Abstract 2693: BA3361, a tumor selective, conditionally active biologic (CAB) anti-nectin4-ADC with a novel NextGen linker system enhances therapeutic efficacy in pancreatic cancer

Abstract Antibody drug conjugates (ADCs) are a unique therapeutic combination of the tumor-targeting monoclonal antibody, high-potency cytotoxic drug, and a chemical linker. Together, these components enable the tumor-specific delivery of the highly potent cytotoxin. However, treatment efficacy is often limited by on-target/off-tumor toxicity due to antigen expression in healthy tissue and by unwanted payload release outside the tumor caused by linker cleavage via circulating proteases. In this study, we present BA3361, a NextGen ADC featuring a conditionally active biologics (CAB) anti-Nectin4-ADC, optimized with novel CAB and linker technologies. BA3361 demonstrates pH-selective enhanced target binding in the tumor microenvironment conditions, improved serum stability, increased solubility, and tumor-specific payload release. These advancements effectively address critical clinical challenges by reducing off-tumor, on-target and off-target toxicities. In vivo efficacy data showed complete tumor regression in several patient derived cancer models. Notably, compared to an Enfortumab vedotin analogue, superior efficacy was observed in patient-derived pancreatic xenograft models, and the in vivo potency was tightly correlated with target expression. Furthermore, we discovered that intracellular glycosidase activity is high in pancreatic tumor tissue, independent of target expression, indicating efficient tumor selective linker cleavage. In conclusion, our NextGen Nectin4-CAB-ADC BA3361 demonstrates comparable or superior activity in lung, breast, and urothelial patient derived cancer models compared to Enfortumab vedotin and outperforms it in pancreatic PDX models. In addition, the conditional binding in the TME should help to reduce side effects of nonCAB ADCs and potentially widen the therapeutic index. Citation Format: Jing Wang, Jian Chen, Gerhard Frey, Haizhen Liu, Cathy Chang, William J. Boyle, Jay M. Short. BA3361, a tumor selective, conditionally active biologic (CAB) anti-nectin4-ADC with a novel NextGen linker system enhances therapeutic efficacy in pancreatic 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 2693.