Redesigning the immunopeptidome: manipulating MHC-I peptide presentation through ubiquibody-directed protein degradation 3985

Abstract Description T-cell-based immunotherapies rely heavily on the efficient presentation of antigenic peptides by class-I major histocompatibility complex (MHC-I) molecules to drive CD8+ T-cell-mediated tumor destruction. Most of these antigenic peptides are generated through the ubiquitin-proteasome system (UPS) and loaded onto MHC-I molecules to form peptide-MHC (pMHC) complexes that are essential for T-cell recognition and immune surveillance. Targeted protein degradation (TPD) technologies, including proteolysis targeting chimeras (PROTACs) and ubiquibodies (uAbs), offer a promising strategy to manipulate the immunopeptidome by directing specific proteins for degradation via the UPS. Our work focuses on investigating the potential of peptide-guided uAbs to enhance the presentation of tumor-associated antigens on MHC-I. By selectively targeting cancer-related proteins, uAbs aim to amplify the generation of specific pMHC complexes, boosting CD8+ T-cell recognition of tumor cells. To further harness this enhanced antigen presentation, the uAb strategy is integrated with T-cell receptor mimic (TCRm) antibodies, which specifically recognize and bind to the upregulated pMHC complexes. This combination approach aims to drive robust and targeted tumor cell killing, providing a synergistic platform for advancing T-cell-based cancer immunotherapy. Funding Sources T32GM138826 Topic Categories Vaccines and Immunotherapy (VAC)