Methods of using interleukin-2 agents
IL-2 agents that comprise IL-2 variants are disclosed as well as methods, compositions, and uses thereof. The IL-2 agents described herein can be used to treat and/or prevent various disorders and conditions.
1. A method of conditioning a subject prior to a skin transplantation, comprising administering to the subject an effective amount of an IL-2 agent,
wherein the IL-2 agent is an IL-2 variant or an IL-2 fusion protein comprising the IL-2 variant, and wherein the IL-2 variant comprises the amino acid sequence of SEQ ID NO: 5,
thereby conditioning the subject prior to the skin transplantation.
2. The method of claim 1 , wherein the conditioning the subject prior to the transplantation comprises increasing the number of T regulatory cells, or the ratio of T regulatory cells over non-T-regulatory T cells or NK cells, in the subject or in a sample from the subject.
3. The method of claim 2 , wherein the ratio is increased by about 20% or more, or about 2-fold or more.
4. The method of claim 1 , wherein the method further comprises administering the IL-2 agent during the skin transplantation and/or after the skin transplantation.
5. The method of claim 1 , wherein the IL-2 fusion protein further comprises an Fc region.
6. The method of claim 5 , wherein the Fc region comprises an Fc region of IgG1 allotype m3 comprising an N297G substitution according to EU numbering.
7. The method of claim 5 , wherein the Fc region comprises the amino acid sequence of SEQ ID NO: 1003, or an amino acid sequence that is at least 95% identical thereto or differs by no more than 10 amino acids therefrom.
8. The method of claim 7 , wherein the Fc region is fused to the C-terminus of the IL-2 variant.
9. The method of claim 1 , wherein the IL-2 fusion protein further comprises a linker.
10. The method of claim 9 , wherein the linker comprises (G4S)4 (SEQ ID NO: 48).
11. The method of claim 1 , wherein the fusion protein forms a dimer.
12. The method of claim 1 , wherein the subject is a human, a non-human primate, or a mouse.
13. The method of claim 1 , further comprising administering to the subject one or more additional immunosuppressive agents chosen from cyclosporine, tacrolimus, mycophenolate mofetil, prednisone, azathioprine, sirolimus, daclizumab, or basiliximab.
14. The method of claim 1 , further comprising determining the activity of T regulatory cells.
15. The method of claim 14 , wherein the activity of T regulatory cells is determined by an ex vivo suppression assay.
16. The method of claim 1 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 1008, or an amino acid sequence that is at least 95% identical thereto or differs by no more than 10 amino acids therefrom.
17. The method of claim 1 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 1008.
18. A method of inducing and/or modulating immunosuppression in a subject, comprising administering to the subject an effective amount of an IL-2 agent,
wherein the subject has undergone, is undergoing, or will receive a skin transplantation,
wherein the IL-2 agent is an IL-2 fusion protein comprising an IL-2 variant, and wherein the IL-2 variant comprises the amino acid sequence of SEQ ID NO: 5,
thereby inducing and/or modulating immunosuppression in the subject.
19. The method of claim 18 , wherein the inducing and/or modulating immunosuppression in the subject comprises increasing the number of T-regulatory cells, or the ratio of T regulatory cells over non-T regulatory T cells or NK cells, in the subject or in a sample from the subject.
20. The method of claim 19 , wherein the ratio is increased by about 20% or more, or about 2-fold or more.
21. The method of claim 18 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO:1008, or an amino acid sequence that is at least 95% identical thereto or differs by no more than 10 amino acids therefrom.
22. The method of claim 18 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 1008.
23. A method of selectively increasing T regulatory cells in a subject, comprising administering to the subject an effective amount of an IL-2 agent,
wherein the subject has undergone, is undergoing, or will receive a skin transplantation, and
wherein the IL-2 agent is an IL-2 fusion protein comprising an IL-2 variant, and wherein the IL-2 variant comprises the amino acid sequence of SEQ ID NO: 5,
thereby selectively increasing T regulatory cells in the subject.
24. The method of claim 23 , wherein the T regulatory cells are increased by about 20% or more relative to non-T regulatory T cells, NK cells, non-T regulatory CD4+ cells, or CD8+ cells.
25. The method of claim 23 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 1008, or an amino acid sequence that is at least 95% identical thereto or differs by no more than 10 amino acids therefrom.
26. The method of claim 23 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 1008.
27. A method of treating a subject, comprising administering to the subject an effective amount of an IL-2 agent, and providing to the subject a skin transplantation,
wherein the IL-2 agent is an IL-2 fusion protein comprising an IL-2 variant, and wherein the IL-2 variant comprises the amino acid sequence of SEQ ID NO: 5,
thereby treating the subject.
28. The method of claim 23 , wherein the method induces and/or modulates immunosuppression, or selectively increases T regulatory cells in the subject.
29. The method of claim 28 , wherein the IL-2 agent is administered to the subject prior to, during, and/or after the transplantation.
30. The method of claim 27 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 1008, or an amino acid sequence that is at least 95% identical thereto or differs by no more than 10 amino acids therefrom.
31. The method of claim 27 , wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 1008.