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 comprises a first variant IL-2 polypeptide and a second variant IL-2 polypeptide, wherein the first and second variant IL-2 polypeptides comprise an amino acid sequence having the amino acid sequence set forth in SEQ ID NO:44, wherein amino acid 16 is Ala and amino acid 42 is Ala, 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.
2. A pharmaceutical composition comprising a fusion polypeptide according to claim 1 .
3. A nucleic acid comprising a nucleotide sequence encoding a fusion polypeptide according to claim 1 .
4. A host cell comprising the nucleic acid of claim 3 .
5. A method of making a fusion polypeptide, the method comprising culturing a host cell according to claim 4 under conditions such that the host cell produces the fusion polypeptide.
6. The fusion polypeptide of claim 1 , wherein the plurality of variant IL-2 polypeptides consists of the first variant IL-2 polypeptide and the second variant IL-2 polypeptide.
7. A pharmaceutical composition comprising a fusion polypeptide according to claim 6 .
8. A nucleic acid comprising a nucleotide sequence encoding a fusion polypeptide according to claim 6 .
9. A host cell comprising the nucleic acid of claim 8 .
10. A method of making a fusion polypeptide, the method comprising culturing a host cell according to claim 9 under conditions such that the host cell produces the fusion polypeptide.
11. A method of making a fusion polypeptide according to claim 5 , wherein the host cell is a mammalian cell.
12. A method of making a fusion polypeptide according to claim 11 , wherein the mammalian cell is a CHO cell.
13. A method of making a fusion polypeptide according to claim 10 , wherein the host cell is a mammalian cell.
14. A method of making a fusion polypeptide according to claim 13 , wherein the mammalian cell is a CHO cell.