Abstract 7317: A novel LY6G6D x CD3 bispecific T-cell engager demonstrates better tumor killing and minimal cytokine release than a benchmark molecule

Abstract Colorectal cancer (CRC) poses a significant global health challenge with high morbidity and mortality rates. Immune checkpoint inhibitors (ICI) have shown remarkable clinical efficacy in patients with mismatch-repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer. However, the vast majority of patients with microsatellite-stable (MSS) or microsatellite instability-low (MSI-L) colorectal cancer cannot benefit from ICI treatment. Recently, lymphocyte Antigen 6 Family Member G6D (LY6G6D) has emerged as a tumor associated antigen selectively expressed in MSS and MSI-low colorectal cancers. By using EpimAb’s proprietary anti-CD3 antibody panel and bispecific antibody platform, we developed EM1034, a novel LY6G6D x CD3 bispecific T-cell engager (TCE). Compared to a clinical stage benchmark TCE which has monovalent target binding arms and asymmetrical knob-into-hole geometry, EM1034 demonstrated hundred folds increased tumor lysis potency while it induced much lower cytokines in vitro. In vivo efficacy studies further demonstrated that EM1034 is more potent than the benchmark molecule in xenografted models with different LY6G6D expression levels. Taken together, this study support EM1034 as a promising molecule for the treatment of mCRC patients with LY6G6D positive MSS/MSI-L tumors. Citation Format: Lini Huang, Mengting Chen, Yu Zhang, Dong Wu, Shiyong Gong, Xuan Wu, Danqing Wu, Chengbin Wu. A novel LY6G6D x CD3 bispecific T-cell engager demonstrates better tumor killing and minimal cytokine release than a benchmark molecule [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 7317.