Abstract 2126: LY6G6D targeting with a T cell engager is a promising therapeutic for MSS colorectal cancer

T cell engagers (TCEs) are proving to be a potent therapeutic strategy for the treatment of solid tumors. Clinical data have shown that TCEs can drive T cell activity in "cold" tumors, including colorectal cancer. However, identifying highly specific tumor antigen targets is crucial for delivering doses that achieve optimal tumor exposure and maximize therapeutic efficacy. Analysis of primary patient samples indicated enrichment of LY6G6D in microsatellite stable (MSS) and instability-low (MSI-L) colorectal cancer (CRC). A highly potent, stable, and manufacturable CB21 TCE was designed to optimally engage LY6G6D and CD3. Strong binding affinity to the LY6G6D target antigen, and an optimized CD3 affinity, maximized T cell activation and cytokine production yielding significant cytotoxic effects across multiple cell lines with differing physiologically relevant levels of LY6G6D. Additionally, in endogenous LY6G6D expressing xenograft models the CB21 TCE displayed robust tumor growth inhibition in a dose-dependent manner. A pharmacokinetics (PK) and tolerability study with the cynomolgus cross-reactive CB21 TCE was administered to nonhuman primates. Exposure levels multiple times higher than the predicted clinical exposures were achieved with no significant cytokine release or meaningful alterations in clinical blood chemistry observed. Human PK were predicted to have antibody-like characteristics. Combined with the PK and PD data, human dose predicts efficacy with a favorable therapeutic window. An accelerated phase I clinical plan is presented. Utilizing our ATLAS platform, we identified LY6G6D as the most promising target in MSS CRC due to its specific expression in malignant cells, high antigen surface stability, and persistence in both primary and metastatic CRC. The data presented support that the CB21 TCE has been meticulously engineered to be a potentially first and best-in-class TCE targeting LY6G6D. Citation Format: Burcu Yigit, Prasuna Paluru, Egle Jurgaityte, Kevin Nuno, Jason Chen, Nathan Fisher, Alex Martinko, Max Mumbach, Ann Easton, Rose Guerrero, Maeve O’Huallachain, Priya Ram, Jeffrey Verboon, Maggie Lu, Jeffrey Granja, Dan Rock, David Kugler. LY6G6D targeting with a T cell engager is a promising therapeutic for MSS colorectal cancer [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 2126.