Discovery and engineering of bispecific TCR-mimic antibodies targeting peptide–HLA complex

Abstract

ABSTRACT TCR-mimic (TCRm) antibodies represent a promising new frontier in cancer immunotherapy, enabling the targeting of intracellular targets previously considered undruggable with antibodies. We developed an integrated platform for generating human antibodies that mimic T-cell receptors (TCRs) and recognize peptide-HLA complexes with high specificity and affinity. These antibody binders were then engineered into highly potent bispecific antibodies capable of redirecting T cells to kill tumor cells. By leveraging high-quality pHLA immunogens, fully human transgenic mice, advanced single B-cell discovery, and whole proteome off-target screening (X-Scan) techniques, this end-to-end platform establishes a new benchmark in TCRm discovery. In this study, we highlight the successful identification and engineering of antibodies targeting the Wilms Tumor 1 (WT1) antigen, demonstrating superior performance compared to competitors’ TCRm antibodies.