Modulation of IL-2- and IL-15-mediated T cell responses

Abstract

The present invention is based, in part, on expression studies of IL-2 and IL-15 receptor subunits by cycling T cells in vivo. In one embodiment, the invention generally features novel combinations of IL-2 and IL-15 antagonists and methods of suppressing the immune response by administering these antagonists. In each case, suppression is achieved by administration of a first agent that targets an IL-15 molecule or an IL-15 receptor (IL-15R) and a second agent that targets an IL-2 molecule or an IL-2 receptor (IL-2R). More generally, the invention features novel combinations of agents that, when administered to a patient (or to a transplant ex vivo), reduce the number of antigen-reactive T cells. For example, the invention features compositions (e.g., pharamaceutically acceptable compositions) that include two or more agents, each of which promote T cell death. Alternatively, the composition can contain at least one agent that promotes T cell death and at least one agent that inhibits T cell proliferation. The agent that promotes T cell death can promote AICD (activation induced cell death), passive cell death, ADCC (antibody dependent cell-mediated cytotoxicity) or CDC (complement directed cytotoxicity).

What is claimed is:  
     
         1 . A therapeutic composition comprising a first agent that targets an interleukin-15 receptor (IL-15R) and a second agent that targets an interleukin-2 receptor (IL-2R).  
     
     
         2 . The therapeutic composition of  claim 1 , wherein the first agent comprises a substantially pure mutant IL-15 polypeptide that binds a subunit of an IL-15R.  
     
     
         3 . The therapeutic composition of  claim 2 , wherein the subunit is an IL-15Rα subunit.  
     
     
         4 . The therapeutic composition of  claim 3 , wherein the mutant IL-15 polypeptide has a mutation at position 156 of SEQ ID NO: 2.  
     
     
         5 . The therapeutic composition of  claim 4 , wherein the mutant IL-15 polypeptide also has a mutation at position 149 of SEQ ID NO: 2.  
     
     
         6 . The therapeutic composition of  claim 4 , wherein the mutation at position 156 of SEQ ID NO: 2 is a substitution of aspartate for glutamine.  
     
     
         7 . The therapeutic composition of  claim 5 , wherein the mutation at position 149 of SEQ ID NO: 2 is a substitution of aspartate for glutamine.  
     
     
         8 . The therapeutic composition of  claim 5  wherein the mutant IL-15 polypeptide has a substitution of aspartate for glutamine at positions 149 and 156 of SEQ ID NO: 2.  
     
     
         9 . The therapeutic composition of  claim 2 , wherein the first agent further comprises a moiety that leads to the elimination of IL-15R-bearing cells.  
     
     
         10 . The therapeutic composition of  claim 9 , wherein the moiety that lyses IL-15R-bearing cells is an Fc region of an IgG molecule.  
     
     
         11 . The therapeutic composition of  claim 1 , wherein the first agent comprises a substantially pure anti-IL15R antibody.  
     
     
         12 . The therapeutic composition of  claim 1 , wherein the second agent comprises an antibody that specifically binds IL-2 or an IL-2R.  
     
     
         13 . A method of suppressing an immune response in a patient, the method comprising administering to the patient a therapeutic composition comprising a first agent that targets an IL-15R and a second agent that targets an IL-2R.  
     
     
         14 . The method of  claim 13 , wherein the patient has an immune disease, particularly autoimmune disease or is at risk of developing an immune disease, particularly autoimmune disease.  
     
     
         15 . The method of  claim 14 , wherein the autoimmune disease is a rheumatic disease selected from the group consisting of systemic lupus erythematosus, Sjögren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, Reiter's syndrome, and Behcet's disease.  
     
     
         16 . The method of  claim 14 , wherein the autoimmune disease is rheumatoid arthritis.  
     
     
         17 . The method of  claim 14 , wherein the autoimmune disease is type I diabetes.  
     
     
         18 . The method of  claim 14 , wherein the autoimmune disease is an autoimmune disease of the thyroid selected from the group consisting of Hashimoto's thyroiditis and Graves' Disease.  
     
     
         19 . The method of  claim 14 , wherein the autoimmune disease is an autoimmune disease of the central nervous system selected from the group consisting of multiple sclerosis, myasthenia gravis, and encephalomyelitis.  
     
     
         20 . The method of  claim 14 , wherein the autoimmune disease is a variety of phemphigus selected from the group consisting of phemphigus vulgaris, phemphigus vegetans, phemphigus foliaceus, Senear-Usher syndrome, and Brazilian phemphigus.  
     
     
         21 . The method of  claim 14 , wherein the autoimmune disease is psoriasis.  
     
     
         22 . The method of  claim 14 , wherein the autoimmune disease is inflammatory bowel disease.  
     
     
         23 . The method of  claim 13 , wherein the patient has acquired immune deficiency syndrome (AIDS).  
     
     
         24 . The method of  claim 13 , wherein the patient has received a transplant of a biological organ, tissue, or cell.  
     
     
         25 . The method of  claim 13 , wherein the patient has a graft versus host disease.  
     
     
         26 . A method of eliminating a cell that expresses a receptor for IL-15, the method comprising exposing the cell to the therapeutic composition comprising a first agent that targets an IL-15R and a second agent that targets an IL-2R.  
     
     
         27 . The method of  claim 26 , wherein the cell is a cell of the immune system.  
     
     
         28 . The cell of  claim 26 , wherein the cell is a malignant cell.  
     
     
         29 . A method of diagnosing a patient as having a disease or condition that can be treated with the therapeutic composition of  claim 1 , the method comprising determining whether a biological sample obtained from the patient contains a cell that is bound by a polypeptide comprising IL-15 and an antigenic tag, the occurrence of binding indicating that the cell can be bound by an agent that targets an IL-15R in vivo and thereby inhibited from proliferating in response to wild-type IL-15 in vivo.  
     
     
         30 . A pharmaceutically acceptable composition comprising two or more agents, each of which promote T cell death.  
     
     
         31 . The pharmaceutical composition of  claim 30 , further comprising an agent that inhibits T cell proliferation.  
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the composition comprises a lytic IL-2/Fc molecule, a mutant IL-15 molecule that antagonizes and IL-15 receptor, and rapamycin.  
     
     
         33 . A pharmaceutically acceptable composition comprising at least one agent that promotes T cell death and at least one agent that inhibits T cell proliferation.  
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein the T cell death is AICD (activation induced cell death), passive cell death, ADCC (antibody dependent cell-mediated cytotoxicity) or CDC (complement directed cytotoxicity).