Multimeric T-cell modulatory polypeptides and methods of use thereof

Inventors

Cemerski, Saso • Seidel, III, Ronald D. • Chaparro, Rodolfo J. • Ross, John F.

Assignees

Cue Biopharma Inc

Abstract

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.

Core Innovation

The disclosure describes WT1-directed T-cell modulatory multimeric polypeptides configured as disulfide-linked heterodimeric TMMPs and homodimers of two heterodimers. The TMMPs include a WT1 peptide, a β2-microglobulin (β2M) polypeptide, an MHC class I heavy chain polypeptide, and an immunoglobulin (Ig) Fc polypeptide, with peptide linkers comprising a Cys residue and engineered cysteine substitutions that form one or two disulfide bonds.

The disclosed TMMP designs include variant IL-2 polypeptides, optionally arranged as tandem or multiple immunomodulatory domains, together with additional immunomodulatory polypeptides such as checkpoint and cytokine immunomodulatory polypeptides. The text also describes alternative N-to-C terminal arrangements, disulfide-bonded heterodimeric frameworks, and Ig Fc scaffold options, including Fc engineering that modulates Fc receptor interactions, including FcRn binding.

The disclosure further specifies epitope-specific T-cell modulation by administering WT1-specific TMMPs in cancer treatment settings for cancers expressing WT1. It also includes nucleic acids encoding TMMP chains, including separate versus single vectors, and reports that TMMPs with double disulfide-bonded heterodimer frameworks exhibit improved in vitro stability, can expand antigen-specific CD8+ T cells, and generate selective cytokine/effector responses.

Claims Coverage

The provided independent claims are directed to treatment of a Wilms Tumor-1-associated cancer by administering a therapeutically effective amount of a homodimer pharmaceutical composition comprising two heterodimers. The inventive features center on a WT1 peptide–β2M module linked by a Cys-containing peptide linker, an MHC class I heavy chain module fused to variant IL-2 and an Ig Fc polypeptide, and disulfide-bond coupling within and between the heterodimers.

Across the independent claims, the coverage is directed to a homodimer pharmaceutical composition formed from two heterodimers, where each heterodimer combines a WT1 peptide–β2M module linked by a Cys-containing linker with an MHC class I heavy chain module containing variant IL-2 and an Ig Fc polypeptide. The claims further define a disulfide-bond topology within each heterodimer and a disulfide-bond coupling between the two heterodimers via the Ig Fc polypeptides for use in treating a WT1-associated cancer.

Stated Advantages

Documented Applications