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 a fusion polypeptide comprising one or more variant IL-2 polypeptides fused to a heterologous fusion partner comprising an antibody Fc region. Each variant IL-2 polypeptide comprises up to four amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:1, with amino acid 42 being an amino acid other than a phenylalanine and amino acid 16 being an amino acid other than a histidine. The variant IL-2 polypeptides exhibit reduced binding affinity to an IL-2 receptor comprising alpha, beta, and gamma polypeptides having amino acid sequences set forth in SEQ ID NOs: 18-20, compared to the binding affinity of the IL-2 amino acid sequence set forth in SEQ ID NO:1 for the IL2R.

The fusion polypeptide further includes an antibody Fc region in which the antibody Fc region comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:57, where the percent sequence identity is determinable by a sequence alignment performed using BLAST. The fusion polypeptide does not comprise a major histocompatibility complex (MHC) polypeptide. In additional claim variations, the number of IL-2 substitutions is reduced, while maintaining the reduced binding affinity to the IL-2 receptor comprising alpha, beta, and gamma polypeptides defined by SEQ ID NOs: 18-20.

Dependent claim aspects further specify allowed amino acid identities at amino acid 16 and amino acid 42, additional amino acid substitutions within the antibody Fc region including L14A, L15A, N77A, and P111S substitutions based on the amino acid numbering of SEQ ID NO:57, and defined total length ranges for the fusion polypeptide. In certain aspects, the heterologous fusion partner comprises an antibody Fc region and an antibody antigen-binding region.

Claims Coverage

The partial content includes three independent claims: clm-00001, clm-00011, and clm-00021. Across these claims, the coverage centers on fusion polypeptides that combine IL-2 variants with reduced IL2R binding and a heterologous antibody Fc region meeting a sequence-identity threshold, while excluding MHC polypeptides; the inventive feature set differs mainly in the number of allowed IL-2 amino-acid substitutions and the dependent refinements.

Across clm-00001, clm-00011, and clm-00021, the claims cover IL-2 variant polypeptides bearing reduced binding affinity to an IL-2 receptor comprising alpha, beta, and gamma polypeptides, fused to a heterologous antibody Fc region having at least 95% identity to SEQ ID NO:57, while excluding any MHC polypeptide. Dependent aspects further narrow residue identities at amino acid 16 and amino acid 42, add specified Fc-region substitutions, optionally include an antibody antigen-binding region, and constrain total fusion polypeptide length ranges.

Stated Advantages

Documented Applications