Antibodies that immunospecifically bind to b lymphocyte stimulator

Abstract

The present invention relates to antibodies and related molecules that immunospecifically bind to B Lymphocyte Stimulator. The present invention also relates to methods and compositions for detecting or diagnosing a disease or disorder associated with aberrant B Lymphocyte Stimulator expression or inappropriate function of B Lymphocyte Stimulator comprising antibodies or fragments or variants thereof or related molecules that immunospecifically bind to B Lymphocyte Stimulator. The present invention further relates to methods and compositions for preventing, treating or ameliorating a disease or disorder associated with aberrant B Lymphocyte Stimulator expression or inappropriate B Lymphocyte Stimulator function comprising administering to an animal an effective amount of one or more antibodies or fragments or variants thereof or related molecules that immunospecifically bind to B Lymphocyte Stimulator.

1 . A method of reducing immunoglobulin levels in a mammal comprising administering a BLyS antagonist and an immunosuppressive drug. 
     
     
         2 . The method of  claim 1 , wherein the BLyS antagonist is a Fc-fusion protein. 
     
     
         3 . The method of  claim 2 , wherein the Fc-fusion protein is selected from the group consisting of a TACI-Fc-fusion protein comprising the extracellular domain of TACI or a functional fragment thereof, a BAFF-R-Fc-fusion protein comprising the extracellular domain of BAFF-R or a functional fragment thereof, and a BCMA-Fc-fusion protein comprising the extracellular domain of BCMA or a functional fragment thereof. 
     
     
         4 . The method of  claim 1 , wherein the BLyS antagonist is a BLyS antibody. 
     
     
         5 . The method of  claim 4 , wherein the BLyS antibody binds BLyS within a region comprising amino acids 162-275 of SEQ ID NO: 3228. 
     
     
         6 . The method of  claim 4 , wherein the BLyS antibody is LymphoStat-B. 
     
     
         7 . The method of  claim 1 , wherein the BLyS antagonist is a TACI antibody. 
     
     
         8 . The method of  claim 1 , wherein the TACI antibody binds TACI within a region comprising amino acids selected from the group consisting of 72-109 of Genbank Accession No. AAC51790 and 82-222 of Genbank Accession No. AAC51790. 
     
     
         9 . The method of  claim 8 , wherein the TACI antibody binds both TACI and BCMA. 
     
     
         10 . The method of  claim 1 , wherein the immunosuppressive drug is selected from the group consisting of cyclophosphamide (CYC), azathioprine (AZA), cyclosporine A (CSA), and mycophenolate mofetil (MMF). 
     
     
         11 . The method of  claim 10 , wherein the immunosuppressive drug is mycophenolate mofetil (MMF). 
     
     
         12 . The method of  claim 1 , wherein the BLyS antagonist and the immunosuppressive drug act synergistically to reduce immunoglobulin levels. 
     
     
         13 . The method of  claim 1 , wherein the immunoglobulin level that is reduced is selected from the group consisting of IgM, IgG, IgA, IgD and IgE. 
     
     
         14 . A method of alleviating a B-cell regulated autoimmune disorder comprising administering to a patient suffering from the disorder a therapeutically effective amount of a BLyS antagonist and an immunosuppressive drug. 
     
     
         15 . The method of  claim 14 , wherein the BLyS antagonist is a Fc-fusion protein. 
     
     
         16 . The method of  claim 15 , wherein the Fc-fusion protein is selected from the group consisting of a TACI-Fc-fusion protein comprising the extracellular domain of TACI or a functional fragment thereof, a BAFF-R-Fc-fusion protein comprising the extracellular domain of BAFF-R or a functional fragment thereof, and a BCMA-Fc-fusion protein comprising the extracellular domain of BCMA or a functional fragment thereof. 
     
     
         17 . The method of  claim 14 , wherein the BLyS antagonist is a BLyS antibody. 
     
     
         18 . The method of  claim 14 , wherein the BLyS antibody binds BLyS within a region comprising amino acids 162-275 of SEQ ID NO: 3228. 
     
     
         19 . The method of  claim 14 , wherein the BLyS antibody is LymphoStat-B. 
     
     
         20 . The method of  claim 14 , wherein the BLyS antagonist is a TACI antibody. 
     
     
         21 . The method of  claim 14 , wherein the TACI antibody binds TACI within a region comprising amino acids selected from the group consisting of 72-109 of Genbank Accession No. AAC51790 and 82-222 of Genbank Accession No. AAC51790. 
     
     
         22 . The method of  claim 20 , wherein the TACI antibody binds both TACI and BCMA. 
     
     
         23 . The method of  claim 14 , wherein the immunosuppressive drug is selected from the group consisting of cyclophosphamide (CYC), azathioprine (AZA), cyclosporine A (CSA), and mycophenolate mofetil (MMF). 
     
     
         24 . The method of  claim 23 , wherein the immunosuppressive drug is mycophenolate mofetil (MMF). 
     
     
         25 . The method of  claim 14 , wherein the BLyS antagonist and the immunosuppressive drug act synergistically to reduce immunoglobulin levels. 
     
     
         26 . The method of  claim 14 , wherein the immunoglobulin level that is reduced is selected from the group consisting of IgM, IgG, IgA, IgD and IgE. 
     
     
         27 . The method of  claim 14 , wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), Wegener's disease, inflammatory bowel disease, idiopathic thrombocytopenic purpuria (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes, mellitus, Reynauld's syndrome, Sjorgen's syndrome, glomerulonephritis, autoimmune hepatitis, and autoimmune thyroiditis. 
     
     
         28 . The method of  claim 27 , wherein the autoimmune disease is lupus nephritis. 
     
     
         29 . The method of  claim 14 , the BLyS antagonist is administered at a dosage of about 1 to about 2.5 mg/kg and the immunosuppressive drug is administered at a dosage of about 1 to about 4 mg/kg. 
     
     
         30 . The method of  claim 14 , wherein the BLyS antagonist and the immunosuppressive drug is administered in conjunction with therapy using a second immunosuppressive drug selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoid, prednisone, and disease-modifying antirheumatic drugs (DMARDs). 
     
     
         31 . A composition comprising a BLyS antagonist and an immunosuppressive drug. 
     
     
         32 . An article of manufacture comprising a BLyS antagonist and an immunosuppressive drug, and a label wherein the label indicates that the composition is for treating a B cell regulated autoimmune disorder. 
     
     
         33 . The method of  claim 1 , wherein said BLyS antagonist is also an APRIL antagonist. 
     
     
         34 . The method of  claim 14 , wherein said BLyS antagonist is also an APRIL antagonist. 
     
     
         35 . The composition of  claim 30 , wherein said BLyS antagonist is also an APRIL antagonist. 
     
     
         36 . The article of manufacture of  claim 31 , wherein said BLyS antagonist is also an APRIL antagonist. 
     
     
         37 . A method of reducing immunoglobulin levels in a mammal comprising administering an APRIL antagonist and an immunosuppressive drug. 
     
     
         38 . A method of alleviating a B-cell regulated autoimmune disorder comprising administering to a patient suffering from the disorder a therapeutically effective amount of an APRIL antagonist and an immunosuppressive drug. 
     
     
         39 . A composition comprising an APRIL antagonist and an immunosuppressive drug. 
     
     
         40 . An article of manufacture comprising an APRIL antagonist and an immunosuppressive drug, and a label wherein the label indicates that the composition is for treating a B cell regulated autoimmune disorder. 
     
     
         41 . A method of reducing an immunoglobulin level in a mammal comprising administering a BLyS antagonist and an immunosuppressive drug. 
     
     
         42 . The method of  claim 41 , wherein the immunoglobulin level is reduced by reducing immunoglobulin production. 
     
     
         43 . The method of  claim 41 , wherein the BLyS antagonist is a Fc-fusion protein. 
     
     
         44 . The method of  claim 43 , wherein the Fc-fusion protein is selected from the group consisting of a TACI-Fc-fusion protein comprising the extracellular domain of TACI or a functional fragment thereof, a BAFF-R-Fc-fusion protein comprising the extracellular domain of BAFF-R or a functional fragment thereof, and a BCMA-Fc-fusion protein comprising the extracellular domain of BCMA or a functional fragment thereof. 
     
     
         45 . The method of  claim 41 , wherein the BLyS antagonist is a BLyS antibody. 
     
     
         46 . The method of  claim 45 , wherein the BLyS antibody binds BLyS within a region comprising amino acid residues 162-285 of SEQ ID NO: 3228. 
     
     
         47 . The method of  claim 45 , wherein the BLyS antibody comprises amino acid residues 1-123 of SEQ ID NO:327 and amino acid residues 141-249 of SEQ ID NO:327. 
     
     
         48 . The method of  claim 41 , wherein the immunosuppressive drug is selected from the group consisting of cyclophosphamide, azathioprine, cyclosporine, and mycophenolate mofetil. 
     
     
         49 . The method of  claim 48 , wherein the immunosuppressive drug is mycophenolate mofetil. 
     
     
         50 . The method of  claim 41 , wherein the immunoglobulin level that is reduced is selected from the group consisting of IgM, IgG, IgA and IgE. 
     
     
         51 . A method of treating or ameliorating an autoimmune disorder comprising administering to a patient suffering from the disorder a therapeutically effective amount of a BLyS antagonist and an immunosuppressive drug. 
     
     
         52 . The method of  claim 51 , wherein the BLyS antagonist is a Fc-fusion protein. 
     
     
         53 . The method of  claim 52 , wherein the Fc-fusion protein is selected from the group consisting of a TACI-Fc-fusion protein comprising the extracellular domain of TACI or a functional fragment thereof, a BAFF-R-Fc-fusion protein comprising the extracellular domain of BAFF-R or a functional fragment thereof, and a BCMA-Fc-fusion protein comprising the extracellular domain of BCMA or a functional fragment thereof. 
     
     
         54 . The method of  claim 51 , wherein the BLyS antagonist is a BLyS antibody. 
     
     
         55 . The method of  claim 54 , wherein the BLyS antibody binds BLyS within a region comprising amino acid residues 162-285 of SEQ ID NO: 3228. 
     
     
         56 . The method of  claim 54 , wherein the BLyS antibody comprises amino acid residues 1-123 of SEQ ID NO:327 and amino acid residues 141-249 of SEQ ID NO:327. 
     
     
         57 . The method of  claim 51 , wherein the immunosuppressive drug is selected from the group consisting of cyclophosphamide, azathioprine, cyclosporine, and mycophenolate mofetil. 
     
     
         58 . The method of  claim 57 , wherein the immunosuppressive drug is mycophenolate mofetil. 
     
     
         59 . The method of  claim 51 , wherein the BLyS antagonist and the immunosuppressive drug reduce an immunoglobulin level. 
     
     
         60 . The method of  claim 59 , wherein the immunoglobulin level is reduced by reducing immunoglobulin production. 
     
     
         61 . The method of  claim 59 , wherein the immunoglobulin level that is reduced is selected from the group consisting of IgM, IgG, IgA and IgE. 
     
     
         62 . The method of  claim 51 , wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, nephritis associated with systemic lupus erythematosus, inflammatory bowel disease, idiopathic thrombocytopenia purpura, autoimmune thrombocytopenic purpura, Multiple Sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, Myasthenia Gravis, vasculitis, diabetes mellitus, Raynaud phenomenon, Sjögren's syndrome, glomerulonephritis, autoimmune hepatitis, and autoimmune thyroiditis. 
     
     
         63 . The method of  claim 62 , wherein the autoimmune disease is nephritis associated with systemic lupus erythematosus. 
     
     
         64 . The method of  claim 51 , wherein the BLyS antagonist is administered at a dosage of 1 mg/kg to 10 mg/kg of the patient's body weight. 
     
     
         65 . The method of  claim 51 , wherein the method further comprises administering a drug selected from the group consisting of nonsteroidal anti-inflammatories, glucocorticoid, prednisone, methotrexate, sulfasalazine, sodium aurothiomalate, auranofin, cyclosporine, penicillamine, azathioprine, an antimalarial drug, cyclophosphamide, chlorambucil, gold, etanercept, infliximab, leflunomide, an anti-TNF antibody, LJP 394, and prednisolone. 
     
     
         66 . A composition comprising a BLyS antagonist and an immunosuppressive drug. 
     
     
         67 . An article of manufacture comprising a BLyS antagonist and an immunosuppressive drug, and a label wherein the label indicates that the composition is for treating an autoimmune disorder. 
     
     
         68 . The method of  claim 41 , wherein the BLyS antagonist is also an APRIL antagonist. 
     
     
         69 . The method of  claim 51 , wherein the BLyS antagonist is also an APRIL antagonist. 
     
     
         70 . The composition of  claim 66 , wherein the BLyS antagonist is also an APRIL antagonist. 
     
     
         71 . The article of manufacture of  claim 67 , wherein the BLyS antagonist is also an APRIL antagonist.