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 fusion polypeptides and T-cell modulatory multimeric polypeptides, including multimeric synTac polypeptides, comprising variant IL-2 polypeptides and a heterologous fusion partner that is an antibody Fc region. The fusion polypeptide includes a plurality of variant IL-2 polypeptides consisting of a first variant IL-2 polypeptide and a second variant IL-2 polypeptide joined by a linker, and the heterologous fusion partner does not comprise a major histocompatibility complex (MHC) polypeptide.

The described embodiments include variant IL-2 polypeptides configured to have reduced IL-2R binding affinity, with design constraints including specific amino-acid substitution positions, amino-acid identity, length, and target reduced IL-2R affinity ranges relative to binding to IL-2 receptor subunits. The disclosure also describes multimeric synTac assemblies in which a variant immunomodulatory domain is combined with immunological binding components to form a multimeric construct.

The multimeric synTac component order is described as including an epitope component, MHC components, a variant IL-2 immunomodulatory domain, and an Ig Fc scaffold. The architecture further includes linkers/spacers and disulfide-linked MHC pairs, and the antibody Fc region is described with sequence identity thresholds to specified Fc domains.

Claims Coverage

The claims coverage centers on one independent fusion-polypeptide claim with dependent claims that refine Fc-region specifics and expand to related composition and support claim categories. The independent claim contains three main inventive feature sets: a multimeric variant IL-2 joined by a linker, a non-MHC heterologous antibody Fc region defined by high sequence identity to a specified Fc sequence, and an overall fusion-polypeptide size limitation.

Overall, the claims coverage is built around a fusion polypeptide that contains two variant IL-2 polypeptides joined by a linker and a heterologous antibody Fc region that lacks MHC polypeptide content and has at least 98% identity to a specified Fc sequence, with the added constraint that the fusion polypeptide is 500 to 600 amino acids.

Stated Advantages

Documented Applications