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 plurality of variant IL-2 polypeptides, wherein the plurality consists of a first variant IL-2 polypeptide and a second variant IL-2 polypeptide, wherein the first and second variant IL-2 polypeptides have the amino acid sequence set forth in SEQ ID NO:84, and wherein the first and second variant IL-2 polypeptides are joined by a linker; 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 is an antibody Fc region having at least 98% sequence identity to the amino acid sequence set forth in SEQ ID NO:57, wherein the percent sequence identity is determinable by a sequence alignment performed using BLAST, and
wherein the fusion polypeptide comprises from 500 to 600 amino acids.
2. The fusion polypeptide of claim 1 , 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.
3. The fusion polypeptide of claim 1 , wherein the antibody Fc region has the amino acid sequence of SEQ ID NO:83.
4. A pharmaceutical composition comprising a fusion polypeptide according to claim 1 .
5. A pharmaceutical composition comprising a fusion polypeptide according to claim 2 .
6. A pharmaceutical composition comprising a fusion polypeptide according to claim 3 .
7. A nucleic acid comprising a nucleotide sequence encoding a fusion polypeptide according to claim 1 .
8. A nucleic acid comprising a nucleotide sequence encoding a fusion polypeptide according to claim 2 .
9. A nucleic acid comprising a nucleotide sequence encoding a fusion polypeptide according to claim 3 .
10. A host cell comprising the nucleic acid of claim 7 .
11. A host cell comprising the nucleic acid of claim 8 .
12. A host cell comprising the nucleic acid of claim 9 .
13. A method of making a fusion polypeptide, the method comprising culturing a host cell according to claim 10 under conditions such that the host cell produces the fusion polypeptide.
14. A method of making a fusion polypeptide, the method comprising culturing a host cell according to claim 11 under conditions such that the host cell produces the fusion polypeptide.
15. A method of making a fusion polypeptide, the method comprising culturing a host cell according to claim 12 under conditions such that the host cell produces the fusion polypeptide.