LEVELS OF BLyS/APRIL HETEROTRIMERS IN SERUM AND USE IN DIAGNOSTIC METHODS

Abstract

The present invention provides a method of measuring the levels of BLyS/APRIL heterotrimers (HT) in a biological sample, in a preferred embodiment, in serum. The diagnostic assays are useful in predicting an individual's likelihood of developing or currently suffering from an autoimmune disease, such as SLE and for methods for treating an individual clinically diagnosed with an autoimmune disease. This diagnostic test serves to predict a patient's likelihood to respond to a specific drug treatment, in particular treatment with HT antagonists, either singly or in combination with other immune suppressive drugs.

1 . A method of detecting increased BLyS/APRIL heterotrimer (HT) levels of an individual comprising:
 (a) measuring a first level of HT in a biological sample and   (b) comparing that level to a second level of HT in a biological sample of a healthy individual and   (c) determining the first level is increased as compared to the second level, wherein said increased HT levels is associated with an autoimmune disease.   
     
     
         2 . The method of  claim 1 , 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 purpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome and glomerulonephritis. 
     
     
         3 . The method of  claim 1  wherein said autoimmune disease is SLE. 
     
     
         4 . The method of  claim 3  wherein measuring utilizes a luminex immunoassay. 
     
     
         5 . A method of treating an individual clinically diagnosed with an autoimmune disease, comprising:
 analyzing a biological sample from an individual clinically diagnosed with autoimmune disease for the presence or absence of elevated BLyS/APRIL heterotrimer (HT) levels, wherein the presence of elevated APRIL protein levels is associated with the clinical diagnosis of autoimmune disease; and   selecting a treatment plan that is most effective for individuals clinically diagnosed as having a condition associated with increased HT levels.   
     
     
         6 . The method of  claim 5  wherein said treatment plan involves administration of an HT antagonist. 
     
     
         7 . The method of  claim 5  wherein said HT antagonist is also a BLyS antagonist. 
     
     
         8 . The method of  claim 5  wherein said HT antagonist is also an APRIL antagonist. 
     
     
         9 . The method of  claim 5 , 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 purpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome and glomerulonephritis. 
     
     
         10 . The method of  claim 5  wherein said autoimmune disease is SLE. 
     
     
         11 . The method of  claim 5  wherein said analysis is with a luminex immunoassay. 
     
     
         12 . A method for predicting a patient's likelihood to respond to a drug treatment for an autoimmune disease, comprising determining the BLyS/APRIL heterotrimer (HT) levels in a biological sample, wherein the presence of elevated HT levels is predictive of the patient's likelihood to respond to a drug treatment for the condition. 
     
     
         13 . The method of  claim 12  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 purpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome and glomerulonephritis. 
     
     
         14 . The method of  claim 12  wherein said autoimmune disease is RA. 
     
     
         15 . The method of  claim 12  wherein said determination is done using a luminex immunoassay. 
     
     
         16 . The method of  claim 12  wherein said drug treatment involves administration of an HT antagonist. 
     
     
         17 . The method of  claim 16  wherein said HT antagonist is also a BLyS antagonist. 
     
     
         18 . The method of  claim 16  wherein said HT antagonist is also an APRIL antagonist. 
     
     
         19 . An in vitro method of detecting increased BLyS/APRIL heterotrimer (HT) levels in the serum of an individual, comprising:
 (a) measuring the level of HT in a test biological sample from the individual;   (b) comparing that level to the level of HT in a sample from a healthy control; and   (c) determining whether the level of HT in the test biological sample is increased as compared to the level in the control sample;   wherein said increased HT levels is associated with an autoimmune disease.   
     
     
         20 . The method of  claim 19 , 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 purpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome and glomerulonephritis. 
     
     
         21 . The method of  claim 19  wherein said autoimmune disease is SLE. 
     
     
         22 . An in vitro method of selecting a treatment plan that is most effective for treating an individual clinically diagnosed with an autoimmune disease, comprising:
 analyzing in vitro a biological sample from an individual clinically diagnosed with autoimmune disease for the presence or absence of elevated BLyS/APRIL heterotrimer (HT) levels in serum, wherein the presence of elevated HT levels is associated with the clinical diagnosis of autoimmune disease.   
     
     
         23 . The method of  claim 22  wherein said treatment plan involves the use of a HT antagonist. 
     
     
         24 . The method of  claim 23  wherein said HT antagonist is also a BLyS antagonist. 
     
     
         25 . The method of  claim 25  wherein said HT antagonist is also an APRIL antagonist. 
     
     
         26 . The method of  claim 22 , 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 purpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome and glomerulonephritis. 
     
     
         27 . The method of  claim 23  wherein said autoimmune disease is RA. 
     
     
         28 . The method of  claim 20  wherein said individual is newly diagnosed with RA. 
     
     
         29 . An in vitro method for predicting a patient's likelihood to respond to a drug treatment for an autoimmune disease, comprising determining the level of BLyS/APRIL heterotrimer (HT) levels in a sample from the patient; wherein the presence of elevated HT levels is predictive of the patient's likelihood to respond to a drug treatment for the condition. 
     
     
         30 . The method of  claim 29  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 purpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen's syndrome and glomerulonephritis. 
     
     
         31 . The method of  claim 29  wherein said autoimmune disease is SLE. 
     
     
         32 . The method of  claim 29  wherein said determination is done utilizing a luminex immunoassay. 
     
     
         33 . The method of  claim 29  wherein said drug treatment comprises a HT antagonist. 
     
     
         34 . The method of  claim 30  wherein said HT antagonist is also a BLyS antagonist. 
     
     
         35 . The method of  claim 30  wherein said HT antagonist is also an APRIL antagonist. 
     
     
         36 . A HT antagonist for use in the treatment of an autoimmune disease in a patient, wherein said patient has elevated levels of BLyS/APRIL heterotrimer (HT) levels in serum. 
     
     
         37 . The antagonist of  claim 36  wherein the autoimmune disease is SLE. 
     
     
         38 . The antagonist of  claim 36  wherein said HT antagonist is also a BLyS antagonist. 
     
     
         39 . The antagonist of  claim 36  wherein said HT antagonist is also an APRIL antagonist. 
     
     
         40 . The antagonist of  claim 36  wherein said antagonist is a receptor-extracellular domain/Fc domain fusion protein selected from the group consisting of TACI-Ig and BCMA-Ig. 
     
     
         41 . The antagonist of  claim 40  wherein said receptor-extracellular domain/Fc domain fusion protein is TACI-Ig. 
     
     
         42 . The antagonist of  claim 41  wherein said TACI-Ig is atacicept.