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WO2017176385A1 - Compositions et méthodes de diagnostic et de traitement d'une lésion cérébrale - Google Patents

Compositions et méthodes de diagnostic et de traitement d'une lésion cérébrale Download PDF

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Publication number
WO2017176385A1
WO2017176385A1 PCT/US2017/019551 US2017019551W WO2017176385A1 WO 2017176385 A1 WO2017176385 A1 WO 2017176385A1 US 2017019551 W US2017019551 W US 2017019551W WO 2017176385 A1 WO2017176385 A1 WO 2017176385A1
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subject
derivative
subsequence
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Patrick Ho
Ravi KOLLA
Heba NOWYHED
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La Jolla Institute for Allergy and Immunology
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La Jolla Institute for Allergy and Immunology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • Technology provided herein relates in part to compositions, devices and methods for diagnosing and treating brain injury.
  • a concussion is a type of traumatic brain injury— or TBI— caused by a bump, blow, or jolt to the head or by a hit to the body that causes the head and brain to move rapidly back and forth.
  • TBI traumatic brain injury
  • the adult brain is surrounded by cerebral spinal fluid, which acts as a shock absorber for minor impacts.
  • a concussion has technically occurred.
  • One common scenario that can lead to a concussion is a direct blow to the head or a whiplash effect to the body. The impact rapidly accelerates the head, causing the brain to strike the inner skull (i.e., the coup). When the head decelerates and stops its motion, the brain then hits the opposite side of the inner skull (i.e., the corcoup).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • an immune response may arise from an inflammatory reaction, together with disturbance of the BBB, which intensifies the leakage of glial proteins in the circulation. This in turn leads to the stimulation of an immune response, including production and activation of B cells and T cells targeting the glial proteins and neuronal components.
  • an immune response may arise from an inflammatory reaction, together with disturbance of the BBB, which intensifies the leakage of glial proteins in the circulation. This in turn leads to the stimulation of an immune response, including production and activation of B cells and T cells targeting the glial proteins and neuronal components. T cells and B cells respond to these proteins as foreign antigens resulting in an autoimmune like response.
  • the resulting immune response may comprise an innate immune response.
  • the subject's immune system may recognize and response to these proteins and components as foreign.
  • the resulting immune response may comprise an adaptive immune response.
  • the subject's immune system may have generated immune cells that specifically recognize the glial proteins and neuronal components and upon subsequent brain injury, the subject may have an adaptive immune response to the glial proteins and neuronal components.
  • This adaptive immune response may include memory B cells and T cells that recognize the glial proteins and neuronal components.
  • the subject's immune system responds to one or more T cell or B cell epitopes, including for example CD8 or CD4 T cell epitopes.
  • the subject's immune system response to one or more of the proteins listed on Table 1 or Table 2, or one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • IVIG Intravenous immunoglobulin
  • a method of treating brain injury in a subject comprising administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • the agent is IVIG or a fraction or active ingredient thereof.
  • the agent is modified IVIG or a modified fraction or modified active ingredient of IVIG.
  • a method of treating brain injury in a subject comprising administering to the subject a therapeutically effective amount of intravenous immunoglobulin (IVIG) or a fraction or active ingredient thereof.
  • IVIG intravenous immunoglobulin
  • a method of treating brain injury in a subject comprising administering to the subject a therapeutically effective amount of modified IVIG or a modified fraction or modified active ingredient of IVIG.
  • the method comprises administering a therapeutically effective amount of modified intravenous IVIG or a modified fraction of IVIG from which autoantibodies have been removed, including for example autoantibodies against one or more of the proteins listed in Table 1 or Table 2, and/or one or more of the peptides listed in any of Tables 3 to 20.
  • the present inventors have identified proteins and peptides that elicit an immune response as a result of brain injury. Further, the present inventors have identified T cell epitopes of proteins, including but not limited to glial proteins, that elicit an immune response and that can be used individually or in combinations in the methods and compositions described herein.
  • a method of determining whether a subject has, is at risk of having, or is in need of treatment for brain injury comprising obtaining a biological sample from the subject and determining whether the subject has an modulated immune response wherein a modulated immune response indicates that the subject has, is at risk of having, or is in need of treatment for brain injury.
  • a method of determining whether a subject has, is at risk of having, or is in need of treatment for brain injury comprising obtaining a biological sample from the subject, measuring an immune response in the subject and comparing the immune response in the biological sample from the subject to the immune response in a control biological sample, wherein a modulated immune response in the biological sample from the subject when compared to the control biological sample indicates that the subject has, is at risk of having, or is in need of treatment for brain injury.
  • the method comprises determining whether the subject has a modulated immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof. In certain embodiments, the method comprises determining whether the subject has one or more of a modulated macrophage, monocyte, dendritic cell, T cell, B cell, immune cell mediator or cytokine response.
  • the method comprises detecting a modulated innate immune response. In other embodiments, the method comprises detecting a modulated adaptive immune response.
  • the method comprises detecting a modulated immune response specific to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the present methods comprises determining whether the subject has a modulated T cell response that comprises one or more of stimulation of T cells, differentiation of T cells, activation of T cells, proliferation of T cells, increased or decreased number of T cells and modulated activity of T cells.
  • the T cell response is to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the modulated T cell response is measured by contacting the biological sample from the subject with one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to determine the level of T cell response in the biological sample from the subject and comparing the level of T cell response in the biological sample to a control biological sample.
  • the method of the present invention comprises determining if the subject has a modulated B cell response comprising one or more of stimulation of B cells, proliferation of B cells, differentiation of B cells, increased or decreased number of B cells and modulated activity of B cells.
  • a modulated B cell response comprising one or more of stimulation of B cells, proliferation of B cells, differentiation of B cells, increased or decreased number of B cells and modulated activity of B cells.
  • the B cell response is to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises detecting B cells generating autoantibodies, including for example, autoantibodies to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the modulated B cell response is measured by contacting the biological sample from the subject with one or more of the proteins listed in Table 1 or Table 2, one or more peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to determine the level of B cell response in the biological sample from the subject and comparing the level of B cell response in the biological sample to a control biological sample.
  • the method of the present invention comprises determining if the subject has a modulated cytokine response by contacting the biological sample from the subject with antibodies that bind one or more cytokines.
  • the method of the present invention comprises detecting an immune complex.
  • the immune complex comprises one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof
  • the method comprises contacting the biological sample with a composition comprising one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • a modulated immune response is measured by contacting the biological sample from the subject with an antibody, antibody fragment, or antibody derivative (e.g. Fab) that binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • an antibody, antibody fragment, or antibody derivative e.g. Fab
  • the method of the present invention determines that the subject has, is at risk of having, or is in need of treatment for a disease or disorder associated with brain injury including mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS) or designates the subject for treatment of a disease or disorder associated with brain injury including mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • the method comprises isolating the biological sample from the subject.
  • the method comprises obtaining the biological sample from the subject prior to brain injury or after brain injury.
  • the subject has had two or more brain injuries.
  • a diagnostic kit comprising one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or an antibody, antibody fragment, or antibody derivative (e.g. Fab) that binds to one or more of the proteins listed in Table 1 or Table 2 or one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • Fab antibody, antibody fragment, or antibody derivative
  • the diagnostic kit further comprises antibodies that bind one or more cytokines.
  • a diagnostic kit comprising reagents for detecting an immune complex
  • the kit comprises a first reagent that binds to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, in the immune complex and a second reagent that binds to an antibody that binds the one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, wherein the binding of the second reagent to the antibody is measured to determine the presence or amount of the IC.
  • a method of treating brain injury in a subject comprising administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • a method of treating brain injury in a subject comprising administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting an innate immune response. In other embodiments, the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting an adaptive immune response.
  • the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting an adaptive immune response that is specific to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent comprises a protein or peptide including for example one or more of the proteins listed in Table 1 or Table 2, or a modification, subsequence, homologue, variant or derivative thereof or one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent is a recombinant protein or peptide, antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, or protein.
  • the method comprises administering an antibody, antibody fragment, or antibody derivative (e.g. Fab) that binds one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent is a therapeutically effective amount of intravenous immunoglobulin (IVIG), a fraction or active ingredient thereof.
  • the agent is a modified IVIG or a modified fraction or modified active ingredient thereof.
  • the method comprises administering a therapeutically effective amount of modified intravenous IVIG or a modified fraction of IVIG from which autoantibodies have been removed.
  • autoantibodies against one or more of the proteins listed in Table 1 or Table 2 one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof have been removed from the modified IVIG or modified fraction thereof.
  • the agent is a pharmaceutical composition for the treatment of inflammatory or immune disorders.
  • the agent is a pharmaceutical composition for the treatment of inflammatory or immune disorders.
  • composition comprises an anti-T F agent, anti-cytokine agent, statin, anti-chemokines, anti-integrins or flavonoid, for example Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin, Ezetimibe/simvastatin, Pitavastatin, Cerivastatin, Mevastatin, Atorvastatin/amlodipine, Niacin/simvastatin, Niacin/lovastatin,
  • the method comprises administering to the subject two or more agents that modulate, inhibit, block, decrease, increase, enhance, promote or elicit an acute or chronic immune response.
  • the method comprises agents selected from two or more of the group consisting of an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, protein and pharmaceutical composition for the treatment of inflammatory or immune disorders in combination.
  • the two or more agents are conjugated.
  • the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting a B cell response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, including stimulation of B cells, proliferation of B cells, differentiation of B cells, increased or decreased number of B cells and modulated activity of B cells.
  • agent modulates the activity, proliferation or activation of B cells generating autoantibodies, including for example autoantibodies to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting a T cell response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof including stimulation of T cells, proliferation of T cells, differentiation of T cells, increased or decreased number of T cells and modulated activity of T cells.
  • the method comprises modulating, inhibiting, blocking, decreasing, increasing, enhancing, promoting or eliciting a cytokine response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises administering the agent to the subject after brain injury or simultaneously with an insult to the brain.
  • the subject has had two or more brain injuries.
  • the method comprises administering the IVIG to the subject after brain injury or simultaneously with a brain injury.
  • the subject has had two or more brain injuries.
  • the method comprises treating the subject for a long- term disease or disorder including mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • a pharmaceutical composition comprising an antibody, antibody fragment, antibody derivative (e.g. Fab) that binds one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • an antibody, antibody fragment, antibody derivative e.g. Fab
  • Fab antibody fragment, antibody derivative
  • a pharmaceutical composition comprising one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises administering IVIG in combination with an anti-inflammatory or immunosuppressive agent, for example an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, protein, or recombinant protein or peptide.
  • an anti-inflammatory or immunosuppressive agent for example an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, protein, or recombinant protein or peptide.
  • the antiinflammatory or immunosuppressive agent is Tocilizumab (Actemra), Rituximab (Rituxan), Ofatumumab (Arzerra), Belimumab (Benlysta), Epratuzumab (Lymphocide), Abatacept (Orencia), Golimumab (Simponi), Certolizumab (Cimzia), Sifalimumab, Anakinra (Kineret), canakinumab (Ilaris) or rilonocept (Arcalyst).
  • the method comprises administering IVIG in combination with an antibody, antibody fragment, antibody derivative (e.g. Fab).
  • an antibody, antibody fragment, antibody derivative e.g. Fab
  • the antibody, antibody fragment, antibody derivative binds one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises administering IVIG in combination with one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, for example to administer specific immunotherapy or allergy immunotherapy treatment to the subject.
  • a pharmaceutical composition comprising IVIG, or a fraction or active ingredient thereof, and an anti-inflammatory or immunosuppressive agent.
  • a pharmaceutical composition comprising modified IVIG, or a modified fraction or modified active ingredient of IVIG.
  • the pharmaceutical composition comprising modified IVIG, or a modified fraction or modified active ingredient of IVIG further comprises an antiinflammatory or immunosuppressive agent.
  • the antiinflammatory or immunosuppressive agent is an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, protein, or recombinant protein or peptide.
  • the anti-inflammatory or immunosuppressive agent is an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, protein, or recombinant protein or peptide.
  • the anti-inflammatory or immunosuppressive agent is an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, protein
  • Tocilizumab Actemra
  • Rituximab Rituxan
  • Ofatumumab Ofatumumab
  • Belimumab Benlysta
  • Epratuzumab Epratuzumab
  • Abatacept Orencia
  • Golimumab Simponi
  • Certolizumab Certolizumab (Cimzia)
  • Sifalimumab Anakinra (Kineret)
  • canakinumab Ilaris
  • rilonocept Arcalyst
  • a pharmaceutical composition comprises IVIG in combination with an antibody, antibody fragment, or antibody derivative.
  • the antibody, antibody fragment, or antibody derivative binds one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the pharmaceutical composition comprises IVIG in combination with one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the pharmaceutical composition modulates, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • the pharmaceutical composition modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the pharmaceutical composition modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an innate immune response.
  • the pharmaceutical composition modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an adaptive immune response, for example, an adaptive immune response that is specific to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the pharmaceutical composition modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits a B cell response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, including stimulation of B cells, proliferation of B cells, differentiation of B cells, increased or decreased number of B cells and modulated activity of B cells.
  • the pharmaceutical composition modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits a T cell response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, including stimulation of T cells, proliferation of T cells, differentiation of T cells, increased or decreased number of T cells and modulated activity of T cells.
  • the pharmaceutical composition modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits a cytokine response to one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the pharmaceutical composition treats a long-term disease or disorder including mild cognitive impairments (MCI's), chronic traumatic
  • CTE encephalopathy
  • PCS post-concussion syndrome
  • a method for determining the efficacy of a treatment for brain injury or an associated disease or disorder in a subject, wherein the method comprises obtaining a biological sample from the subject following administration of the treatment, measuring an immune response in the subject and comparing the immune response in the biological sample from the subject to the immune response in a control biological sample, wherein a modulated immune response in the biological sample from the subject when compared to the control biological sample indicates that the treatment is effective in treating the brain injury or associated disease or disorder.
  • a reduced immune response in the biological sample from the subject when compared to the control biological sample indicates that the treatment is effective in treating the brain injury or associated disease or disorder.
  • control biological sample is a biological sample taken from the subject prior to treatment.
  • the method comprises determining the subject's immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell, immune cell mediator or cytokine response.
  • method for determining the efficacy of a treatment for a brain injury or an associated disease or disorder in a subject, wherein the method comprises administering to the subject an agent that can detect a modulation in the immune response in the subject after the treatment from the immune response in the subject prior to treatment.
  • the method comprises
  • the method comprises detecting binding of the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to an antibody in the subject, wherein a decrease in the amount of binding of the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to an antibody in the subject when compared to the amount of binding of the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to an antibody in the subject prior to treatment indicates that the treatment is effective in treating the brain injury or associated disease or disorder.
  • the method comprises administering to the subject after treatment an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof in the subject, wherein a decrease in the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof in the subject when compared to the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of the peptides
  • the method comprises administering to the subject after treatment a multimer comprising a peptide listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof wherein a decrease in the amount of T cells that bind the multimer in the subject after treatment when compared to the amount of T cells that bind the multimer in the subject prior to treatment indicates that the treatment is effective in treating the brain injury or associated disease or disorder.
  • the method comprises determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell, immune cell mediator or cytokine response.
  • a method for determining an appropriate treatment for a subject to be treated for a brain injury or an associated disease or disorder, wherein the method comprises administering to the subject an agent that can detect a modulated immune response in the subject.
  • the method comprises determining the subject's immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, wherein detection of an immune response to a protein listed in Table 1 or Table 2, a peptide listed in any of Tables 3 to 20, or modification, subsequence, homologue, variant or derivative thereof, indicates that the subject should be treated by modulating the immune response to that protein or peptide, or modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises obtaining a biological sample from the subject, measuring an immune response in the sample to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, wherein detection of an immune response in the sample to a protein listed in Table 1 or Table 2, a peptide listed in any of Tables 3 to 20, or modification, subsequence, homologue, variant or derivative thereof, indicates that the subject should be treated by modulating the immune response to that protein or peptide, or modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises administering:
  • active ingredient refers to a component that provides the therapeutic activity or effect in the treatment of a condition, symptom, disease or disorder.
  • the active ingredient of IVIG is one or more of, by way of example and not by way of limitation, antibodies, immune complexes, cytokines, ligands for Fc receptors, complement, albumin and clotting factors.
  • brain injury refers to any nondegenerative, noncongenital insult to the brain from an external mechanical force resulting in permanent or temporary impairment of cognitive, physical, or psychosocial functions that may be associated with diminished or altered state of consciousness.
  • Symptoms caused by or associated with brain injury include but are not limited to a new onset or worsening of one or more of the following clinical signs, immediately following the insult to the brain that may or may not be transient: any period of loss of or a decreased level of consciousness (LOC); any loss of memory for events immediately before or after the injury (post-traumatic amnesia); any alteration in mental state at the time of the injury (confusion,
  • LOC level of consciousness
  • the brain injury is caused by a bump, blow, or jolt to the head or by a hit to the body that causes the head and brain to move rapidly back and forth.
  • the brain injury is a concussion including a rotational concussion.
  • brain injury involves damage to the neural pathways in the brain.
  • An "associated disease or disorder” as used herein refers to a disease or disorder that develops following brain injury or that commonly occurs in subjects who have experienced brain injury. This includes acute and chronic diseases or disorders, short and long term disease and disorders, as well as related symptoms thereof.
  • dose refers to the amount of active ingredient given to an individual at each administration.
  • the dose may generally refer to the amount of condition or disease (e.g.
  • dose refers to the amount of IVIG administered. The dose will vary depending on a number of factors, including the range of normal doses for a given therapy, frequency of
  • a dosage form refers to the particular format of the pharmaceutical or pharmaceutical composition, and depends on the route of administration.
  • a dosage form can be in a liquid form for nebulization, e.g., for inhalants, in a tablet or liquid, e.g., for oral delivery, or a saline solution, e.g., for injection.
  • IVIG intravenous immunoglobulin therapy as understood by a person of skill in the art.
  • IVIG refers to a therapy containing pooled immunoglobulins for use in the treatment of diseases, disorders, conditions or symptoms.
  • IVIG includes IVIG that has been modified (“modified IVIG") including for example modified to produce higher yield of IVIG or specific activity or therapeutic utility of IVIG.
  • Modified IVIG can also include modified active ingredients of IVIG, including modifications to antibodies, immune complexes, cytokines, complement, albumin and clotting factors.
  • modified IVIG can include modifying or removing regions or parts of the active ingredient or adding regions or elements to the active ingredient.
  • IVIG may be administered through intravenous, subcutaneous or intramuscular routes.
  • Non-limiting examples of IVIG include HyQvia®, Hizentria®, Gamunex-C®, Gammaked®, Flebogamma®, Gamunex®, Privigen®, Gammagard®, Venoglobulin®, Gammimune®, Sandoglobulin®, Gammar®, Ivegaam®, Globuman®, Gammabulin®, Liogamma®, Boehrigamma® and
  • fraction refers to a part of an IVIG, that is a one or more components, proteins, cells, antibodies etc. separated from an IVIG formulation.
  • patient does not necessarily have a given disease, but may be merely seeking medical advice.
  • Bio sample includes but is not limited to bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, immune cells, macrophages, T cells, B cells, monocytes, dendritic cells etc.
  • bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, immune cells, macrophages, T cells, B cells, monocytes, dendritic cells etc.
  • a biological sample is typically obtained from a eukaryotic organism, most preferably a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, Mouse; rabbit; or a bird; reptile; or fish.
  • a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, Mouse; rabbit; or a bird; reptile; or fish.
  • a "standard control" “control” or “control biological sample” refers to a sample, measurement, or value that serves as a reference, usually a known reference, for comparison to a subject biological sample, test sample, measurement, or value.
  • a test biological sample can be taken from a patient suspected of brain injury and compared to samples from a known patient with brain injury or a known normal individual without brain injury.
  • a standard control can also represent an average measurement or value gathered from a population of similar individuals that do not have a given disease or condition (i.e. standard control population), e.g., healthy individuals with a similar medical background, same age, weight, etc. that do not have brain injury.
  • a standard control value can also be obtained from the same individual, e.g., from an earlier-obtained sample, prior to disease or condition (e.g. brain injury), or prior to treatment.
  • disease or condition e.g. brain injury
  • standard controls can be designed for assessment of any number of parameters (e.g. RNA levels, protein levels, individual, specific cell types, specific bodily fluids, specific tissues, T cells, B cells, microglia, macrophages, cytokines, etc.).
  • Standard controls are valuable in a given situation and be able to analyze data based on comparisons to standard control values. Standard controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.
  • antigen refers to any protein, peptide, biological component, molecule or compound that induces an immune response.
  • autoantibody refers to an antibody that is generated against a "self antigen", that is an antigen (e.g. protein or peptide) that is expressed by the host or subject as opposed to an antigen from a foreign source (e.g. virus, bacteria).
  • an antigen e.g. protein or peptide
  • a foreign source e.g. virus, bacteria
  • autoreactive refers to a cell that recognizes or is reactive to a self-antigen.
  • an autoreactive B cell is a B cell that recognizes and is reactive to or stimulated by a self-antigen.
  • An autoreactive T cell is a T cell that recognizes and is reactive to or stimulated by a self- antigen.
  • innate immune response means a non-specific immune response to an antigen in a generic way that does not result in immune memory for that antigen in the subject.
  • the method comprises measuring the innate immune response of a subject to a glial protein.
  • the innate immune response is to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • "adaptive immune response” includes a naive or recall immune response that is specific to a particular antigen and that results in the
  • a recall response means an immune response to an antigen to which a subject has previously been exposed.
  • a recall or memory response is therefore an immune response subsequent to the initial antigen exposure and immune response.
  • a recall response may occur following exposure of the subject to the antigen for a second (secondary), third (tertiary), fourth, fifth, sixth, seventh, eighth, ninth, tenth, or any subsequent antigen exposure.
  • a recall or memory response is distinguished from a primary response to an antigen; a primary response is an immune response that occurs when a subject is exposed to an antigen for the first time. In a primary response, naive T cells expand. In contrast, recall immune responses are believed to be attributed to reactivation of long-lived, antigen-primed T lymphocytes that arise from differentiated effector T cells in a quiescent state. Thus, a "recall response” is an immune response in which antigen-primed cells participate. Recall immune responses can result in undesirable or adverse symptoms and physiological complications, such as inflammation.
  • the method comprises measuring the adaptive or recall immune response of a subject, for example, the adaptive or recall immune response of a subject to a glial protein.
  • the recall immune response is to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • treatment and may refer to any delay in onset, reduction in the frequency or severity of symptoms, amelioration of symptoms, improvement in patient comfort or function, decrease in the occurrence of a given condition or disease or condition or disease symptoms in a patient, decrease in severity of the condition or disease state, etc.
  • the effect of treatment can be compared to an individual or pool of individuals not receiving a given treatment, or to the same patient prior to, or after cessation of, treatment.
  • treatment may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.
  • terapéuticaally effective dose or amount as used herein is meant a dose that produces effects for which it is administered (e.g. treating a disease).
  • dose and formulation will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%), 80%), 90%), or at least 100%>.
  • Therapeutic efficacy can also be expressed as "-fold" increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a standard control.
  • therapeutically effective dose or amount may ameliorate one or more symptoms of a disease.
  • a therapeutically effective dose or amount may delay the onset of a disease or one or more symptoms of a disease when the effect for which it is being administered is to treat a person who is at risk of developing the disease.
  • prognosis refers to a relative probability that a disease or condition (e.g. brain injury) is present in the subject.
  • prognosis refers to a relative probability that a certain future outcome may occur in the subject with respect to a disease state.
  • prognosis can refer to the likelihood that an individual will develop a disease or condition (mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS), or the likely severity of the disease (e.g., duration of disease).
  • MCI's cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • the terms are not intended to be absolute, as will be appreciated by any one of skill in the field of medical diagnostics.
  • correlating and “associated,” and “determining” in reference to the measurement and/or analysis of a disease or condition (e.g. brain injury, mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS)) risk factor, refers to comparing the presence or amount of the risk factor (modulation in response to a protein or peptide including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, amount of autoantibodies, amount of autoreactive immune cells, number of B cells or T cells; B and/or T cell stimulation, differentiation, activation, proliferation, activity; or cytokine production or activity) in an individual to its presence or amount in persons known to suffer from, or known to be at risk of, the disease or condition (e.g.
  • MCI's mild cognitive impairment
  • an autoimmune, inflammatory autoimmune, cancer, infectious, immune, or other disease or in persons known to be free of the disease (e.g. brain injury, mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS)), and assigning an increased or decreased probability of having/ developing the disease or condition (e.g. brain injury, mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS)) to an individual based on the assay result(s).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • determining whether a subject has or is at risk of having a disease or condition includes one or more of the following actions: collecting a sample from a subject, exposing the subject or tissue of sample to an antigen, antibody, antibody fragment, antibody derivative, multimer, protein, peptide, nucleic acid, synthetic chemical, small chemical molecule, ligand mimetic, or epitope, purifying the sample, measuring a characteristic of the sample, analyzing the results of the measurement; to be followed by assigning a probability of the subject having or developing the disease or condition. "Indicating" in reference to correlating a measured quantity with whether a patient has or is at risk of developing a disease or condition (e.g.
  • MCI mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • Nucleic acid or “oligonucleotide” or “polynucleotide” or grammatical equivalents used herein means at least two nucleotides covalently linked together.
  • Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length.
  • Nucleic acids and polynucleotides are a polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc.
  • a nucleic acid of the present invention will generally contain phosphodiester bonds, although in some cases, nucleic acid analogs are included that may have alternate backbones, comprising, e.g.,
  • phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphophoroamidite linkages see Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press
  • peptide nucleic acid backbones and linkages Other analog nucleic acids include those with positive backbones; non-ionic backbones, and non-ribose backbones, including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, Carbohydrate Modifications in Antisense Research, Sanghui & Cook, eds.
  • Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose- phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.
  • a particular nucleic acid sequence also implicitly encompasses "splice variants.”
  • a particular protein encoded by a nucleic acid implicitly encompasses "splice variants.”
  • splice variants are products of alternative splicing of a gene. After transcription, an initial nucleic acid transcript may be spliced such that different
  • nucleic acid splice products encode different polypeptides.
  • Mechanisms for the production of splice variants vary, but include alternate splicing of exons.
  • Alternate polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of the splice products, are included in this definition.
  • An example of potassium channel splice variants is discussed in Leicher, et al., J. Biol. Chem. 273(52): 35095-35101 (1998).
  • Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence.
  • DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or
  • a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • "operably linked” means that the DNA sequences being linked are near each other, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • probe or “primer”, as used herein, is defined to be one or more nucleic acid fragments whose specific hybridization to a sample can be detected.
  • a probe or primer can be of any length depending on the particular technique it will be used for.
  • PCR primers are generally between 10 and 40 nucleotides in length, while nucleic acid probes for, e.g., a Southern blot, can be more than a hundred nucleotides in length.
  • the probe may be unlabelled or labeled as described below so that its binding to the target or sample can be detected.
  • the probe can be produced from a source of nucleic acids from one or more particular (preselected) portions of a chromosome, e.g., one or more clones, an isolated whole chromosome or chromosome fragment, or a collection of polymerase chain reaction (PCR) amplification products.
  • PCR polymerase chain reaction
  • the length and complexity of the nucleic acid fixed onto the target element is not critical to the invention. One of skill can adjust these factors to provide optimum hybridization and signal production for a given hybridization procedure, and to provide the required resolution among different genes or genomic locations.
  • the probe may also be isolated nucleic acids immobilized on a solid surface (e.g., nitrocellulose, glass, quartz, fused silica slides), as in an array.
  • a solid surface e.g., nitrocellulose, glass, quartz, fused silica slides
  • the probe may be a member of an array of nucleic acids as described, for instance, in WO 96/17958.
  • Techniques capable of producing high density arrays can also be used for this purpose (see, e.g., Fodor (1991) Science 767-773; Johnston (1998) Curr. Biol. 8: R171-R174; Schummer (1997) Biotechniques 23 : 1087-1092; Kern (1997) Biotechniques 23 : 120-124; U.S. Patent No. 5,143,854).
  • a "labeled nucleic acid probe or oligonucleotide” is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic, van der Waals, electrostatic, or hydrogen bonds to a label such that the presence of the probe may be detected by detecting the presence of the label bound to the probe.
  • method using high affinity interactions may achieve the same results where one of a pair of binding partners binds to the other, e.g., biotin, streptavidin, etc.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site at ncbi.nlm.nih.gov/BLAST/ or the like).
  • sequences are then said to be “substantially identical.”
  • This definition also refers to, or may be applied to, the compliment of a test sequence.
  • the definition also includes sequences that have deletions and/or additions, as well as those that have substitutions.
  • the preferred algorithms can account for gaps and the like.
  • identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.
  • sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
  • test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated.
  • sequence algorithm program parameters Preferably, default program parameters can be used, or alternative parameters can be designated.
  • sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.
  • a “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
  • Methods of alignment of sequences for comparison are well known in the art.
  • Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith &
  • a preferred example of algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990), respectively.
  • BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins of the invention.
  • Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information
  • HSPs high scoring sequence pairs
  • Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always ⁇ 0).
  • M forward score for a pair of matching residues; always > 0
  • N penalty score for mismatching residues; always ⁇ 0.
  • a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • W wordlength
  • E expectation
  • the phrase "selectively (or specifically) hybridizes to” refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence with a higher affinity, e.g., under more stringent conditions, than to other nucleotide sequences (e.g., total cellular or library DNA or RNA).
  • stringent hybridization conditions refers to conditions under which a nucleic acid will hybridize to its target sequence, typically in a complex mixture of nucleic acids, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Probes, "Overview of principles of hybridization and the strategy of nucleic acid assays” (1993). Generally, stringent hybridization conditions are selected to be about 5- lOoC lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength pH.
  • Tm thermal melting point
  • the Tm is the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at Tm, 50% of the probes are occupied at equilibrium).
  • Stringent hybridization conditions may also be achieved with the addition of destabilizing agents such as formamide.
  • a positive signal is at least two times background, preferably 10 times background hybridization.
  • Exemplary stringent hybridization conditions can be as following: 50% formamide, 5x SSC, and 1% SDS, incubating at 42oC, or, 5x SSC, 1% SDS, incubating at 65oC, with wash in 0.2x SSC, and 0.1% SDS at 65oC.
  • Exemplary "moderately stringent hybridization conditions" include a
  • hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37oC, and a wash in IX SSC at 45oC is at least twice background.
  • Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency. Additional guidelines for determining hybridization parameters are provided in numerous reference, e.g., and Current Protocols in Molecular Biology, ed. Ausubel, et al., John Wiley & Sons.
  • Nucleic acids may be substantially identical if the polypeptides that they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, selenocysteine, pyrrolysine, and O-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to a naturally occurring amino acid.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-R7B Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • sequence refers to a portion of a protein or peptide that is that at least one amino acid less in length than the full-length protein or peptide.
  • variant refers to a protein or peptide that deviates from a reference protein or peptide sequence. Modified and variant proteins or peptides may therefore have greater or less activity or function than a reference protein or peptide but at least retain partial activity or function of the reference protein or peptide.
  • Constantly modified variants applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of
  • Every nucleic acid sequence herein that encodes a polypeptide also describes every possible silent variation of the nucleic acid.
  • each codon in a nucleic acid except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan
  • TGG which is ordinarily the only codon for tryptophan
  • amino acid sequences one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid.
  • the following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).
  • a "modified” or “modification” also refers to a change to a protein or peptide that results in a deviation from a reference protein or peptide that can include for example Phosphorylation; De-phosphorylation; Oxidization; Reduction;
  • Glycatation including but not limited to: prenylation, myristylation, palmitoylation; isoprenylation; farnesylation; geranylgeranylation; glpiation); Acylation; Alkylation; Amidation; Arginylation; Polyglutamylation; Polyglycylation;
  • a "label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means.
  • useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.
  • recombinant when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified.
  • recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.
  • heterologous when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature.
  • the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source.
  • a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).
  • Antibody refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen.
  • the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • antibodies or fragments of antibodies may be derived from different organisms, including humans, mice, rats, hamsters, camels, etc.
  • Antibodies of the invention may include antibodies that have been modified or mutated at one or more amino acid positions to improve or modulate a desired function of the antibody (e.g. glycosylation, expression, antigen recognition, effector functions, antigen binding, specificity, etc.).
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kD) and one "heavy” chain (about 50-70 kD).
  • the N- terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.
  • Antibodies exist, e.g., as intact immunoglobulins or as a number of well- characterized fragments produced by digestion with various peptidases.
  • pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond.
  • the F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer.
  • the Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)).
  • the method described herein comprises administering an antibody, antibody fragment, antibody derivative (e.g. Fab) that binds a protein, including but not limited to a glial protein.
  • the method described herein comprises administering an antibody, antibody fragment, antibody derivative (e.g. Fab) that binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, one or more immune cell and/or one or more cytokines.
  • the antibody, antibody fragment, antibody derivative (e.g. Fab) binds a combination of proteins, immune cells and/or cytokines.
  • the genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody.
  • Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)).
  • Techniques for the production of single chain antibodies or recombinant antibodies U.S. Patent 4,946,778, U.S. Patent No.
  • transgenic mice or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825;
  • phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g.,
  • Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829, Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121 :210 (1986)).
  • Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Patent No. 4,676,980, WO 91/00360; WO 92/200373; and EP 03089).
  • a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non- human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81 :6851-6855 (1984), Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments.
  • Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells.
  • a "chimeric antibody” is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity.
  • the preferred antibodies of, and for use according to the invention include humanized and/or chimeric monoclonal antibodies.
  • the antibody binds a protein, including but not limited to a glial protein.
  • the antibody binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, one or more immune cells or one or more cytokines.
  • the antibody binds a combination of proteins, immune cells and/or cytokines.
  • the antibody is conjugated to an "effector" moiety.
  • the effector moiety can be any number of molecules, including labeling moieties such as radioactive labels or fluorescent labels, or can be a therapeutic moiety.
  • the antibody modulates the activity of a protein or immune cell.
  • effector moieties include, but are not limited to, an anti-inflammatory drug, autoimmune disease drug, a toxin, a radioactive agent, a cytokine, a second antibody or an enzyme.
  • the invention provides an embodiment wherein the antibody of the invention is linked to an enzyme that converts a prodrug into a cytotoxic or immune response modulating agent.
  • the immunoconjugate can be used for targeting the effector moiety to an immune cell (e.g. B cell, T cell, macrophage, monocyte, dendritic cell etc.).
  • the immunoconjugate can be used to target immune cells involved in an innate immune response.
  • the immunoconjugate can be used to target immune cells involved in an adaptive immune response.
  • the immunoconjugate can be used to target immune cells involved in an immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the immunoconjugate can be used to target immune cells involved in an immune response that is specific to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the recombinant protein of the invention comprising the antigen-binding region of any of the monoclonal antibodies of the invention can be used to treat brain injury or an associated disease, disorder or symptom.
  • the antigen-binding region of the recombinant protein is joined to at least a functionally active portion of a second protein having therapeutic activity.
  • the antibody binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof, one or more immune cells or one or more cytokines. In other embodiments, the antibody binds a combination of proteins, peptides immune cells and/or cytokines.
  • the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background.
  • Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein.
  • polyclonal antibodies can be selected to obtain only those polyclonal antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules.
  • a variety of immunoassay formats may be used to select antibodies specifically
  • solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity) .
  • an immune response that is specific to when referring to a protein or peptide, refers to an immune response that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologies.
  • the immune response detected is an immune response that is specific to that protein or peptide, e.g. T cells or B cells that specifically recognize that protein or peptide or have a detectably greater response to that specific protein or peptide when compared to the response to other proteins or peptides.
  • a "protein level” refers to an amount (relative or absolute) of protein form (as distinguished from its precursor RNA form).
  • a protein indicative of an immune response may include a full-length protein (e.g. the protein translated from the complete coding region of the gene, which may also include post-translational modifications), functional fragments of the full length protein (e.g. sub-domains of the full length protein that possess an activity or function in an assay), or protein fragments which may be any peptide or oligopeptide of the full length protein.
  • the method comprises measuring the protein level of a cytokine or other protein expressed by an immune cell (e.g. B cell, T cell, macrophage, monocyte, dendritic cell etc.)
  • RNA level refers to an amount (relative or absolute) of RNA present that may be translated to form a protein.
  • the RNA may be a full-length RNA sufficient to form a full-length protein.
  • the RNA may also be a fragment of the full length RNA thereby forming a fragment of the full-length protein.
  • the fragment of the full length RNA may form a functional fragment of the protein.
  • composition will generally comprise agents for buffering and
  • preservation in storage and can include buffers and carriers for appropriate delivery, depending on the route of administration.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable carrier” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • an "agent” as used herein refers to any molecule (e.g. antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, or protein) that can be administered to a subject.
  • the agent detects an immune response.
  • the agent characterizes an immune response, e.g. identifies the type of immune cell that is stimulated, activated, differentiated or proliferate in the immune response.
  • the agent modulates an immune response.
  • An agent that modulates an immune response is a molecule (e.g.
  • the agent modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • the agent modulates stimulation, activation proliferation, number or activity of immune proteins or cells (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines etc.)
  • the agent modulates an innate immune response.
  • the agent modulates a adaptive immune response.
  • the agent modulates an immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • an agent administered to a subject treats brain injury or an associated disease or disorder when administered to a subject in a therapeutically effective dose or amount.
  • the agent depletes B cells and/or T cells, including for example autoreactive B cell and T cells, and autoreactive B cells and T cells specific for one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or subsequence, homologue, variant or derivative thereof.
  • an agent is an agent that binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof (e.g. an antibody, antibody fragment, antibody derivative (e.g. Fab)).
  • the agent is an agent (e.g. an antibody or antibody derivative [e.g.
  • the agent may compete with autoantibodies for binding to the protein and may be selected or designed as an agent that modifies or inhibits pathogenic autoimmune responses.
  • the agent is a multimer, for example a multimer (e.g. a tetramer or dextramer) comprising a peptide listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • interaction refers to a physical interaction at the molecular level or functional interaction between two or more of an agent, protein, peptide, molecule, immune cell, immune protein or nucleic acid.
  • a functional interaction need not require physical binding. Accordingly, binding between two or more of an agent, protein, peptide, molecule, immune cell, immune protein or nucleic acid can be direct or indirect.
  • a particular example of an indirect interaction is where one entity acts upon an intermediary molecule, which in turn acts upon the second referenced entity.
  • the agent modulates disrupts the interaction between an immune cell or immune protein and a physiological or natural ligand.
  • immune protein refers to a protein involved in an immune response including but not limited to proteins expressed by an immune cell (e.g. T cell, B cell, macrophage, monocyte, dendritic cell etc.) including but not limited to cytokines, integrin and tumor necrosis factor (TNF) proteins.
  • the agent binds a physiological or natural ligand of the immune cell or immune protein.
  • the agent binds the complex an immune cell or immune protein bound to a ligand.
  • the agent disrupts the interaction between an immune cell or immune protein and one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent binds an immune cell or immune protein that interacts with one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • the agent binds the complex of an immune cell or immune protein bound to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent modulates the activity or expression of one or more type of immune cell or protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof.
  • the agent modulates the stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof.
  • the agent modulates the stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof.
  • the agent modulates stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g.
  • the agent modulates production or activity of cytokines. In some embodiments, the agent modulates activity or expression of immune cells or proteins involved in an immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response.
  • the agent modulates stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent modulates stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent modulates stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies.
  • the agent preferentially binds to an RNA that is translatable to a protein involved in an immune response (e.g. cytokine, T F proteins, integrin etc.) compared to an RNA that is translatable to another nucleic acids.
  • the RNA is mRNA.
  • the agent is an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, or protein.
  • the agent binds a full-length protein (e.g.
  • the agent binds a fragment of the full length protein, RNA that is translatable to a fragment of the immune protein or DNA that is transcribable to a fragment of the immune protein or a functional fragment of the full length immune protein, RNA that is translatable to a functional fragment of the immune protein, or DNA that is transcribable to a functional fragment of the immune protein.
  • the agent binds one or all splice variants of an immune protein.
  • the agent is an antisense nucleic acid that is capable of hybridizing to an RNA that is translatable to an immune protein.
  • the antisense nucleic acid is typically capable of decreasing the amount of immune protein that is translated in a cell.
  • RNAi molecule is an siRNA, shRNA, miRNA, shmiRNA that is capable of inducing RNAi and hybridizing to an RNA that is translatable to an immune protein.
  • the RNAi molecule is typically capable of decreasing the amount of immune protein that is translated in a cell.
  • a "ligand mimetic” is a synthetic chemical compound designed to mimic, in structure or in binding mode, a known ligand.
  • a ligand mimetic may bind the same amino acids or a subset of the same amino acids on an immune protein that a natural ligand of the immune protein binds during the physiological functioning of the immune protein.
  • Ligand mimetics include biopolymers (e.g.
  • the synthetic chemical compound is greater than two hundred fifty thousand (250,000) Daltons.
  • the agent is less than five hundred (500) Daltons.
  • a ligand mimetic is a small chemical molecule.
  • a "small chemical molecule” is a molecule that has a molecular weight of less than two thousand (2000) Daltons. In some embodiments, a small chemical molecule is a molecule that has a molecular weight of less than one thousand (1000) Daltons. In other embodiments, a small chemical molecule is a molecule that has a molecular weight of less than five hundred (500) Daltons.
  • An agent may "target" a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell by preferentially binding to the protein, peptide, immune protein or immune cell, or RNA of a protein, peptide, immune protein or immune cell compared to its binding to other molecules of a similar form.
  • An agent preferentially binds to a molecule, for example, when the binding to the targeted molecule is greater than the binding to other molecules of a similar form.
  • the preferential binding is 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5- fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8- fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, 6000-fold, 7000-fold, 8000-fold, 9000-fold, 10000 fold, 100,000-fold, 1,000,000-fold greater.
  • An agent may also "target" a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell by decreasing or increasing the amount of a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell in a cell or organism relative to the absence of the agent.
  • a person having ordinary skill in the art, using the guidance provided herein, may easily determine whether an agent decreases or increases the amount of a protein, peptide, immune protein, immune cell or a RNA of a protein, peptide, immune protein or immune cell a cell or organism.
  • Brain injury is associated with a modulated immune response in the subject relative to individuals who do not have or are not at risk of developing brain injury.
  • the methods of the present invention can also determine whether a subject has, is at risk of having, or is in need of treatment for a disease or disorder associated with brain injury including but not limited mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • the methods of the present invention can also determine the severity of a brain injury or a disease or disorder associated with brain injury in a subject.
  • the increased activity of one or more type of immune cell or immune protein is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • immune protein refers to a protein involved in an immune response including but not limited to proteins expressed by an immune cell (e.g. T cell, B cell, macrophage, monocyte, dendritic cell etc.) including but not limited to cytokines, integrin and tumor necrosis factor (TNF) proteins.
  • TNF tumor necrosis factor
  • the increased expression of one or more type of immune cell or immune protein e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines
  • the increased expression of one or more type of immune cell or immune protein e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines
  • a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies e.g.
  • autoantibodies to a protein including but not limited to a glial protein one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof) is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increase in production or activity of cytokines is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increase in activity or expression of immune cells or immune proteins results from an immune response to a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response.
  • an increased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • an increased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased activity of one or more type of immune cell or immune protein e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines
  • the decreased expression of one or more type of immune cell or immune protein e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines
  • the decreased expression of one or more type of immune cell or immune protein is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies e.g.
  • autoantibodies to a protein including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof) is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased production or activity of cytokines is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decrease in activity or expression of immune cells or immune proteins results from an immune response to protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response.
  • a decreased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • a decreased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased expression or activity of a first immune cell or immune protein and the decreased expression or activity of a second immune cell or immune protein is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • a method of determining whether a subject has, is at risk of having, or is in need of treatment for brain injury comprising obtaining a biological sample from the subject and determining whether the subject has a modulated immune response wherein a modulated immune response indicates that the subject has, is at risk of having, or is in need of treatment for brain injury.
  • Non-limiting examples of conditions, diseases or disorder that may be associated with a differential expression or activity of immune cells or proteins as detected in the methods of the present invention include mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post- concussion syndrome (PCS).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post- concussion syndrome
  • a modulated RNA level or protein level associated with an immune response, modulated immune response level or other measured quantity relative to a control standard is a measured amount (e.g. of the RNA level, protein level, etc.) that differs from the measured or calculated amount of the same quantity in the standard control.
  • the measured quantity is greater than or elevated above or increased over the standard control.
  • the measured quantity is greater by or elevated above or increased over the standard control by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • the measured quantity is less than or decreased compared to the standard control.
  • the measured quantity is less than or decreased as compared to the standard control by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • the modulated level or amount of a measured quantity e.g. immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof
  • a measurable can be at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 5-fold, or larger-fold greater (e.g. elevated over) or less than a standard control.
  • a subject who is "at risk of developing" a condition or disease has greater chance to having the condition or disease than a person who is not at risk of developing the condition or disease.
  • a standard control is derived from the person who is not at risk of developing the condition or disease (i.e. standard control subject)
  • the amounts or levels of protein or RNA or immune cells or level of immune response may be measured in known assays or tests to determine if a subject is at risk of developing a condition or disease (e.g. brain injury or associated disease or disorders".
  • a condition or disease e.g. brain injury or associated disease or disorders.
  • the person at risk of developing the condition or disease has at least a 5%, 10%, 15%, 20%, 25%,30%, 35%, 40%, 50%, 60%, 75%, 80%, 90%), or at least a 100% greater likelihood of having the disease at some future time relative to a standard control.
  • future time is one or more weeks, one or more months, or one or more years from the time at which the risk is assessed.
  • the subject at risk of developing the condition or disease is or is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 5-fold, 10-fold, 20-fold more likely to develop the condition or disease at some time in the future.
  • the standard control is a threshold level of a measurable quantity established by previous testing.
  • the person at risk of developing the condition or disease may be a person that has the measurable quantity (e.g. immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof) in excess of or below the established threshold, depending on the measurable quantity.
  • the threshold in the previous embodiment may be established by determining the differences between subjects who do not have the condition or disease (e.g. standard control) and subjects who have the condition disease, and assigning a threshold that separates one group from the other group in terms of one or more measurable quantities.
  • condition or disease e.g. standard control
  • the method of determining whether a subject has or is at risk of developing brain injury or an associated disease or disorder may also be a method of diagnosing a subject (e.g. a patient) or providing the subject with a prognosis.
  • the method includes determining whether a subject has or is at risk of developing a brain injury.
  • the method includes determining whether a subject expresses a modulated immune response relative to a standard control. The presence of a modulated immune response indicates the subject has or is at risk of developing a brain injury.
  • the methods of the present invention includes determining whether the subject has a modulated immune response to a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • the method includes determining whether the subject has a modulated T cell, B cell, immune cell mediator or cytokine response. In particular embodiments, the method includes determining whether the subject has one or more of stimulation of T cells, proliferation of T cells, differentiation of T cells, increased or decreased number of T cells, modulated activity of T cells, one or more of stimulation of B cells, proliferation of B cells, differentiation of B cells, increased or decreased number of B cells, modulated activity of B cells, or increased production or activity of immune cell mediators such as cytokines.
  • the methods of the present invention include detecting B cells generating autoantibodies.
  • the methods described herein the method comprises detecting B cells generating autoantibodies to a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the methods of the present invention include detecting a modulated innate immune response. In other embodiments, the methods of the present invention include detecting an adaptive immune response. In certain embodiments,
  • the methods of the present invention include detecting an immune response (e.g. adaptive immune response) specific to a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • an immune response e.g. adaptive immune response
  • a protein including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the methods described herein comprise detection of an immune complex (IC).
  • the immune complex detected comprises a protein or peptide bound to an autoantibody.
  • the IC comprises complement proteins bound to one or both of the protein or peptide or the autoantibody in the IC.
  • the protein in the immune complex is a protein listed in Table 1 or Table 2 or a modification, subsequence, homologue, variant or derivative thereof.
  • the peptide in the IC is a peptide listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof.
  • the autoantibody in the IC is an antibody against one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • pre-existing autoantibody in the blood from previous TBI events may bind protein that has become released from the brain, which allows for rapid detection of ICs that doesn't require the 12-24 hour wait for new antibodies to be generated.
  • the presence of ICs may be detected from 1 to 30 minutes after brain injury.
  • the methods of the present invention comprise detecting two or more different ICs each comprising different proteins listed in Table 1 or Table 2, or peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method of diagnosing a TBI, chronic injury or an associated disease or disorder or risk of developing chronic injury or associated disease or disorder is implemented in a diagnostic kit that measures an immune complex.
  • the specific immune complex comprises at least one antibody and at least one antigen (e.g. protein or peptide).
  • the methods and kits of the present invention include one or more reagents to bind the IC.
  • the present invention includes a first reagent to bind the antigen and a second reagent to bind the antibody wherein the binding of the second reagent to the antibody is measured to determine the presence or amount of an IC.
  • the present invention contains a first reagent to bind the antigen and a second reagent to bind a complement protein wherein the binding of the second reagent to the complement protein is measured to determine the presence or amount of an IC.
  • the antigen is a protein, including for example a protein listed in Table 1 or Table 2, or a modification, subsequence, homologue, variant or derivative thereof.
  • the antigen comprises a peptide, including for example a peptide listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the antibody is an autoantibody, including for example an autoantibody that binds a protein listed in Table 1 or Table 2, a peptide listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises one or more reagents that can detect biomarkers of particular interest.
  • the method uses a reagent for detecting an IC comprising one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method further comprises a reagent for detecting one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, a cytokine generated in response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • the reagent for detecting the IC is a derivative of a protein, antibody, antibody fragment, or antibody derivative (e.g. Fab) that binds the IC.
  • methods and kits of the present invention comprise an antibody, antibody fragment, antibody derivative (e.g. Fab) that binds an IC comprising one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method described herein further comprises an antibody, antibody fragment, or antibody derivative (e.g.
  • the antibody, antibody fragment, or antibody derivative binds a combination of proteins, peptides immune cells and/or cytokines.
  • the IC is detected using a reagent that does not bind to an immunogenic epitope from the lists in any of Tables 3 to 20.
  • use of a reagent that binds to sites on a protein of an immune complex other than immunogenic epitopes of that protein generates a significantly more accurate measurement of the presence of an immune complex that is related to a breach in the BBB.
  • a reagent that does not bind to an immunogenic epitope may provide more effective binding to a protein listed in Table 1 or Table 2 as it does not bind the protein at the same site as an auto-antibody and therefore does not need to compete with auto-antibodies for binding of the protein.
  • the concentration of the IC is analyzed against a known concentration baseline for the IC and subsequent post brain injury measurements of the IC.
  • the present invention comprises detecting an IC in combination with one or more of a protein cytokine, auto-antibody, T cell, B cell, protein-specific T cell response or protein-specific B cell response.
  • the concentrations of the biomarkers are analyzed against a known concentration baseline for each type of biomarker.
  • the concentrations of each biomarker are analyzed in cross-references to each other and over multiple time points either prior to or post a TBI event or multiple TBI events.
  • the present method comprises detecting or measuring one or more IC comprising one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • subsequence, homologue, variant or derivative thereof alone or in combination with other biomarkers selected from the group consisting of one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof, one or more cytokine, one or more auto-antibody that binds one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, one or more T cell responding to one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, one or more B cell responding to one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • subsequence, homologue, variant or derivative thereof one or more T cell response to one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, one or more B cell response to one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20 or a modification,
  • the present method comprises detecting one or more IC comprising one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof in combination with biomarkers selected from two or more, three or more, four or more, five or more, six or more or seven of the group consisting of one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof, one or more cytokine, one or more auto-antibody that binds one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, one or more T cell responding to one or more protein listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20,
  • multiple TBI events can be recorded, concentrations of one or more ICs alone or in combination with one or more proteins, one or more cytokines, one or more auto-antibodies, one or more T cells, one or more B cells and one or more B cell and/or T cell responses can be measured prior to and post the TBI event, where proteins from the brain may have previously leaked into the blood previously.
  • groups of thresholds can be determined for the concentration of each biomarker at specific points in time.
  • the thresholds are correlated to a probability of whether immune-mediated damage can occur.
  • the threshold data groups are compared with a subject's immune response over the same time periods.
  • the up regulation of the auto-specific immune response and waning of the immune response can be a key indicator of the severity of a concussion and pathogenesis of chronic injury following TBI.
  • detecting the risk of the subject developing a chronic disease is determined by an initial detection of a biomarker (e.g. T cell, B cell, protein, antibody, IC, cytokine) indicating an onset of an adaptive immune response, which increases risk of chronic disease development.
  • a biomarker e.g. T cell, B cell, protein, antibody, IC, cytokine
  • the concentration of the biomarker can indicate the level of risk for chronic disease development.
  • an analysis of the concentration levels of the biomarker on initial detection can indicate the level of risk for chronic disease
  • initial detection of biomarkers may identify a subject for treatment of brain injury or treatment of diseases or disorders associated with a brain injury, including chronic diseases.
  • the present methods comprise determining or developing an immune profile of a subject by characterization of immune responses that have occurred or are likely to occur in a subject.
  • the methods may include detecting proteins or peptides that have elicited an immune response in a subject or that are likely to elicit an immune response in a subject, for example determining which proteins or peptides (including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof) have elicited an immune response in a subject or are likely to elicit an immune response in a subject.
  • proteins or peptides including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof
  • the methods may include detecting biomarkers, including for example B cells, T cells, ICs, antibodies or cytokines.
  • the methods including detecting biomarkers for one or more proteins or peptides, such as B cells, T cells, ICs, or antibodies that are reactive or that bind to a particular protein of interest.
  • the methods of the present invention may include obtaining a biological sample from a subject, exposing the sample to a protein or peptide including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and detecting whether there are autoreactive T cells to the protein or peptide in the biological sample.
  • a protein or peptide including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and detecting whether there are autoreactive T cells to the protein or peptide in the biological sample.
  • one of skill in the art is able to determine a profile of which proteins or peptides have elicited an immune response in a subject or are likely to elicit an immune response in a subject and what kind of immune response has been elicited, e.g. B cell, T cell, antibody or cytokines. This information can inform diagnosis of brain injury or associated disease and disorders as well as identify what treatment options are
  • measurements are taken at a single time point, for example after the occurrence of a brain injury. In other embodiments, measurements are taken at multiple time points to detect the severity of particular brain injury and/or risk of development of chronic disease over time.
  • the methods include measuring the concentration of specific biomarkers (e.g. T cell, B cell, protein, antibody, IC, cytokine) over multiple points in time including for example over a series of TBI events.
  • specific biomarkers e.g. T cell, B cell, protein, antibody, IC, cytokine
  • initial measurements of specific biomarkers are taken at a point in time where it is known that a subject has not experienced a brain injury.
  • initial measurement of specific biomarker(s) are taken at a point in time before a subject engages in activity that may result in a TBI e.g. prior to a sports event. In an embodiment these initial
  • measurements act as a baseline or control to subsequent measurements where it is known that a subject has experienced a TBI or an associated disorder or disease.
  • these initial measurements act as a baseline or control to subsequent measurements after a subject has engaged in activity that may have resulted in a TBI.
  • the methods include measuring the
  • concentration of specific biomarkers e.g. T cell, B cell, protein, antibody, IC, cytokine
  • initial measurements of specific biomarkers are taken at a point in time where it is known that the subject has experienced a brain injury.
  • these initial measurements act as a baseline or control to subsequent measurements, which are taken following subsequent TBI events or an associated disorder or disease.
  • the subsequent measurements are taken prior to and post multiple TBI events that may occur.
  • subsequent measurements are taken when an associated disease or disorder is thought to have or is developing.
  • the methods include measuring the
  • initial measurements of specific biomarkers are taken at a point in time before administration of the treatment. In an embodiment, these initial measurements act as a baseline or control to subsequent measurements, which are taken following treatment of the subject. In an embodiment, the subsequent measurements are taken post treatment. In a further embodiment, subsequent measurements are taken following subsequent administration of the treatment.
  • the measurements taken over multiple points can provide a profile for the immune response in a subject, which can reveal trends in the immune response in the subject. This information can provide insight with regard to the severity of a specific TBI, the likelihood that the subject will develop a chronic condition or the efficacy of a treatment that is being administered to the subject to treat brain injury. In other embodiments, this information can be used to determine if or when a subject should begin treatment for a disease or disorder associated with a brain injury.
  • measuring biomarkers over multiple TBIs allows determination of trends of the presence and amount of biomarkers in a subject. This information can be used to determine risk for that subject in developing a chronic condition and to make decisions regarding game and career strategies. For example, a trend of a continuous increase in amount of biomarkers detected following each subsequent TBI may indicate that the subject is at an increased risk of a chronic condition. Alternatively, in a subject receiving treatment for brain injury, a trend of decreased in amount to biomarkers detected following each subsequent treatment and continuing TBIs, may indicate that the treatment is effective.
  • a method of the present invention is used to determine the efficacy of a therapeutic method or conventional treatment method.
  • the invention is used with conventional diagnostic and treatment methods as a companion diagnostic tool.
  • the methods of the present invention are used to determine the efficacy of a treatment for a brain injury or an associated disease or disorder in a subject.
  • a biological sample is obtained from the subject following administration of the treatment and an immune response in the subject is measured. This is compared with the immune response in a control biological sample and a reduced immune response in the biological sample from the subject when compared to the control biological sample indicates that the treatment is effective in treating the brain injury or associated disease or disorder.
  • the control biological sample is a biological sample taken from the subject prior to treatment.
  • the method comprises determining the subject's immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell and cytokine response.
  • methods for determining the efficacy of a treatment of a brain injury or an associated disease or disorder in a subject comprising administering to the subject an agent that can detect a modulation in the immune response in the subject after the treatment from the immune response in the subject prior to treatment.
  • the method may comprise administering to the subject after treatment a modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises detecting binding of the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to an antibody in the subject, wherein a decrease in the amount of binding of the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to an antibody in the subject when compared to the amount of binding of the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to an antibody in the subject prior to treatment indicates that the treatment is effective in treating a brain injury or associated disease or disorder.
  • the present methods for determining treatment efficacy comprise administering to the subject after treatment an antibody that binds to a modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and detecting binding of the antibody to a modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof in the subject, wherein a decrease in the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • subsequence, homologue, variant or derivative thereof in the subject when compared to the amount of binding of the antibody to the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof in the subject prior to treatment indicates that the treatment is effective in treating the brain injury or associated disease or disorder.
  • the present methods for determining treatment efficacy comprise administering to the subject after treatment a multimer comprising a peptide listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof wherein a decrease in the amount of T cells that bind the multimer in the subject after treatment when compared to the amount of T cells that bind the multimer in the subject prior to treatment indicates that the treatment is effective in treating the brain injury or associated disease or disorder.
  • the methods for determining efficacy of treatment comprise determining whether the treatment has resulted in modulation of macrophage, monocyte, dendritic cell, T cell, B cell, antibody, immune cell mediator or cytokine response.
  • the agent e.g. modified protein or peptide, including for example a modified form of the one or more the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, variant or derivative thereof; antibody or multimer
  • binding of the agent e.g. modified protein or peptide, including for example a modified form of the one or more the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, variant or derivative thereof; antibody or multimer
  • an antibody, protein, peptide, modified protein, modified peptide or immune cell in the subject can be detected by various means known in the art including fluorescence, magnetic resonance imaging etc.
  • the invention is used stratify patient population for treatment or determine an appropriate treatment for a subject to be treated for brain injury or an associated disease or disorder. For example, if the immune response has been triggered, then diagnosed using the present invention, then this may indicate that certain treatments for preventing long-term chronic conditions should be administered.
  • the diagnostic kit and its methods are implemented as screening tools for subjects who are suspected to have experienced TBI, are at risk of developing a chronic disease or disorder or would benefit from the knowledge of profiling.
  • Such methods comprise administering to the subject an agent that can detect a modulated immune response in the subject.
  • such method comprises administering: (a) a modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and detecting of binding of the modified form of one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • detection or measurement of IC is done using antibody, antibody fragments, antibody derivatives (e.g. Fab), protein or peptides that bind the protein contained in the IC and antibodies, antibody fragments, antibody derivatives (e.g. Fab), proteins or peptides that bind the auto-antibody contained in the IC.
  • detection or measurement of IC is done using antibodies, antibody fragments, antibody derivatives (e.g. Fab), protein or peptides that bind one or more complement protein bound to one or both of the protein or autoantibody in the IC.
  • detection or measurement of proteins and peptides can be done using antibodies, antibody fragments, antibody derivatives (e.g. Fab), nucleic acids, synthetic chemicals, multimers, small chemical molecules, proteins, peptides or ligand mimetics that bind the protein or peptide.
  • detection or measurement of cytokines can be done using antibodies, antibody fragments, or antibody derivatives (e.g. Fab) that bind the cytokine.
  • detection or measurement of autoantibodies is done using a protein or peptide that binds the autoantibody.
  • the presence of an elevated RNA level, protein level protein, immune cell level or immune response level indicates the subject has a brain injury or a disease or disorder associated with brain injury. In some embodiments, the presence of an elevated RNA level, protein level protein, immune cell level or immune response level indicates the subject is at risk of developing a brain injury or a disease or disorder associated with brain injury.
  • the method of determining includes isolating a biological sample from the subject thereby forming and isolated including but not limited to isolated immune cells (e.g. T cells, B cells, macrophages, monocytes, dendritic cells)
  • isolated immune cells e.g. T cells, B cells, macrophages, monocytes, dendritic cells
  • isolated e.g. T cells, B cells, macrophages, monocytes, dendritic cells
  • isolated purified or biologically pure
  • biological molecules e.g. nucleic acids or proteins
  • a protein that is the predominant species present in a preparation is substantially purified.
  • an isolated cell or isolated sample cells are a single cell type that is substantially free of many of the components which normally accompany the cells when they are in their native state or when they are initially removed from their native state.
  • an isolated cell sample retains those components from its natural state that are required to maintain the cell in a desired state.
  • an isolated (e.g. purified, separated) cell or isolated cells are cells that are substantially the only cell type in a sample.
  • a purified cell sample may contain at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of one type of cell.
  • An isolated cell sample may be obtained through the use of a cell marker or a combination of cell markers, either of which is unique to one cell type in an unpurified cell sample.
  • the cells are isolated through the use of a cell sorter.
  • antibodies against cell proteins are used to isolate cells.
  • the isolated cells may be of any appropriate type.
  • the isolated cells are immune cells, including but not limited to T cells, B cells, macrophages, monocytes and dendritic cells.
  • the biological sample is whole blood, plasma, serum, urine, sputum or saliva.
  • Immune cells include neutrophils, eosinophils, basophils, lymphocytes, B- cells, T-cells, Natural Killer cells (NK-cells), monocytes, macrophages, dendritic cells, or any cells derived from these cells.
  • Nucleic acids of interest may also be amplified using a variety of known amplification techniques. For instance, polymerase chain reaction (PCR) technology may be used to amplify target sequences directly from DNA, RNA, or cDNA.
  • PCR polymerase chain reaction
  • a stretch of nucleic acids is amplified using primers on either side of a targeted genetic variation, and the amplification product is then sequenced to detect the targeted genetic variation (using, e.g., Sanger sequencing, Pyrosequencing, Next gen sequencing technologies).
  • the primers can be designed to hybridize to either side of the upstream regulatory region of a protein expressed during an immune response, and the intervening sequence determined to detect a SNP in the promoter region.
  • one of the primers can be designed to hybridize to the targeted genetic variant.
  • Amplification techniques can also be useful for cloning nucleic acid sequences, to make nucleic acids to use as probes for detecting the presence of a target nucleic acid in samples, for nucleic acid sequencing, for control samples, or for other purposes.
  • Probes and primers are also readily available from commercial sources, e.g., from Invitrogen, Clonetech, etc.
  • RNA e.g., mRNA
  • Sample levels can be compared to a standard control level.
  • RNA to be detected can include mRNA or pRNA (promoter-associated RNA, see, e.g., Schmitz et al. (2010) Genes Dev. 24:2264-69).
  • a reverse transcriptase reaction is carried out and the targeted sequence is then amplified using standard PCR.
  • Quantitative PCR qPCR
  • RT-PCR real time PCR
  • Nucleic acid arrays are also useful for detecting nucleic acid expression. Customizable arrays are available from, e.g., Affimatrix.
  • Protein levels can be detected using antibodies or antibody fragments specific for that protein, natural ligands, small molecules, aptamers, etc.
  • Multimers can be used in the present methods to detect immune cells, for example T cells.
  • the present methods comprise multimers comprising one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the present methods comprise use of the multimers to detect or measure the amount of immune cells that are specific for a protein or peptide including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • the present methods comprise use of a mul timer to characterize immune cells, for example to identify the type of immune cell that is stimulated, activated, differentiated or proliferated in a immune response (e.g. memory immune cell, naive immune cell, effector immune cell).
  • a mul timer to characterize immune cells, for example to identify the type of immune cell that is stimulated, activated, differentiated or proliferated in a immune response (e.g. memory immune cell, naive immune cell, effector immune cell).
  • Antibody based techniques are known in the art, and described, e.g., in Harlow & Lane (1988) Antibodies: A Laboratory Manual and Harlow (1998) Using Antibodies: A Laboratory Manual; Wild, The Immunoassay Handbook, 3d edition (2005) and Law, Immunoassay: A Practical Guide (1996).
  • the assay can be directed to detection of a molecular target (e.g., protein or antigen), or a cell, tissue, biological sample, liquid sample or surface suspected of carrying an antibody or antibody target.
  • a molecular target e.g., protein or antigen
  • Immune response including the stimulation, activation, proliferation of immune cells and the number and/or the number and activity of immune cells can be detected using assays known in the art.
  • immunoassays includes: competitive and non-competitive formats, enzyme linked immunosorption assays (ELISA), microspot assays, Western blots, gel filtration and chromatography,
  • immunochromatography immunohistochemistry
  • flow cytometry flow cytometry or fluorescence activated cell sorting (FACS)
  • microarrays ELISPOT.
  • FACS fluorescence activated cell sorting
  • ELISPOT ELISPOT
  • Aptamers are nucleic acids that are designed to bind to a wide variety of targets in a non-Watson Crick manner. An aptamer can thus be used to detect or otherwise target nearly any molecule of interest, including an inflammatory or immune response associated protein. Methods of constructing and determining the binding characteristics of aptamers are well known in the art. For example, such techniques are described in U.S. Patent Nos. 5,582,981, 5,595,877 and 5,637,459. Aptamers are typically at least 5 nucleotides, 10, 20, 30 or 40 nucleotides in length, and can be composed of modified nucleic acids to improve stability. Flanking sequences can be added for structural stability, e.g., to form 3-dimensional structures in the aptamer.
  • a diagnostic method of the present invention may include, but is not limited to, alone or in combination, analysis of individual protein, mRNA levels, and/or immune cell levels or activity.
  • the above methods of detection can be applied to additional markers of immune response. That is, the expression level or activity of a protein or immune cell that is a marker for modulated immune response can be determined, and compared to a standard control marker.
  • the examination of additional proteins or immune cells that are markers for an modulated immune response can be used to confirm a diagnosis of brain injury, monitor condition or disease progression, or determine the efficacy of a course of treatment in a subject.
  • the method comprises administering to the subject a multimer comprising a peptide listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof. Detection of binding of such a multimer to immune cells (e.g. T cells) in the subject determines that the subject has, is at risk of having, or is in need of treatment of brain injury or an associated disorder.
  • the multimer is a tetramer or a dextramer.
  • the multimer is used to detect the presence of immune cells responsive to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method of determining comprises administering to a subject or exposing a subject or tissue from the subject to an antigen or epitope a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, and determining if there is an immune response.
  • a protein including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, and determining if there is an immune response.
  • the method includes administering an antigen, protein, or epitope, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, subcutaneously or intradermally, and detecting whether there is an immune reaction (e.g. swelling or redness of the skin).
  • an antigen, protein, or epitope including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, subcutaneously or intradermally, and detecting whether there is an immune reaction (e.g. swelling or redness of the skin).
  • the methods of determining comprise contacting the subject or a biological sample from the subject with a multimer comprising a protein, including but not limited to a glial protein, a protein listed in Table 1 or Table 2, or a peptide listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the multimer is a tetramer or a dextramer.
  • the multimer is used to detect the presence of immune cells responsive to the protein or peptide.
  • kits for detection of immune response markers in a subject can be for personal use or provided to medical
  • the kit can be a kit for diagnosing or prognosing a brain injury or an associated disease or disorder, or for monitoring the progression of the brain injury, disease or disorder or the efficacy of treatment.
  • the kit includes components for assessing immune response, including but not limited to components for detecting the expression level or activity of a RNA, protein or immune cells, e.g. a nucleic acid, protein, peptide, multimer, synthetic chemical, small chemical molecule, ligand mimetic, antibody, antibody derivative, antibody fragment (e.g. Fab) or other agent capable of detecting the number or activity of immune cells or level of proteins expressed by immune cells.
  • a RNA, protein or immune cells e.g. a nucleic acid, protein, peptide, multimer, synthetic chemical, small chemical molecule, ligand mimetic, antibody, antibody derivative, antibody fragment (e.g. Fab) or other agent capable of detecting the number or activity of immune cells or level of proteins expressed by immune cells.
  • an immune response can be determined by measuring immune cell (e.g. B cell, T cell, macrophage, monocyte, dendritic cell etc.) stimulation, activation, proliferation, number and activity.
  • the kit can further include assay containers (tubes), buffers, or enzymes necessary for carrying out the detection assay.
  • Other components in a kit can include, DNA sequencing assay components, Taqman ® genotyping assay components, Meta Analysis, one or more detection system(s), one or more control samples or a combination thereof.
  • kits of the present invention include an agent that can detect the presence of a B cell generating autoantibodies.
  • the kit includes an agent that can detect B cells generating autoantibodies wherein the autoantibodies are against a protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof,
  • the kit includes components to examine more than one immune response marker.
  • the kit can include marker detection agents, such as marker specific primers or probes attached to an addressable array.
  • Exemplary markers include T cells, B cells cytokines, or immune response associated cells or proteins.
  • the genetic sequence of the markers is detected instead of the expression level of the markers.
  • the stimulation, activation, proliferation, or activity of markers is detected.
  • the kit includes one or more protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • the kit includes one or more protein, including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof to detect the level of immune cell response in the biological sample.
  • the kit includes a multimer (e.g.
  • a tetramer or dextramer comprising a protein, including but not limited to a glial protein, one or more proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the kit comprises an antibody or antibody fragment or derivative (e.g. Fab) that can bind one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the kit may include one or more antibodies or antibody fragments or derivatives (e.g. a panel of antibodies and/or antibody fragments and/or antibody derivatives) each of which binds different peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the kit also includes means to measure B cell and/or T cell stimulation, proliferation, differentiation, number or activity.
  • the kit includes means to measure autoreactive immune cells (e.g. B cell and T cells) including for example immune cells reactive to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the kit includes means to measure autoantibodies to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the kit includes antibodies to detect the presence or amount of mediators immune cell activity (e.g. T cell activity) or cytokines in the biological sample.
  • the diagnostic kit comprises one or more reagents that can detect biomarkers of particular interest, which result from a brain injury, disorder or disease. These reagents are specifically selected for the desired biomarker indication.
  • the biomarkers are generally located on an exterior surface of a component of a biological sample or are extracellular.
  • the biomarkers comprise unique configurations and binding mechanisms allowing for a directed selection through specific corresponding reagents.
  • the diagnostic kit has one or more reagents wherein the one or more reagents detect the presence of a biomarker in the biological sample. These reagents are configured to detect the quantity of the biomarker in a biological sample.
  • the biological samples can be taken at one point in time, or at one point in time then subsequent times.
  • the diagnostic kit has one or more reagents to bind the IC.
  • the diagnostic kit contains a first reagent to bind the protein or peptide in the IC and a second reagent to bind the antibody of the IC that is binding the protein or peptide wherein the binding of the second reagent to the antibody is measured to determine the presence or amount of an IC.
  • the diagnostic kit contains a reagent to bind one or more complement proteins bound to one or both of the protein, peptide or autoantibody in the IC.
  • the diagnostic kit has at least one reagent for detecting an IC comprising one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the diagnostic kit further comprises a least one reagent for detecting one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof, a cytokine generated in response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20,or a modification, subsequence, homologue, variant or derivative thereof or an autoantibody to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the diagnostic kit has at least one reagent for detecting one or more IC comprising one or more of one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof and an autoantibody to one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the diagnostic kit further comprises a least one reagent for detecting one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, a cytokine generated in response to one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof or an autoantibody to one or more of the peptides listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof.
  • a reagent is configured to not target specific regions of the biomarker, for example known epitopes of the biomarker. These specific regions are known to exist and the reagent will selectively avoid them to target desired regions existing on the biomarker (e.g. protein, peptide or antigen), for example during a breach of the BBB during or after a TBI.
  • specific regions e.g. protein, peptide or antigen
  • the diagnostic kit has reagents for the detection of the biomarkers of interest individually or in combination.
  • the diagnostic kit has reagents for detecting an IC and protein; IC and cytokine; IC and autoantibody; IC, protein and cytokine; IC, protein and autoantibody; or IC, cytokine and autoantibody.
  • the reagent for detecting the IC is a protein, antibody, antibody fragment, or antibody derivative (e.g. Fab) that binds the IC.
  • the reagent for detecting a cytokine is an antibody that binds the cytokine.
  • the reagent for detecting an autoantibody is a protein or peptide that binds the autoantibody.
  • the reagent for detecting the protein is a protein, antibody, antibody fragment, or antibody derivative (e.g. Fab) that binds the protein.
  • the kit may also include at least one vial, test tube, flask, bottle, syringe or other container means, into which the testing agent, can be suitably reacted or aliquoted.
  • Kits can also include components for comparing results such as a suitable control sample, for example a positive and/or negative control.
  • the kit can also include a collection device for collecting and/ or holding the sample from the subject.
  • the collection device can include a sterile swab or needle (for collecting bodily fluids), and/or a sterile tube (e.g., for holding the swab or a bodily fluid sample).
  • kits for treating a subject who has or may be at risk of developing a brain injury or disease or disorder associated with a brain injury by administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • the present invention provides methods of treating a subject who has or may be at risk of developing a brain injury or disease or disorder associated with a brain injury by administering to the subject a therapeutically effective amount of IVIG or a fraction or active ingredient thereof.
  • the present invention provides methods of treating a subject who has or may be at risk of developing a brain injury or disease or disorder associated with a brain injury by administering to the subject a therapeutically effective amount of modified IVIG or a modified fraction or modified active ingredient of IVIG.
  • the IVIG is modified to produce higher yield of IVIG or specific activity or therapeutic utility of IVIG.
  • IVIG is modified to remove particular components, e.g. antibodies, immune complexes, cytokines, ligands for Fc receptors, complement, albumin and clotting factors.
  • One non- limiting example is modified IVIG for which autoantibodies have been removed.
  • modified IVIG in which autoantibodies against one or more proteins listed in Table 1 or Table 2, or one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof have been removed.
  • the method comprises administration of IVIG, or a fraction or active ingredient thereof wherein an active ingredient has been modified.
  • the method comprised administering modified antibodies, immune complexes, cytokines, complement, albumin and clotting factors.
  • Modifying of IVIG may include modifying or removing regions or parts of an active ingredient or adding regions or elements to the active ingredient.
  • a modifying an active ingredient of IVIG is modifying or removing the Fab or Fc regions of immunoglobulins.
  • an active ingredient can be modified by glycosylation.
  • IVIG may be administered through intravenous, subcutaneous or intramuscular routes.
  • IVIG include HyQvia®, Hizentria®, Gamunex-C®, Gammaked®, Flebogamma®, Gamunex®, Privigen®, Gammagard®, Venoglobulin®, Gammimune®, Sandoglobulin®, Gammar®, Ivegaam®, Globuman®, Gammabulin®, Liogamma®, Boehrigamma® and Umangamma®.
  • the brain injury or disease or disorder associated with a brain injury is associated with increased activity of one or more type of immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • one or more type of immune cell or immune protein e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines
  • the increased expression of one or more type of immune cell or immune protein e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines
  • a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies e.g.
  • autoantibodies to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof) is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increase production or activity of cytokines is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increase in activity or expression of immune cells or proteins results from an immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the immune response is an innate immune response.
  • the immune response is an adaptive immune response.
  • an increased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • an increased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the brain injury or disease or disorder associated with a brain injury is associated with decreased activity of one or more type of immune cell or immune protein (e.g.
  • T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased expression of one or more type of immune cell or immune protein e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines
  • the decreased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decreased stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies e.g. autoantibodies to one or more of the proteins listed in Table 1 or Table 2, or a modification, subsequence, homologue, variant or derivative thereof
  • the decreased production or activity of cytokines is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the decrease in activity or expression of immune cells or proteins results from an immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response.
  • a decreased stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • a decreased stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • the increased expression or activity of a first immune cell or immune protein and the decreased expression or activity of a second immune cell or immune protein is associated with brain injury or a risk of developing brain injury or an associated disease or disorder.
  • a modulation in the expression or activity of autoreactive immune cells is associated with brain injury or an associated disease or disorder or risk of developing brain injury or an associated disease or disorder.
  • a modulation in the expression or activity of autoreactive immune cells e.g. T cells or B cells
  • a modulation in the expression or activity of autoreactive immune cells that are reactive to one or more proteins or peptides including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, is associated with brain injury or an associated disease or disorder or risk of developing brain injury or an associated disease or disorder.
  • the method is a method of treating a subject who has a brain injury or an associated disease or disorder by administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • the method is a method of treating a subject who may be at risk of developing a brain injury or an associated disease or disorder by administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • Non-limiting examples of conditions, diseases or disorder that may be associated with brain injury include mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • brain injury or a risk of developing brain injury or an associated disease or disorder is associated with increased stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies.
  • the B cells generate autoantibodies against one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the agent is an agonist of one or more immune cells or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, immune cell mediators, cytokines) or a combination thereof.
  • the agent is an antagonist of one or more immune cells or immune proteins (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof.
  • the agent is an agonist for a first immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) and an antagonist for a second immune cell or immune protein (e.g. T cells, B cells,
  • the agent is an agonist or antagonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) immune cells or immune proteins (e.g. T cells, B cells,
  • the method comprises administering to the subject an agonist or antagonist of T cell stimulation, activation, proliferation, number or activity, or a combination thereof. In some embodiments, the method comprises administering to the subject an agonist or antagonist of B cell stimulation, activation, proliferation, number or activity, or a combination thereof. In some embodiments, the method comprises administering to the subject and agonist or antagonist of activation, proliferation, number or activity, or a combination thereof, of autoreactive immune cells (e.g. B cells or T cells). In certain embodiments, the method comprises administering to the subject and agonist or antagonist of autoreactive immune cells wherein the
  • autoreactive immune cells are reactive to one or more proteins or peptides including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • B cells and/or T cells are completely depleted in the subject.
  • B cells and/or T cells are partially depleted in a subject.
  • autoreactive immune cells are partially or completely depleted in a subject.
  • autoreactive immune cells that are reactive to one or more proteins or peptides including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • methods of treatment comprising administering a multimer to deplete immune cells in a subject.
  • the methods comprise administering multimers comprising one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof, to deplete immune cells (e.g. T cells).
  • the methods comprise use of the multimers to deplete immune cells that are specific for a protein or peptide including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the methods of treatment presently described comprises administering to the subject an agonist or antagonist of activation
  • the method comprises administering to the subject an agonist or antagonist of production or activity, or a combination thereof, of mediators of immune cell activity e.g. cytokines.
  • the method comprises administering to the subject an agonist or antagonist of activity or expression of immune cells or immune proteins in response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises
  • the method comprises administering to the subject an agonist or antagonist of an innate immune response.
  • the method comprises administering to the subject an agonist or antagonist of an adaptive immune response.
  • the method comprises administering to the subject an agonist or antagonist of stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises administering to the subject an agonist or antagonist of stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises administering to the subject an agonist or antagonist of B cells generating autoantibodies to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent is an agonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) immune cells or immune proteins. In some embodiments, the therapeutic agent is an antagonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) immune cells or immune proteins.
  • An agonist is an agent that increases expression, activity and/or one or more functional effects associated with an immune cell or immune protein.
  • An antagonist is an agent that decreases expression, activity and/or one or more functional effects associated with an immune cell or immune protein.
  • the phrase "functional effects" as used herein refers to any parameter that is indirectly or directly under the influence of the immune cell or immune protein, e.g., functional, physical and chemical effects. It includes ligand binding, signal transduction, receptor-ligand interactions, second messenger concentrations, in vitro, in vivo, and ex vivo and also includes other physiologic effects such increases or decreases in immune or inflammatory signals or immune or inflammatory signaling cascades.
  • the method including administering to the subject a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • the method further includes, prior to said administering, determining whether a subject has an increased or decreased immune response in comparison to a suitable control, including but not limited to increased or decreased immune protein or immune cell expression or activity.
  • the method involves determining if the subject has increased or decreased T cell or B cell stimulation, activation, proliferation or cytokine activity or production.
  • the method involves determining if the subject has increased or decreased T cell or B cell stimulation, activation, proliferation or cytokine activity or production in response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the increased or decreased immune response is an innate immune response.
  • the increased or decreased immune response is an adaptive immune response.
  • the method further includes administering the agent in combination with a second therapeutic agent.
  • the second therapeutic agent is selected from a disease-modifying drug known in the art, including but not limited drugs for the treatment of mild cognitive impairments (MCI's), chronic traumatic encephalopathy (CTE), mild traumatic brain injury, and post-concussion syndrome (PCS).
  • MCI's mild cognitive impairments
  • CTE chronic traumatic encephalopathy
  • PCS post-concussion syndrome
  • the subject is administered a combination of agents including known anti-inflammatory or immunosuppressive drugs, (e.g. anti-T F agent, anti-cytokine agent, statin, anti-chemokines, anti-integrins or flavonoids).
  • agents including known anti-inflammatory or immunosuppressive drugs, (e.g. anti-T F agent, anti-cytokine agent, statin, anti-chemokines, anti-integrins or flavonoids).
  • an agent described herein can be administered in combination with a second agent, drug or treatment, such as an antiinflammatory, immunosuppressive drug or treatment.
  • the present methods comprise administration of IVIG, or a fraction or active ingredient thereof, or modified IVIG or a modified fraction or modified active ingredient of IVIG in combination with an antibody, antibody fragment, or antibody derivative (e.g. Fab).
  • the antibody, antibody fragment, or antibody derivative e.g. Fab
  • Fab binds one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the modified IVIG or a modified fraction or modified active ingredient of IVIG comprises an antibody, antibody fragment, antibody derivative (e.g.
  • Fab for example an antibody, antibody fragment, or antibody derivative that binds one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the present methods comprise administration of IVIG fraction or active ingredient thereof, or modified IVIG or a modified fraction or modified active ingredient of IVIG, wherein the IVIG, or fraction or active ingredient thereof, or modified IVIG or modified fraction or modified active ingredient of IVIG, in combination with one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method comprises administration of the IVIG, or fraction or active ingredient thereof, or modified IVIG or modified fraction or modified active ingredient of IVIG, in combination with one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof for specific immunotherapy or allergy immunotherapy treatment.
  • the modified IVIG or a modified fraction or modified active ingredient of IVIG comprises one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • Agents as described herein can be used alone, sequentially, or in combination according to the methods described herein.
  • agent is used in combination with one or more other drug or treatment, e.g. agonist or antagonist of an immune protein or immune cell, anti-inflammatory or immunosuppressive agent.
  • the subject has suffered one or more brain injuries, concussion, traumatic incidents or insults to the brain.
  • the subject has suffered one or more brain injuries, concussions, traumatic incidents or insults to the brain prior to treatment in accordance with the methods of the present invention or administration of the compositions of the present invention.
  • the subject is administered a pharmaceutical composition as described herein.
  • the methods of treatment presently described comprises administering an antibody fragment or derivative (e.g. Fab) that blocks binding of an autoantibody to one or more proteins or peptides including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification,
  • an antibody fragment or derivative e.g. Fab
  • the antibody fragment or derivative administered competes with autoantibodies for binding to one or more proteins or peptides including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • a subject with a brain injury or an associated disease or disorder is administered one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the subject with the brain injury or associated disease or disorder may be administered one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof in order to modulate immune response, including for example inducting immune tolerance, in the subject against the one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or subsequence, homologue, variant or derivative thereof.
  • Such methods would incorporate methods comparable to those known in the art for antigen-specific immunotherapy.
  • the method or composition for treating a subject with a brain injury or an associated disease or disorder comprises two or more proteins, peptides or epitopes including but not limited to the proteins listed in Table 1 or Table 2, the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the method or composition comprises peptides or epitopes derived from two or more of the proteins listed in Table 1 or Table 2.
  • the method or composition for treating a subject with a brain injury or an associated disease or disorder comprises peptides or epitopes from two or more, three or more, four or more, or five different proteins listed in Table 1 or Table 2.
  • each T cell epitope binds only a subset of naturally occurring HLA Class II molecules in the human population and this repertoire of HLA Class II molecules varies from one person to another and from one ethnic population to another
  • it is desirable to select peptides that elicit an immune response e.g. T cell response or an immune response (e.g. T cell response) in a significant fraction of subjects.
  • an epitope or combination of epitopes that have a ULA Class II repertoire covering a high fraction of a worldwide population, which also produce an immune response (e.g. T cell response) and which also produce an immune response (e.g. T cell response) in a significant fraction of subjects with the disease, disorder or condition to be treated.
  • an immune response e.g. T cell response
  • an immune response e.g. T cell response
  • the methods or compositions of the present invention it is desirable for the methods or compositions of the present invention to include as few peptides as possible, but at the same time to be able to treat the majority of patients in a worldwide population with the same method or composition.
  • Such a method or composition should contain a combination of peptides capable of binding to a ULA Class II repertoire covering a high fraction of a worldwide population, and the resulting peptide-HLA complexes should be recognized as epitopes (e.g. T cell epitopes) in the subject so as to induce an immune response.
  • compositions for treating a subject who has or may be at risk of developing a brain injury or an associated disease or disorder and methods for treating a subject who has or may be at risk of developing a brain injury or an associated disease or disorder by administering the pharmaceutical compositions described herein to the subject.
  • the pharmaceutical compositions described herein are administered to the subject.
  • compositions described herein comprise a therapeutically effective amount of an agent as described herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions are for treating a subject who has a brain injury or an associated disease or disorder by administering to the subject a pharmaceutical composition including a therapeutically effective amount of an agent and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions are for treating a subject who may be at risk of developing a brain injury or an associated disease or disorder by administering to the subject a pharmaceutical composition including a therapeutically effective amount of an agent and a
  • the associated disease or disorder comprises mild cognitive impairments (MCI's), chronic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary
  • CTE encephalopathy
  • PCS post-concussion syndrome
  • the pharmaceutical composition comprises an agent that is a therapeutic agent.
  • the therapeutic agent is an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, or protein.
  • the therapeutic agent modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response.
  • the therapeutic agent modulates stimulation, activation proliferation, number or activity of immune proteins or cells (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines etc.)
  • the therapeutic agent modulates an innate immune response.
  • the therapeutic agent modulates a adaptive immune response.
  • the therapeutic agent modulates an immune response to one or more of the proteins listed in Table 1 or Table 2, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent when administered to a subject treats brain injury or an associated disease or disorder when administered to a subject in a therapeutically effective dose or amount.
  • the therapeutic agent is an agent that binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof (e.g. an antibody, antibody fragment, or antibody derivative (e.g. Fab)).
  • the agent or therapeutic agent is IVIG, or a fraction or active ingredient thereof, or modified IVIG or a modified fraction or modified active ingredient of IVIG.
  • IVIG include HyQvia®, Hizentria®, Gamunex-C®, Gammaked®, Flebogamma®, Gamunex®, Privigen®, Gammagard®, Venoglobulin®, Gammimune®, Sandoglobulin®, Gammar®, Ivegaam®, Globuman®, Gammabulin®, Liogamma®, Boehrigamma® and Umangamma®.
  • the pharmaceutical composition comprises an agent described herein in combination with a second agent, drug or treatment, such as an anti-inflammatory, immunosuppressive drug or treatment.
  • the present compositions comprise IVIG, or a fraction or active ingredient thereof, or modified IVIG or a modified fraction or modified active ingredient of IVIG, in combination with an antibody, antibody fragment, or antibody derivative (e.g. Fab).
  • an antibody, antibody fragment, or antibody derivative e.g. Fab
  • the antibody, antibody fragment, or antibody derivative binds one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification
  • the present compositions comprise IVIG, or a fraction or active ingredient thereof, or modified IVIG or a modified fraction or modified active ingredient of IVIG, wherein the IVIG, or fraction or active ingredient thereof, or modified IVIG or modified fraction or modified active ingredient of IVIG, comprises one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the composition comprises the IVIG, or fraction or active ingredient thereof, or modified IVIG or modified fraction or modified active ingredient of IVIG, comprising one or more of the proteins in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof and the composition is for use in specific immunotherapy or allergy immunotherapy treatment.
  • the therapeutic agent disrupts the interaction between an immune cell or immune protein and a physiological or natural ligand. In some embodiments, the therapeutic agent binds a physiological or natural ligand of the immune cell or immune protein. In some embodiments, the therapeutic agent binds the complex an immune cell or immune protein bound to a ligand. In some embodiments, the therapeutic agent disrupts the interaction between an immune cell or immune protein and one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent binds an immune cell or immune protein that interacts with one or more of the proteins listed in Table 1 or Table 2, or a modification, subsequence, homologue, variant or derivative thereof. In some embodiments, the therapeutic agent binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof. In some embodiments, the therapeutic agent binds the complex of an immune cell or immune protein bound to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent modulates the activity or expression of one or more type of immune cell or protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof.
  • the therapeutic agent modulates the stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof.
  • the therapeutic agent modulates the stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof.
  • the therapeutic agent modulates stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies (e.g. autoantibodies to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof).
  • the therapeutic agent completely or partially depletes immune cells in the subject (e.g. B cells or T cells). In some embodiments, the therapeutic agent completely or partially depletes autoreactive immune cells.
  • the therapeutic agent completely or partially depletes autoreactive immune cells that are reactive to one or more proteins or peptides including but not limited to a glial protein, one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent modulates production or activity of mediators of immune activity (e.g. cytokines).
  • mediators of immune activity e.g. cytokines
  • the therapeutic agent modulates activity or expression of immune cells or proteins involved in an immune response to one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the immune response is an innate immune response. In other embodiments, the immune response is an adaptive immune response.
  • the therapeutic agent modulates stimulation of T cells, activation of T cells, proliferation of T cells, number of T cells or activity of T cells, or a combination thereof, wherein the T cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent modulates stimulation of B cells, activation of B cells, proliferation of B cells, number of B cells or activity of B cells, or a combination thereof, wherein the B cells are specific for one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent modulates stimulation, activation, proliferation, number or activity, or a combination thereof, of B cells generating autoantibodies.
  • the therapeutic agent is an agonist of one or more immune cells or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof.
  • the therapeutic agent is an antagonist of one or more immune cells or immune proteins (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) or a combination thereof.
  • the therapeutic agent is an agonist for a first immune cell or immune protein (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines) and an antagonist for a second immune cell or immune protein (e.g.
  • the therapeutic agent is an antagonist or agonist for one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) immune cells or immune proteins (e.g. T cells, B cells, macrophages, monocytes, dendritic cells, cytokines).
  • the therapeutic agent is selected from an antibody, antibody fragment, antibody derivative (e.g. Fab), nucleic acid, synthetic chemical, multimer, small chemical molecule, ligand mimetic, peptide, or protein.
  • the therapeutic agent is an antibody, antibody fragment, or antibody derivative (e.g. Fab).
  • the pharmaceutical composition includes an antibody, antibody fragment, or antibody derivative (e.g. Fab) and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition include an antibody, antibody fragment, or antibody derivative (e.g. Fab) that binds one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the therapeutic agent is an anti-inflammatory or immunosuppressive drugs, (e.g. anti-TNF agent, anti-cytokine agent, statin, anti-chemokines, anti-integrins or flavonoids).
  • the therapeutic agents is Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin, Ezetimibe/simvastatin, Pitavastatin, Cerivastatin, Mevastatin, Atorvastatin/amlodipine, Niacin/simvastatin, Niacin/lovastatin, Simvastatin/sitagliptin, 3,6'-dithiothalidomide or Enzogenol,
  • anti-inflammatory or immunosuppressive drugs e.g. anti-TNF agent, anti-cytokine agent, statin, anti- chemokines, anti-
  • the pharmaceutical composition is useful for treating for treating a subject who has or may be at risk of developing a brain injury or an associated disease or disorder.
  • the pharmaceutical compositions are useful for treating an for treating a subject who has or may be at risk of developing a brain injury or an associated disease or disorder by administering to the subject a pharmaceutical composition including a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions are for treating a subject who may be at risk of developing a brain injury or an associated disease or disorder by administering to the individual to the subject a pharmaceutical composition including a therapeutically effective amount of an agent that modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an acute or chronic immune response and a
  • brain injury or associated disease or disorder is mild cognitive impairments (MCI's), chronic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic traumatic pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary pulmonary
  • CTE encephalopathy
  • mild traumatic brain injury CTE
  • post-concussion syndrome CTE
  • compositions disclosed herein can be administered by any means known in the art.
  • compositions may include administration to a subject intravenously, intradermally, intraarterially, intraperitoneally, intralesionally,
  • Administration can be local or systemic.
  • Solutions of the active compounds as free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
  • compositions can be delivered via intranasal or inhalable solutions or sprays, aerosols or inhalants.
  • Nasal solutions can be aqueous solutions designed to be administered to the nasal passages in drops or sprays.
  • Nasal solutions can be prepared so that they are similar in many respects to nasal secretions.
  • the aqueous nasal solutions usually are isotonic and slightly buffered to maintain a pH of 5.5 to 6.5.
  • antimicrobial preservatives similar to those used in ophthalmic preparations, and appropriate drug stabilizers, if required, may be included in the formulation.
  • Various commercial nasal preparations are known and can include, for example, antibiotics and antihistamines.
  • Oral formulations can include excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.
  • oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds may be
  • compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75% of the weight of the unit, or preferably between 25-60%.
  • the amount of active compounds in such compositions is such that a suitable dosage can be obtained.
  • aqueous solutions for parenteral administration in an aqueous solution, for example, the solution should be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • Aqueous solutions in particular, sterile aqueous media, are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion.
  • Sterile injectable solutions can be prepared by incorporating the active compounds or constructs in the required amount in the appropriate solvent followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle, which contains the basic dispersion medium. Vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredients, can be used to prepare sterile powders for reconstitution of sterile injectable solutions.
  • the preparation of more, or highly, concentrated solutions for direct injection is also contemplated.
  • DMSO can be used as solvent for extremely rapid penetration, delivering high concentrations of the active agents to a small area.
  • the invention provides methods of treating and/or ameliorating brain injury or associated disease or disorder in a subject in need thereof.
  • the course of treatment is best determined on an individual basis depending on the particular characteristics of the subject and the type of treatment selected.
  • the treatment such as those disclosed herein, can be administered to the subject on a daily, twice daily, biweekly, monthly or any applicable basis that is therapeutically effective.
  • the treatment can be administered alone or in combination with any other treatment disclosed herein or known in the art.
  • the additional treatment can be administered simultaneously with the first treatment, at a different time, or on an entirely different therapeutic schedule (e.g., the first treatment can be daily, while the additional treatment is weekly).
  • Administration of a composition for treating a brain injury or associated disease or disorder can be a systemic or localized administration.
  • treating a subject having a brain injury or associated disease or disorder can include administering an oral or injectable form of a therapeutic agent as described herein on a daily basis or otherwise regular schedule.
  • the treatment is only on an as-needed basis, e.g., upon occurrence of a concussion or traumatic incident or insult to the brain or during or after participation in a particular activity, for example a physical activity where there is a likelihood a subject will experience a concussion or insult the brain.
  • the pharmaceutical composition is administered to the subject after a brain injury, concussion or a traumatic incident or insult to the brain.
  • the pharmaceutical composition is administered to the subject simultaneously with a brain injury, concussion or a traumatic incident or insult to the brain.
  • the methods and compositions of the present invention comprise administering an optimized package comprising one or more antigens.
  • the optimized package included one or more epitopes from an antigen that elicits an immune response following brain injury e.g. one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the optimized package comprises one or more CD4 or CD8 T cell epitopes, for example, one or more of the epitopes listed in any of Tables 3 to 20 or a modification, subsequence, homologue, variant or derivative thereof.
  • the optimized package contains epitopes selected for their broad recognition by HLA molecules of subjects from diverse ethnic and geographically backgrounds.
  • the method and compositions of the present invention comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty of more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the peptides are derived from one or more different proteins, including for example the proteins listed in Table 1 or Table 2, or a modification, subsequence, homologue, variant or derivative thereof.
  • first, second, third, fourth, fifth, etc. predictor gene or a “positive or negative predictor gene” includes a plurality of such first, second, third, fourth, fifth, etc., genes, or a plurality of positive and/or negative predictor genes.
  • Reference to a number with more (greater) or less than includes any number greater or less than the reference number, respectively.
  • a reference to less than 30,000 includes 29,999, 29,998, 29,997, etc. all the way down to the number one (1); and less than 20,000, includes 19,999, 19,998, 19,997, etc. all the way down to the number one (1).
  • Reference to a range ofl-5 fold therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.
  • Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series.
  • 2-72 hours, 2-48 hours, 4-24 hours, 4-18 hours and 6-12 hours includes ranges of 2-6 hours, 2-18 hours, 2-24 hours, etc., and 4-27 hours, 4-48 hours, 4-6 hours, etc.
  • the invention is generally disclosed herein using affirmative language to describe the numerous embodiments and aspects.
  • the invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, or procedures.
  • materials and/or method steps are excluded.
  • the invention is generally not expressed herein in terms of what the invention does not include aspects that are not expressly excluded in the invention are nevertheless disclosed herein.
  • a blood sample is obtained from a subject that is believed to have suffered a concussion.
  • T cells and B cells are isolated from the blood of the concussed individual.
  • the cells are plated with one or more of the proteins listed in Table 1 or Table 2, or a modification, subsequence, homologue, variant or derivative thereof and re-activity of the T cells and/or B cells is measured e.g. through measurement of T cell and/or B cell proliferation, cytokine production etc.
  • the blood sample is optionally exposed to antibodies that detect modified proteins derived from glial or neuronal cell, modified forms one or more of the proteins listed in Table 1 or Table 2, modified forms one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof or the presence of mediators of immune cell activity and the level of expression of such modified proteins, peptides, or mediators of immune cell activity is measured by methods known in the art.
  • the activation of the adaptive immune system is inhibited through the administration of an antibody, antibody fragment or antibody derivative (e.g. Fab) targeted against proteins and peptides released during a concussion, traumatic incident or insult to the brain.
  • Antibodies, antibody fragments and antibody derivatives include those that bind one or more of the proteins listed in Table 1 or Table 2, one or more of the peptides listed in any of Tables 3 to 20, or a modification, subsequence, homologue, variant or derivative thereof.
  • the antibodies, antibody fragments and antibody derivatives are administered to the subject and bind the relevant proteins or peptides to block T cells and B cells from becoming activated by these antigenic proteins.

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Abstract

L'invention concerne des compositions, des dispositifs, des kits et des méthodes pour le diagnostic et le traitement d'une lésion cérébrale. Certains agents permettent de détecter, d'inhiber, de supprimer, de neutraliser ou de moduler une réponse immunitaire aiguë ou chronique associée à une lésion cérébrale.
PCT/US2017/019551 2016-04-08 2017-02-25 Compositions et méthodes de diagnostic et de traitement d'une lésion cérébrale Ceased WO2017176385A1 (fr)

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JP2023502198A (ja) * 2019-11-25 2023-01-23 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 診断及び処置のための抗原ニューロン特異的エノラーゼペプチド
JP7770314B2 (ja) 2019-11-25 2025-11-14 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 診断及び処置のための抗原ニューロン特異的エノラーゼペプチド
WO2024054987A1 (fr) * 2022-09-08 2024-03-14 The Children's Hospital Of Philadlphia Gpcr latrophiline-3 utilisé en tant que biomarqueur pour détecter un risque accru de lésion cérébrale légère et méthodes d'utilisation associées pour le diagnostic et le traitement de celui-ci

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