T-cell modulatory multimeric polypeptide with conjugation sites and methods of use thereof

Inventors

Seidel, III, Ronald D. • Chaparro, Rodolfo J. • Ross, John F. • Low, Chee Meng

Assignees

Cue Biopharma Inc

Abstract

The present disclosure provides T-cell modulatory multimeric polypeptides (“T-Cell-MMPs”) comprising an immunomodulatory polypeptide (“MOD”) that may be selected to exhibit reduced binding affinity to a cognate co-immunomodulatory polypeptide (“Co-MOD”) and a location for covalently attaching a molecule that can serve as an epitope, such as an epitope peptide. Once the epitope molecule is attached the resulting 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 IL-2R, to the T-cells in an epitope selective/specific manner, and accordingly, for modulating an immune response in an individual.

Core Innovation

The invention provides a T-cell modulatory multimeric polypeptide (T-Cell-MMP) that includes a first polypeptide with a beta-2-microglobulin (β2M) polypeptide and a second polypeptide with a class I MHC heavy chain polypeptide having a binding pocket. The first and second polypeptides can include a peptide linker and optionally an immunoglobulin (Ig) Fc polypeptide or a non-Ig polypeptide scaffold, forming an MHC-based multimeric platform.

A key feature is placement of an epitope peptide into the MHC binding pocket for presentation to a T-cell receptor specific for the epitope. This is achieved through first and/or second polypeptide chemical conjugation sites that covalently bind a molecule comprising an epitope peptide, directly or indirectly through a linker, to position the epitope peptide in the binding pocket.

The T-Cell-MMP further incorporates one or more independently selected wild-type or variant immunomodulatory polypeptides (MODs), with MOD location defined at one or more of the C-terminus of the first polypeptide, the N-terminus of the second polypeptide, the C-terminus of the second polypeptide, and/or the C-terminus of the first polypeptide and the N-terminus of the second polypeptide. The described framework supports T-Cell-MMP-epitope conjugates that incorporate MODs and can include binding and affinity constraints involving a Co-MOD, including reduced-affinity variant MOD interactions.

Claims Coverage

The consolidated claim coverage defines one MHC-based T-Cell-MMP with covalent epitope-peptide conjugation sites and one or more MODs at defined termini. The independent claim content resolves to three main inventive features, with additional limitations on scaffold choice, conjugation-site classes, variant MOD selection, affinity ratio constraints, and sequence-identity thresholds.

The core inventive concept combines an MHC-based T-Cell-MMP architecture with β2M and an MHC heavy chain binding pocket, chemical conjugation sites that covalently attach an epitope peptide into that binding pocket for TCR-specific presentation, and one or more independently selected wild-type or variant MODs positioned at defined termini. Dependent claim refinements further constrain scaffold type, MOD identity and reduced-affinity behavior, allowed conjugation-site classes, and sequence-identity thresholds.

Stated Advantages

Documented Applications