g., one or more, two or more, or all three) heavy chain CDR sequences described herein, e.g., shown below.
  • Natalizumab heavy chain amino acid sequence where Q 1 can be a glutamine or a pyroglutamic acid and where K can be a lysine or no amino acid residue (SEQ ID NO: 6) (the CDRs
  • variable heavy chain (VH) sequence is underlined:
  • Natalizumab VH sequence where Q can be a glutamine or a glutamine cyclized to pyroglutamic acid (SEQ ID NO: 7) (the CDRs (according to the Kabat numbering scheme) are boxed):
  • HCDR Natalizumab heavy chain CDRs
  • HCDR1 DTYIH (SEQ ID NO: 8)
  • HCDR2 RIDPANGYTKYDPKFQG (SEQ ID NO: 9)
  • HCDR3 EGYYGNYGVYAMDY (SEQ ID NO: 10)
  • VLA-4 binding antibody molecules recognize epitopes of the a4 subunit that are involved in binding to a cognate ligand, e.g., VCAM- 1 or fibronectin. Many such antibody molecules inhibit binding of VLA-4 to cognate ligands (e.g., VCAM-1 and fibronectin).
  • VLA-4 binding antibodies can interact with VLA-4 on cells, e.g., lymphocytes, but do not cause cell aggregation. However, other VLA-4 binding antibodies have been observed to cause such aggregation. HP 1/2 does not cause cell aggregation.
  • the HP 1/2 monoclonal antibody (Sanchez-Madrid et ah , 1986) has an extremely high potency, blocks VLA- 4 interaction with both VCAM1 and fibronectin, and has the specificity for epitope B on VLA-4.
  • This antibody and other B epitope-specific antibodies represent one class of VLA-4 binding antibodies that can be used in the methods described herein.
  • Antibodies that compete for binding with a VLA-4 binding antibody e.g., natalizumab, can also be used in the methods described herein.
  • An exemplary VLA-4 binding antibody molecule has one or more CDRs, e.g., all three HC CDRs and/or all three LC CDRs of a particular antibody disclosed herein, or CDRs that are, in sum, at least 80, 85, 90, 92, 94, 95, 96, 97, 98, 99% identical to such an antibody, e.g., natalizumab.
  • the HI and H2 hypervariable loops have the same canonical structure as those of an antibody described herein.
  • hypervariable loops have the same canonical structure as those of an antibody molecule described herein.
  • the amino acid sequence of the HC and/or LC variable domain sequence is at least 70, 80, 85, 90, 92, 95, 97, 98, 99, or 100% identical to the amino acid sequence of the HC and/or LC variable domain of an antibody described herein, e.g.,
  • the amino acid sequence of the HC and/or LC variable domain sequence can differ by at least one amino acid, but no more than ten, eight, six, five, four, three, or two amino acids from the corresponding sequence of an antibody described herein, e.g., natalizumab. For example, the differences may be primarily or entirely in the framework regions.
  • the amino acid sequences of the HC and LC variable domain sequences can be encoded by a nucleic acid sequence that hybridizes under high stringency conditions to a nucleic acid sequence described herein or one that encodes a variable domain or an amino acid sequence described herein.
  • the amino acid sequences of one or more framework regions (e.g., FRl, FR2, FR3, and/or FR4) of the HC and/or LC variable domain are at least 70, 80, 85, 90, 92, 95, 97, 98, 99, or 100% identical to corresponding framework regions of the HC and LC variable domains of an antibody described herein.
  • one or more heavy or light chain framework regions e.g., HC FRl, FR2, and FR3 are at least 70, 80, 85, 90, 95, 96, 97, 98, or 100% identical to the sequence of corresponding framework regions from a human germline antibody.
  • the VLA-4 antagonist can be a soluble form of a ligand.
  • Soluble forms of the ligand proteins include soluble VCAM-I or fibronectin peptides, VCAM-I fusion proteins, or bifunctional VCAM-I/Ig fusion proteins.
  • a soluble form of a VLA-4 ligand or a fragment thereof may be administered to bind to VLA-4, and in some instances, compete for a VLA-4 binding site on cells, thereby leading to effects similar to the administration of antagonists such as anti- VLA-4 antibodies.
  • antagonists such as anti- VLA-4 antibodies.
  • soluble VLA-4 integrin mutants that bind VLA-4 ligand but do not elicit integrin-dependent signaling are suitable for use in the described methods.
  • Soluble forms of the natural binding proteins for VLA-4 include soluble VCAM-1 peptides, VCAM-1 fusion proteins, bifunctional VCAM-l/lg fusion proteins (e.g. "chimeric" molecules, discussed above), fibronectin, fibronectin having an alternatively spliced non-type III connecting segment, and fibronectin peptides containing the amino acid sequence EILDV or a similar conservatively substituted amino acid sequence.
  • a "soluble VLA-4 peptide” or a "soluble VCAM-1 peptide” is an VLA4 or VCAM-1 polypeptide incapable of anchoring itself in a membrane.
  • Such soluble polypeptides include, for example, VLA-4 and VCAM polypeptides that lack a sufficient portion of their membrane spanning domain to anchor the polypeptide or are modified such that the membrane spanning domain is non-functional.
  • binding agents can act by competing with the cell-surface binding protein for VLA-4 or by otherwise altering VLA-4 function.
  • a soluble form of VCAM-1 see, e.g., Osborn et al. 1989, Cell, 59: 1203-1211
  • a fragment thereof may be administered to bind to VLA-4, and preferably compete for a VLA-4 binding site on VCAM-1- bearing cells, thereby leading to effects similar to the administration of antagonists such as small molecules or anti- VLA-4 antibodies.
  • Small molecules are agents that mimic the action of peptides to disrupt VLA-4/ligand interactions by, for instance, binding VLA-4 and blocking interaction with a VLA-4 ligand ⁇ e.g., VCAM-I or fibronectin), or by binding a VLA-4 ligand and preventing the ligand from interacting with VLA-4.
  • VLA-4 ligand ⁇ e.g., VCAM-I or fibronectin
  • One exemplary small molecule is an oligosaccharide that mimics the binding domain of a VLA-4 ligand ⁇ e.g., fibronectin or VCAM-I) and binds the ligand-binding domain of VLA-4.
  • a “small molecule” may be chemical compound, e.g., an organic compound, or a small peptide, or a larger peptide-containing organic compound or non-peptidic organic compound.
  • a “small molecule” is not intended to encompass an antibody or antibody fragment. Although the molecular weight of small molecules is generally less than 2000 Daltons, this figure is not intended as an absolute upper limit on molecular weight.
  • VLA-4 inhibitors examples have been reported, for example, in Adams et al. "Cell Adhesion Inhibitors", PCT US97/13013, describing linear peptidyl compounds containing beta- amino acids which have cell adhesion inhibitory activity.
  • International patent applications WO 94/15958 and WO 92/00995 describe cyclic peptide and peptidomimetic compounds with cell adhesion inhibitory activity.
  • International patent applications WO 93/08823 and WO 92/08464 describe guanidinyl-, urea- and thiourea-containing cell adhesion inhibitory compounds.
  • U.S. Pat. No. 5,260,277 describes guanidinyl cell adhesion modulation compounds.
  • Such small molecule agents may be produced by synthesizing a plurality of peptides (e.g., 5 to 20 amino acids in length), semi-peptidic compounds or non-peptidic, organic compounds, and then screening those compounds for their ability to inhibit the VLA-4/VCAM interaction. See generally U.S. Pat. No. 4,833,092, Scott and Smith, "Searching for Peptide Ligands with an Epitope Library", Science, 249, pp. 386-90 (1990), and Devlin et al, "Random Peptide Libraries: A Source of Specific Protein Binding Molecules", Science, 249, pp. 40407 (1990).
  • Antibodies that bind to VLA-4 can be generated by immunization, e.g., using an animal, or by in vitro methods such as phage display. All or part of VLA-4 can be used as an immunogen. For example, the extracellular region of the a4 subunit can be used as an immunogen.
  • the immunized animal contains immunoglobulin producing cells with natural, human, or partially human immunoglobulin loci.
  • the non-human animal includes at least a part of a human immunoglobulin gene. For example, it is possible to engineer mouse strains deficient in mouse antibody production with large fragments of the human Ig loci.
  • antigen-specific monoclonal antibodies derived from the genes with the desired specificity may be produced and selected. See, e.g., Xeno MouseTM, Green et al., Nature Genetics 7: 13-21 (1994), US 2003-0070185, U.S. Patent No.: 5,789,650, and WO
  • Non-human antibodies to VLA-4 can also be produced, e.g., in a rodent.
  • the non-human antibody can be humanized, e.g., as described in U.S. Patent No.: 6,602,503, EP 239 400, U.S. Patent No.: 5,693,761, and U.S. Patent No.: 6,407,213.
  • EP 239 400 (Winter et al.) describes altering antibodies by substitution (within a given variable region) of their complementarity determining regions (CDRs) for one species with those from another.
  • CDR-substituted antibodies can be less likely to elicit an immune response in humans compared to true chimeric antibodies because the CDR-substituted antibodies contain considerably less non-human components (Riechmann et al., 1988, Nature 332, 323-327;
  • CDRs of a murine antibody substituted into the corresponding regions in a human antibody by using recombinant nucleic acid technology to produce sequences encoding the desired substituted antibody.
  • Human constant region gene segments of the desired isotype usually gamma I for CH and kappa for CL
  • the humanized heavy and light chain genes can be co-expressed in mammalian cells to produce soluble humanized antibody. Queen et al. (Proc. Natl. Acad. Sci. U.S.A.
  • WO 90/07861 have described a process that includes choosing human V framework regions by computer analysis for optimal protein sequence homology to the V region framework of the original murine antibody, and modeling the tertiary structure of the murine V region to visualize framework amino acid residues that are likely to interact with the murine CDRs. These murine amino acid residues are then superimposed on the homologous human framework. See also U.S. Patent Nos.: 5,693,762; 5,693,761; 5,585,089; and 5,530,101.
  • Tempest et al, 1991, Biotechnology 9:266-271 utilize, as standard, the V region frameworks derived from NEWM and REI heavy and light chains, respectively, for CDR-grafting without radical introduction of mouse residues.
  • An advantage of using the Tempest et al. approach to construct NEWM and REI based humanized antibodies is that the three dimensional structures of NEWM and REI variable regions are known from x-ray crystallography and thus specific interactions between CDRs and V region framework residues can be modeled.
  • Non-human antibodies can be modified to include substitutions that insert human immunoglobulin sequences, e.g., consensus human amino acid residues at particular positions, e.g., at one or more (preferably at least five, ten, twelve, or all) of the following positions: (in the FR of the variable domain of the light chain) 4L, 35L, 36L, 38L, 43L, 44L, 58L, 46L, 62L, 63L, 64L, 65L, 66L, 67L, 68L, 69L, 70L, 71L, 73L, 85L, 87L, 98L, and/or (in the FR of the variable domain of the heavy chain) 2H, 4H, 24H, 36H, 37H, 39H, 43H, 45H, 49H, 58H, 60H, 67H, 68H, 69H, 70H, 73H, 74H, 75H, 78H, 91H, 92H, 93H, and/or
  • Fully human monoclonal antibodies that bind to VLA-4 can be produced, e.g., using in vitro-primed human splenocytes, as described by Boerner et al., 1991, J. Immunol., 147, 86-95. They may be prepared by repertoire cloning as described by Persson et al., 1991, Proc. Nat. Acad. Sci. USA, 88: 2432-2436 or by Huang and Stollar, 1991, J. Immunol. Methods 141, 227- 236; also U.S. Pat. No. 5,798,230.
  • phage display libraries may also be used to isolate high affinity antibodies that can be developed as human therapeutics using standard phage technology (see, e.g., Vaughan et al, 1996; Hoogenboom et al. (1998)
  • Transgenic animals e.g., transgenic mice, expressing human antibody gene sequences may be used to produce human monoclonal antibodies using technology as described in, e.g., Lonberg N. (2005) Nat. Biotechnol. 23(9): 1117-25.
  • Antibodies can be produced in prokaryotic and eukaryotic cells.
  • the antibodies e.g., scFv's
  • the antibodies are expressed in a yeast cell such as Pichia (see, e.g., Powers et al. (2001) J Immunol Methods. 251 : 123-35), Hanseula, or Saccharomyces.
  • antibodies are produced in mammalian cells.
  • mammalian host cells for recombinant expression include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in Kaufman and Sharp (1982) Mol. Biol.
  • lymphocytic cell lines e.g., NS0 myeloma cells and SP2 cells, COS cells, K562, and a cell from a transgenic animal, e.g., a transgenic mammal.
  • the cell is a mammary epithelial cell.
  • the recombinant expression vectors may carry additional nucleic acid sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Patent Nos.: 4,399,216, 4,634,665 and 5, 179,017).
  • Exemplary selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr " host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr " CHO cells by calcium phosphate-mediated transfection.
  • the antibody heavy and light chain genes are each operatively linked to enhancer/promoter regulatory elements (e.g., derived from SV40, CMV, adenovirus and the like, such as a CMV enhancer/ AdMLP promoter regulatory element or an SV40 enhancer/ AdMLP promoter regulatory element) to drive high levels of transcription of the genes.
  • the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification.
  • the selected transformant host cells are cultured to allow for expression of the antibody heavy and light chains and intact antibody is recovered from the culture medium.
  • Standard molecular biology techniques are used to prepare the recombinant expression vector, to transfect the host cells, to select for transformants, to culture the host cells, and to recover the antibody from the culture medium. For example, some antibodies can be isolated by affinity chromatography with a Protein A or Protein G.
  • Antibodies may also include modifications, e.g., modifications that alter Fc function, e.g., to decrease or remove interaction with an Fc receptor or with C lq, or both.
  • modifications e.g., modifications that alter Fc function, e.g., to decrease or remove interaction with an Fc receptor or with C lq, or both.
  • the human IgGl constant region can be mutated at one or more residues, e.g., one or more of residues 234 and 237, e.g., according to the numbering in U.S. Patent No.: 5,648,260.
  • Other exemplary modifications include those described in U.S. Patent No.: 5,648,260.
  • the antibody production system may be designed to synthesize antibodies in which the Fc region is glycosylated.
  • the Fc domain of IgG molecules is glycosylated at asparagine 297 in the CH2 domain. This asparagine is the site for modification with biantennary-type oligosaccharides. This glycosylation
  • the Fc domain can be produced in a mammalian expression system that appropriately glycosylates the residue corresponding to asparagine 297.
  • the Fc domain can also include other eukaryotic post- translational modifications.
  • Antibodies can also be produced by a transgenic animal.
  • U.S. Pat. No. 5,849,992 describes a method for expressing an antibody in the mammary gland of a transgenic mammal.
  • a transgene is constructed that includes a milk-specific promoter and nucleic acid sequences encoding the antibody of interest, e.g., an antibody described herein, and a signal sequence for secretion.
  • the milk produced by females of such transgenic mammals includes, secreted-therein, the antibody of interest, e.g., an antibody described herein.
  • the antibody can be purified from the milk, or for some applications, used directly.
  • Antibodies can be modified, e.g., with a moiety that improves its stabilization and/or retention in circulation, e.g., in blood, serum, lymph, bronchoalveolar lavage, or other tissues, e.g., by at least 1.5, 2, 5, 10, or 50 fold.
  • a VLA-4 binding antibody can be associated with a polymer, e.g., a substantially non-antigenic polymer, such as a polyalkylene oxide or a polyethylene oxide.
  • Suitable polymers will vary substantially by weight. Polymers having molecular number average weights ranging from about 200 to about 35,000 daltons (or about 1,000 to about 15,000, and 2,000 to about 12,500) can be used.
  • a VLA-4 binding antibody can be conjugated to a water soluble polymer, e.g., a hydrophilic polyvinyl polymer, e.g. polyvinylalcohol or polyvinylpyrrolidone.
  • a water soluble polymer e.g., a hydrophilic polyvinyl polymer, e.g. polyvinylalcohol or polyvinylpyrrolidone.
  • a non- limiting list of such polymers include polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof, provided that the water solubility of the block copolymers is maintained.
  • Additional useful polymers include polyoxyalkylenes such as polyoxyethylene, polyoxypropylene, and block copolymers of polyoxyethylene and polyoxypropylene (Pluronics); polymethacrylates; carbomers; branched or unbranched polysaccharides that comprise the saccharide monomers D-mannose, D- and L-galactose, fucose, fructose, D-xylose, L-arabinose, D-glucuronic acid, sialic acid, D-galacturonic acid, D-mannuronic acid (e.g.
  • polymannuronic acid or alginic acid
  • D-glucosamine D-galactosamine
  • D-glucose and neuraminic acid including homopolysaccharides and heteropolysaccharides such as lactose, amylopectin, starch, hydroxyethyl starch, amylose, dextrane sulfate, dextran, dextrins, glycogen, or the polysaccharide subunit of acid mucopolysaccharides, e.g., hyaluronic acid; polymers of sugar alcohols such as polysorbitol and polymannitol; heparin or heparan.
  • a VLA-4 antagonist e.g., a VLA-4 binding agent, such as a VLA-4 binding antibody, (e.g., a natalizumab-like antibody molecule (e.g., natalizumab)) can be formulated as a pharmaceutical composition.
  • a pharmaceutical composition includes a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see, e.g., Berge, S. M., et al. (1977) J. Pharm. Sci. 66: 1-19). Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as ⁇ , ⁇ '-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline,
  • VLA-4 antagonists e.g., a VLA-4 binding antibody, e.g., a natalizumab- like antibody molecule (e.g., natalizumab), and other agents described herein can be formulated according to standard methods.
  • Exemplary pharmaceutical formulation is described in Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20.sup.th ed., Lippincott, Williams & Wilkins (2000) (ISBN: 0683306472); Ansel et al , Pharmaceutical Dosage Forms and Drug Delivery Systems, 7.sup.th Ed., Lippincott Williams & Wilkins Publishers (1999) (ISBN:
  • a VLA-4 antagonist e.g., a VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab) or another agent (e.g., another antibody)
  • excipient materials such as sodium chloride, sodium dibasic phosphate heptahydrate, sodium monobasic phosphate, and polysorbate 80. It can be provided, for example, in a buffered solution at a concentration of about 20 mg/ml and can be stored at 2-8 C.
  • Natalizumab can be formulated as described on the manufacturer's label.
  • compositions may also be in a variety of other forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form can depend on the intended mode of administration and therapeutic application.
  • compositions for the agents described herein are in the form of injectable or infusible solutions.
  • compositions can be administered by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection).
  • parenteral mode e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • administered parenterally mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage. A pharmaceutical composition can also be tested to insure it meets regulatory and industry standards for administration.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating an agent described herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating an agent described herein into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze- drying that yields a powder of an agent described herein plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. Administration
  • a VLA-4 antagonist e.g., a VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), can be administered to a subject, e.g., a human subject, by a variety of methods.
  • the route of administration is one of: intravenous injection or infusion, subcutaneous injection, or intramuscular injection.
  • a VLA-4 binding antibody, such as a natalizumab-like antibody molecule (e.g., natalizumab) can be administered as a fixed dose, or in a mg/kg dosage.
  • the antibody can be administered intravenously (IV) or subcutaneously (SC). In embodiments, the antibody is administered IV.
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a natalizumab-like antibody molecule e.g., natalizumab
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • tl the time at which a first dosage is administered
  • t2 the time at which a second dosage is administered
  • t3 the time at which a third dosage is administered
  • t3 the time at which a third dosage is administered
  • the time interval between each dosage is at least 1 day (e.g., at least 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, or 6 weeks, or 1, 2, 3, 4, 5, or 6 months or more). In embodiments, the time interval between each dosage (e.g., between tl and t2, and/or between t2 and t3, and so on) is about 2 days (e.g., 36-60 hours, e.g., 40-56 hours, e.g., 44-52 hours, e.g., about 48 hours).
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of 250 to 350 e.g., about 300, e.g., 300, mg; 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg; or 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g., a natalizumab- like antibody molecule (e.g., natalizumab)
  • a dosage of 600 mg e.g., IV
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of 300 mg e.g., IV, e.g., at a single dosage of 300 mg IV.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g. a
  • natalizumab-like antibody molecule e.g., natalizumab
  • IV a dosage that results in an AUC (e.g., over a period of time of 0- 10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0- 120 days) of at least about 20,000 to 30,000, e.g., at least about 20,000, 25,000, or 30,000 mg*hr/L.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • LKN a specified period from LKN, e.g., within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less), or within 9 hours of less (e.g., within 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour or less) after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a natalizumab-like antibody molecule e.g., natalizumab
  • the VLA-4 antagonist e.g., the VLA- 4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA- 4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 binding antibody e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a treatment window greater than 12 hours to and including 5 days after LKN is administered within a treatment window greater than 12 hours to and including 5 days after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of about 250 to 350 e.g., about 300, e.g., 300, mg; 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg; or 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of about 250 to 350 e.g., about 300, e.g., 300, mg; 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg; or 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg within 9 hours or less, e.g., approximately 1 to 9 hours, e.g., 9 to 2 hours, e.g., 9 to 3 hours, e.g., 9 to 4 hours, e.g., 9 to 5 hours, after LKN
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g.
  • a dosage of 250 to 350 e.g., about 300, e.g., 300, mg; 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg; or 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • each dosage e.g., at tl, t2, or t3 can be any dosage described herein.
  • the dosage at tl, t2, and/or t3 is 100 to 350 mg, e.g., 150 to 300 mg, e.g., administered IV.
  • the dosage at tl, t2, and/or t3 is 150 +/- 5%, e.g., about 150 mg, e.g., 150 mg; or 300 +/- 5%, e.g., about 300 mg, e.g., 300 mg, e.g., administered IV.
  • the dosage at tl is administered to a subject within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • methods herein comprise administering a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), subcutaneously.
  • a subcutaneous dosage of the VLA-4 antagonist is calculated by dividing an IV dosage (e.g., an IV dosage described herein) by 0.7.
  • a subcutaneous dosage is calculated by dividing an IV dosage by 0.7, and rounding up or down to the nearest number divisible by 50.
  • an IV dosage of 300 mg corresponds to a subcutaneous dosage of 300 mg divided by 0.7 (429), rounded up or down to the nearest 50; i.e., an IV dosage of 300 mg corresponds to a subcutaneous dosage of 400 mg or 450 mg.
  • an IV dosage of 450 corresponds to a subcutaneous dosage of 450 mg divided by 0.7 (643), rounded up or down to the nearest 50; i.e., an IV dosage of 450 mg corresponds to a subcutaneous dosage of 600 mg or 650 mg.
  • an IV dosage of 600 mg corresponds to a subcutaneous dosage of 600 mg divided by 0.7 (857), rounded up or down to the nearest 50; i.e., an IV dosage of 600 mg corresponds to a subcutaneous dosage of 850 mg or 900 mg.
  • an IV dosage of 600 mg corresponds to a subcutaneous dosage of 850 mg or 900 mg.
  • the antibody e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a fixed unit dose of between 50- 1000 mg IV e.g., between 100- 600 mg IV, e.g., between 200 and 400 mg IV, e.g., about 300 mg IV.
  • the antibody when administered subcutaneously, is administered at a dosage between 50-100 mg SC (e.g., 75 mg). It can also be administered in a bolus at a dosage of between 1 and 10 mg/kg, e.g., about 6.0, 4.0, 3.0, 2.0, 1.0 mg/kg.
  • continuous administration may be provided, e.g., via a subcutaneous pump.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 binding antibody molecule e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • is administered within 24 hours or less e.g., within 24, 23, 22, 21, 20, 19, 18, 17,
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 binding antibody molecule e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a natalizumab-like antibody molecule e.g., natalizumab
  • a subject having an NIHSS score of greater than 15 points, e.g., 16 to 23 points e.g., 16 to 23 points.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of between 200 and 400 mg within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of between 200 and 400 mg within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of between 200 and 400 mg within 24 hours or less e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less
  • LKN e.g., in a subject having an NIHSS score of less than 15 points, e.g., 5 to 15.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist is administered, e.g., IV, at a dosage of about 300 mg within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of about 300 mg within 6 hours or less e.g., 6, 5, 4, 3, 2 or 1 hour after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist is administered, e.g., IV, at a dosage of 300 mg within 6 hours after LKN, e.g., in a subject having an NIHSS score of greater than 15 points, e.g., 16 to 23 points.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of between 150 and 450 mg within 24 hours or less e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16,
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist is administered at a dosage of between 150 and 450 mg within 9 hours or less, e.g., approximately 1 to 9 hours, e.g., 9 to 2 hours, e.g., 9 to 3 hours, e.g., 9 to 4 hours, e.g., 9 to 5 hours, after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist is administered at a dosage of about 150 mg within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g.,
  • natalizumab is administered at a dosage of about 150 mg within 9 hours or less, e.g., approximately 1 to 9 hours, e.g., 9 to 2 hours, e.g., 9 to 3 hours, e.g., 9 to 4 hours, e.g., 9 to 5 hours, after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist is administered at a dosage of 150 mg within 9 or 6 hours or less, e.g., 9, 8, 7, or fewer hours after LKN, e.g., in a subject having an NIHSS score of greater than 15 points, e.g., 16 to 23 points.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist is administered, e.g., IV, at a dosage of about 450 mg within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of about 450 mg within 9 hours or less e.g., approximately 1 to 9 hours, e.g., 9 to 2 hours, e.g., 9 to 3 hours, e.g., 9 to 4 hours, e.g., 9 to 5 hours, after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • LKN e.g., in a subject having an NIHSS score of greater than 15 points, e.g., 16 to 23 points.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage of about 600 mg e.g., 600 mg
  • 24 hours or less e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g.,
  • natalizumab is administered, e.g., IV, at a dosage of about 600 mg (e.g., 600 mg) within 9 or 6 hours or less, e.g., 9, 8, 7, 6, 5, 4, 3, 2 or 1 hour after LKN.
  • the VLA-4 antagonist e.g., the VLA-4 binding antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the dosage can also be chosen to reduce or avoid production of antibodies against the VLA-4 binding antibody, to achieve greater than 40, 50, 70, 75, or 80% saturation of the a4 subunit, to achieve to less than 80, 70, 60, 50, or 40% saturation of the a4 subunit, or to prevent an increase the level of circulating white blood cells.
  • a method of treating a human subject having a disorder described herein comprising:
  • a dosage of a VLA-4 antagonist e.g., an anti-alpha4 antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)-like antibody molecule, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), thereby treating the human subject.
  • the selected dosage is administered to the subject.
  • the dosage can be selected based on the severity of stroke. For example, a dosage-A (e.g., higher) dosage of the VLA-4 antagonist is selected (e.g., and administered) if the stoke is determined to be a severe stroke. For example, a dosage-B (e.g., lower) dosage is selected (e.g., and administered) if the stroke is determined to be a less than severe stroke. In some examples, dosage-A is higher than dosage-B, e.g., at least 10, 20 or 30% higher.
  • the dosage-A is 350 to 500, e.g., 390 to 450, or 450+/- 5%, or about 450, e.g., 450, mg; or 550 to 650, e.g., 575 to 625, e.g., 600+/- 5%, e.g., about 600, e.g., 600, mg; and/or results in an AUC (e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days) of at least about 20,000 to 30,000, e.g., at least about 20,000, 25,000, or 30,000 mg*hr/L.
  • AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • dosage-B is 250 to 390, e.g., 275 to 325, e.g., 300 +/- 5%, or about 300 mg; and/or results in an AUC (e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days) of at least about 20,000 to 30,000, e.g., at least about 20,000, 25,000, or 30,000 mg*hr/L.
  • AUC e.g., over a period of time of 0-10 days, 0-20 days, 0-30 days, 0-60 days, 0-90 days, or 0-120 days
  • Severity of stroke can be determined by methods described herein. Use of such methods to determine severity of stroke are described in greater detail herein.
  • VLA-antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • AUC a natalizumab-like antibody molecule
  • natalizumab a natalizumab-like antibody molecule
  • multiple dosages of a VLA-antagonist are administered to the subject.
  • the subject is administered a first dosage of a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), at time 1 (tl); a second dosage of the VLA-4 antagonist (e.g., a natalizumab-like antibody molecule (e.g., natalizumab)) at time 2 (t2); and optionally, a third dosage of the VLA-4 antagonist (e.g., a natalizumab-like antibody molecule (e.g., natalizumab)) at time 3 (t3).
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • the formulation comprises biodegradable and biocompatible polymers, e.g., polyanhydrides, collagen, ethylene vinyl acetate, polyglycolic acid, poly lactic acid, and/or polyorthoesters.
  • biodegradable and biocompatible polymers e.g., polyanhydrides, collagen, ethylene vinyl acetate, polyglycolic acid, poly lactic acid, and/or polyorthoesters.
  • a composition described herein is delivered in a microencapsulated delivery system or a medical device, e.g., implant.
  • the composition is delivered by a needleness hypodermic injection device (see, e.g., US Pat. No. 5,399, 163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556).
  • the composition is delivered in an implantable micro-infusion pump that dispenses at a controlled rate (see, e.g., US Pat. No. 4,487,603).
  • the composition is delivered through the skin in a device such as that described in US Pat. No. 4,486, 194.
  • the composition is delivered in an infusion pump (see, e.g., US Pat. No. 4,447,233 or 4,447,224). In embodiments, the composition is delivered in an osmotic delivery system with multi-chamber compartments (see, e.g., US Pat. No. 4,475,196).
  • Methods described herein can also include administering a VLA-4 antagonist in combination with another therapeutic modality, e.g., an additional agent (e.g., a pharmacological agent) or a procedure.
  • Administered "in combination”, as used herein means that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons.
  • the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous" or "concurrent delivery".
  • the delivery of one treatment ends before the delivery of the other treatment begins.
  • the treatment is more effective because of combined administration.
  • the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
  • delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive.
  • the delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
  • the VLA-4 antagonist and the at least one additional therapeutic agent can be any VLA-4 antagonist and the at least one additional therapeutic agent.
  • the antagonist can be administered first, and the additional agent can be administered second, or the order of administration can be reversed.
  • the additional agent is preferably an agent with some degree of therapeutic efficacy in treating acute brain injury.
  • agents may include, but are not limited to, thrombolytic agents such as plasminogen, tissue plasminogen activator (t-PA) or urokinase, agents that target excitotoxic mechanisms such as SelfotelTM or AptiganelTM, agents that target nitric oxide associated neuronal damage such as LubeluzoleTM, agents that target ischemia associated neuronal cellular membrane damage such as TirilizadTM, agents that target anti-inflammatory mechanisms such as EnlimomabTM.
  • thrombolytic agents such as plasminogen, tissue plasminogen activator (t-PA) or urokinase
  • agents that target excitotoxic mechanisms such as SelfotelTM or AptiganelTM
  • agents that target nitric oxide associated neuronal damage such as LubeluzoleTM
  • agents that target ischemia associated neuronal cellular membrane damage such as Tirilizad
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a stroke e.g., an ischemic stroke (e.g., an acute ischemic stroke), a hemorrhagic stroke (e.g., an intracerebral hemorrhage or a subarachnoid hemorrhage), or a TBI.
  • the treatment ameliorates one or more symptoms of the stroke, subarachnoid hemorrhage, or TBI, improves a functional outcome (e.g., an endpoint described herein) of the stroke, subarachnoid hemorrhage, or TBI, and/or prevents further deterioration from the disease.
  • a functional outcome e.g., an endpoint described herein
  • the VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a natalizumab-like antibody molecule e.g., natalizumab
  • TBI a specified period from LKN of the stroke, subarachnoid hemorrhage, or TBI, e.g., within 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN of the stroke, subarachnoid hemorrhage, or TBI.
  • the VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a natalizumab-like antibody molecule e.g., natalizumab
  • the VLA-4 antagonist is administered within 6-9 hours (e.g., within 6-7, 7-8, or 8-9 hours) after LKN of the stroke, subarachnoid hemorrhage, or TBI.
  • onset time of stroke, subarachnoid hemorrhage, or TBI is determined by a medical professional, e.g., by questioning regarding one or more symptoms of stroke, subarachnoid hemorrhage, or TBI, e.g., start of symptom(s) of stroke, subarachnoid hemorrhage, or TBI, or time of subject awakening with a stroke, subarachnoid hemorrhage, or TBI,.
  • brain imaging e.g., MRI, is used to determine the time of onset and/or duration of stroke, subarachnoid hemorrhage, or TBI in a subject. See, e.g., Petkova et al.
  • the stroke, subarachnoid hemorrhage, or TBI onset time is determined by the last time the subject was known, e.g., as identified by the subject or another individual, to be well (e.g., last known normal (LKN)).
  • the onset of a TBI is the time of trauma/impact to the head or body, e.g., determined by the subject or another individual (e.g., observer).
  • a subject is administered a therapy described herein, e.g., a natalizumab- like antibody molecule (e.g., natalizumab), within 6 hours (e.g., within 0, 1, 2, 3, 4, 5, or 6 hours) of the last known normal (LKN).
  • a subject is administered a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), >6 hours and ⁇ 9 hours of the LKN (e.g., >6, 6.5, 7, 7.5, 8, or 8.5 hours and ⁇ 9, 8.5, 8, 7.5, 7, 6.5 hours of the LKN).
  • a subject is administered a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), within 12 hours (e.g., within 12, 11, 10, 9 hours or less) of the last known normal (LKN).
  • a subject is administered a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), within 24 hours (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) of the last known normal (LKN).
  • the subject suffers from a stroke, e.g., ischemic stroke (e.g., acute ischemic stroke), or hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage).
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • sufferer e.g., ischemic stroke, e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the subject has previously had a stroke (e.g., ischemic stroke, e.g., acute ischemic stroke; or hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid hemorrhage)).
  • ischemic stroke e.g., acute ischemic stroke
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • the subject suffers from an acute middle cerebral artery (MCA) ischemic stroke.
  • MCA middle cerebral artery
  • thrombosis e.g., venous thrombosis
  • embolism or systemic hypoperfusion causes a disruption of the blood supply to the brain, causing ischemia (lack of oxygen and glucose supply), and as a result, the subject develops a loss of brain function(s).
  • Loss of brain function(s) in the affected area causes functional disabilities, e.g., inability to move one or more limbs on one side of the body, inability to formulate or understand speech, and/or inability to see one side of the visual field.
  • a stroke can cause permanent neurological damage, complications, and/or death.
  • Exemplary symptoms of ischemic stroke include but are not limited to numbness;
  • hemorrhagic stroke e.g., intracerebral hemorrhage or subarachnoid hemorrhage
  • blood vessels in the brain leak or rupture, resulting in bleeding in or around the brain. Damage can occur rapidly due to the pressure of growing amounts of blood and/or because of the blood itself, which irritates the brain tissue, causing it to swell. Symptoms include loss of
  • a type of hemorrhagic stroke includes intracerebral hemorrhage.
  • intracerebral hemorrhage a blood vessel inside the brain bursts and leaks blood into surrounding brain tissue. The bleeding causes death of brain cells and loss of normal function in the affected part of the brain. The most common causes of this type of stroke are high blood pressure and aging blood vessels.
  • intracerebral hemorrhagic stroke can be caused by an arteriovenous malformation (AVM), which is a genetic condition causing an abnormal connection between veins and arteries that most commonly occurs in the brain or spine. AVM that occurs in the brain can cause vessel breakage and bleeding into the brain.
  • AVM arteriovenous malformation
  • the subject suffers from subarachnoid hemorrhage (SAH).
  • SAH subarachnoid hemorrhage
  • Subarachnoid hemorrhage is characterized by bleeding around the brain and is caused by bleeding into the subarachnoid space (the area between the brain and the tissue covering the brain). Bleeding can happen spontaneously, e.g., from a ruptured cerebral aneurysm, or may result from a head injury, AVM, bleeding disorders or blood thinners. Exemplary symptoms of SAH include a severe headache with a rapid onset, vomiting, confusion or a lowered level of consciousness, and seizures in some cases. Diagnosis of SAH can be made by a CT scan or lumbar puncture. Current treatment methods include neurosurgery or radiologically guided interventions with medications to prevent recurrence of the bleeding and other complications.
  • the subject suffers from a traumatic brain injury (TBI).
  • TBI traumatic brain injury
  • Traumatic brain injury occurs when an external mechanical force (e.g., by a violent blow or jolt to the body or head, or an object that penetrates the skull) results in brain dysfunction.
  • an external mechanical force e.g., by a violent blow or jolt to the body or head, or an object that penetrates the skull
  • ild TBI can cause temporary dysfunction of brain cells.
  • More serious TBI can result in torn tissues, bruising, bleeding and other physical damage to the brain that can lead to long-term complications or death.
  • a TBI includes a concussion or post-concussion syndrome.
  • Symptoms of mild TBI include loss of consciousness for a few seconds to a few minutes; a state of being dazed, confused or disoriented; headache; nausea or vomiting; fatigue or drowsiness; difficulty sleeping; sleeping more than usual; dizziness or loss of balance; blurred vision; ringing in the ears; a bad taste in the mouth; changes in the ability to smell; sensitivity to light or sound; memory or concentration problems; mood changes or mood swings; feeling depressed or anxious.
  • Symptoms of moderate to severe TBI include loss of consciousness from several minutes to hours persistent headache or headache that worsens; repeated vomiting or nausea; convulsions or seizures; dilation of one or both pupils of the eyes; clear fluids draining from the nose or ears; inability to awaken from sleep; weakness or numbness in fingers and toes; loss of coordination; profound confusion; agitation, combat iveness or other unusual behavior; slurred speech; and coma and other disorders of consciousness.
  • a test/diagnosis of TBI is the Glasgow Coma Scale, which is a 15-point test that permits the assessment of the initial severity of a brain injury by checking a subject's ability to follow directions and move their eyes and limbs. Higher scores indicate less severe injuries.
  • Other tests/diagnoses of TBI arc imaging tests, for example, computerized tomography (CT) scans or magnetic resonance imaging (MRI).
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • An intracranial pressure monitor may also be used to determine amount of tissue swelling from a TBI, as tissue swelling can increase pressure inside the skull and cause additional damage to the brain.
  • TBI Treatment/procedures for TBI include diuretics, anti-seizure drugs, coma- inducing drags, surgery, removal of clotted blood (hematomas), repair of skull fractures, opening of a window in the skull, and/or rehabilitation.
  • the methods comprise treating the subject with a therapy described herein, e.g., VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), in combination with a second therapy or procedure, e.g., thrombolysis (e.g., tissue plasminogen activator (tPA), thrombectomy, angioplasty, stenting, therapeutic hypothermia, and/or a medication (e.g., aspirin, clopidrogrel, and/or dipyridamole).
  • the second therapy comprises a thrombolytic agent, anti-inflammatory agent, cytokine, growth factor, steroid, or neuroprotective agent.
  • Exemplary thrombolytic agents include tPA and urokinase.
  • Exemplary neuroprotective agents include an agonist to a receptor, such as N-Methyl-D aspartate (NMD A) receptor, glycine receptor, calcium channel receptor, a-amino-3-hydroxy-5-methyl-4- isoxazoleproprionic acid (AMPA) receptor, sodium channel receptor, bradykinin B2 receptor, bradykinin B l receptor, adenosine Al receptor, or a-amino butyric acid (GAB A) receptor.
  • NMD A N-Methyl-D aspartate
  • AMPA a-amino-3-hydroxy-5-methyl-4- isoxazoleproprionic acid
  • GAB A a-amino butyric acid
  • anti-inflammatory agents include tumor necrosis family members and interleukin- 1 (IL-1).
  • the second therapy or procedure is administered or performed concurrently with (e.g., within 2 days or day of) administration of the therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab). In embodiments, the second therapy or procedure is administered or performed prior to or subsequent to administration of the therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the disclosure provides methods of treating (e.g., stabilizing, reducing, or eliminating one or more symptoms or stabilizing the subject's score on a stroke scale) stroke, e.g., acute ischemic stroke, by administering a VLA-4 antagonist to a subject having or suspected of having a stroke).
  • stroke e.g., ischemic stroke (e.g., acute ischemic stroke), hemorrhagic stroke (e.g., intracerebral hemorrhage or subarachnoid
  • a VLA-4 antagonist to a subject at risk of developing a stroke (e.g., a subject that has experienced systemic hypoperfusion) or a
  • the subject has a severe stroke, e.g., a high NIHSS score (e.g., at least 15, e.g., at least 21, e.g., 21-42) at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a severe stroke e.g., a high NIHSS score (e.g., at least 15, e.g., at least 21, e.g., 21-42)
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the methods described herein comprise identifying a subject having a severe stroke at baseline, and administering a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), to the subject.
  • a subject identified as having a severe stroke has a NIHSS score at baseline of at least 15, e.g., at least 21, e.g., 21-42, e.g., 21- 25, 25-30, or 30-42.
  • the subject having (e.g., identified as having) a severe stroke at baseline is administered a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), at a dosage described herein, e.g., via a route of administration described herein, e.g., at 12 hours or less (e.g., 12, 11, 10, 9, 8, 7, 6, 5, 4 3, 2, 1, or less, or within 9 hours, or within 6-9 hours) after LKN.
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage described herein e.g., via a route of administration described herein, e.g., at 12 hours or less (e.g., 12, 11, 10, 9, 8, 7, 6, 5, 4 3, 2, 1, or less, or within 9 hours, or within 6-9 hours) after LKN.
  • the subject has a less than severe stroke, e.g., a NIHSS score of less than 15 at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the methods described herein comprise identifying a subject having a less than severe stroke at baseline, and administering a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), to the subject.
  • a subject identified as having a less than severe stroke has a NIHSS score at baseline of less than 15.
  • the subject having e.g., identified as having a less than severe stroke at baseline is administered a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), at a dosage described herein, e.g., via a route of administration described herein, e.g., at 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage described herein e.g., via a route of administration described herein, e.g., at 24 hours or less (e.g., within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 hours or less) after LKN.
  • the subject has a small to medium sized infarct at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject does not have a large sized infarct at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject has a lesion size of ⁇ 4.6 cm in diameter (e.g., less than 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5 cm, or less in diameter) at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject has a lesion size of no greater than 4.6 cm in diameter (e.g., no greater than 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5 cm, or less in diameter) at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject has a lesion size of 2-4 cm in diameter at baseline, e.g., prior to treatment with a therapy described herein, e.g., a
  • natalizumab-like antibody molecule e.g., natalizumab.
  • the subject has an infarct volume of less than one-third of the middle cerebral artery (MCA) territory, e.g., the region of brain tissue supplied by the MCA. In embodiments, the subject has an infarct volume of no greater than one-third of the MCA territory.
  • MCA middle cerebral artery
  • the methods described herein comprise identifying a subject having a small to medium sized infarct at baseline, and administering a VLA-4 antagonist, e.g., a natalizumab- like antibody molecule (e.g., natalizumab), to the subject.
  • a VLA-4 antagonist e.g., a natalizumab- like antibody molecule (e.g., natalizumab)
  • a subject identified as having a small to medium sized infarct has a lesion size of ⁇ 4.6 cm in diameter (e.g., less than 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5 cm, or less in diameter) at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a natalizumab-like antibody molecule e.g., natalizumab
  • a subject identified as having a small to medium sized infarct subject has a lesion size of no greater than 4.6 cm in diameter (e.g., no greater than 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5 cm, or less in diameter) at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab- like antibody molecule (e.g., natalizumab).
  • a natalizumab- like antibody molecule e.g., natalizumab
  • a subject identified as having a small to medium sized infarct subject has a lesion size of 2-4 cm in diameter at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a subject identified as having a small to medium sized infarct subject has an infarct volume of less than one-third of the middle cerebral artery (MCA) territory, e.g., the region of brain tissue supplied by the MCA. In embodiments, a subject identified as having a small to medium sized infarct subject has an infarct volume of no greater than one-third of the MCA territory.
  • MCA middle cerebral artery
  • the subject having e.g., identified as having a small to medium sized infarct at baseline is administered a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), at a dosage described herein, e.g., via a route of administration described herein, e.g., at 12 hours or less (e.g., 12, 11, 10, 9, 8, 7, 6, 5, 4 3, 2, 1, or less, or within 9 hours, or within 6-9 hours) after LKN.
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage described herein e.g., via a route of administration described herein, e.g., at 12 hours or less (e.g., 12, 11, 10, 9, 8, 7, 6, 5, 4 3, 2, 1, or less, or within 9 hours, or within 6-9 hours) after LKN.
  • the subject has a large sized infarct at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule
  • the subject does not have a small to medium sized infarct at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject has a lesion size of at least 4.6 cm in diameter (e.g., at least 4.6, 4.8, 5, 5.2, 5.4, 5.6 5.8, 6, 7, 8, 9, 10 cm, or more in diameter) at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject has an infarct volume of at least one-third (e.g. at least one-third, two-thirds, or three-fourths, or more) of the middle cerebral artery (MCA) territory, e.g., the region of brain tissue supplied by the MCA.
  • MCA middle cerebral artery
  • the methods described herein comprise identifying a subject having a large sized infarct at baseline, and administering a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), to the subject.
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a subject identified as having a large sized infarct has a lesion size of at least 4.6 cm in diameter (e.g., at least 4.6, 4.8, 5, 5.2, 5.4, 5.6 5.8, 6, 7, 8, 9, 10 cm, or more in diameter) at baseline, e.g., prior to treatment with a therapy described herein, e.g., a natalizumab- like antibody molecule (e.g., natalizumab).
  • a subject identified as having a small to medium sized infarct subject has an infarct volume of at least one-third (e.g. at least one-third, two-thirds, or three-fourths, or more) of the middle cerebral artery (MCA) territory, e.g., the region of brain tissue supplied by the MCA.
  • MCA middle cerebral artery
  • the subject having (e.g., identified as having) a large sized infarct at baseline is administered a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), at a dosage described herein, e.g., via a route of administration described herein, e.g., at 12 hours or less (e.g., 12, 11, 10, 9, 8, 7, 6, 5, 4 3, 2, 1, or less, or within 9 hours, or within 6-9 hours) after LKN.
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a dosage described herein e.g., via a route of administration described herein, e.g., at 12 hours or less (e.g., 12, 11, 10, 9, 8, 7, 6, 5, 4 3, 2, 1, or less, or within 9 hours, or within 6-9 hours) after LKN.
  • the subject has been treated with a tissue plasminogen activator (tPA) prior to administration with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a tissue plasminogen activator (tPA) at least 1 day prior (e.g., at least 1, 2, 3, 4, 5, 6, 7 days, 1, 2, 3, 4, 5, 6, 7, 8 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9 10, 11, or 12 months prior) to administration with a therapy described herein, e.g., a natalizumab- like antibody molecule (e.g., natalizumab).
  • the subject has been treated with a tPA within 12 months (e.g., within 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month, within 8, 7, 6, 5, 4, 3, 2, or 1 week, within 7, 6, 5, 4, 3, 2, or 1 day) of administration with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject has not been treated with a tPA prior to administration with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject is administered a tPA in combination with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject is administered a tPA concurrently with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 24 hours, 12 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or less, prior to
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject is administered a tPA subsequent to (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 24 hours, 12 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, or less, subsequent to) a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the subject is not administered a tPA is combination in with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • Standard tests for neurological recovery can be employed by skilled artisans to determine efficacy or rehabilitation.
  • the NIHSS classifies the severity of a stroke based on a subject's ability to answer questions and perform activities relating to level of consciousness, language, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, sensory loss and extinction and inattention. There are 15 items and ratings for each item are scored with 3 to 5 grades with 0 as normal and a maximum severity score of 42 for all items.
  • a NIHSS of 1-5 is indicative of a mild stroke; a score of 5-14 is indicative of a mild to moderate stroke, a score of 15-24 is indicative of a severe stroke; and a score of greater than 25 is indicative of a very severe stroke. See, e.g., Brott et al. Stroke. 20(1989):864-70.
  • a patient is evaluated by one or more endpoints to assess the efficacy of a treatment described herein and/or the
  • Exemplary endpoints include endpoints assessed by imaging techniques, such as magnetic resonance imaging (MRI), clinical efficacy endpoints, or safety/tolerability endpoints.
  • Exemplary endpoints include but are not limited to infarct volume (e.g., change in infarct volume from baseline, e.g., detected by imaging); clinical endpoints, such as modified Rankin Scale (mRS), NIHSS, Barthel index, stroke-impact scale- 16, Montreal cognitive assessment; and safety/tolerability endpoints. Stroke outcomes/endpoints measure different but related aspects of disability.
  • the mRS measures functional independence
  • the NIHSS measures key components of standard neurological exam
  • the Barthel index assesses activity related to self care and mobility. See, e.g., Kasner Lancet Neurology 5.7(2006):603-12.
  • Imaging e.g., by MRI
  • the infarct volume is measured in a patient after stroke, e.g., before and/or after treatment with a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • imaging e.g., by MRI
  • Infarct volume refers to the lesion size in a brain of a subject who has suffered a stroke, e.g., ischemic stroke. Lesions occur after ischemic stroke because the lack of oxygen delivered to tissues at the site of the lesion cause tissue damage and necrosis.
  • Infarct volume can be useful in determining the stroke sub-type and predicting the clinical condition and outcome of a stroke subject. Measurements of infarct volume can also be used to assess the efficacy of stroke therapies. Infarct volume can be measured using imaging
  • infarct volume is measured using diffusion weighted imaging (DWI), which is a form of MRI.
  • DWI diffusion weighted imaging
  • infarct volume is measured using diffusion weighted imaging (DWI), which is a form of MRI.
  • DWI diffusion weighted imaging
  • MRI magnetic resonance imaging
  • DWI permits early identification (e.g., within several hours) of ischemic stroke, e.g., acute ischemic stroke.
  • imaging e.g., by MRI is used to detect a change in infarct volume growth from baseline after administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • the change in infarct volume from baseline is measured 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • mRS scale (a clinical endpoint)
  • a patient is evaluated for improvement in functional independence after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • the patient is evaluated by the modified Rankin Scale (mRS), which is a measure of functional independence.
  • mRS modified Rankin Scale
  • Table 1 describes the scoring method on the mRS scale. A lower score indicates greater functional independence. A higher score indicates less functional independence/greater disability.
  • the mRS score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12,
  • a therapy described herein e.g., a
  • a patient has a lower mRS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15,
  • a patient has a mRS score of 3 or less after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3,
  • a patient has a mRS score of 0 or 1 after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy).
  • a mRS score of 0 or 1 after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy).
  • an excellent outcome is defined as an mRS of 0 or 1 (0,1).
  • an excellent outcome on the mRS scale indicates that the therapy is efficacious, e.g., that the patient improved in functional independence after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a lower mRS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment indicates improvement, e.g., that the patient improved in functional independence after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g.,
  • a mRS score of 3 or less after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) indicates improvement, e.g., that the patient improved in functional independence after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • the BI is a measure of activities of daily living and how independent a patient is in performing various activities.
  • a description of the scoring method for BI is shown in Figure 9.
  • a patient's score for each activity is summed. Higher scores indicate greater independence; lower scores indicate greater disability.
  • the BI score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab- like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab- like antibody molecule (e.g., natalizumab).
  • a patient has a higher BI score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • a patient has a BI score of 85 or more after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first BI score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first BI score after treatment
  • a patient has a BI score of at least 95 after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy).
  • an excellent outcome is defined as a BI score of at least 95.
  • an excellent outcome on the BI scale indicates that the therapy is efficacious, e.g., that the patient improved in functional independence in daily activities after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a treatment described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a functional outcome is defined as a BI score of at least 85.
  • a functional outcome on the BI scale indicates that the therapy is efficacious, e.g., that the patient improved in functional independence in daily activities after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a treatment described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a higher BI score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment indicates that improvement, e.g., that the patient improved in functional independence in daily activities after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • NIH National Institutes of Health
  • NIHSS National Institutes of Health Stroke Scale
  • NIHSS can also be a measure of a patient's neurologic function after stroke.
  • NIHSS is an 11 item assessment scored from 0 to 42.
  • the NIHSS score is determined in a patient 6 hours or later (e.g., 6, 8, 10,
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has a lower NIHSS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • 6 hours or more e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy
  • a patient has a NIHSS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) that is at least 8 points less than before treatment.
  • a NIHSS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) that is at least 8 points less than before treatment.
  • a patient has a NIHSS score of 0 or 1 after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy).
  • the NIHSS score of a patient does not change after administration of the therapy compared to at baseline.
  • an excellent outcome is defined as a NIHSS score of 0 or 1 (0,1) or at least 8 points lower than baseline score.
  • an excellent outcome on the NIHSS scale indicates that the therapy is efficacious, e.g., that the patient improved in neurological function after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a lower NIHSS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment indicates improvement, e.g., that the patient improved in neurological function after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a NIHSS score decrease of at least 8 points after treatment compared to baseline (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) indicates that the therapy is efficacious, e.g., that the patient improved in neurological function after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • Stroke Impact Scale- 16 (SIS-16) (a clinical endpoint)
  • the SIS-16 is a self-report scale assessing the activities of daily living (ADLs) and physical domains after stroke, such as hand function, mobility, communication, emotion, memory and thinking, and participation. See, e.g., Duncan et al. Neurology. 60.2(2003):291-6.
  • the SIS-16 includes 16 items, e.g., 7 ADL items, 8 mobility items, and 1 hand function item.
  • the SIS-16 includes items that cover body function (e.g., bladder and bowel control), activity (e.g., bathing self), and participation (e.g., shopping), with total scores ranging from 0 to 100.
  • the SIS-16 score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has a higher SIS-16 score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • 6 hours or more e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy
  • a favorable SIS-16 outcome after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), is a score greater than the median score.
  • a favorable outcome on the SIS-16 scale indicates that the therapy is efficacious, e.g., that the patient improved in self-perceived ADLs and physical capabilities after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a higher SIS-16 score after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), compared to at baseline, indicates improvement, e.g., that the patient improved in self-perceived ADLs and physical capabilities after treatment.
  • the Montreal Cognitive Assessment is a cognitive evaluation method.
  • the MoCA is a 30-point test administrable in about 10 minutes that evaluates cognitive domains, such as attention and concentration, language, visuoconstructional skills, visuospatial abilities, conceptual thinking, calculations, executive functions, memory (e.g., short term memory, working memory), recall, and orientation (e.g., to time and space).
  • the MoCA is useful for evaluating a subject who has suffered from a stroke or a subject who is experiencing memory difficulties. See, e.g., Nasreddine et al.
  • the Montreal Cognitive Assessment (MoCA) A brief cognitive screening tool for detection of mild cognitive impairment.
  • the MoCA score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has a higher MoCA score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • 6 hours or more e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy
  • a favorable MoCA outcome after administration of a therapy described herein is a score greater than or equal to 26.
  • a favorable outcome on the MoCA scale indicates that the therapy is efficacious, e.g., that the patient improved in cognitive function after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)), e.g., that the patient has normal function.
  • a higher MoCA score after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), compared to at baseline, indicates improvement, e.g., that the patient improved in cognitive function after treatment.
  • FIM The Functional Independent Measure
  • a subject's ability to function independently during rehabilitation e.g., from a stroke, traumatic brain injury, spinal cord injury, or cancer. See, e.g., Mackintosh S (2009) Functional Independence Measure. The Australian Journal of Physiotherapy . 55 (1): 65.
  • FIM may comprise a motor evaluation, e.g., subscale, and a cognition evaluation, e.g., subscale.
  • the motor subscale comprises evaluation of one or more (e.g., all) of eating, grooming, bathing, dressing (e.g., upper and/or lower body), toileting, bladder management, transfers (e.g., to or between bed or chair or wheelchair, to the toilet, or to the bath or shower), walking/wheelchair, and/or stairs.
  • the cognition subscale comprises evaluation of one or more (e.g., all) of comprehension, expression, social interaction, problem solving, and/or memory.
  • a total motor FIM score is a value ranging from 13 to 91
  • a total cognition FIM score is a value ranging from 5-35
  • a total FIM score is a value ranging from 18-126.
  • the FIM score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has a higher FIM score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • FIM score after treatment 6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • a favorable FIM outcome after administration of a therapy described herein e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a favorable outcome on the FIM scale indicates that the therapy is efficacious, e.g., that the patient improved in self -perceived ADLs and physical capabilities after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a higher FIM score after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), compared to at baseline, indicates improvement, e.g., that the patient improved motor and/or cognitive capabilities after treatment.
  • a therapy described herein e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • EQ-5D is a standardized measure of health developed by EuroQoL Group (see e.g., van Reenen and Oppe, EQ-5D-3L User Guide, EuroQoL Research Foundation 2015), a group of international interdisciplinary researchers.
  • EQ-5D comprises surveys that can be administered remotely (e.g., by post or electronically), in a clinic setting, or in an interview setting.
  • EQ-5D 3 level (EQ-5D-3L) is a two part survey, wherein the first part evaluates five health dimensions: mobility, self-care, usual activities (e.g., work, study, housework, family, or leisure activities),
  • the subject determines which of three levels applies to each dimension, each approximately being no problems, some problems, or extreme problems (e.g., unable to walk, unable to perform usual activities).
  • the second part of the EQ-5D-3L is an analogue evaluation of the subject's overall health state, e.g., the subject draws a mark on a scale from 0 to 100 to represent their overall health, where 100 is the best imaginable health state and 0 is the worst imaginable health state. Scoring criteria and data processing methods for using EQ-5D-3L are known in the art.
  • the EQ-5D-3L data is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has more favorable or improved EQ-5D-3L data (e.g., in one, two, three, four, or five health
  • a favorable EQ-5D-3L outcome after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), is a EQ-5D-3L index value better than the median index value.
  • a favorable outcome of EQ-5D-3L data indicates that the therapy is efficacious, e.g., that the patient improved in self-perceived health and capabilitiesties after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • improved EQ-5D-3L data after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), compared to at baseline, indicates improvement, e.g., that the patient improved in a health dimension after treatment.
  • SDMT The Symbol Digit Modalities Test
  • the Symbol Digit Modalities Test is a method of evaluating cognitive impairment (see, e.g., Smith, A. SDMT - Symbol Digit Modalities Test. Western Psychological Services, 1973, or any later edition, e.g., 13 ed.). SDMT can be used to screen for cerebral dysfunction in children and adults. SDMT tests visual-spatial processing and information processing of a subject, including evaluating one or more of attention, reaction time, motor execution, incidental learning, visual- spatial memory, working memory, visual acuity, oral fluency, and executive functioning. SDMT has an advantage that it does not require expensive equipment or specially trained personnel to administer, and can be administered in written form or orally. In the SDMT test, a subject performs a substitution test where they use a reference key to pair numbers with geometric figures.
  • the SDMT score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has a higher SDMT score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • 6 hours or more e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy
  • a favorable SDMT outcome after administration of a therapy described herein e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a favorable outcome on the SDMT scale indicates that the therapy is efficacious, e.g., that the patient improved in cognitive capabilities after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a higher SDMT score after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), compared to at baseline, indicates improvement, e.g., that the patient improved cognitive capabilities after treatment.
  • the Fatigue Severity Scale is a 9-item self -reporting questionnaire that can be administered to subjects to evaluate fatigue symptoms (see, e.g., Valko et al. Sleep. 2008 Nov 1; 31(11): 1601— 1607). Each item asks the subject to rate an aspect of their fatigue on a scale from 1 to 7, where 1 indicates strong disagreement and 7 strong agreement.
  • the final FSS score (the FSS score) represents the mean of the 9 individual scores.
  • the 9 items comprise or comprise items similar to: 1) My motivation is lower when I am fatigued, 2) Exercise brings on my fatigue, 3) I am easily fatigued, 4) Fatigue interferes with my physical functioning, 5) Fatigue causes frequent problems for me, 6) My fatigue prevents sustained physical functioning, 7) Fatigue interferes with carrying out certain duties and responsibilities, 8) Fatigue is among my three most disabling symptoms, and/or 9) Fatigue interferes with my work, family, or social life.
  • the FSS score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has a lower FSS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • a lower FSS score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • a favorable FSS outcome after administration of a therapy described herein e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a favorable outcome on the SDMT scale indicates that the therapy is efficacious, e.g., that the patient had decreased fatigue or fatigue-related symptoms after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a lower FSS score after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), compared to at baseline, indicates improvement, e.g., that the patient had decreased fatigue or fatigue-related symptoms after treatment.
  • the Beck Depression Inventory 2 (BDI-2) is a method of evaluating the severity of depression symptoms in a subject, e.g., a subject aged 13 or older (see, e.g., Beck et al. Beck Depression Inventory - II (BDI - II). 1996. Pearson).
  • BDI-2 comprises a 21 question multiple choice self report questionnaire. Each question asks a subject to rate an aspect of their depression symptoms, with answers given a score from 0 to 3. Higher total scores indicate more severe depressive symptoms, while lower total scores indicate an absence of symptoms or milder depressive symptoms.
  • a BDI-2 score of 0-13 indicates minimal depression, 14-19 indicates mild depression, 20-28 indicates moderate depression, and 29-63 indicates severe depression.
  • the BDI-2 score is determined in a patient 6 hours or later (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more) after a first administration of a therapy described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a patient has a lower BDI-2 score after treatment (6 hours or more (e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy) compared to before treatment.
  • 6 hours or more e.g., 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 h, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 days or more after a first administration of the therapy
  • a favorable BDI-2 outcome after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), is a score less than the median score.
  • a favorable outcome on the BDI-2 scale indicates that the therapy is efficacious, e.g., that the patient had decreased depression or depression-related symptoms after treatment (e.g., with a treatment described herein, e.g., a natalizumab-like antibody molecule (e.g., natalizumab)).
  • a lower BDI-2 score after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab), compared to at baseline, indicates improvement, e.g., that the patient had decreased depression or depression-related symptoms after treatment.
  • a subject is evaluated for one or more adverse effects after administration of a therapy described herein, e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a VLA-4 antagonist, e.g., a natalizumab-like antibody molecule (e.g., natalizumab).
  • a therapy described herein e.g., a VLA-4 antagonist, e.g., a
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab)
  • a natalizumab-like antibody molecule e.g., natalizumab
  • minimal adverse effects e.g., no adverse effects.
  • a dosage of a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab) administered to the subject is chosen to reduce or avoid production of antibodies against the VLA-4 binding antibody and/or to prevent an increase the level of circulating white blood cells.
  • a VLA-4 antagonist e.g., a natalizumab-like antibody molecule (e.g., natalizumab) administered to the subject is chosen to reduce or avoid production of antibodies against the VLA-4 binding antibody and/or to prevent an increase the level of circulating white blood cells.
  • thrombolysis e.g., tissue plasminogen activator (tPA)
  • thrombectomy e.g., tissue plasminogen activator (tPA)
  • thrombectomy e.g., angioplasty and stenting
  • therapeutic hypothermia e.g., aspirin, clopidogrel and dipyridamole
  • a medication e.g., aspirin, clopidogrel and dipyridamole
  • the second therapy is, e.g., a thrombolytic agent, a neuroprotective agent, an anti-inflammatory agent, a steroid, a cytokine or a growth factor.
  • the thrombolytic agent used can be tissue plasminogen activator or urokinase.
  • the neuroprotective agent used can be an agonist to a receptor selected from the group consisting of: N-Methyl-D aspartate receptor (NMD A), a-amino-3-hydroxy-5- methyl-4-isoxazoleproprionic acid receptor (AMPA), glycine receptor, calcium channel receptor, bradykinin B2 receptor and sodium channel receptor, or from the group consisting of: the bradykinin B l receptor, a- amino butyric acid (GAB A) receptor, and Adenosine Al receptor.
  • Anti-inflammatory agents for use can be interleukin- 1 and tumor necrosis factor family members.
  • a VLA-4 antagonist described herein may be provided in a kit.
  • the kit includes a VLA-4 antagonist described herein and, optionally, a container, a pharmaceutically acceptable carrier and/or informational material.
  • the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the a4 antagonist for the methods described herein.
  • the informational material of the kits is not limited in its form.
  • the informational material can include information about production of the VLA-4 antagonist, physical properties of the a4 antagonist, concentration, date of expiration, batch or production site information, and so forth.
  • the informational material relates to methods for administering the VLA-4 antagonist, e.g., by a route of administration described herein and/or at a dosage and/or dosing schedule described herein.
  • the informational material can include instructions to administer a VLA-4 antagonist described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dosage, dosage form, or mode of administration (e.g., a dosage, dosage form, or mode of administration described herein).
  • the informational material can include instructions to administer a VLA-4 antagonist to a suitable subject, e.g., a human, e.g., a human having a stroke, e.g., within 12 hours or less, e.g., 12, 11, 10, 9 hours or less, e.g., 8, 7, 6, 5 or fewer hours after LKN.
  • the informational material of the kits is not limited in its form.
  • the informational material e.g., instructions
  • the informational material is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet.
  • the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording.
  • the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about an a4 antagonist described herein and/or its use in the methods described herein.
  • the informational material can also be provided in any combination of formats.
  • the composition of the kit can include other ingredients, such as a surfactant, a lyoprotectant or stabilizer, an antioxidant, an antibacterial agent, a bulking agent, a chelating agent, an inert gas, a tonicity agent and/or a viscosity agent, a solvent or buffer, a stabilizer, a preservative, a pharmaceutically acceptable carrier and/or a second agent for treating a condition or disorder described herein.
  • the other ingredients can be included in the kit, but in different compositions or containers than an a4 antagonist described herein.
  • a component of the kit is stored in a sealed vial, e.g., with a rubber or silicone closure (e.g., a polybutadiene or polyisoprene closure).
  • a component of the kit is stored under inert conditions (e.g., under Nitrogen or another inert gas such as Argon).
  • a component of the kit is stored under anhydrous conditions (e.g., with a desiccant).
  • a component of the kit is stored in a light blocking container such as an amber vial.
  • a VLA-4 antagonist described herein can be provided in any form, e.g., liquid, frozen, dried or lyophilized form. It is preferred that a composition including the VLA-4 antagonist described herein be substantially pure and/or sterile.
  • a VLA-4 antagonist described herein such as a natalizumab-like antibody molecule (e.g., natalizumab) is provided in a liquid solution
  • the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred.
  • the VLA-4 antagonist is supplied with a diluents or instructions for dilution.
  • the diluent can include for example, a salt or saline solution, e.g., a sodium chloride solution having a pH between 6 and 9, lactated Ringer's injection solution, D5W, or PLASMA- LYTE A Injection pH 7.4 ® (Baxter, Deerfield, IL).
  • a salt or saline solution e.g., a sodium chloride solution having a pH between 6 and 9, lactated Ringer's injection solution, D5W, or PLASMA- LYTE A Injection pH 7.4 ® (Baxter, Deerfield, IL).
  • the kit can include one or more containers for the composition containing a VLA-4 antagonist described herein.
  • the kit contains separate containers, dividers or compartments for the composition and informational material.
  • the composition can be contained in a bottle, vial, IV admixture bag, IV infusion set, piggyback set or syringe, and the informational material can be contained in a plastic sleeve or packet.
  • the separate elements of the kit are contained within a single, undivided container.
  • the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label.
  • the containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.
  • Example 1 Effect of natalizumab in acute ischemic stroke
  • Mononuclear cell infiltration that would be blocked by natalizumab is thought to be a later phenomenon in acute stroke, peaking days after the infarct.
  • experimental studies have explored limited time windows after the onset of ischemia.
  • the 6-hour time window for intervention in this study is based on findings from a rodent model of stroke [Hoyte 2010] as well as the time course of soluble VCAM- 1 in stroke patients [Lynch 2004], showing that VCAM-1 is increased within 6 hours of stroke onset. Elevated levels of soluble VCAM- 1 are also associated with increased risk for recurrent stroke [Castillo 2007] .
  • Natalizumab decreases migration of lymphocytes into the peri-infarct region by blocking the alpha-4 subunit of VLA4.
  • Protocol Acute ischemic stroke (AIS) patients were screened by magnetic resonance imaging (MRI) and National Institutes of Health Stroke Scale (NIHSS). At the screening stage, eligibility, demographics, medical history, physical and neurological examination were assessed. At baseline, vital signs, hematology, blood chemistry, pharmacodynamics (PD) serum
  • Each group was treated with a single dosage of either natalizumab (single intravenous 300 mg dosage) or placebo. There were 40 patients in each treatment group. Patients were evaluated for endpoints at several timepoints during the study— baseline, 24 +/- 6 hrs, day 5, day 30, and day 90. At baseline, patients were evaluated by brain MRI (to measure infarct volume) and NIHSS (a neurologic exam used to quantify stroke severity). At 24 +/- 6hrs, patients were assessed by physical and neurological examination, e.g., evaluated by brain MRI (to measure infarct volume change from baseline) and NIHSS, as well as hematology for PD/PK
  • MRI was used to measure infarct volume.
  • NIHSS, mRS and Barthel index were used to measure functional outcomes.
  • AE Adverse events
  • SAE Adverse events
  • the primary endpoint was change in infarct volume growth from baseline to day 5 (determined by imaging— MRI).
  • Secondary endpoints included clinical endpoints and safety and tolerability.
  • Clinical endpoints included the modified Rankin Scale (mRS) that measures functional independence, the NIHSS scale that measures bedside neurologic function, Barthel's index that measures activities of daily living, stroke-impact scale 16 (SIS -16) that measures patient perceived physical impact of stroke, and the Montreal Cognitive Assessment that measures cognitive ability.
  • mRS modified Rankin Scale
  • SIS -16 stroke-impact scale 16
  • the odds ratios and confidence intervals (CI) were derived from a logistic regression model, adjusting for log Baseline diffusion weighted imaging (DWI) volume ( ⁇ median versus ⁇ median), treatment time window, location of stroke, and tPA use).
  • DWI log Baseline diffusion weighted imaging
  • Subgroups of patients were also evaluated during the study— patients with tissue plasminogen activator (tPA) use or without, patients having a lesion size of 2-4 cm or >4 cm at baseline, and patients treated within 0-6 hours after LKN or within 6-9 hours of LKN. Patients with tPA use were those that received tPA within a few hours of receiving natalizumab.
  • the modified intent-to-treat ( ⁇ ) subgroup included all subjects randomized and have received the entire infusion of study treatment.
  • the per protocol (PP) subgroup included all subject randomized, have received the entire infusion of study treatment, have no major VE criteria violations, and no non-petechial hemorrhagic transformation of stroke or ICH.
  • Efficacy Endpoint Imaging The primary endpoint in the study was imaging (MRI) to detect a change in infarct volume growth from baseline to day 5. Natalizumab did not affect infarct volume growth as defined by MRI. See Figure 2.
  • mRS modified Rankin Scale
  • a lower score indicates more functional independence or less disability.
  • mRS functional outcomes at 30 days after treatment or 90 days after treatment were evaluated.
  • a shift to more patients with lower mRS scores indicates natalizumab efficacy.
  • Natalizumab significantly improved functional outcomes at days 30 and 90 on the mRS. See Figure 3.
  • natalizumab resulted in a trend to greater independence at days 30 and 90 on mRS (global shift of mRS, i.e., improvement relative to baseline).
  • An odds ratio of less than 1 favors placebo, while an odds ratio of greater than 1 favors natalizumab.
  • the odds ratio of patients with mRS scores of 0 or 1 (excellent outcome) was determined.
  • Table 4 shows the percent of patients (MITT subgroup) in the placebo or natalizumab group having a mRS score of 0 or 1 (excellent outcome) and the odds ratios at days 5, 30 and 90 after treatment.
  • An odds ratio of less than 1 favors placebo, while an odds ratio of greater than 1 favors natalizumab.
  • Natalizumab increased the proportion of patients achieving an excellent outcome (0,1) on the mRS.
  • the odds ratio of a subset of patients having an infarct volume less than median at baseline was determined.
  • Median infarct size (4.6 cm in diameter) is the typical infarct size for stroke clinical trials. Patients having largest infarcts were excluded from this subset.
  • This subset of patients having an infarct volume less than median at baseline had excellent outcomes on mRS (scores of 0,1).
  • Table 5 shows the odds ratios based on mRS for this subset of patients.
  • BI scores in natalizumab and placebo groups were compared at various time points.
  • Tables 6 and 7 show the proportion of patients (MITT subgroup) achieving an excellent outcome (BI >95) and a favorable outcome (BI >85), respectively.
  • BI >95 an excellent outcome
  • BI >85 a favorable outcome
  • natalizumab increased the proportion of patients achieving an excellent outcome (BI >95) on the BI.
  • Odds ratios based on BI scores were determined for the subset of patients having an infarct volume less than median at baseline, where median is a typical infarct size for stroke clinical trials (4.6 cm in diameter) and excludes largest infarcts. Table 8 shows the proportion of this subset of patients having an excellent outcome by BI (a BI score >95) and the odds ratios.
  • NIHSS Bedside neurologic function
  • NIHSS scores were compared in natalizumab and placebo groups at various time points. Natalizumab was no different from placebo in reducing overall change from baseline to days 30 and 90 on the proportion of subject with an excellent outcome (0,1) on the NIHSS. See Figure 5. The proportion of subjects with an excellent outcome on the NIHSS (score of 0, 1 or at least 8 points lower than baseline score) is shown in Table 9. Table 9 also shows the odds ratios, where a ratio of less than 1 favors placebo, and a ratio of greater than 1 favors natalizumab.
  • Odds ratios based on NIHSS scores were determined for the subset of patients having lesion sizes (volumes) less than median at baseline and are shown in Table 10.
  • Stroke Impact Scale-16 Patient perceived physical impact of stroke; and Montreal Cognitive Assessment: Cognitive ability
  • the global or composite clinical outcomes/endpoints of patients in the intent-to-treat population were calculated at day 30 and day 90.
  • the intent-to-treat subgroup included all patients including those who did not complete the trial; the per protocol subgroup consisted of patients who completed the trial.
  • a global outcome odds ratio (OR) was calculated based on the proportion of patients having excellent mRS, BI, and NIHSS scores. Table 12 shows the proportion of patients having a mRS score of 0,1, BI score of >95, and NIHSS score of 0,1 at 30 days, as well as the calculated OR's for each endpoint and the OR for global outcome.
  • Table 13 shows the proportion of patients having a mRS score of 0,1, BI score of >95, and NIHSS score of 0,1 at 90 days, as well as the calculated OR's for each endpoint and the OR for global outcome. The OR's were adjusted for age and baseline NIHSS score.
  • the global outcome analysis is a multidimensional calculation of a favorable outcome defined by the outcome in each individual scale.
  • the Barthel index assesses the ability to perform activities of daily living on a scale that ranges from 0 (complete dependence on help with activities of daily living) to 100
  • the global outcome analysis is a multidimensional calculation of a favorable outcome defined by the outcome in each individual scale.
  • the Barthel index assesses the ability to perform activities of daily living on a scale that ranges from 0 (complete dependence on help with activities of daily living) to 100 (independence). The analysis was based on logistic regression with the same covariates as above..
  • Table 14 shows the day 30 odds ratio for clinical endpoints in this subpopulation.
  • Table 15 shows the day 90 odds ratio for clinical endpoints in this subpopulation.
  • the odds ratios were age and baseline NIHSS score adjusted.
  • Sub-population Defined as Baseline Infarct Size ⁇ 4.6 cm in diameter
  • the global outcome analysis is a multidimensional calculation of a favorable outcome defined by the outcome in each individual scale.
  • the Barthel index assesses the ability to perform activities of daily living on a scale that ranges from 0 (complete dependence on help with activities of daily living) to 100
  • Sub-population Defined as Baseline Infarct Size ⁇ 4.6 cm in diameter Natalizumab Placebo Odds Ratio One-sided
  • the global outcome analysis is a multidimensional calculation of a favorable outcome defined by the outcome in each individual scale.
  • the statistical approach is a global odds ratio test based on a linear logistic regression model (using generalized estimation
  • the Barthel index assesses the ability to perform activities of daily living on a scale that ranges from 0 (complete dependence on help with activities of daily living) to 100
  • neurologic impairment ( ⁇ 5, mild impairment; >25, very severe impairment).
  • the analysis was based on logistic regression with the same covariates as above.
  • the global outcome from treatment with natalizumab was compared to the 90 day global outcome outcome of a reference treatment, e.g., t-PA at 3-4.5 hours after stroke, which is described in a European Cooperative Acute Stroke Study (ECASS) inhacke et al. New Engl. J. Med. 359.13(2008): 1317-29.
  • ECASS European Cooperative Acute Stroke Study
  • the odds ratio was 1.34 based on an endpoint of a mRS score of 0 or 1 (by an unadjusted analysis); and the odds ratio was 1.28 based on global outcome (factoring in mRS score of 0,1, BI score of >95, NIHSS score of 0,1, and GOS score of 1.
  • the PK of natalizumab was also examined in the stroke patients and compared to that observed in multiple sclerosis (MS) patients. As shown in Figure 8, there was an overlap of PK profiles in stroke patients compared to PK profiles in MS patients. Thus, there was no significant difference in PK observed between MS and stroke patients.
  • MS multiple sclerosis
  • post-stroke inflammation may be relevant to functional/clinical outcomes after stroke, even if not detected as focal infarct volume expansion on MRI.
  • inflammatory injury in stroke e.g., post-ischemic inflammation
  • Inflammation can occur longer for weeks to months as demonstrated by the presence of Immunoglobulins in the cerebrospinal fluid occurring in weeks to months after the onset of a stroke (see, e.g., Pruss et al. Arch. Neurol. 69.6(2012):714-17).
  • the chronic inflammation may be deleterious (such as cognitive dysfunction) in regions of the brain not contiguous with the infarct lesion (see, e.g., Doyle et al. J. Neurosci.
  • the results provide evidence that reducing post-stroke inflammation with a single dosage of natalizumab likely leads to gains in higher order domains such as cognition and likely contributes to functional independent at 90 days after treatment. Receptor saturation was consistent with previous multiple sclerosis studies.
  • the Phase 2 trial demonstrated that in acute ischemic stroke, natalizumab (as compared to placebo) did not change MRI-defined infarct growth (primary endpoint). Beneficial effects on clinical outcomes were seen on 2 out of 3 secondary endpoints and 4 out of 5 clinical outcome measures overall. The positive clinical effects reflected gains in higher order domains such as cognition and functional independence in daily living.
  • the results herein provide evidence of benefit on modified Rankin scale, which is the most commonly used Phase 3 registrational endpoint in acute stroke.
  • Example 1 The exposure response of subjects in the Phase II trial described in Example 1 was examined.
  • the natalizumab treated subjects were separated into three tertiles based on their exposure (AUC)— with the first tertile having the lowest AUC and third tertile having the highest AUC.
  • Tertile 1 had an AUC of 6970 to 17340 mg*hr/L.
  • Tertile 2 had an AUC of 17990 to 27580 mg*hr/L.
  • Tertile 3 had an AUC of 27720 to 43300 mg*hr/L.
  • Clinical outcomes at day 90 were compared among the three AUC tertiles in order to assess the relationship between exposure (AUC) and clinical outcome.
  • Table 20 shows the percentage of subjects (in each AUC tertile) having an excellent NIHSS score (0 or 1) on day 90.
  • the percentage of subjects having a NIHSS score of 0 or 1 was higher in the subset of subjects having an AUC in the third tertile (higher AUC).
  • the odds ratio to placebo for this subset of subjects was also greater than the other tertiles (the odds ratio for the third tertile was greater than 1, whereas the other tertiles had odds ratios less than 1).
  • Table 20 The odds ratio for the third tertile was greater than 1, whereas the other tertiles had odds ratios less than 1).
  • Table 21 shows the percentage of subjects (in each AUC tertile) having an excellent mRS score (0 or 1) on day 90.
  • the percentage of subjects having a mRS score of 0 or 1 was higher in the subset of subjects having an AUC in the third tertile (higher AUC).
  • the odds ratio to placebo for this subset of subjects was greater than the other tertiles (the odds ratio for the third tertile was greater than 1, whereas the other tertiles had odds ratios less than 1).
  • Table 22 shows the percentage of subjects (in each AUC tertile) having an excellent BI score (> 95) on day 90.
  • the percentage of subjects having a BI score of > 95 was higher in the subset of subjects having an AUC in the second or third tertiles (higher AUC).
  • the odds ratio to placebo for these subsets of subjects was also greater than for the first tertile (the odds ratio for the second and third tertiles was greater than 1, whereas the first tertile had odds ratios less than 1).
  • the AUC is a measure of exposure to drug, with a higher AUC indicating greater exposure to drug.
  • Higher natalizumab exposure (AUC) was correlated with a better clinical response than lower exposure.
  • Higher exposure was correlated with reduced infarct volume growth on MRI at day 5; higher proportion of subjects with an excellent outcome on the NIHSS (0,1) scores on day 90; mRS scores (0,1) on day 90; and higher BI (>95) scores on day 90.
  • the results also show that patients with larger stroke severity at baseline, larger infarct volume at baseline, or higher weight tended to have lower exposure to natalizumab, e.g., over 30 days, with minimal to no impact on Cmax.
  • Stroke is a leading cause of mortality and serious long-term disability. There is a substantial unmet medical need for new therapies that can improve the outcome of acute ischemic stroke.
  • the inflammatory response is closely coupled to the initial ischemia and activates both the innate and adaptive immune systems. Without being bound by theory, inflammation begins in the intravascular compartment within the first 6 hours (hyperacute period).
  • the production of reactive oxygen species activates platelets and endothelial cells. Oxidative stress reduces the vasodilatory effects of nitric oxide, which is a potent inhibitor of platelet aggregation and leukocyte adhesion to the vascular wall.
  • Intravascular leukocytes loosely adhere to P-selectin, which is upregulated minutes after the onset of ischemia, and subsequently firmly binds to adhesion molecules, such as intercellular adhesion molecule- 1 and VCAM-1.
  • Natalizumab has been evaluated in a Phase 2a study assessing patients with acute ischemic stroke.
  • Study 101SK201 (referred to as "ACTION" in Example 1) explored the efficacy and safety of a single dose of 300 mg natalizumab IV administered at ⁇ 6 hours or at >6 to ⁇ 9 hours from when the subjects were last known normal (LKN).
  • 161 subjects 79 subjects in the natalizumab group and 82 subjects in the placebo group
  • the primary efficacy analysis demonstrated that natalizumab did not decrease acute infarct volume growth defined by MRI.
  • natalizumab treatment was associated with improved clinical outcomes.
  • mRS modified Rankin Scale
  • Study 101SK201 A stratified randomization process was adopted in Study 101SK201, e.g., as described in Example 1, to evaluate the potential time dependency of treatment effect when administering 300 mg of natalizumab in a 9-hour window as compared to placebo.
  • Half of the subjects in the intent-to-treat population were assigned to receive study treatment at ⁇ 6 hours from last known normal (LKN), while the other half had study treatment administered within the >6 to ⁇ 9 hour window.
  • LNN last known normal
  • Results from Study 101SK201 indicated that estimates of treatment effect favored natalizumab against placebo at both treatment windows, with no evidence of time dependency for the treatment benefit (Figure 14).
  • the safety profile of natalizumab treatment was comparable in the ⁇ 6 hour and the >6 to ⁇ 9 hour treatment windows, with a small decrease in the proportion of deaths (21% and 15%, respectively) and serious adverse events (47% and 45%, respectively) being reported among subjects treated in the later treatment window.
  • natalizumab in patients with acute ischemic stroke by enrolling a limited number of subjects within the treatment window of >9 to ⁇ 24 hours from LKN.
  • Study 101SK201 indicated that a dose of 300 mg natalizumab was associated with improved clinical outcomes after stroke.
  • Post hoc analyses demonstrated that those subjects with greater area under the serum concentration versus time curve (AUC; but not maximum serum concentration [Cmax]) following administration of 300 mg) were more likely to have better clinical and MRI defined outcomes compared to placebo treated subjects and subjects with lowe AUC following 300 mg.
  • Dosing instructions and details regarding administration will be provided in the Directions for Handling and Administration (DHA). Doses as high as 6 mg/kg of natalizumab have been studied previously in subjects with MS with the highest dose of 697 mg given monthly.
  • the Phase 2b Study AN100226-231 evaluated the safety, tolerability, and efficacy of multiple administrations of natalizumab (3 mg/kg versus 6 mg/kg) given every 28 days for 6 months in subjects with MS.
  • Monthly infusions of natalizumab at doses of 3 and 6 mg/kg were well tolerated and were associated with a safety profile similar to that of placebo. There was no significant difference in the incidence of adverse events (AEs) between treatment groups. The majority of AEs in each treatment group were reported by the Investigator as mild or moderate in severity and not related to study drug.
  • AEs adverse events
  • LNN normal
  • This study will assess dose response and overall safety and efficacy of natalizumab in subjects with acute ischemic stroke over a 90-day period. Time dependency of treatment effects will also be assessed through a treatment window of up to 24 hours from LKN. Approximately 270 subjects are expected to be enrolled and this study will be conducted at approximately 67 sites in the Unites States and Europe. See Figure 15 for a schematic of the study design.
  • eligible subjects in each of 2 treatment windows ( ⁇ 9 hours and >9 to ⁇ 24 hours from LKN) will be randomized in a 1: 1: 1 ratio to 1 of 3 treatment groups, each of which will receive a single dose at 0 Hours (Day 1) according to one of the following 3 regimens: 600 mg IV natalizumab in approximately 90 subjects, 300 mg IV natalizumab in approximately 90 subjects, or placebo IV in approximately 90 subjects. Randomization will occur separately within each treatment window.
  • NIHSS category NIHSS scores from 5 to 15 or 16 to 23
  • tissue plasminogen activator (tPA) use yes or no
  • region region
  • tPA use yes or no
  • Post-treatment assessments will be performed at the following timepoints after the start of study treatment administration: within 1 hour after the start of the infusion, 12 + 3 hours after the start of the infusion, 24 + 6 hours after the start of the infusion, Day 5, Day 30 (+5 days), and the Day 90 Follow-Up visit (+5 days).
  • the number of subjects enrolling in the treatment window of >9 to ⁇ 24 hours from LKN will be limited to no more than 90.
  • Severe stroke defined by imaging criteria based on either one of the following

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des méthodes de traitement d'un accident vasculaire cérébral qui consistent à administrer un antagoniste de VLA-4 à un sujet après l'apparition de l'accident vasculaire cérébral, par exemple, un AVC ischémique (par exemple, un AVC ischémique aigu) ou un accident vasculaire cérébral hémorragique (par exemple, une hémorragie intracérébrale ou une hémorragie sous-arachnoïdienne), ou une lésion cérébrale traumatique. L'invention concerne également des kits et des articles manufacturés associés.
PCT/US2018/015068 2017-01-25 2018-01-24 Composition et méthodes de traitement d'un accident vasculaire cérébral et d'autres troubles du snc WO2018140510A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201762450445P 2017-01-25 2017-01-25
US62/450,445 2017-01-25
US201762587261P 2017-11-16 2017-11-16
US62/587,261 2017-11-16

Publications (1)

Publication Number Publication Date
WO2018140510A1 true WO2018140510A1 (fr) 2018-08-02

Family

ID=61163838

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/015068 WO2018140510A1 (fr) 2017-01-25 2018-01-24 Composition et méthodes de traitement d'un accident vasculaire cérébral et d'autres troubles du snc

Country Status (1)

Country Link
WO (1) WO2018140510A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3757127A1 (fr) * 2019-06-28 2020-12-30 Institute for Research in Biomedicine Anticorps déimmunisés se liant à l'intégrine alpha-4 et leurs utilisations
WO2023086768A1 (fr) * 2021-11-09 2023-05-19 Truebinding, Inc. Méthodes de traitement ou d'inhibition de maladies cardiovasculaires

Citations (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4475196A (en) 1981-03-06 1984-10-02 Zor Clair G Instrument for locating faults in aircraft passenger reading light and attendant call control system
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US4833092A (en) 1985-04-22 1989-05-23 Commonwealth Serum Laboratories Commission Method for determining mimotopes
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
WO1990007861A1 (fr) 1988-12-28 1990-07-26 Protein Design Labs, Inc. IMMUNOGLOBULINES CHIMERIQUES SPECIFIQUES CONTRE LA PROTEINE TAC p55 DU RECEPTEUR D'IL-2
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
WO1992000995A1 (fr) 1990-07-09 1992-01-23 Tanabe Seiyaku Co. Ltd. Composes de modulation de l'adherence cellulaire cyclique
WO1992008464A1 (fr) 1990-11-15 1992-05-29 Tanabe Seiyaku Co. Ltd. Composes d'uree substitues et composes associes utilises dans la modulation de l'adhesion cellulaire
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
WO1993008823A1 (fr) 1991-11-06 1993-05-13 Tanabe Seiyaku Co., Ltd. Composes de guanidinyle et composes apparentes modulant l'adhesion cellulaire
US5260277A (en) 1990-09-10 1993-11-09 Tanabe Seiyaku Co., Ltd. Guanidinyl and related cell adhesion modulation compounds
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
WO1994015958A2 (fr) 1993-01-08 1994-07-21 Tanabe Seiyaku Co., Ltd. Inhibiteurs peptidiques de l'adhesion cellulaire
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
WO1995015973A1 (fr) 1993-12-06 1995-06-15 Cytel Corporation Peptidomimetiques cs-1, compositions et procedes pour les utiliser
WO1996001644A1 (fr) 1994-07-11 1996-01-25 Athena Neurosciences, Inc. Inhibiteurs de l'adhesion leucocytaire
WO1996006108A2 (fr) 1994-08-25 1996-02-29 Cytel Corporation Composes peptidomimetiques cs-1 cycliques, compositions et leurs procedes d'utilisation
US5510332A (en) 1994-07-07 1996-04-23 Texas Biotechnology Corporation Process to inhibit binding of the integrin α4 62 1 to VCAM-1 or fibronectin and linear peptides therefor
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
WO1996020216A1 (fr) 1994-12-24 1996-07-04 Zeneca Limited Inhibiteurs d'adhesion de la fibronectine
WO1996022966A1 (fr) 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1996040781A1 (fr) 1995-06-07 1996-12-19 Tanabe Seiyaku Co., Ltd. INHIBITEURS PEPTIDIQUES CYCLIQUES D'ADHERENCE CELLULAIRE INDUITE PAR INTEGRINE β1 ET β¿2?
WO1997002289A1 (fr) 1995-07-06 1997-01-23 Zeneca Limited Inhibiteurs peptidiques de la fibronectine
WO1997003094A1 (fr) 1995-07-11 1997-01-30 Biogen, Inc. Composes inhibiteurs d'adherence cellulaire
US5648260A (en) 1987-03-18 1997-07-15 Scotgen Biopharmaceuticals Incorporated DNA encoding antibodies with altered effector functions
US5789650A (en) 1990-08-29 1998-08-04 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5798230A (en) 1995-11-09 1998-08-25 Gsf-Forschungszentrum Fur Umwelt Und Gesundheit Gmbh Process for the preparation of human monoclonal antibodies and their use
US5840299A (en) 1994-01-25 1998-11-24 Athena Neurosciences, Inc. Humanized antibodies against leukocyte adhesion molecule VLA-4
WO1998053814A1 (fr) 1997-05-29 1998-12-03 Merck & Co., Inc. Composes d'amide heterocycliques utilises en tant qu'inhibiteurs de l'adhesion cellulaire
US5849992A (en) 1993-12-20 1998-12-15 Genzyme Transgenics Corporation Transgenic production of antibodies in milk
US5888507A (en) 1993-02-09 1999-03-30 Biogen, Inc. Treatment for insulin dependent diabetes
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
US20030070185A1 (en) 1996-12-03 2003-04-10 Aya Jakobovits Transgenic mammals having human Ig loci including plural Vh and Vk regions and antibodies produced therefrom
US6602503B1 (en) 1993-01-12 2003-08-05 Biogen, Inc. Recombinant anti-VLA-4 antibody molecules
US20030232333A1 (en) 2000-04-17 2003-12-18 Dyax Corp. Novel methods of constructing librabries comprising displayed and/or expressed members of a diverse family of peptides, polypeptides or proteins and the novel librabries
WO2013057092A1 (fr) * 2011-10-17 2013-04-25 Westfaelische Wilhelms-Universitaet Muenster Méthodes d'évaluation du risque de lemp et appareil associé
WO2015003156A1 (fr) * 2013-07-05 2015-01-08 Biogen Idec Ma Inc. Compositions et méthodes pour traiter un accident vasculaire cérébral
US9104862B2 (en) 2013-04-01 2015-08-11 Uniquesoft, Llc Secure computing device using new software versions
US9713013B2 (en) 2013-03-15 2017-07-18 Elwha Llc Protocols for providing wireless communications connectivity maps

Patent Citations (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4475196A (en) 1981-03-06 1984-10-02 Zor Clair G Instrument for locating faults in aircraft passenger reading light and attendant call control system
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US4833092A (en) 1985-04-22 1989-05-23 Commonwealth Serum Laboratories Commission Method for determining mimotopes
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
US5648260A (en) 1987-03-18 1997-07-15 Scotgen Biopharmaceuticals Incorporated DNA encoding antibodies with altered effector functions
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
WO1990007861A1 (fr) 1988-12-28 1990-07-26 Protein Design Labs, Inc. IMMUNOGLOBULINES CHIMERIQUES SPECIFIQUES CONTRE LA PROTEINE TAC p55 DU RECEPTEUR D'IL-2
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US5693761A (en) 1988-12-28 1997-12-02 Protein Design Labs, Inc. Polynucleotides encoding improved humanized immunoglobulins
US5693762A (en) 1988-12-28 1997-12-02 Protein Design Labs, Inc. Humanized immunoglobulins
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
WO1992000995A1 (fr) 1990-07-09 1992-01-23 Tanabe Seiyaku Co. Ltd. Composes de modulation de l'adherence cellulaire cyclique
US5789650A (en) 1990-08-29 1998-08-04 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5260277A (en) 1990-09-10 1993-11-09 Tanabe Seiyaku Co., Ltd. Guanidinyl and related cell adhesion modulation compounds
WO1992008464A1 (fr) 1990-11-15 1992-05-29 Tanabe Seiyaku Co. Ltd. Composes d'uree substitues et composes associes utilises dans la modulation de l'adhesion cellulaire
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
WO1993008823A1 (fr) 1991-11-06 1993-05-13 Tanabe Seiyaku Co., Ltd. Composes de guanidinyle et composes apparentes modulant l'adhesion cellulaire
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
US5399163A (en) 1992-07-24 1995-03-21 Bioject Inc. Needleless hypodermic injection methods and device
WO1994015958A2 (fr) 1993-01-08 1994-07-21 Tanabe Seiyaku Co., Ltd. Inhibiteurs peptidiques de l'adhesion cellulaire
US6602503B1 (en) 1993-01-12 2003-08-05 Biogen, Inc. Recombinant anti-VLA-4 antibody molecules
US5888507A (en) 1993-02-09 1999-03-30 Biogen, Inc. Treatment for insulin dependent diabetes
WO1995015973A1 (fr) 1993-12-06 1995-06-15 Cytel Corporation Peptidomimetiques cs-1, compositions et procedes pour les utiliser
US5849992A (en) 1993-12-20 1998-12-15 Genzyme Transgenics Corporation Transgenic production of antibodies in milk
US5840299A (en) 1994-01-25 1998-11-24 Athena Neurosciences, Inc. Humanized antibodies against leukocyte adhesion molecule VLA-4
US5510332A (en) 1994-07-07 1996-04-23 Texas Biotechnology Corporation Process to inhibit binding of the integrin α4 62 1 to VCAM-1 or fibronectin and linear peptides therefor
WO1996001644A1 (fr) 1994-07-11 1996-01-25 Athena Neurosciences, Inc. Inhibiteurs de l'adhesion leucocytaire
WO1996006108A2 (fr) 1994-08-25 1996-02-29 Cytel Corporation Composes peptidomimetiques cs-1 cycliques, compositions et leurs procedes d'utilisation
WO1996020216A1 (fr) 1994-12-24 1996-07-04 Zeneca Limited Inhibiteurs d'adhesion de la fibronectine
WO1996022966A1 (fr) 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1996040781A1 (fr) 1995-06-07 1996-12-19 Tanabe Seiyaku Co., Ltd. INHIBITEURS PEPTIDIQUES CYCLIQUES D'ADHERENCE CELLULAIRE INDUITE PAR INTEGRINE β1 ET β¿2?
WO1997002289A1 (fr) 1995-07-06 1997-01-23 Zeneca Limited Inhibiteurs peptidiques de la fibronectine
WO1997003094A1 (fr) 1995-07-11 1997-01-30 Biogen, Inc. Composes inhibiteurs d'adherence cellulaire
US5798230A (en) 1995-11-09 1998-08-25 Gsf-Forschungszentrum Fur Umwelt Und Gesundheit Gmbh Process for the preparation of human monoclonal antibodies and their use
US20030070185A1 (en) 1996-12-03 2003-04-10 Aya Jakobovits Transgenic mammals having human Ig loci including plural Vh and Vk regions and antibodies produced therefrom
WO1998053814A1 (fr) 1997-05-29 1998-12-03 Merck & Co., Inc. Composes d'amide heterocycliques utilises en tant qu'inhibiteurs de l'adhesion cellulaire
US20030232333A1 (en) 2000-04-17 2003-12-18 Dyax Corp. Novel methods of constructing librabries comprising displayed and/or expressed members of a diverse family of peptides, polypeptides or proteins and the novel librabries
WO2013057092A1 (fr) * 2011-10-17 2013-04-25 Westfaelische Wilhelms-Universitaet Muenster Méthodes d'évaluation du risque de lemp et appareil associé
US9713013B2 (en) 2013-03-15 2017-07-18 Elwha Llc Protocols for providing wireless communications connectivity maps
US9104862B2 (en) 2013-04-01 2015-08-11 Uniquesoft, Llc Secure computing device using new software versions
WO2015003156A1 (fr) * 2013-07-05 2015-01-08 Biogen Idec Ma Inc. Compositions et méthodes pour traiter un accident vasculaire cérébral

Non-Patent Citations (74)

* Cited by examiner, † Cited by third party
Title
"Current Protocols in Molecular Biology", 1989, JOHN WILEY & SONS, pages: 6.3.1 - 6.3.6
"Handbook of Pharmaceutical Excipients American Pharmaceutical Association", 2000
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT, WILLIAMS & WILKINS
"Sustained and Controlled Release Drug Delivery Systems", 1978, MARCEL DEKKER, INC.
A. F. WILLIAMS; A. N. BARCLAY, ANN. REV IMMUNOL., vol. 6, 1988, pages 381 - 405
ADAMS ET AL., CELL ADHESION INHIBITORS
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS
BARRETT ET AL., STROKE, vol. 40, 2009, pages 2422 - 27
BECK ET AL., BECK DEPRESSION INVENTORY - II (BDI - II, 1996
BECKER ET AL., STROKE, vol. 32, 2001, pages 206 - 211
BECKER K ET AL: "ANTIBODY TO THE ALPHA4 INTEGRIN DECREASES INFARCT SIZE IN TRANSIENTFOCAL CERABRAL ISCHEMIA IN RATS", STROKE, LIPPINCOTT WILLIAMS & WILKINS, US, vol. 32, no. 1, 1 January 2001 (2001-01-01), pages 206 - 211, XP000993038, ISSN: 0039-2499 *
BERGE, S. M. ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426
BOERNER ET AL., J. IMMUNOL., vol. 147, 1991, pages 86 - 95
BROTT ET AL., STROKE, vol. 20, 1989, pages 864 - 70
BURTON; WOOF, ADV. IMMUNOL., vol. 51, 1992, pages 1 - 84
CHOTHIA, C. ET AL., J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
D. COX ET AL.: "The Pharmacology of the Integrins", MEDICINAL RESEARCH REV, 1994
D. M. NOWLIN ET AL.: "A Novel Cyclic Pentapeptide Inhibits Alpha4Betal Integrin-mediated Cell Adhesion", J. BIOL. CHEM., vol. 268, no. 27, 1993, pages 20352 - 59, XP000396661
D. Y. JACKSON ET AL.: "Potent α4β1 peptide antagonists as potential anti-inflammatory agents", J. MED. CHEM., vol. 40, 1997, pages 3359, XP002148351, DOI: doi:10.1021/jm970175s
DEVLIN ET AL., SCIENCE, vol. 249, 1990, pages 400 - 406
DEVLIN ET AL.: "Random Peptide Libraries: A Source of Specific Protein Binding Molecules", SCIENCE, vol. 249, 1990, pages 40407
DOYLE ET AL., J NEUROSCI, vol. 35, 2015, pages 2133 - 2145
DOYLE ET AL., J. NEUROSCI., vol. 35, no. 5, 2015, pages 2133 - 45
DUNCAN ET AL., NEUROLOGY, vol. 60, no. 2, 2003, pages 291 - 6
E. C. BUTCHER, CELL, vol. 67, 1991, pages 1033
GELDERBLOM ET AL., STROKE, vol. 40, 2009, pages 1849 - 1857
GREEN ET AL., NATURE GENETICS, vol. 7, 1994, pages 13 - 21
H. SHROFF ET AL.: "Small peptide inhibitors of α4β7 mediated MadCAM-1 adhesion to lymphocytes", BIO. MED, CHEM. LETT., 1996, pages 1 2495
HACKE ET AL., NEW ENGL. J. MED., vol. 359, no. 13, 2008, pages 1317 - 29
HEMLER ET AL., J. BIOL. CHEM., vol. 2, 1987, pages 11478 - 11485
HOOGENBOOM ET AL., IMMUNOL TODAY, vol. 2, 2000, pages 371 - 8
HOOGENBOOM ET AL., IMMUNOTECHNOLOGY, vol. 4, 1998, pages 1 - 20
HUANG; STOLLAR, J. IMMUNOL. METHODS, vol. 141, 1991, pages 227 - 236
HUSTON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883
ISSEKUTZ; WYKRETOWICZ, J. IMMUNOL., vol. 147, 1991, pages 109
JACOB ELKINS ET AL: "Primary Results of the ACTION Trial of Natalizumab in Acute Ischemic Stroke (AIS)", 19 February 2016 (2016-02-19), XP055334951, Retrieved from the Internet <URL:https://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_481668.pdf> [retrieved on 20180410] *
JEFFERIS ET AL., IMMUNOL. REV., vol. 163, 1998, pages 59 - 76
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH
KABAT, E. A. ET AL.: "US Department of Health and Human Services", 1991, NIH PUBLICATION NO. 91-3242, article "Sequences of Proteins of Immunological Interest"
KASNER, LANCET NEUROLOGY, vol. 5, no. 7, 2006, pages 603 - 12
KAUFMAN; SHARP, MOL. BIOL., vol. 159, 1982, pages 601 - 621
KOMORIYA ET AL.: "The Minimal Essential Sequence for a Major Cell Type-Specific Adhesion Site (CS1) Within the Alternatively Spliced Type III Connecting Segment Domain of Fibronectin Is Leucine-Aspartic Acid-Valine", J. BIOL. CHEM., vol. 266, no. 23, 1991, pages 15075 - 79, XP002095733
LIESZ ET AL., BRAIN: A JOURNAL OF NEUROLOGY, vol. 134, 2011, pages 704 - 720
LLOVERA ET AL., SCIENCE TRANSLATIONAL MEDICINE, vol. 7, no. 299, 2015
LONBERG N., NAT. BIOTECHNOL., vol. 23, no. 9, 2005, pages 1117 - 25
MACKINTOSH S: "Functional Independence Measure", THE AUSTRALIAN JOURNAL OF PHYSIOTHERAPY, vol. 55, no. 1, 2009, pages 65
NASREDDINE ET AL.: "The Montreal Cognitive Assessment (MoCA): A brief cognitive screening tool for detection of mild cognitive impairment", NEUROLOGY, vol. 62, no. 7, pages 5
OSBORN ET AL., CELL, vol. 59, 1989, pages 1203 - 1211
PERSSON ET AL., PROC. NAT. ACAD. SCI. USA, vol. 88, 1991, pages 2432 - 2436
PETKOVA ET AL., RADIOLOGY, vol. 257, no. 3, 2010, pages 782 - 92
POWERS ET AL., J IMMUNOL METHODS, vol. 251, 2001, pages 123 - 35
PRUSS ET AL., ARCH. NEUROL., vol. 69, no. 6, 2012, pages 714 - 17
PULIDO ET AL., J. BIOL. CHEM., vol. 266, no. 16, 1991, pages 10241 - 10245
QUEEN ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 86, 1989, pages 10029 - 33
RELTON ET AL., STROKE, vol. 32, 2001, pages 199 - 205
RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 327
S. M. WAHL ET AL.: "Synthetic Fibronectin Peptides Suppress Arthritis in Rats by Interrupting Leukocyte Adhesion and Recruitment", J. CLIN. INVEST., vol. 94, 1994, pages 655 - 62, XP000952746, DOI: doi:10.1172/JCI117382
SANCHEZ-MADRID ET AL., EUR. J. IMMUNOL., vol. 16, 1986, pages 1343 - 1349
SCOTT; SMITH, SCIENCE, vol. 249, 1990, pages 386 - 390
SCOTT; SMITH: "Searching for Peptide Ligands with an Epitope Library", SCIENCE, vol. 249, 1990, pages 386 - 90, XP000571645, DOI: doi:10.1126/science.1696028
SHICHITA ET AL., NAT MED, vol. 15, 2009, pages 946 - 950
SMITH, A.: "SDMT - Symbol Digit Modalities Test", WESTERN PSYCHOLOGICAL SERVICES, 1973
T. A. FERGUSON ET AL.: "Two integrin Binding Peptides Abrogate T-cell-Mediated Immune Responses In Vivo", PROC. NATL. ACAD. SCI. USA, vol. 88, 1991, pages 8072 - 76, XP002115562, DOI: doi:10.1073/pnas.88.18.8072
TEMPEST ET AL., BIOTECHNOLOGY, vol. 9, 1991, pages 266 - 271
TONG ET AL., STROKE, vol. 43, 2012, pages 1912 - 1917
URLAUB; CHASIN, PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216 - 4220
V. W. ENGLEMAN ET AL.: "Ann. Report in Medicinal Chemistry", vol. 31, 1996, ACAD. PRESS, article "Cell Adhesion Integrins as Pharmaceutical Targets", pages: 191
VALKO ET AL., SLEEP, vol. 31, no. 11, 1 November 2008 (2008-11-01), pages 1601 - 1607
VAN EVERDINGEN ET AL., STROKE, vol. 29, 1998, pages 1783 - 90
VAN REENEN; OPPE: "EQ-5D-3L User Guide", EUROQOL RESEARCH FOUNDATION, 2015
VELTKAMP ROLAND ET AL: "Clinical Trials of Immunomodulation in Ischemic Stroke", NEUROTHERAPEUTICS, ELSEVIER INC, US, vol. 13, no. 4, 13 July 2016 (2016-07-13), pages 791 - 800, XP036275815, ISSN: 1933-7213, [retrieved on 20160713], DOI: 10.1007/S13311-016-0458-Y *
VERHOEYEN ET AL., SCIENCE, vol. 239, 1988, pages 1534 - 1536
WARD ET AL., NATURE, vol. 341, 1989, pages 54 - 546

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3757127A1 (fr) * 2019-06-28 2020-12-30 Institute for Research in Biomedicine Anticorps déimmunisés se liant à l'intégrine alpha-4 et leurs utilisations
WO2020260315A1 (fr) * 2019-06-28 2020-12-30 Institute For Research In Biomedicine Anticorps désimmunisés se liant à l'intégrine alpha-4 et leurs utilisations
WO2023086768A1 (fr) * 2021-11-09 2023-05-19 Truebinding, Inc. Méthodes de traitement ou d'inhibition de maladies cardiovasculaires

Similar Documents

Publication Publication Date Title
US20200255530A1 (en) Compositions and methods for treatment of stroke and other cns disorders
EP2034830B1 (fr) Anti-vla-1 anticorps pour le traitement des accidents vasculaires cérébraux
AU2005277343B2 (en) Extended treatment of multiple sclerosis
TWI462744B (zh) 類固醇節約劑及彼之使用方法
JP2020019811A (ja) 抗ｖｌａ−４抗体
JP2013060469A (ja) 多発性硬化症の発症の遅延または予防
US20170216434A1 (en) Compositions and methods for treatment of sickle cell disease
US20160340433A1 (en) Selection and treatment of subjects
AU2005306399B2 (en) Treatment for multiple sclerosis
JP2008522971A5 (fr)
WO2018140510A1 (fr) Composition et méthodes de traitement d&#39;un accident vasculaire cérébral et d&#39;autres troubles du snc
AU2014285086A1 (en) Compositions and methods for treatment of stroke
AU2012202575B2 (en) Treatment for Multiple Sclerosis
AU2011232775B2 (en) Extended Treatment of Multiple Sclerosis
AU2012202571A1 (en) Delaying or Preventing Onset of Multiple Sclerosis
CA2478455A1 (fr) Methodes de traitement de la sclerose en plaques

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18703446

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18703446

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载