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 heterodimer comprising:
a) a first polypeptide comprising:
i) a human papillomavirus epitope, wherein the epitope comprises the amino acid sequence YMLDLQPETT (SEQ ID NO:13); and
ii) a first major histocompatibility complex (MHC) polypeptide, wherein the first MHC polypeptide is a β2-microglobulin (β2M) polypeptide comprising an amino acid sequence as set forth in SEQ ID NO:17, and
b) a second polypeptide comprising:
i) two copies of an IL-2 polypeptide, each copy comprising an amino acid sequence set forth in SEQ ID NO:84;
iii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide comprising an amino acid sequence as set forth in SEQ ID NO:19; and
iv) an immunoglobulin (Ig) Fc polypeptide,
wherein the first polypeptide and the second polypeptide are covalently linked to one another via a disulfide bond.
2. A heterodimer according to claim 1 ,
wherein the Ig Fc polypeptide 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 the Ig Fc polypeptide comprises an L14A substitution and an L15A substitution based on the amino acid numbering depicted in SEQ ID NO:57,
wherein the first and second polypeptides are covalently linked to one another via a disulfide bond between 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,
wherein the first polypeptide comprises a peptide linker between the epitope and the β2M 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 homodimer comprising two heterodimers according to claim 1 , 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.
4. A homodimer comprising two heterodimers according to claim 2 , 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.
5. A pharmaceutical composition comprising a heterodimer of claim 1 .
6. A pharmaceutical composition comprising a heterodimer of claim 2 .
7. A pharmaceutical composition comprising a homodimer of claim 3 .
8. A pharmaceutical composition comprising a homodimer of claim 4 .
9. A method of treating an HPV16-associated cancer or an HPV16-attributable cancer in a patient in need of such treatment, the method comprising administering a pharmaceutical composition of claim 5 to the patient in an amount effective to treat said cancer.
10. The method of claim 9 , wherein said cancer is a head and neck cancer.
11. The method of claim 9 , wherein said cancer is a cervical cancer or a genitoanal cancer.
12. The method according to claim 9 , 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.
13. The method according to claim 9 , wherein the heterodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight or from about 5 mg/kg to about 10 mg/kg of body weight.
14. A method of treating an HPV16-associated cancer or an HPV16-attributable cancer in a patient in need of such treatment, the method comprising administering a pharmaceutical composition of claim 6 to the patient in an amount effective to treat said cancer.
15. The method of claim 14 , wherein said cancer is a head and neck cancer.
16. The method of claim 14 , wherein said cancer is a cervical cancer or a genitoanal cancer.
17. The method according to claim 14 , 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.
18. The method according to claim 14 , wherein the heterodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight or from about 5 mg/kg to about 10 mg/kg of body weight.
19. A method of treating an HPV16-associated cancer or an HPV16-attributable cancer in a patient in need of such treatment, the method comprising administering a pharmaceutical composition of claim 7 to the patient in an amount effective to treat said cancer.
20. The method of claim 19 , wherein said cancer is a head and neck cancer.
21. The method of claim 19 , wherein said cancer is a cervical cancer or a genitoanal cancer.
22. The method according to claim 19 , 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.
23. The method according to claim 19 , wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight or from about 5 mg/kg to about 10 mg/kg of body weight.
24. The method of claim 19 , wherein
the patient has become refractory to a prior treatment for the cancer or has failed to respond to a prior treatment for the cancer, and
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 an HPV16-associated cancer or an HPV16-attributable cancer in a patient in need of such treatment, the method comprising administering a pharmaceutical composition of claim 8 to the patient in an amount effective to treat said cancer.
26. The method of claim 25 , wherein said cancer is a head and neck cancer.
27. The method of claim 25 , wherein said cancer is a cervical cancer or a genitoanal cancer.
28. The method according to claim 25 , 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.
29. The method according to claim 25 , wherein the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.
30. The method of claim 26 , 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, and
the homodimer is administered in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.