Superagonists, partial agonists and antagonists of interleukin-2
Novel human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2RP receptor and a decreased binding capacity for IL-2RΥ c receptor, as compared to wild-type IL-2. Such IL-2 muteins are useful, for example, as IL-2 partial agonist and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is useful (e.g., in the treatment of graft versus host disease (GVHD) and adult T cell leukemia). Also provided are nucleic acids encoding such IL-2 muteins, methods of making such IL-2 muteins, pharmaceutical compositions that include such IL-2 muteins and methods of treatment using such pharmaceutical compositions.
1. An IL-2 mutein having an increased binding affinity for IL-2Rβ and a decreased binding affinity for IL-2Rγc receptor as compared to wild-type human IL-2 (hIL-2), wherein said IL-2 mutein comprises amino acid substitutions L18R, Q22E, Q126T, and S130R, numbered in accordance with wild-type hIL-2.
2. The IL-2 mutein of claim 1 , wherein the IL-2 mutein further comprises one or more amino acid substitutions that increase IL-2Rβ binding affinity, wherein the one or more amino acid substitutions that increase IL-2Rβ binding affinity are selected from the group consisting of: Q74N, Q74H, Q74S, L80F, L8V, R81D, R81T, L85V, I86V, I89V, and I93V.
3. The IL-2 mutein of claim 2 , wherein the IL-2 mutein comprises amino acid substitutions L80F, R81D, L85V, I86V, and I92F, and which increase IL-2β binding affinity.
4. The IL-2 mutein of claim 2 , wherein the IL-2 mutein comprises amino acid substitutions Q74N, L80F, R81D, L85V, I86V, I89V, and I92F, and which increase IL-2Rβ binding affinity.
5. The IL-2 mutein of claim 2 , wherein the IL-2 mutein comprises amino acid substitutions Q74N, L80V, R81T, L85V, I86V, and I92F, and which increase IL-2Rβ binding affinity.
6. The IL-2 mutein of claim 2 , wherein the IL-2 mutein comprises amino acid substitutions Q74H, L80F, R81D, L85V, I86V, and I92F, and which increase IL-2Rβ binding affinity.
7. The IL-2 mutein of claim 2 , wherein the IL-2 mutein comprises amino acid substitutions Q74S, L80F, R81D, L85V, I86V, and I92F, and which increase IL-2Rβ binding affinity.
8. The IL-2 mutein of claim 2 , wherein the IL-2 mutein comprises amino acid substitutions Q74N, L80F, R81D, L85V, I86V, and I92F, and which increase IL-2Rβ binding affinity.
9. The IL-2 mutein of claim 2 , wherein the IL-2 mutein comprises amino acid substitutions Q74S, R81T, L85V, and I92F, and which increase IL-2Rβ binding affinity.
10. The IL-2 mutein of claim 1 , wherein the mutein has a decreased capability to stimulate STAT5 phosphorylation in an IL-2Rβ+ T cell as compared to wild-type hIL-2.
11. The IL-2 mutein of claim 10 , wherein the T cell is a CD8+ T cell.
12. The IL-2 mutein of claim 1 , wherein the mutein has a decreased capability to stimulate the pERK1/ERK2 signaling in a IL-2Rβ+ cell as compared to wild-type hIL-2.
13. The IL-2 mutein of claim 1 , wherein the mutein is an IL-2 or IL-15 antagonist.
14. The IL-2 mutein of claim 13 , wherein the mutein is an inhibitor of IL-2 or IL-15 STAT5 phosphorylation in CD8+ T cells.
15. The IL-2 mutein of claim 13 , wherein the mutein is an inhibitor of IL-2 or IL-15 induced proliferation of CD8+ T cells.
16. The IL-2 mutein of claim 13 , wherein the mutein is an inhibitor of IL-2 dependent, TCR-induced cell proliferation.
17. The IL-2 mutein of claim 13 , wherein the mutein is an inhibitor of IL-2 dependent Th1, Th9 or Treg differentiation.
18. The IL-2 mutein of claim 13 , wherein the mutein is a promoter of Th17 differentiation.
19. The IL-2 mutein of claim 13 , wherein the mutein is an inhibitor of IL-2 dependent activation of NK cells.
20. An IL-2 mutein fusion protein comprising the IL-2 mutein of claim 1 linked to a human Fc antibody fragment.
21. An IL-2 mutein fusion protein comprising the IL-2 mutein of claim 1 and a heterologous polypeptide.
22. An IL-2 mutein fusion protein comprising the IL-2 mutein of claim 1 and an albumin polypeptide.
23. An IL-2 mutein having an increased binding affinity for IL-2Rβ and a decreased binding affinity for IL-2Rγc receptor as compared to wild-type human IL-2, wherein the IL-2 mutein comprises the amino acid substitutions L80F, R81D, L85V, I86V, I92F, L18R, Q22E, Q126T, and S130R, numbered in accordance with wild-type hIL-2.
24. An IL-2 mutein fusion protein comprising the IL-2 mutein of claim 23 linked to a human Fc antibody fragment.
25. An IL-2 mutein fusion protein comprising the IL-2 mutein of claim 23 and a heterologous polypeptide.
26. An IL-2 mutein fusion protein comprising the IL-2 mutein of claim 23 and an albumin polypeptide.