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 hybridomaTOL101 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. The present invention also provides methods of treating inflammatory and/or autoimmune disease, and/or transplanted tissue rejection using a therapeutic amount of ex vivo expanded regulatory T-cells.

1 . A method for ex vivo expansion of regulatory T cells comprising:
 (i) obtaining peripheral blood cells from a patient or donor; and   (ii) culturing the peripheral blood cells in vitro in media comprising anti-αβTCR antibody or fragment thereof.   
     
     
         2 . The method of  claim 1 , wherein the anti-αβTCR antibody is the antibody produced by TOL101 MCB. 
     
     
         3 . The method of  claim 1 , wherein the anti-αβ TCR antibody or antigen binding fragment thereof preferentially binds to the alpha chain of the TCR. 
     
     
         4 . The method of  claim 1 , wherein the peripheral blood cells are cultured in the presence of increasing concentrations of anti-αβTCR antibody. 
     
     
         5 . A method for treating or preventing an inflammatory disease, autoimmune disease, or transplant tissue rejection comprising administering a therapeutically effective amount of ex vivo expanded regulatory T-cells to a patient in need thereof, wherein the regulatory T-cells are expanded ex vivo by an anti-αβTCR antibody or antigen binding fragment thereof. 
     
     
         6 . The method according to  claim 5 , wherein the anti-αβTCR antibody is the antibody produced by TOL101 MCB. 
     
     
         7 . The method of  claim 5 , wherein the anti-αβ TCR antibody or antigen binding fragment thereof is glycosylated at equivalent or corresponding amino acid residues as the antibody produced by the hybridoma TOL101 MCB. 
     
     
         8 . The method of  claim 5 , wherein the anti-αβ TCR antibody or antigen binding fragment thereof is comprises the three light chain complementarity determining regions (CDRL1, CDRL2 and CDRL3) and the three heavy chain complementarity determining regions (CDRH1, CDRH2 and CDRH3) of the antibody produced by the hybridoma TOL101 MCB. 
     
     
         9 . The method of  claim 5 , wherein the anti-αβ TCR antibody or fragment thereof comprises an amino acid sequence according to SEQ ID NOs: 6, 7, and 8. 
     
     
         10 . The method of  claim 5 , wherein the anti-αβ TCR antibody or antigen binding fragment thereof preferentially binds to the alpha chain of the TCR. 
     
     
         11 . The method of  claim 5 , wherein the peripheral blood cells are cultured in the presence of increasing concentrations of anti-αβTCR antibody. 
     
     
         12 . The method according to  claim 5 , 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 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. 
     
     
         13 . The method according to  claim 5 , wherein the autoimmune disease is Type 1 Diabetes Mellitus or Multiple Sclerosis. 
     
     
         14 . The method according to  claim 5 , wherein the transplanted tissue rejection comprises organ graft rejection or graft-versus-host disease. 
     
     
         15 . The method according to  claim 5 , wherein the ex vivo expanded regulatory T-cells are administered to the patient prior to, during, or after a tissue transplant surgery. 
     
     
         16 . The method according to  claim 15 , wherein the tissue transplant surgery is a solid organ transplant surgery. 
     
     
         17 . The method according to  claim 5 , wherein the regulatory T-cells are expanded ex vivo in the presence of an antigen. 
     
     
         18 . 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 ex vivo expanded regulatory T-cells cells to a patient in need thereof, wherein the regulatory T-cells are expanded ex vivo by an anti-αβTCR antibody or antigen binding fragment thereof. 
     
     
         19 . The method according to  claim 18 , wherein the anti-αβTCR antibody is the antibody produced by TOL101 MCB. 
     
     
         20 . The method of  claim 18 , wherein the anti-αβ TCR antibody or antigen binding fragment thereof is glycosylated at equivalent or corresponding amino acid residues as the antibody produced by the hybridoma TOL101 MCB. 
     
     
         21 . The method of  claim 18 , wherein the anti-αβ TCR antibody or antigen binding fragment thereof is comprises the three light chain complementarity determining regions (CDRL1, CDRL2 and CDRL3) and the three heavy chain complementarity determining regions (CDRH1, CDRH2 and CDRH3) of the antibody produced by the hybridoma TOL101 MCB. 
     
     
         22 . The method of  claim 18 , wherein the anti-αβ TCR antibody or fragment thereof comprises an amino acid sequence according to SEQ ID NOs: 6, 7, and 8. 
     
     
         23 . The method of  claim 18 , wherein the anti-αβ TCR antibody or antigen binding fragment thereof preferentially binds to the alpha chain of the TCR. 
     
     
         24 . The method of  claim 18 , wherein the peripheral blood cells are cultured in the presence of increasing concentrations of anti-αβTCR antibody. 
     
     
         25 . The method according to  claim 18 , 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 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. 
     
     
         26 . The method according to  claim 18 , wherein the autoimmune disease is Type 1 Diabetes Mellitus or Multiple Sclerosis. 
     
     
         27 . The method according to  claim 18 , wherein the transplanted tissue rejection comprises organ graft rejection or graft-versus-host disease. 
     
     
         28 . The method according to  claim 18 , wherein the ex vivo expanded regulatory T-cells are administered to the patient prior to, during, or after a tissue transplant surgery. 
     
     
         29 . The method according to  claim 28 , wherein the tissue transplant surgery is a solid organ transplant surgery. 
     
     
         30 . The method according to  claim 18 , wherein the regulatory T-cells are expanded ex vivo in the presence of an antigen.