Abstract 3508: Breaking down solid tumor barriers with a bispecific T cell engager against a novel pHLA target

Abstract

Abstract Recent clinical results show the ability to target intracellular proteins through peptides presented by human leukocyte antigen (pHLA), opening up a unique avenue to targets inaccessible to conventional biologics. Bispecific T cell engagers are an effective therapeutic modality to redirect T cell immune responses towards tumors. However, there is still significant unmet need in a number of solid tumor indications with limited treatment options and few pHLA targets. Using a high-throughput discovery platform utilizing experimental screening and machine learning approaches to map patient T cell immune responses to their respective pHLA targets, a novel wildtype tumor-associated pHLA target with sufficient tumor versus normal expression has been identified. This target contributes directly to tumor stability and growth and is widely expressed in colorectal cancer, triple-negative breast cancer, and squamous non-small cell lung cancer among other indications. 3T-403, a CD3 bispecific T cell engager utilizing a T cell receptor mimic (TCRm) antibody has been developed to this novel target. The pHLA binding arm of 3T-403 has undergone specificity analysis using classical alanine scan as well as analysis via a novel high-throughput combinatorial library to de-risk potential pHLA off-targets. Potency assays conducted with 3T-403 show lysis against a panel of tumor cell lines, while minimal cytotoxicity was observed on primary healthy tissues, which provides a therapeutic window. Investigational new drug (IND) application completion is expected early 2026. Such a bispecific T cell engager against a novel target shows significant promise to address multiple solid tumor indications. Citation Format: Marvin H. Gee, Joshua Goldsmith, Ryan Stafford, Christine Cheng, Bindu Hegde, Tina Giese, Tamson Moore, Lisa Kirkemo, Tanmayee Khadilkar, Lena Flood, Jake Kleiner, Florian Schustek, Aurelien Sarde, Joanna Dreux, Alaina K. Cagalingan, Ricardo Herrada, Gabriel Michaels, Kyle Pelot, Azita Tabrizi, Stefan Scherer. Breaking down solid tumor barriers with a bispecific T cell engager against a novel pHLA target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3508.