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 pharmaceutical composition comprising a homodimer of two heterodimers, wherein each heterodimer comprises:
a) a first polypeptide comprising:
i) a cancer-associated epitope other than a human papillomavirus epitope; and
ii) a first major histocompatibility complex (MHC) Class I polypeptide, wherein the first MHC polypeptide is a β2-microglobulin (β2M) polypeptide comprising an amino acid sequence having at least 95% percent amino acid sequence identity to amino acids 21 to 119 of SEQ ID NO:95, and
b) a second polypeptide comprising:
i) two copies of a variant IL-2 polypeptide, each copy comprising an amino acid sequence having at least 98% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:44, wherein amino acid 16 is other than a His and amino acid 42 is other than a Phe, wherein the two variant IL-2 polypeptides are linked by a peptide linker;
ii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC Class I heavy chain polypeptide; and
iii) an immunoglobulin (Ig) Fc polypeptide, and
wherein each heterodimer comprises a disulfide bond that covalently links a Cys residue in the β2M polypeptide to a Cys residue in the MHC class I heavy chain polypeptide, and
wherein the two heterodimers are joined to each other by one or more disulfide bonds that join the Ig Fc polypeptide of one heterodimer to the Ig Fc polypeptide of the other heterodimer, and
wherein the percent sequence identity is determinable by a sequence alignment performed using BLAST.
2. The pharmaceutical composition of 1, wherein each heterodimer comprises an IgG1 Fc polypeptide that comprises an amino acid sequence having at least about 95% percent amino acid sequence identity to SEQ ID NO:57, wherein the percent sequence identity is determinable by a sequence alignment performed using BLAST, and
wherein amino acid 16 in each of the variant IL-2 polypeptides in each heterodimer is Ala, Glu, Thr, or Asp.
3. The pharmaceutical composition of claim 2 , wherein amino acid 42 in each of the variant IL-2 polypeptides in each heterodimer is Ala.
4. The pharmaceutical composition of claim 3 , wherein the Ig Fc polypeptide of each heterodimer comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO:57, and wherein amino acid 16 in each of the variant IL-2 polypeptides in each heterodimer is Ala.
5. The pharmaceutical composition of claim 1 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-A heavy chain polypeptide.
6. The pharmaceutical composition of claim 1 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-A heavy chain polypeptide.
7. The pharmaceutical composition of claim 3 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-A heavy chain polypeptide.
8. The pharmaceutical composition of claim 4 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-A heavy chain polypeptide.
9. The pharmaceutical composition of claim 1 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-E heavy chain polypeptide.
10. The pharmaceutical composition of claim 2 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-E heavy chain polypeptide.
11. The pharmaceutical composition of claim 3 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-E heavy chain polypeptide.
12. The pharmaceutical composition of claim 4 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-E heavy chain polypeptide.
13. The pharmaceutical composition of claim 1 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-B heavy chain polypeptide or HLA-C heavy chain polypeptide.
14. The pharmaceutical composition of claim 2 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-B heavy chain polypeptide or HLA-C heavy chain polypeptide.
15. The pharmaceutical composition of claim 3 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-B heavy chain polypeptide or HLA-C heavy chain polypeptide.
16. The pharmaceutical composition of claim 4 , wherein the MHC Class I heavy chain polypeptide in each heterodimer is an HLA-B heavy chain polypeptide or HLA-C heavy chain polypeptide.
17. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 1 , to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
18. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 2 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
19. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 3 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
20. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 4 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
21. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 5 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
22. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 6 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
23. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 7 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
24. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 8 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
25. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 9 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
26. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 10 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
27. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 11 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
28. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 12 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
29. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 15 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
30. A method of treating cancer in a patient in need of such treatment, the method comprising administering the pharmaceutical composition of claim 16 to the patient, wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.