Antagonists of interleukin-15
Antagonists of mammalian interleukin-15 (“IL-15”) are disclosed and include muteins of IL-15 and modified IL-15 molecules that are each capable of binding to the IL-15Rα-subunit and that are incapable of transducing a signal through either the β- or γ-subunits of the IL-15 receptor complex. Also included are monoclonal antibodies against IL-15 that prevent IL-15 from effecting signal transduction through either the β- or γ-subunits of the IL-15 receptor complex. Methods of treating various disease states are disclosed, including treating allograft rejection and graft-versus-host disease.
1. A method for reducing IL-15 activity in a mammal in need of such treatment comprising administering an antagonist of IL-15 activity that prevents IL-15 from transducing a signal through either of the β- or γ-subunits of the Il-15 receptor complex, wherein the antagonist is a monoclonal antibody against IL-15 that interferes with binding of (i) amino acid Asp 56 of the IL-15 molecule to the β-subunit of the IL-15 receptor complex or (ii) amino acid Gln 156 of the IL-15 molecule to the γ-subunit of the IL-15 receptor complex.
2. The method of claim 1 wherein the antibody is a monoclonal antibody obtained from a hybridoma having an ATCC accession number selected from the group consisting of HB-12061, HB-12062, and HB-12063.
3. The method of claim 1 wherein the monoclonal antibody is humanized.
4. The method of claim 2 wherein the monoclonal antibody is humanized.
5. The method of claim 1 wherein the antibody is transgenic.
6. The method of claim 1 wherein the mammal has a disease or condition selected from the group consisting of organ transplant rejection, graft-versus-host disease, autoimmune disease, rheumatoid arthritis, inflammatory bowel disease, lymphoma, carcinoma, leukemia, rhabdosarcoma, a dermatologic disorder, a disorder of the gastrointestinal tract, insulin-dependent diabetes mellitus, an ocular disorder, idiopathic nephrotic syndrome/idiopathic membranous nephropathy, and HTLV I-induced leukemia-lymphoma.
7. The method of claim 6 wherein the mammal has a disease or condition selected from the group consisting of rheumatoid arthritis, lymphoma, carcinoma, leukemia, and a dermatologic disorder.
8. The method of claim 7 wherein the mammal has rheumatoid arthritis.
9. The method of claim 7 wherein the mammal has lymphoma.
10. The method of claim 7 wherein the mammal has carcinoma.
11. The method of claim 7 wherein the mammal has leukemia.
12. The method of claim 2 wherein the mammal has a dermatologic disorder.
13. The method of claim 2 wherein the mammal has a disease or condition selected from the group consisting of organ transplant rejection, graft-versus-host disease, autoimmune disease, rheumatoid arthritis, inflammatory bowel disease, lymphoma, carcinoma, leukemia, rhabdosarcoma, a dermatologic disorder, a disorder of the gastrointestinal tract, insulin-dependent diabetes mellitus, an ocular disorder, idiopathic nephrotic syndrome/idiopathic membranous nephropathy, and HTLV I-induced leukemia-lymphoma.
14. The method of claim 13 wherein the mammal has a disease or condition selected from the group consisting of rheumatoid arthritis, lymphoma, carcinoma, leukemia, and a dermatologic disorder.
15. The method of claim 3 wherein the mammal has a disease or condition selected from the group consisting of organ transplant rejection, graft-versus-host disease, autoimmune disease, rheumatoid arthritis, inflammatory bowel disease, lymphoma, carcinoma, leukemia, rhabdosarcoma, a dermatologic disorder, a disorder of the gastrointestinal tract, insulin-dependent diabetes mellitus, an ocular disorder, idiopathic nephrotic syndrome/idiopathic membranous nephropathy, and HTLV I-induced leukemia-lymphoma.
16. The method of claim 15 wherein the mammal has a disease or condition selected from the group consisting of rheumatoid arthritis, lymphoma, carcinoma, leukemia, and a dermatologic disorder.
17. The method of claim 4 wherein the mammal has a disease or condition selected from the group consisting of organ transplant rejection, graft-versus-host disease, autoimmune disease, rheumatoid arthritis, inflammatory bowel disease, lymphoma, carcinoma, leukemia, rhabdosarcoma, a dermatologic disorder, a disorder of the gastrointestinal tract, insulin-dependent diabetes mellitus, an ocular disorder, idiopathic nephrotic syndrome/idiopathic membranous nephropathy, and HTLV I-induced leukemia-lymphoma.
18. The method of claim 17 wherein the mammal has a disease or condition selected from the group consisting of rheumatoid arthritis, lymphoma, carcinoma, leukemia, and a dermatologic disorder.