Antagonists of interleukin-2 receptor
Novel human interleukin-2 (IL-2) muteins or variants thereof, and nucleic acid molecules and variants thereof are provided. Methods for producing these muteins as well as methods for stimulating the immune system of an animal are also disclosed. In addition, the invention provides recombinant expression vectors comprising the nucleic acid molecules of this invention and host cells into which expression vectors have been introduced. Pharmaceutical compositions are included comprising a therapeutically effective amount of a human IL-2 mutein of the invention and a pharmaceutically acceptable carrier. The IL-2 muteins can be used in pharmaceutical compositions for use in treatment of cancer and in stimulating the immune response.
1. An interleukin-2 receptor β (IL-2Rβ) binding protein, wherein the equilibrium dissociation constant for the IL-2Rβ of said binding protein is less than that of wild-type human IL-2 (hIL-2), and wherein said IL-2Rβ binding protein comprises the following amino acid substitutions: L80F, R81D, L85V, I86V, and I92F, numbered in accordance with wild-type hIL-2.
2. The binding protein of claim 1 , wherein the binding protein further comprises one or more amino acid substitutions at positions selected from the group consisting of I24, F42, K43, P65, Q74, I89, and V93.
3. The binding protein of claim 1 , wherein the binding protein further comprises one or more amino acid substitutions at positions selected from the group consisting of F42 and K43.
4. The binding protein of claim 1 , wherein the binding protein further comprises the following amino acid substitution: K43N.
5. The binding protein of claim 1 , wherein the binding protein further comprises the following amino acid substitution: F42A.
6. The binding protein of claim 1 , wherein the binding protein comprises the following substitutions: F42A, L80F, R81D, L85V, I86V, I89V, and I92F.
7. The binding protein of claim 1 , wherein the binding protein further comprises one or more amino acid substitutions selected from the group consisting of I24V, P65H, Q74R, Q74H, Q74N, Q74S, I89V, and V93I.
8. The binding protein of claim 7 , wherein the binding protein comprises the following amino acid substitution: Q74N.
9. The binding protein of claim 1 , wherein the binding protein comprises the following substitutions: Q74N, L80F, R81D, L85V, I86V, I89V, and I92F.
10. The binding protein of claim 1 , wherein the binding protein comprises the following substitutions: L80F, R81D, L85V, I86V, I89V, I92F, and V93I.
11. The binding protein of claim 1 , wherein the binding protein comprises the following substitutions: Q74H, L80F, R81D, L85V, I86V, and I92F.
12. The binding protein of claim 1 , wherein the binding protein comprises the following substitutions: Q74S, L80F, R81D, L85V, I86V, and I92F.
13. The binding protein of claim 1 , wherein the binding protein comprises the following substitutions: Q74N, L80F, R81D, L85V, I86V, and I92F.
14. The binding protein of claim 3 , which exhibits reduced binding to an IL-2Rα relative to wild-type IL-2.
15. The binding protein of claim 1 , wherein the binding protein comprises the following substitutions: T18R, P22E, L80F, R81D, L85V, I86V, I89V, I92F, V93I, and E126T.
16. The binding protein of claim 15 , wherein said binding protein inhibits interaction between IL-2Rβ and IL-2Rγ.
17. The binding protein of claim 15 , which exhibits reduced binding to IL-2Rγ relative to wild-type IL-2.
18. The binding protein of claim 15 , which exhibits reduced signaling through IL-2Rγ relative to wild-type IL-2.