T-cell modulatory multimeric polypeptides and methods of use thereof
The present disclosure provides variant immunomodulatory polypeptides, and fusion polypeptides comprising the variant immunomodulatory peptides. The present disclosure provides T-cell modulatory multimeric polypeptides, and compositions comprising same, where the T-cell modulatory multimeric polypeptides comprise a variant immunomodulatory polypeptide of the present disclosure. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the T-cell modulatory multimeric polypeptides, and host cells comprising the nucleic acids. The present disclosure provides methods of modulating the activity of a T cell; the methods comprise contacting the T cell with a T-cell modulatory multimeric polypeptide of the present disclosure.
1. A fusion polypeptide comprising:
a) a variant IL-2 polypeptide, wherein the variant IL-2 polypeptide comprises up to five amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:1, and wherein amino acid 16 is Glu and amino acid 42 is Ala; and
b) an antibody Fc region,
wherein the fusion polypeptide does not comprise a major histocompatibility complex (MHC) polypeptide, and
wherein the fusion polypeptide comprises from 300 to 700 amino acids.
2. The fusion polypeptide of claim 1 , wherein the fusion polypeptide comprises from 300 to 400 amino acids.
3. The fusion polypeptide of claim 2 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
4. The fusion polypeptide of claim 1 , wherein the fusion polypeptide comprises from 400 to 500 amino acids.
5. The fusion polypeptide of claim 4 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
6. The fusion polypeptide of claim 1 , wherein the fusion polypeptide comprises from 500 to 600 amino acids.
7. The fusion polypeptide of claim 6 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
8. The fusion polypeptide of claim 1 , wherein the fusion polypeptide comprises from 600 to 700 amino acids.
9. The fusion polypeptide of claim 8 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
10. A fusion polypeptide comprising:
a) a variant IL-2 polypeptide, wherein the variant IL-2 polypeptide comprises up to four amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:1, and wherein amino acid 16 is Glu and amino acid 42 is Ala; and
b) an antibody Fc region,
wherein the fusion polypeptide does not comprise a major histocompatibility complex (MHC) polypeptide, and
wherein the fusion polypeptide comprises from 300 to 700 amino acids.
11. The fusion polypeptide of claim 10 , wherein the fusion polypeptide comprises from 300 to 400 amino acids.
12. The fusion polypeptide of claim 11 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
13. The fusion polypeptide of claim 10 , wherein the fusion polypeptide comprises from 400 to 500 amino acids.
14. The fusion polypeptide of claim 13 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
15. The fusion polypeptide of claim 10 , wherein the fusion polypeptide comprises from 500 to 600 amino acids.
16. The fusion polypeptide of claim 15 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
17. The fusion polypeptide of claim 10 , wherein the fusion polypeptide comprises from 600 to 700 amino acids.
18. The fusion polypeptide of claim 17 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
19. A fusion polypeptide comprising:
a) a variant IL-2 polypeptide, wherein the variant IL-2 polypeptide comprises up to five amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:1, and wherein amino acid 16 is Glu and amino acid 42 is Ala; and
b) a heterologous fusion partner, wherein the heterologous fusion partner does not comprise a major histocompatibility complex (MHC) polypeptide, and
wherein the heterologous fusion partner comprises an antibody Fc region and an antigen-binding region of an antibody.
20. The fusion polypeptide of claim 19 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
21. A fusion polypeptide comprising:
a) a variant IL-2 polypeptide, wherein the variant IL-2 polypeptide comprises up to four amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:1, and wherein amino acid 16 is Glu and amino acid 42 is Ala; and
b) a heterologous fusion partner,
wherein the heterologous fusion partner does not comprise a major histocompatibility complex (MHC) polypeptide, and
wherein the heterologous fusion partner comprises an antibody Fc region and an antigen-binding region of an antibody.
22. The fusion polypeptide of claim 21 , wherein the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and wherein the Ig Fc region comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO: 57.
23. The fusion polypeptide of claim 19 , wherein the fusion polypeptide comprises from 500 to 600 amino acids.
24. The fusion polypeptide of claim 19 , wherein the fusion polypeptide comprises from 600 to 700 amino acids.
25. The fusion polypeptide of claim 2 , wherein the fusion polypeptide comprises from 500 to 600 amino acids.
26. The fusion polypeptide of claim 20 , wherein the fusion polypeptide comprises from 600 to 700 amino acids.
27. The fusion polypeptide of claim 21 , wherein the fusion polypeptide comprises from 500 to 600 amino acids.
28. The fusion polypeptide of claim 21 , wherein the fusion polypeptide comprises from 600 to 700 amino acids.
29. The fusion polypeptide of claim 22 , wherein the fusion polypeptide comprises from 500 to 600 amino acids.
30. The fusion polypeptide of claim 22 , wherein the fusion polypeptide comprises from 600 to 700 amino acids.