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 protein comprising two heterodimers, wherein each heterodimer comprises:
a) a first polypeptide comprising, in order from N-terminus to C-terminus:
i) an HPV16 E7 epitope comprising amino acid sequence YMLDLQPETT (SEQ ID NO:13);
ii) a linker comprising amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:89); and
iii) a β2-microglobulin (β2M) polypeptide comprising an amino acid sequence as set forth in SEQ ID NO:17; and
b) a second polypeptide comprising two variant IL-2 polypeptides, a class I MHC heavy chain polypeptide, and a variant immunoglobulin Fc polypeptide, wherein the second polypeptide comprises an amino acid sequence as set forth in SEQ ID NO:72,
wherein the first polypeptide and the second polypeptide of each heterodimer 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, and
wherein the two heterodimers are joined to each other by one or more disulfide bonds that join the variant immunoglobulin Fc polypeptide of one heterodimer to the variant immunoglobulin Fc polypeptide of the other heterodimer.
2. A pharmaceutical composition comprising the protein of claim 1 .
3. A method of treating cancer in a patient in need of such treatment, the method comprising administering the protein of claim 1 to the patient in an amount effective to treat said cancer.
4. 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 in an amount effective to treat said cancer.
5. The method of claim 4 , wherein said cancer is head and neck cancer.
6. The method of claim 4 , wherein said cancer is cervical cancer.
7. The method of claim 4 , wherein said cancer is genitoanal cancer.
8. The method of claim 4 , wherein said administering is subcutaneous, intravenous, or intramuscular.
9. The method according to claim 4 , wherein the individual has become refractory to a prior treatment for the cancer.
10. The method according to claim 4 , wherein the individual has failed to respond to a prior treatment for the cancer.
11. A method according to claim 4 , wherein the protein is administered in an amount of 1-5 mg per kg of body weight.
12. A method according to claim 4 , wherein the protein is administered in an amount of 5-10 mg per kg of body weight.
13. A method according to claim 4 , wherein the protein is administered in an amount of 10-15 mg per kg of body weight.
14. A method according to claim 4 , wherein the protein is administered in an amount of 15-20 mg per kg of body weight.
15. A method according to claim 4 , wherein the protein is administered in an amount of 20-25 mg per kg of body weight.
16. A method of detecting, in a mixed population of T cells obtained from an individual, the presence of target T cells that bind an HPV16 E7 epitope comprising the amino acid sequence YMLDLQPETT (SEQ ID NO:13), the method comprising:
a) contacting in vitro the mixed population of T cells with the protein of claim 1 ; and
b) detecting activation and/or proliferation of target T cells in response to said contacting.