Multimeric t-cell modulatory polypeptides and methods of use thereof

A T-cell modulatory multimeric polypeptide comprising:

• at least one heterodimer comprising:
• a) a first polypeptide comprising:
• i) an alpha-feto protein (AFP) peptide epitope, wherein the AFP peptide has a length of from about 4 amino acids to about 25 amino acids;
• and
• ii) a first class I major histocompatibility complex (MHC) polypeptide, wherein the first MHC polypeptide is a β2-microglobulin (β2M) polypeptide;
• b) a second class I polypeptide comprising a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide, and
• c) at least one immunomodulatory polypeptide that can cause an increase in the cytotoxic activity of a T cell and/or the number of T cells,
• wherein the first and/or the second polypeptide comprises the at least one immunomodulatory polypeptide,
• wherein the first or the second polypeptide comprises an immunoglobulin (Ig) Fc polypeptide, and wherein the T-cell modulatory multimeric polypeptide comprises:
• a first disulfide bond formed between (i) a Cys residue in a Cys-containing linker between the AFP peptide epitope and the β2M polypeptide, and (ii) a Cys residue in the MHC class I heavy chain polypeptide;
• and
• a second disulfide bond formed between a Cys residue in the β2M polypeptide and a Cys residue in the MHC class I heavy chain polypeptide,
• optionally wherein the T-cell modulatory multimeric polypeptide comprises a linker between one or more of:
• i) the first or the second class I MHC polypeptide and the Ig Fc polypeptide;
• ii) an immunomodulatory polypeptide and the first or the second class I MHC polypeptide;
• and iii) a first and a second immunomodulatory polypeptide.