T-cell modulatory multimeric polypeptides and methods of use thereof

Inventors

Seidel, III, Ronald D. • Chaparro, Rodolfo J.

Assignees

Cue Biopharma Inc

Abstract

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.

Core Innovation

The invention relates to IL-2-based synTac and multimeric T-cell modulatory polypeptides, including variant IL-2 polypeptides defined by specific amino acid substitutions relative to SEQ ID NO:1, with amino acid 16 being Glu and amino acid 42 being Ala. The disclosed variants are characterized by substitution patterns and are described in the context of reduced IL-2R binding affinity relative to wild-type IL-2.

The invention provides fusion polypeptides that include an antibody Fc region and a variant IL-2 polypeptide while explicitly excluding major histocompatibility complex (MHC) polypeptides in the fusion constructs. In embodiments described, the fusion polypeptides include defined overall amino acid length ranges, including 300 to 700 amino acids, and heterologous fusion partners that include an antibody Fc region and an antigen-binding region of an antibody, again with the fusion partner not comprising an MHC polypeptide.

Overall, the invention supports multimeric polypeptide formats and multivalency, including heterodimer/trimer formats and single- versus multivalent designs. Epitope specificity and epitope length options are also described for T-cell epitope embodiments, including cancer-associated and HPV epitopes.

Claims Coverage

The independent claims cover related fusion polypeptide formats defined by a variant IL-2 polypeptide, an antibody Fc-containing fusion architecture, exclusion of MHC polypeptides, and defined overall amino-acid lengths. The inventive features are distinguished primarily by whether the heterologous partner is an antibody Fc region alone or an antibody Fc plus an antigen-binding region, and by whether the variant IL-2 allows up to five or up to four substitutions relative to SEQ ID NO:1.

The independent claims collectively cover IL-2 variant fusion polypeptides that specify the IL-2 substitution pattern relative to SEQ ID NO:1 with amino acid 16 = Glu and amino acid 42 = Ala, require an antibody Fc region either as part of the fusion or as part of a heterologous fusion partner that additionally includes an antibody antigen-binding region, exclude MHC polypeptides, and define overall fusion-polypeptide length ranges, including 300 to 700 amino acids in the Fc-only embodiments.

Stated Advantages

Documented Applications