Combination of BLyS and/or APRIL inhibition and immunosuppressants for treatment of autoimmune disease
The invention relates to novel combination therapies involving BLyS or BLyS/APRIL inhibition and immunosuppressants for the treatment of autoimmune diseases. One preferred method is where the BLyS and/or APRIL 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 the immunosuppressive drugs contemplated include cyclophosphamide (CYC), azathioprine (AZA), cyclosporine A (CSA), or mycophenolate mofetil (MMF), although any drug that suppresses the immune system may be suitable. The methods of the present invention reduce the levels of various immunoglobulins in patients in need of such reduction, such as those suffering from autoimmune diseases.
1. A method of reducing immunoglobulin levels in a mammal comprising administering a BLyS antagonist and mycophenolate mofetil (MMF), wherein said B Lymphocyte Stimulator (BLyS) antagonist and said MMF are administered in an amount such that the combination of the MMF and the BlyS antagonist act at synergistically to reduce immunoglobulin levels said BLyS antagonist comprises the TACI-Fc protein set forth in SEQ ID NO: 23, wherein the modified tissue plasminogen activation signal sequence has been removed from the protein set forth in SEQ ID NO: 23.
2. The method of claim 1 wherein the immunoglobulin level that is reduced is selected from the group consisting of IgM, IgG, and IgA.
3. 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 B Lymphocyte Stimulator (BLyS) antagonist and mycophenolate mofetil (MMF), wherein the B-cell regulated autoimmune disorder arises from antibodies that are directed against said patient's own (self) antigens or tissues wherein said BLyS antagonist and said MMF are administered in an amount wherein the combination of the MMF and the BlyS antagonist act synergistically to reduce immunoglobulin levels, said BLyS antagonist comprises the TACI-Fc protein set forth in SEQ ID NO: 23 and wherein the modified tissue plasminogen activation signal sequence has been removed from the protein set forth in SEQ ID NO: 23.
4. The method of claim 3 , wherein the immunoglobulin level that is reduced is selected from the group consisting of IgM, IgG, and IgA.
5. The method of claim 3 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.
6. The method of claim 5 wherein the autoimmune disease is lupus nephritis.
7. The method of claim 3 wherein the BLyS antagonist is administered at a dosage of about 1 to about 2.5 mg/kg and the MMF is administered at a dosage of about 1 to about 4 mg/kg.
8. The method of claim 3 wherein the BLyS antagonist and the MMF 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).
9. A method of reducing immunoglobulin levels in a mammal comprising administering an A Proliferation Inducing Ligand (APRIL) antagonist and mycophenolate mofetil (MMF), wherein said April antagonist and said MMF are administered in an amount such that the combination of the MMF and the APRIL antagonist act to synergistically reduce immunoglobulin levels, said APRIL antagonist comprises the TACI-Fc protein set forth in SEQ ID NO: 23 wherein the modified tissue plasminogen activation signal sequence has been removed from the protein set forth in SEQ ID NO: 23.
10. 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 A Proliferation Inducing Ligand (APRIL) antagonist and mycophenolate mofetil (MMF), wherein the B-cell regulated autoimmune disorder arises from antibodies that are directed against said patient's own (self) antigens or tissues wherein said April antagonist and said MMF are administered in an amount wherein the combination of the MMF and the APRIL antagonist act synergistically to reduce immunoglobulin levels, said APRIL antagonist comprises the TACI-Fc protein set forth in SEQ ID NO: 23 wherein the modified tissue plasminogen activation signal sequence has been removed from said protein set forth in SEQ ID NO: 23.
11. The method of claim 9 , wherein the immunoglobulin level that is reduced is selected from the group consisting of IgM, IgG, and IgA.
12. The method of claim 10 , 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.
13. The method of claim 11 , wherein the autoimmune disease is lupus nephritis.
14. The method of claim 10 , wherein the APRIL antagonist and the MMF 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).