COMBINATION OF BLyS INHIBITION AND ANTI-CD 20 AGENTS FOR TREATMENT OF AUTOIMMUNE DISEASE

Abstract

The invention relates to novel combination therapies involving BLyS or BLyS/APRIL inhibition and anti-CD20 agents for the treatment of autoimmune diseases. One preferred method is where the BLyS antagonist is a Fc-fusion protein which can be 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, or a BCMA-Fc-fusion protein comprising the extracellular domain of BCMA or a functional fragment thereof. In the methods of the present invention some of anti-CD20 agents contemplated include RITUXAN®, ocrelizumab, ofatumumab (HuMax-CD20®), TRU-015, and DXL625, although any agent that binds to CD 20 may be suitable. The methods of the present invention reduce the levels of B cells in patients in need of such reduction, such as those suffering from autoimmune diseases.

We claim: 
     
         1 . A method of reducing B cell numbers in a mammal comprising administering a BLyS antagonist comprising a polypeptide comprising the sequence of SEQ ID NO:26 and an anti-CD-20 agent. 
     
     
         2 . The method of  claim 1  wherein the BLyS antagonist and the anti-CD20 agent act synergistically to reduce B cell levels. 
     
     
         3 . The method of  claim 2  wherein the B cell level that is reduced is the number of memory B cells. 
     
     
         4 . The method of  claim 1 , wherein the anti-CD 20 agent is selected from the group consisting of RITUXAN®, ocrelizumab, ofatumumab, TRU-015, and DXL625. 
     
     
         5 . 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 comprising a polypeptide comprising the sequence of SEQ ID NO:26 and an anti-CD 20 agent. 
     
     
         6 . The method of  claim 5 , wherein the anti-CD 20 agent is selected from the group consisting of RITUXAN®, ocrelizumab, ofatumumab, TRU-015, and DXL625. 
     
     
         7 . The method of  claim 6  wherein the anti-CD 20 agent is RITUXAN®. 
     
     
         8 . The method of  claim 5  wherein the BLyS antagonist and the anti-CD20 agent act synergistically to reduce B cell levels. 
     
     
         9 . The method of  claim 8  wherein the B cell level that is reduced is the number of memory B cells. 
     
     
         10 . 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 purpuria (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune throbyctopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myasthenia gravis, vasculitis, diabetes, mellitus, Reynauld's syndrome, Sjorgen's syndrome, and glomerulonephritis. 
     
     
         11 . The method of  claim 10  wherein the autoimmune disease is systemic lupus erythmatosus (SLE). 
     
     
         12 . The method of  claim 11  wherein the anti-CD20 agent is RITUXAN®. 
     
     
         13 . The method of  claim 6  wherein the BLyS antagonist is administered at a dosage of about 1 to about 25 mg/kg and the anti-CD20 is administered at a dosage of about 1 to about 25 mg/kg. 
     
     
         14 . The method of  claim 13  wherein the BLyS antagonist is administered at a dosage of about 20 mg/kg and the anti-CD20 is administered at a dosage of about 20 mg/kg. 
     
     
         15 . The method of  claim 6  wherein the BLyS antagonist and the anti-CD20 agent is administered in conjunction with therapy using an immunosuppressive drug selected from the group consisting of cyclophosphamide (CYC), azathioprine (AZA), cyclosporine A (CSA), mycophenolate mofetil (MMF), nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoid, prednisone, and disease-modifying antirheumatic drugs (DMARDs). 
     
     
         16 . A composition comprising a BLyS antagonist comprising a polypeptide comprising the sequence of SEQ ID NO:26 and an anti-CD 20 agent. 
     
     
         17 . The composition of  claim 16  wherein the anti-CD20 agent is RITUXAN®. 
     
     
         18 . An article of manufacture comprising a BLyS antagonist comprising a polypeptide comprising the sequence of SEQ ID NO:26 and an anti-CD20 agent, and a label wherein the label indicates that the composition is for treating a B cell regulated autoimmune disorder. 
     
     
         19 . The article of manufacture of  claim 18  wherein the anti-CD20 agent is RITUXAN®.