CD80 variant immunomodulatory proteins and uses thereof
Provided herein are variant CD80 polypeptides, immunomodulatory proteins comprising variant CD80 polypeptides, and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.
1. An engineered T cell, comprising a nucleic acid encoding a fusion protein of the formula CD80-linker-Fc, wherein CD80 is a variant CD80 polypeptide comprising the amino acid substitutions H18Y, A26E, E35D, M47L, V68M, A71G and D90G in the amino acid sequence set forth in SEQ ID NO: 2 or a portion thereof comprising the IgV domain, wherein the IgV domain is amino acids 35-141 of SEQ ID NO:1.
2. The engineered T cell of claim 1 , wherein a homodimer of the fusion protein is secretable from the engineered cell.
3. The engineered T cell of claim 1 , wherein the cell further comprises a chimeric antigen receptor (CAR) or an engineered T cell receptor (TCR).
4. The engineered T cell of claim 1 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO: 2276.
5. The engineered T cell of claim 1 , wherein the linker has 1-20 amino acid residues.
6. The engineered T cell of claim 1 , wherein the linker is GSGGGS (SEQ ID NO: 1716).
7. The engineered T cell of claim 1 , wherein the Fc is a variant human IgG1 Fc with reduced effector function.
8. The engineered T cell of claim 1 , wherein the Fc is set forth in SEQ ID NO:1712, SEQ ID NO:1713, SEQ ID NO:1714 or SEQ ID NO:1715.
9. The engineered T cell of claim 1 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716 and the Fc is set forth in SEQ ID NO:1712.
10. The engineered T cell of claim 1 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1713.
11. The engineered T cell of claim 1 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1714.
12. The engineered T cell of claim 1 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1715.
13. The engineered T cell of claim 2 , wherein the cell further comprises a chimeric antigen receptor (CAR) or an engineered T cell receptor (TCR).
14. The engineered T cell of claim 2 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO: 2276.
15. The engineered T cell of claim 2 , wherein the linker is GSGGGS (SEQ ID NO: 1716).
16. The engineered T cell of claim 2 , wherein the Fc is a variant human IgG1 Fc with reduced effector function.
17. The engineered T cell of claim 2 , wherein the Fc is set forth in SEQ ID NO:1712, SEQ ID NO:1713, SEQ ID NO:1714 or SEQ ID NO:1715.
18. The engineered T cell of claim 2 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716 and the Fc is set forth in SEQ ID NO:1712.
19. The engineered T cell of claim 2 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1713.
20. The engineered T cell of claim 2 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1714.
21. An engineered T cell, comprising: (i) a nucleic acid encoding a fusion protein of the formula CD80-linker-Fc, wherein CD80 is a variant CD80 polypeptide set forth in SEQ ID NO:2276, wherein a homodimer of the fusion protein is secretable from the engineered cell; and (ii) a chimeric antigen receptor (CAR).
22. The engineered T cell of claim 21 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716 and the Fc is set forth in SEQ ID NO:1712.
23. The engineered T cell of claim 21 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1713.
24. The engineered T cell of claim 21 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1714.
25. The engineered T cell of claim 21 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1715.
26. An engineered T cell, comprising: (i) a nucleic acid encoding a fusion protein of the formula CD80-linker-Fc, wherein CD80 is a variant CD80 polypeptide set forth in SEQ ID NO:2276, wherein a homodimer of the fusion protein is secretable from the engineered cell; and (ii) an engineered T cell receptor (TCR).
27. The engineered T cell of claim 26 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716 and the Fc is set forth in SEQ ID NO:1712.
28. The engineered T cell of claim 26 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1713.
29. The engineered T cell of claim 26 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1714.
30. The engineered T cell of claim 26 , wherein the variant CD80 polypeptide is set forth in SEQ ID NO:2276, the linker is set forth in SEQ ID NO: 1716, and the Fc is set forth in SEQ ID NO:1715.