Engineered PD-1 variants
Isolated polypeptides comprising engineered mutant PD-1 polypeptide are provided, as are fusion polypeptides comprising the mutant and methods of use thereof. Bispecific PD-L1 and PD-L2 binding mutant PD-1 polypeptides are provided. PD-L2-specific binding mutant PD-1 polypeptides are also provided.
1. An isolated mutant programmed cell death 1 (PD-1) polypeptide comprising: (i) SEQ ID NO:2, wherein position 41 is an A and position 91 is an I, (ii) SEQ ID NO:3, wherein position 41 is an A and position 91 is an I, or (iii) an amino acid sequence having at least 95% identity to SEQ ID NO:2 or SEQ ID NO:3, wherein position 41 is an A and position 91 is an I, with the proviso that the mutant PD-1 polypeptide does not comprise SEQ ID NO:1.
2. The PD-1 polypeptide of claim 1 , comprising SEQ ID NO:2.
3. The PD-1 polypeptide of claim 1 , comprising SEQ ID NO:3.
4. The PD-1 polypeptide of claim 1 in monovalent form.
5. The PD-1 polypeptide of claim 1 , comprising SEQ ID NO:16.
6. A homo-oligomer comprising the PD-1 polypeptide of claim 1 .
7. The homo-oligomer of claim 6 , comprising two mutant PD-1 polypeptides.
8. A composition comprising the PD-1 polypeptide of claim 1 .
9. A fusion polypeptide comprising the mutant PD-1 polypeptide of claim 1 fused to an immunoglobulin domain polypeptide.
10. A method for stimulating T cell activation or treating a tumor in a subject comprising administering to the subject the PD-1 polypeptide of claim 1 , in an amount sufficient to stimulate T cell activation or treat the tumor, respectively, in the subject, wherein the tumor is a PD-L1-expressing tumor, PD-L2-expressing tumor, or a PD-L1 and PD-L2-expressing tumor.
11. The method of claim 10 , wherein the method is for treating a tumor.
12. The method of claim 10 , wherein the PD-1 polypeptide comprises SEQ ID NO: 2 or 3.
13. The method of claim 10 , wherein the PD-1 polypeptide comprises SEQ ID NO:16.
14. A composition comprising the fusion polypeptide of claim 9 .
15. The fusion polypeptide of claim 9 , wherein the mutant PD-1 polypeptide is fused to the immunoglobulin domain polypeptide by a peptide bond between a terminal amino acid of the mutant PD-1 polypeptide and a terminal amino acid of the immunoglobulin domain polypeptide.
16. The fusion polypeptide of claim 9 , wherein the immunoglobulin domain polypeptide comprises an immunoglobulin IgG1 Fc domain.
17. The fusion polypeptide of claim 16 , wherein the immunoglobulin IgG1 Fc domain is human.
18. The fusion polypeptide of claim 9 in monovalent form.
19. A homo-oligomer comprising the fusion polypeptide of claim 9 .
20. The homo-oligomer of claim 19 , comprising two fusion polypeptides.
21. The fusion polypeptide of claim 9 , comprising SEQ ID NO:16.
22. The fusion polypeptide of claim 9 , wherein the immunoglobulin domain polypeptide comprises an immunoglobulin IgV.
23. A method for stimulating T cell activation or treating a tumor in a subject comprising administering to the subject the PD-1 polypeptide of claim 9 , in an amount sufficient to stimulate T cell activation or treat the tumor, respectively, in the subject, wherein the tumor is a PD-L1-expressing tumor, PD-L2-expressing tumor, or a PD-L1 and PD-L2-expressing tumor.
24. The method of claim 23 , wherein the fusion polypeptide, comprises SEQ ID NO:2 or 3.
25. The method of claim 23 , wherein the method is for treating a tumor.
26. The method of claim 23 , wherein the fusion polypeptide comprises SEQ ID NO:16.
27. The method of claim 23 , wherein the fusion polypeptide comprises an immunoglobulin IgV.