PD-1 targeted IL-15/IL-15Rα Fc fusion proteins with improved properties
The present invention relates to fusion proteins comprising variant IL-15 proteins, fusion proteins comprising variant anti-PD-1 antigen binding domains, and fusion proteins comprising variant IL-15 proteins and variant anti-PD-1 antigen binding domains. The present invention also relates to nucleic acid molecules, expression vectors, host cells and methods for making such fusion proteins and the use of such fusion proteins in the treatment of cancer.
1. A composition comprising a variant IL-15 protein as compared to SEQ ID NO:2, said variant IL-15 protein comprising an amino acid modification selected from the group consisting of N71Q, N79Q, N112Q, S114del and S114A.
2. A pharmaceutical composition comprising the composition comprising a variant IL-15 protein according to claim 1 and a pharmaceutically acceptable carrier.
3. The composition according to claim 1 , wherein said variant IL-15 protein further comprises an amino acid modification selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D and Q108E.
4. The composition according to claim 1 , wherein said variant IL-15 protein comprises amino acid modifications selected from the group consisting of N71Q/N79Q, N71Q/N79Q/N112Q, N71Q/N79Q/S114del and N71Q/N79Q/S114A.
5. The composition according to claim 1 , wherein said variant IL 15 protein comprises amino acid modifications selected from the group consisting of N1D/N4D/D8N, N1D/N4D/N65D, N1D/D30N, N1D/D61N, N1D/D61N/E64Q/Q108E, N1D/E64Q, N1D/N65D, N1D/Q108E, N4D/D30N, N4D/D61N, N4D/D61N/N65D, N4D/D61N/E64Q/Q108E, N4D/E64Q, N4D/N65D, D8N/D61N, D8N/E64Q, D30N/E64Q, D30N/N65D, D30N/E64Q/N65D, D30N/Q180E, D61N/E64Q/N65D, E64Q/N65D, E64Q/Q108E and N65D/Q108E.
6. The composition according to claim 1 , wherein said variant IL 15 protein comprises the amino acid modifications N71Q/N79Q/N112Q.
7. The composition according to claim 1 , wherein said variant IL 15 protein comprises the amino acid modifications N71Q/N79Q/N112Q and D30N/N65D.
8. The composition according to claim 1 , wherein said variant IL-15 protein comprises the amino acid modifications N71Q/N79Q/N112Q and D30N/E64Q/N65D.
9. The pharmaceutical composition according to claim 2 , wherein said variant IL-15 protein further comprises an amino acid modification selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D and Q108E.
10. The pharmaceutical composition according to claim 2 , wherein said variant IL-15 protein comprises amino acid modifications selected from the group consisting of N71Q/N79Q, N71Q/N79Q/N112Q, N71Q/N79Q/S114del and N71Q/N79Q/S114A.
11. The pharmaceutical composition according to claim 2 , wherein said variant IL 15 protein comprises amino acid modifications selected from the group consisting of N1D/N4D/D8N, N1D/N4D/N65D, N1D/D30N, N1D/D61N, N1D/D61N/E64Q/Q108E, N1D/E64Q, N1D/N65D, N1D/Q108E, N4D/D30N, N4D/D61N, N4D/D61N/N65D, N4D/D61N/E64Q/Q108E, N4D/E64Q, N4D/N65D, D8N/D61N, D8N/E64Q, D30N/E64Q, D30N/N65D, D30N/E64Q/N65D, D30N/Q180E, D61N/E64Q/N65D, E64Q/N65D, E64Q/Q108E and N65D/Q108E.
12. The pharmaceutical composition according to claim 2 , wherein said variant IL 15 protein comprises the amino acid modifications N71Q/N79Q/N112Q.
13. The composition according to claim 2 , wherein said variant IL 15 protein comprises the amino acid modifications N71Q/N79Q/N112Q and D30N/N65D.
14. The composition according to claim 2 , wherein said variant IL-15 protein comprises the amino acid modifications N71Q/N79Q/N112Q and D30N/E64Q/N65D.
15. The composition according to claim 14 , wherein said variant IL-15 protein comprises the amino acid sequence of SEQ ID NO: 319.