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

Authors

Jennifer Watkins-Yoon, Wei-Cheng Lu, Elyse M Petrunak, Noah J Tubo, Sara Halmos, William McConaughy, Rodolfo Ciuffa, Cédric Weber, Simon Friedensohn, Sune Justesen, Marie Skovgaard, Rennard Rachel, Caity Goshert, Lucy Liu, Piotr Bobrowicz, Jeffrey J Molldrem, Dongxing Zha

Published in

mAbs. Volume 18. Issue 1. Pages 2731282. Epub Sep 12, 2026.

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.

PMID:
42731891
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.

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