Cue Biopharma, Inc.

The present disclosure provides a T-cell modulatory multimeric polypeptide (TMMP) comprising at least one heterodimer, where the heterodimer comprises first and second polypeptide chains and where the heterodimer includes an NKG2 peptide, an HLA-E heavy chain polypeptide, a beta-2 microglobulin polypeptide, and an immunoglobulin Fc polypeptide. The heterodimer can also include an immunomodulatory polypeptide and/or a cancer-targeting polypeptide. The TMMPs are useful in methods of modulating an immune response, which methods are also provided.

The present disclosure provides a single-chain T-cell modulatory polypeptide (TMP) that includes an NKG2 peptide, an HLA-E heavy chain polypeptide, a beta-2 microglobulin polypeptide, and an immunoglobulin Fc polypeptide. The TMP can also include an immunomodulatory polypeptide and/or a cancer-targeting polypeptide. The TMPs are useful in methods of modulating an immune response, which methods are also provided.

The present disclosure provides a peptide-major histocompatibility complex (pMHC) polypeptide comprising a peptide epitope and class I MHC polypeptides. The present disclosure provides fusion molecules comprising a pMHC polypeptide and a heterologous fusion partner. The present disclosure provides single-chain T-cell modulatory polypeptides that comprise a pMHC polypeptide, one or more immunomodulatory polypeptide, and an immunoglobulin (Ig) Fc or a non-Ig scaffold. A TMP is useful for modulating the activity of a T cell, and for modulating an immune response in an individual.

The present disclosure provides a peptide-major histocompatibility complex (pMHC) polypeptide comprising a KRAS peptide and class I MHC polypeptides. The present disclosure provides fusion molecules comprising a pMHC polypeptide and a heterologous fusion partner. The present disclosure provides single-chain T-cell modulatory polypeptides that comprise a pMHC polypeptide, one or more immunomodulatory polypeptide, and an immunoglobulin (Ig) Fc or a non-Ig scaffold. A TMP is useful for modulating the activity of a T cell, for modulating an immune response in an individual, and/or for treating an individual who has a KRAS-associated cancer.

The present disclosure provides T-cell modulatory multimeric polypeptides that comprise an immunomodulatory polypeptide and that comprise an epitope-presenting Wilms tumor peptide. A T-cell modulatory multimeric polypeptide is useful for modulating the activity of a T cell, and for modulating an immune response in an individual.

The present disclosure provides a chimeric molecule comprising: a) a T-cell modulatory multimeric polypeptide (TMMP); and b) a nucleic acid component, where the nucleic acid component comprises a nucleic acid comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR) comprising an antibody that binds a cancer-associated antigen. The TMMP binds to and activates a target T cell; the nucleic acid component is taken up by the target T cell such that the target T cell expresses the CAR on its surface. The present disclosure provides methods of making the chimeric molecule. The present disclosure provides treatment methods comprising administering the chimeric molecule.

The present disclosure provides in vitro modified cytotoxic T cells (CTLs) that comprise: a) a T-cell receptor (TCR) specific for a preselected antigen in a human; and b) a nucleic acid(s) encoding a chimeric antigen receptor (CAR) specific for a cancer-associated antigen. The present disclosure provides methods of producing the modified CTLs. The present disclosure provides methods of treating cancer, comprising administering the modified CTLs to an individual in need 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.

The present disclosure provides T-cell modulatory multimeric polypeptides (T-Cell-MMP) and their epitope conjugates comprising at least one immunomodulatory polypeptide (“MOD”) that may be selected to exhibit reduced binding affinity to a cognate co-immunomodulatory polypeptide (“Co-MOD”). The epitope may be, for example, a cancer-associated epitope, an infectious disease-associated epitope, or a self-epitope. The T-Cell-MMP-epitope conjugates are useful for modulating the activity of a T-cell by delivering immunomodulatory peptides, such as IL-2 or IL-2 variants that exhibit reduced binding affinity for the IL-2R, to T-cells in an epitope selective/specific manner, and accordingly, for treating individuals with a cancer, infectious disease or autoimmune disorder.

The present disclosure provides T-cell modulatory multimeric polypeptides (TMMPs) that comprise comprise (i) an optional immunomodulatory polypeptide such as a variant IL-2 polypeptide, (ii) class I HLA major histocompatibility complex (MHC) polypeptides (a class I HLA heavy chain polypeptide and a β2 microglobulin polypeptide), (iii) a peptide that presents an epitope to a T-cell receptor, which together with the class I MHC polypeptides forms a peptide-MHC complex (pMHC), (iv) a tumor-targeting polypeptide, and (v) an optional Ig Fc polypeptide or other scaffold. Such TMMP is useful for modulating the activity of a T cell, and for modulating an immune response in an individual, and for “redirecting” a patient's repertoire of antiviral T cells to attack and kill cancer cells.