Methods and compositions for modulating interleukin-21 receptor activity
Methods and compositions for modulating interleukin-21 (IL-21)/IL-21 receptor (MU-1) activity using agonists or antagonists of IL-21 or IL-21 receptor (“IL-21R” or “MU-1”), are disclosed. IL-21/IL-21R antagonists can be used to induce immune suppression in vivo, e.g., for treating or preventing immune cell-associated pathologies (e.g., pathologies associated with aberrant activity of one or more of mature T cells (mature CD8+, mature CD4+ T cells), mature NK cells, B cells, macrophages and megakaryocytes, including transplant rejection and autoimmune disorders). IL-21/IL-21R agonists can be used by themselves or in combination with an antigen, e.g., as an adjuvant (e.g., a vaccine adjuvant), to up-regulate an immune response in vivo, e.g., for example, for use in treating cancer and infectious disorders.
1. A method of treating an arthritic disorder in a subject, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to IL-21R in an amount sufficient to inhibit or reduce immune cell activity in the subject, thereby treating the arthritic disorder, wherein said IL-21R has a sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
2. The method of claim 1 , further comprising administering to the subject a therapeutic agent selected from the group consisting of cytokine inhibitors, growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, cytotoxic agents, and cytostatic agents.
3. The method of claim 2 , wherein the therapeutic agent is selected from the group consisting of TNF antagonists, anti-TNF agents, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL-18 antagonists, IL-22 antagonists, T cell-depleting agents, B cell-depleting agents, cyclosporin, FK506, CCI-779. etanercept, infliximab, rituximab, adalimumab, prednisolone, azathioprine, gold, sulphasalazine, hydroxychloroquine, minocycline, anakinra, atabacept, methotrexate, leflunomide, rapamycin, rapamycin analogs, Cox-2 inhibitors, cPLA2 inhibitors, NSAIDs, p38 inhibitors, antagonists of B7.1, B7.2, ICOSL, ICOS, and CD28, and CTLA4 agonists.
4. The method of claim 1 , wherein the arthritic disorder is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and ankylosing spondylitis.
5. The method of claim 4 , wherein the arthritic disorder is rheumatoid arthritis.
6. The method of claim 4 , wherein said arthritic disorder is psoriatic arthritis.
7. The method of claim 4 , wherein said arthritic disorder is osteoarthritis.
8. The method of claim 4 , wherein said arthritic disorder is juvenile rheumatoid arthritis.
9. The method of claim 4 , wherein said arthritic disorder is ankylosing spondylitis.
10. The method of claim 1 , wherein the subject is a mammal.
11. The method of claim 1 , wherein said IL-21R comprises the sequence of SEQ ID NO:2.
12. The method of either claim 1 or 4 , wherein said antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously.
13. The method of either claim 1 or 4 , wherein said subject is a human.
14. The method of either claim 1 or 4 , wherein said IL-21R has a sequence at least about 95% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
15. The method of either claim 1 or 4 , wherein said IL-21R comprises the sequence of SEQ ID NO:2 from about amino acids 20–538.
16. The method of either claim 1 or 4 , wherein said antibody, or antigen-binding fragment thereof, binds to an epitope found in the extracellular domain of IL-21R.
17. The method of either claim 1 or 4 , wherein said antibody, or antigen-binding fragment thereof, is a neutralizing antibody.
18. The method of either claim 1 or 4 , wherein said antibody, or antigen-binding fragment thereof, is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a CDR-grafted antibody and a humanized antibody.
19. The method of either claim 1 or 4 , wherein said antibody, or antigen-binding fragment thereof, is a human antibody.
20. A method of ameliorating a symptom associated with arthritis in a subject, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to IL-21R in an amount sufficient to ameliorate the symptom in the subject, wherein the IL-21R has a sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
21. The method of claim 20 , wherein said antibody, or antigen-binding fragment thereof, is administered therapeutically.
22. The method of claim 20 , wherein said antibody, or antigen-binding fragment thereof, is administered prophylactically.
23. The method of claim 20 , wherein said IL-21R has a sequence at least about 95% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
24. The method of claim 20 , wherein said IL-21R comprises the sequence of SEQ ID NO:2 from about amino acids 20–538.
25. The method of claim 20 , wherein said IL-21R comprises the sequence of SEQ ID NO:2.
26. The method of claim 20 , wherein said antibody, or antigen-binding fragment thereof, binds to an epitope found in the extracellular domain of IL-21R.
27. The method of claim 26 , wherein said arthritic symptom is associated with a disorder selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and ankylosing spondylitis.
28. The method of claim 27 , wherein said disorder is rheumatoid arthritis.
29. The method of claim 27 , wherein said disorder is psoriatic arthritis.
30. The method of claim 27 , wherein said disorder is osteoarthritis.
31. The method of claim 27 , wherein said disorder is juvenile rheumatoid arthritis.
32. The method of claim 27 , wherein said disorder is ankylosing spondylitis.
33. The method of claim 20 , further comprising administering to the subject a therapeutic agent selected from the group consisting of cytokine inhibitors, growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, cytotoxic agents, and cytostatic agents.
34. The method of claim 33 , wherein said therapeutic agent is selected from the group consisting of TNF antagonists, anti-TNF agents, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL-18 antagonists, IL-22 antagonists, T cell-depleting agents, B cell-depleting agents, cyclosporin, FK506, CCI-779, etanercept, infliximab, rituximab, adalimumab, prednisolone, azathioprine, gold, sulphasalazine, hydroxychloroquine, minocycline, anakinra, atabacept, methotrexate, leflunomide, rapamycin, rapamycin analogs, Cox-2 inhibitors, cPLA2 inhibitors, NSAIDs, p38 inhibitors, antagonists of B7.1, B7.2, ICOSL, ICOS, and CD28, and CTLA4 agonists.
35. The method of either claim 20 or 26 , wherein said antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously.
36. The method of either claim 20 or 26 , wherein said subject is a human.
37. The method of either claim 20 or 26 , wherein said antibody, or antigen-binding fragment thereof, is a neutralizing antibody.
38. The method of either claim 20 or 26 , wherein said antibody, or antigen-binding fragment thereof, is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a CDR-grafted antibody and a humanized antibody.
39. The method of either claim 20 or 26 , wherein said antibody, or antigen-binding fragment thereof, is a human antibody.
40. A method of treating rheumatoid arthritis in a subject, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to IL-21R in an amount sufficient to treat rheumatoid arthritis in the subject, wherein the IL-21R has a sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
41. The method of claim 40 , wherein said IL-21R has a sequence at least about 95% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
42. The method of claim 40 , wherein said IL-21R comprises the sequence of SEQ ID NO:2 from about amino acids 20–538.
43. The method of claim 40 , wherein said IL-21R comprises the sequence of SEQ ID NO:2.
44. The method of claim 40 , wherein said antibody, or antigen-binding fragment thereof, binds to an epitope found in the extracellular domain of IL-21R.
45. The method of claim 40 , further comprising administering to the subject a therapeutic agent selected from the group consisting of cytokine inhibitors, growth factor inhibitors, immunosuppressants, anti-inflammatory agents, metabolic inhibitors, enzyme inhibitors, cytotoxic agents, and cytostatic agents.
46. The method of claim 45 , wherein said therapeutic agent is selected from the group consisting of TNF antagonists, anti-TNF agents, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL-18 antagonists, IL-22 antagonists, T cell-depleting agents, B cell-depleting agents, cyclosporin, FK506, CCI-779, etanercept, infliximab, rituximab, adalimumab, prednisolone, azathioprine, gold, sulphasalazine, hydroxychloroquine, minocycline, anakinra, atabacept, methotrexate, leflunomide, rapamycin, rapamycin analogs, Cox-2 inhibitors, cPLA2 inhibitors, NSAIDs, p38 inhibitors, antagonists of B7.1, B7.2, ICOSL, ICOS, and CD28, and CTLA4 agonists.
47. The method of either claim 40 or 44 , wherein said antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously.
48. The method of either claim 40 or 44 , wherein said subject is a human.
49. The method of either claim 40 or 44 , wherein said antibody, or antigen-binding fragment thereof, is a neutralizing antibody.
50. The method of either claim 40 or 44 , wherein said antibody, or antigen-binding fragment thereof, is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a CDR-grafted antibody and a humanized antibody.
51. The method of either claim 40 or 44 , wherein said antibody, or antigen-binding fragment thereof, is a human antibody.
52. A method of treating an immune cell-associated pathology selected from the group consisting of an arthritic disorder, psoriasis, systemic lupus erythematosus, Crohn's disease, inflammatory bowel disease (IBD) and transplant rejection, in a subject, comprising administering to the subject an antibody against IL-21R, or an antigen-binding fragment thereof, in an amount sufficient to treat said pathology, wherein said IL-21R has a sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
53. The method of claim 52 , wherein said IL-21R has a sequence at least about 95% identical to the amino acid sequence of SEQ ID NO:2 and is capable of binding to an IL-21 polypeptide.
54. The method of claim 52 , wherein said IL-21R comprises the sequence of SEQ ID NO:2 from about amino acids 20–538.
55. The method of claim 52 , wherein said IL-21R comprises the sequence of SEQ ID NO:2.
56. The method of claim 52 , wherein said antibody, or antigen-binding fragment thereof, binds to an epitope found in the extracellular domain of IL-21 R.
57. The method of claim 52 , wherein said pathology is psoriasis.
58. The method of claim 52 , wherein said pathology is systemic lupus erythematosus.
59. The method of claim 52 , wherein said pathology is IBD.
60. The method of claim 52 , wherein said pathology is Crohn's disease.
61. The method of claim 52 , wherein said pathology is transplant rejection.
62. The method of claim 52 , wherein said antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously.
63. The method of claim 52 , wherein said subject is a human.
64. The method of claim 52 , wherein said antibody, or antigen-binding fragment thereof, is a neutralizing antibody.
65. The method of claim 52 , wherein said antibody, or antigen-binding fragment thereof, is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a CDR-grafted antibody and a humanized antibody.
66. The method of claim 52 , wherein said antibody, or antigen-binding fragment thereof, is a human antibody.