B lymphocyte stimulator assays

Abstract

The present invention relates to nucleic acid molecules encoding Neutrokine-alpha and/or Neutrokine-alphaSV polypeptides, including soluble forms of the extracellular domain. Neutrokine-alpha and/or Neutrokine-alphaSV polypeptides are also provided as are vectors, host cells and recombinant methods for producing the same. The invention further relates to antibodies or portions thereof that specifically bind Neutrokine-alpha and/or Neutrokine-alphaSV and diagnostic and therapeutic methods using these antibodies. Also provided are diagnostic methods for detecting immune system-related disorders and therapeutic methods for treating immune system-related disorders using the compositions of the invention.

What is claimed is: 
     
         1 . A method for monitoring B cell levels in a subject comprising the steps of determining the serum BAFF levels in a test sample of the subject, determining the serum BAFF levels in a control sample, and calculating the B cell levels in the subject relative to the control, which calculation comprises the step of comparing the serum BAFF level in the test sample to the serum BAFF level in the control sample. 
     
     
         2 . The method according to  claim 1 , wherein the control sample is from the subject before treatment with a therapeutic agent and the test sample is from the subject after treatment with the therapeutic agent. 
     
     
         3 . The method according to  claim 1 , wherein the test sample is from the subject who is suffering from a disease and the control sample is from a subject that is not suffering from the disease. 
     
     
         4 . A method for treating a subject suffering from a disease comprising the steps of (1) administering a therapeutically effective amount of a therapeutic agent to the subject, (2) determining the serum BAFF levels in a test sample of the subject, (3) comparing the B cell level in the test sample relative to a control sample and (4) administering a therapeutically effective amount of the same or different therapeutic agent at a time point dependent on the serum BAFF level in the subject. 
     
     
         5 . A method for treating a subject suffering from a disease comprising the steps of (1) administering a therapeutically effective amount of a therapeutic agent to the subject, (2) determining the serum BAFF levels in a test sample of the subject, and (3) administering a therapeutically effective amount of the same or different therapeutic agent at a time point dependent on the serum BAFF level in the test sample. 
     
     
         6 . A method of maintenance therapy for a subject previously treated with a B cell depletion agent for a disease comprising the step of determining the serum BAFF levels in the subject and treating the subject with a B cell depletion agent at a time point after maximum B cell depletion and while serum BAFF levels are decreasing. 
     
     
         7 . The method according to  claim 4  or  5 , wherein the time point is at the time of or after the maximum B cell depletion phase. 
     
     
         8 . The method according to  claim 4  or  5 , wherein the time point is during the B cell recovery phase. 
     
     
         9 . The method according to  claim 8 , wherein the B cell recovery phase is characterized by decreasing serum BAFF levels. 
     
     
         10 . The method according to  claim 6 , wherein the maximum B cell depletion phase is characterized by maximum levels of BAFF in the sera of a subject. 
     
     
         11 . The method according to  claim 7 , wherein the maximum B cell depletion phase is characterized by maximum levels of BAFF in the sera of a subject. 
     
     
         12 . The method according to  claim 4  or  5 , wherein the therapeutic agent is a B cell depletion agent. 
     
     
         13 . The method according to  claim 4  or  5 , wherein the therapeutic agent is not a BAFF antagonist that binds to BAFF. 
     
     
         14 . The method according to  claim 4  or  5 , wherein the therapeutic agent does bind BAFF and block BAFF from binding to BCMA, TACI or BR3. 
     
     
         15 . The method according to  claim 4  or  5 , wherein the therapeutic agent is a B cell promoting agent. 
     
     
         16 . The method according to  claim 12 , wherein the therapeutic agent is a B cell depletion agent that binds to a B cell surface antigen selected from the group consisting of CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD40, CD52, D53, CD72, CD73, CD74, CDw75, CDw76, CD77, CDw78, CD79a, CD79b, CD80, CD81, CD82, CD83, CDw84, CD85, CD86, CD180 (RP105), FcRH2 (IRTA4), CD79A, C79B, CR2, CCR6, CD72, P2.times.5, HLA-DOB, CXCR5 (BLR1), FCER2, BR3 (aka BAFF-R), TACI, BTLA, NAG14 (aka LRRC4), SLGC16270 (ala LOC283663), FcRH1 (IRTA5), FcRH5 (IRTA2), ATWD578 (aka MGC15619), FcRH3 (IRTA3), FcRH4 (IRTA1), FcRH6 (aka LOC343413) and BCMA (aka TNFRSF17), HLA-DO, HLA-Dr10 and MHC ClassII. 
     
     
         17 . The method according to  claim 16 , wherein the B cell depletion agent is an antibody. 
     
     
         18 . The method according to any one of  claims 4 - 6 , wherein the disease is an immunological disorder. 
     
     
         19 . The method according to  claim 4  or  5 , wherein the disease is an immunodeficiency disease. 
     
     
         20 . The method according to any one of  claims 4 - 6 , wherein the disease is an autoimmune disease elected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), Wegener's disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome, glomerulonephritis, Neuromyelitis Optica (NMO) and IgG neuropathy. 
     
     
         21 . The method according to any one of  claims 4 - 6 , wherein the disease is a cancer selected from the group consisting of B cell lymphoma, B cell leukemia and multiple myeloma. 
     
     
         22 . The method according to any one of  claims 4 - 6 , wherein the B cells express CD19. 
     
     
         23 . The method according to any one of  claims 4 - 6 , wherein the B cells express CD20. 
     
     
         24 . The method according to any one of  claims 4 - 6 , wherein the subject is a mammal. 
     
     
         25 . The method according to  claim 23 , wherein the subject is a human. 
     
     
         26 . The method according to  claim 12 , wherein the B cell depletion agent is selected from the group consisting of an anti-CD20 antibody, an anti-BR3 antibody, an anti-CD22 antibody and an anti-CD52 antibody. 
     
     
         27 . The method according to  claim 26 , wherein the anti-CD20 antibody is rituximab or 2H7. 
     
     
         28 . The method according to  claim 15 , wherein the B cell promoting agent is a cytokine. 
     
     
         29 . The method according to any one of  claims 4 - 5 , wherein the different therapeutic agent is selected from the group consisting of a T cell depleting agent, an immunosuppressive agent, a DMARD and a vaccine. 
     
     
         30 . The method according to any one of  claims 4 - 6 , wherein the time point is before or during tissue B cell recovery that is prior to peripheral blood B cell recovery. 
     
     
         31 . A kit comprising a BAFF binding reagent and a package insert comprising instructions for determining serum BAFF levels using the BAFF binding reagent and for relating serum BAFF levels to B cell levels in the patient after treatment with a B cell depleting or promoting agent. 
     
     
         32 . A method for monitoring B Lymphocyte Stimulator expression in an individual comprising the steps of assaying the level of B Lymphocyte Stimulator expression in a biological sample of the individual using one or more antibodies or fragments thereof that immunospecifically bind B Lymphocyte Stimulator; and comparing the level of B Lymphocyte Stimulator assayed in the biological sample with a standard level of B Lymphocyte Stimulator. 
     
     
         33 . The according to  claim 32 , wherein the level of B Lymphocyte Stimulator is assayed before a treatment regimen and during or after the treatment regimen. 
     
     
         34 . The according to  claim 32 , wherein the individual has a disease and wherein the standard B Lymphocyte Stimulator level is from an individual without the disease. 
     
     
         35 . A method for treating an individual suffering from a disease comprising the steps of (1) administering a therapeutically effective amount of a therapeutic agent to the individual; (2) assaying for the level of B Lymphocyte Stimulator in a biological sample of the subject; (3) comparing the level of B Lymphocyte Stimulator with a standard B Lymphocyte Stimulator level; and (4) administering a therapeutically effective amount of the same or a different therapeutic agent to the individual. 
     
     
         36 . A method for treating an individual suffering from a disease comprising the steps of (1) administering a therapeutically effective amount of a therapeutic agent of a treatment regimen to the subject; (2) assaying for the level of B Lymphocyte Stimulator in a biological sample of the individual; and (3) administering a therapeutically effective amount of the same or a different therapeutic agent to the individual. 
     
     
         37 . A method for treating aberrant B Lymphocyte Stimulator levels in an individual comprising (1) assaying for the level of B Lymphocyte Stimulator in a biological sample of the individual; (2) treating the individual with a therapeutically effective amount of an agent that inhibits B cell proliferation, differentiation, survival, or activation; (3) assaying for the level of B Lymphocyte Stimulator in a biological sample of the individual; and (4) if B Lymphocyte Stimulator levels as determined in (3) are lower than those in (1), administering a therapeutic agent that inhibits B cell proliferation, differentiation or survival. 
     
     
         38 . The method according to  claim 35  or  36 , wherein the therapeutic agent is administered after assayed levels of B Lymphocyte Stimulator indicate that maximum effectiveness of a therapeutic agent that inhibits B cell proliferation, differentiation, survival, or activation has been reached. 
     
     
         39 . The method according to  claim 35  or  36 , wherein the therapeutic agent inhibits B cell proliferation, differentiation, survival, or activation. 
     
     
         40 . The method according to  claim 35  or  36 , wherein the therapeutic agent is not a B Lymphocyte Stimulator antagonist that binds to B Lymphocyte Stimulator. 
     
     
         41 . The method according to  claim 35  or  36 , wherein the therapeutic agent binds B Lymphocyte Stimulator and substantially blocks B Lymphocyte Stimulator from binding to BCMA, BAFF-R, or TACI. 
     
     
         42 . The method according to  claim 35  or  36 , wherein the therapeutic agent promotes B cell differentiation, proliferation or activation. 
     
     
         43 . The method according to  claim 39 , wherein the therapeutic agent binds to an antigen selected from the group consisting of CD19, CD20, CD22, CD40, CCR6, BAFF-R, TACI, and BCMA, and HLA-Dr10. 
     
     
         44 . The method according to  claim 43 , wherein the therapeutic agent is an antibody. 
     
     
         45 . The method according to any one of  claims 35 - 37 , wherein the disease is an immune disorder. 
     
     
         46 . The method according to  claim 35  or  36 , wherein the disease is an immunodeficiency disease. 
     
     
         47 . The method according to any one of  claims 35  or  36 , wherein the disease is an autoimmune disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE), granulomatosis, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome, and glomerulonephritis. 
     
     
         48 . The method according to any one of  claims 35 - 37 , wherein the disease is a cancer selected from the group consisting of B cell lymphoma, B cell leukemia and multiple myeloma. 
     
     
         49 . The method according to any one of  claims 35 - 37 , wherein the B cells express CD19. 
     
     
         50 . The method according to any one of  claims 35 - 37 , wherein the biological sample comprises one or more CD20 positive B cells. 
     
     
         51 . The method according to any one of  claims 35 - 37 , wherein the subject is a mammal. 
     
     
         52 . The method according to  claim 51 , wherein the subject is a human. 
     
     
         53 . The method according to  claim 39 , wherein the therapeutic agent is selected from the group consisting of an anti-CD20 antibody, an anti-BAFF-R antibody, and an anti-CD22 antibody. 
     
     
         54 . The method according to  claim 53 , wherein the anti-CD20 antibody is rituximab. 
     
     
         55 . The method according to  claim 42 , wherein the therapeutic agent is a cytokine. 
     
     
         56 . The method according to any one of  claims 35 - 37 , wherein the different therapeutic agent is selected from the group consisting of a T cell suppressive agent, an immunosuppressive agent, a vaccine, methotrexate, and a steroid. 
     
     
         57 . A kit comprising a B Lymphocyte Stimulator binding reagent and a package insert comprising instructions for determining serum B Lymphocyte Stimulator levels using the B Lymphocyte Stimulator binding reagent and for determining whether aberrant levels of B Lymphocyte Stimulator are present.