Methods for modulating an immune response
The present disclosure provides methods of modulating an immune response in an individual. The present disclosure provides methods of treatment. The present disclosure provides methods comprising administering a multimeric polypeptide (synTac) and an immune checkpoint inhibitor to an individual. The present disclosure provides methods comprising administering a multimeric polypeptide (synTac) to an individual who is undergoing treatment with immune checkpoint inhibitor.
1. A method of treating an individual having a cancer that expresses an HPV16 E7 antigen, the method comprising administering to the individual a combination of (i) an effective amount of an immune checkpoint inhibitor that targets PD-1, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, and (ii) an effective amount of a protein that is a homodimer of two multimeric polypeptides, wherein each multimeric polypeptide comprises:
a) a first polypeptide comprising from N-terminus to C-terminus:
i) an HPV16 E7 epitope comprising amino acid sequence YMLDLQPETT (SEQ ID NO:77);
ii) a linker comprising amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:207); and
iii) a β2-microglobulin (β2M) polypeptide comprising the amino acid sequence set forth in SEQ ID NO:48; and
b) a second polypeptide comprising:
i) two copies of an IL-2 polypeptide, each copy comprising the amino acid sequence set forth in SEQ ID NO:49;
ii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide comprising the amino acid sequence as set forth in SEQ ID NO:50; and
iii) an immunoglobulin (Ig) Fc polypeptide, and
wherein the multimeric polypeptides are joined to each other by one or more disulfide bonds that join the Ig Fc polypeptide of one multimeric polypeptide to the Ig Fc polypeptide of the other multimeric polypeptide, and
wherein the immune checkpoint inhibitor and the protein are administered at the same time or at different times.
2. A method of treating according to claim 1 ,
wherein the Ig Fc polypeptide comprises an amino acid sequence having at least about 95% amino acid sequence identity to SEQ ID NO:21, and wherein the Ig Fc polypeptide comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO:44;
wherein each multimeric polypeptide comprises a disulfide bond joining the Cys residue at amino acid 12 of the β2M polypeptide and the Cys residue at amino acid 236 of the class I MHC heavy chain polypeptide, and
wherein the second polypeptide comprises a peptide linker between one or more of:
a) a first copy of the IL-2 polypeptide and a second copy of the IL-2 polypeptide;
b) one of the two copies of the IL-2 polypeptide and the MHC class I heavy chain polypeptide; and
c) the MHC class I heavy chain polypeptide and the Ig Fc polypeptide.
3. A method according to claim 1 , wherein the cancer is a head and neck cancer.
4. A method according to claim 2 , wherein the cancer is a head and neck cancer.
5. A method according to claim 1 , wherein the cancer is a cervical cancer, or a genitoanal cancer.
6. A method according to claim 2 , wherein the cancer is a cervical cancer, or a genitoanal cancer.
7. A method according to claim 1 , wherein the individual has become refractory to a prior treatment for the cancer or has failed to respond to a prior treatment for the cancer.
8. A method according to claim 2 , wherein the individual has become refractory to a prior treatment for the cancer or has failed to respond to a prior treatment for the cancer.
9. A method according to claim 1 , wherein the protein is administered in an amount of administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.
10. A method according to claim 2 , wherein the protein is administered in an amount of administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.
11. A method according to claim 3 , wherein the protein is administered in an amount of administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.
12. A method according to claim 4 , wherein the protein is administered in an amount of administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.
13. A method according to claim 5 , wherein the protein is administered in an amount of administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.
14. A method according to claim 6 , wherein the protein is administered in an amount of administered in an amount of from 1 mg/kg to 5 mg/kg of body weight.
15. A method according to claim 1 , wherein the immune checkpoint inhibitor is nivolumab.
16. A method according to claim 2 , wherein the immune checkpoint inhibitor is nivolumab.
17. A method according to claim 3 , wherein the immune checkpoint inhibitor is nivolumab.
18. A method according to claim 4 , wherein the immune checkpoint inhibitor is nivolumab.
19. A method according to claim 5 , wherein the immune checkpoint inhibitor is nivolumab.
20. A method according to claim 6 , wherein the immune checkpoint inhibitor is nivolumab.
21. A method according to claim 7 , wherein the immune checkpoint inhibitor is nivolumab.
22. A method according to claim 8 , wherein the immune checkpoint inhibitor is nivolumab.
23. A method according to claim 9 , wherein the immune checkpoint inhibitor is nivolumab.
24. A method according to claim 10 , wherein the immune checkpoint inhibitor is nivolumab.
25. A method according to claim 11 , wherein the immune checkpoint inhibitor is nivolumab.
26. A method according to claim 12 , wherein the immune checkpoint inhibitor is nivolumab.
27. A method according to claim 13 , wherein the immune checkpoint inhibitor is nivolumab.
28. A method according to claim 14 , wherein the immune checkpoint inhibitor is nivolumab.