Antibody and methods for selective inhibition of t-cell responses

Abstract

The present invention provides compositions, methods, and assays for treating an inflammatory and/or autoimmune disease, and/or transplanted tissue rejection using anti-αβ TCR antibodies and antibody fragments. Anti-αβ TCR antibodies are antibodies which bind to a αβ TCR. Anti-αβ TCR antibodies produced by the hybridoma TOL101 MCB are also provided. Methods for treatment of an inflammatory disease, an autoimmune disease and for tissue transplant rejection using therapeutic dosing regimen of anti-αβ TCR antibodies and antibody fragments and for upregulating the numbers of Treg T-cells are also provided

1 - 10 . (canceled) 
     
     
         11 . A method of inhibiting a T cell immune response in an inflammatory disease, autoimmune disease, or transplanted tissue rejection, the method comprising administering a therapeutically effective amount of an anti-αβ TCR antibody or antigen binding fragment thereof to a subject in need thereof. 
     
     
         12 . The method according to  claim 11 , wherein the inflammatory disease, autoimmune disease or transplanted tissue rejection is selected from the group consisting of: asthma, allergy, allergic airway inflammation, allergic encephalomyelitis, autoimmune arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, reactive arthritis, psoriatic arthritis, sacroiliitis, isolated acute anterior uveitis, undifferentiated spondyloarthropathy, Type 1 Diabetes Mellitus, Multiple Sclerosis, Systemic Lupus Erythematosus, glomerulonephritis, Hashimoto's thyroiditis, Graves' disease, Scleroderma, Celiac disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis, Sjogren's syndrome, psoriasis, contact dermatitis, Goodpasture's syndrome, Addison's disease, Wegener's granulornatosis, Primary biliary cirrhosis, Sclerosing cholangitis, Autoimmune hepatitis, Polymyalgia Rheumatica, Bechet's disease, Guillain-Barre syndrome, various vasculitides, uveoretinitis, thyroditis, myasthenia gravis, immunoglobulin nephropathies, myocarditis, progressive systemic sclerosis, organ graft rejection, mixed connective tissue rejection, and graft-versus-host disease. 
     
     
         13 . The method according to  claim 12 , wherein the autoimmune disease is Type 1 Diabetes Mellitus or Multiple Sclerosis. 
     
     
         14 . The method according to  claim 12 , wherein the transplanted tissue rejection comprises organ graft rejection or graft-versus-host disease. 
     
     
         15 . The method according to  claim 11 , wherein the anti-αβ TCR antibody is the antibody produced by hybridoma TOL101 MCB deposited with the ATCC under the accession number PTA-13293. 
     
     
         16 . The method according to  claim 11 , wherein the anti-αβ TCR antibody or antigen-binding fragment thereof comprises an amino acid sequence containing SEQ ID NOs: 6, 7, and 8. 
     
     
         17 . The method according to  claim 11 , wherein the anti-αβ TCR antibody or antigen-binding fragment thereof is administered in a dosing schedule comprising: 14 mg at day 1, 21 mg at day 2, 28 mg at day 3, 42 mg at day 4, and 42 mg at day 5. 
     
     
         18 . The method according to  claim 17 , further comprising administering to the subject 42 mg of the anti-αβ TCR antibody or antibody fragment thereof at day 6. 
     
     
         19 . The method according to  claim 11 , wherein the anti-αβ TCR antibody or antibody fragment thereof is administered once per day. 
     
     
         20 . The method according to  claim 11 , wherein the anti-αβ TCR antibody or antibody fragment thereof is administered in an amount of about 7 mg/day to about 58 mg/day. 
     
     
         21 . The method according to  claim 20 , wherein the anti-αβ TCR antibody or antibody fragment thereof is administered in an amount of about 7 mg/day, 14 mg/day, 21 mg/day, 28 mg/day, 30 mg/day, 32 mg/day, 34 mg/day, 35 mg/day, 36 mg/day, 38 mg/day, 40 mg/day, 42 mg/day, 44 mg/day, 46 mg/day, 48 mg/day, 50 mg/day, 52 mg/day, 54 mg/day, 56 mg/day or 58 mg/day, or combinations thereof. 
     
     
         22 . The method according to  claim 11 , wherein the anti-αβ TCR antibody or antibody fragment thereof is administered in an amount of about 14 mg/day. 
     
     
         23 . A method for upregulating T reg  cells in a subject in need thereof, the method comprising administering an anti-αβ TCR antibody or an antigen-binding fragment thereof to the subject. 
     
     
         24 . A method for inducing T reg  cells in a subject in need thereof, the method comprising: administering an anti-αβ TCR antibody or antibody fragment thereof in a dosing schedule comprising: 14 mg at day 1, 21 mg at day 2, 28 mg at day 3, 42 mg at day 4, and 42 mg at day 5. 
     
     
         25 . The method according to  claim 23  or  24 , wherein the T reg  cells are phenotypically CD2+ CD4+ CD25+ FOXP3+ CD127lo. 
     
     
         26 . The method according to  claim 25 , wherein the subject is in need of inhibiting alioreactive T-cells, or inhibiting cytotoxic T-cell (CTL) activity, or immunosuppressing an alloresponse, or inhibiting an autoimmune response, or inhibiting, preventing or blocking an alloresponse or an autoimmune response prior to, during or subsequent to tissue transplantation, or inhibiting, suppressing or blocking graft vs. host disease, or preventing, treating or suppressing an autoimmune response in an inflammatory disease, autoimmune disease or during transplanted tissue rejection. 
     
     
         27 . The method according to  claim 26 , wherein the inflammatory disease, autoimmune disease or transplanted tissue rejection is selected from the group consisting of: asthma, allergy, allergic airway inflammation, allergic encephalomyelitis, autoimmune arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, reactive arthritis, psoriatic arthritis, sacroiliitis, isolated acute anterior uveitis, undifferentiated spondyloarthropathy, Type I Diabetes Mellitus, Multiple Sclerosis, Systemic Lupus Erythematosus, glomerulonephritis, Hashimoto's thyroiditis, Graves disease, Scleroderma, Celiac disease, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ankylosing spondylitis, Sjogren's syndrome, psoriasis, contact dermatitis, Goodpasture's syndrome, Addison's disease, Wegener's granulomatosis, Primary biliary cirrhosis, Sclerosing cholangitis, Autoimmune hepatitis, Polymyalgia Rheumatica, Bechet's disease, Guillain-Barre syndrome, various vasculitides, uveoretinitis, thyroditis, myasthenia gravis, immunoglobulin nephropathies, myocarditis, progressive systemic sclerosis, organ graft rejection, mixed connective tissue rejection, and graft-versus-host disease.