Abstract 2876: BR116: An antibody drug conjugate targeting CDH17 for gastrointestinal cancer therapy

Abstract Cadherins are Ca2+-dependent cell adhesion molecules that mediates cell-to-cell adhesion and plays a key role in tissue development. Classical cadherins, such as E-cadherin (CDH1), N-cadherin (CDH2), P-cadherin (CDH3), and VE-cadherin (CDH5) are implicated in cancer progression, invasion, and metastasis when their expression or function changes. CDH17 (Cadeherin-17, LI-cadherin) is a structurally unique member of the cadherin superfamily, with seven extracellular EC repeats, a transmembrane domain, and a shorter cytoplasmic domain. Originally discovered in rat liver and intestine, CDH17 is also called liver and intestine cadherin. In humans, the expression of CDH17 is mainly limited to the digestive tract, including the duodenum, jejunum, ileum, colon, pancreas, and is rarely detected in other tissues. In the intestinal epithelium, CDH17 is mainly localized to lateral and basolateral cell membranes. CDH17 overexpression is observed in various gastrointestinal malignancies, such as gastric cancer, colorectal cancer, bile duct cancer, pancreatic cancer and hepatocellular carcinoma, with almost no expression in normal tissues and organs. High expression of CDH17 is also associated with poor prognosis. The tumorigenic role of CDH17 involves interaction with α2β1 integrin to regulate cell adhesion, proliferation and migration, particularly in colon cancer liver metastasis, making CDH17 a promising therapeutic target in cancer research. BR116 is a novel anti-CDH17 ADC that consists of a humanized, highly specific monoclonal antibody, stably conjugated to an innovative topoisomerase I inhibitor with hydrophilic linker. Notably, our unique conjugation platform CysX™ offers site-specific, stable and irreversible conjugation. CysX™ not only prevents payload detachment during circulation and reducing the off-target toxicity, improved therapeutic window, but also enables a uniformed drug-to-antibody ratio (DAR) of 4. The toxin was carefully selected based on the target characterization and cancer cell sensitivity. BR116 has demonstrated remarkable antitumor activity in both in vitro and in vivo studies. Preclinical evaluations have shown strong safety profile in cynomolgus monkeys, indicating its potential as a therapeutic treatment for gastrointestinal cancers. With its enhanced safety profile and promising efficacy, BR116 holds significant potential for further clinical development. BR116 is aiming to file for an IND in 2025. Citation Format: Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Yiqun Li, Cindy Wu, Lei Nie, Haibin Wang, Gang Chen. BR116: An antibody drug conjugate targeting CDH17 for gastrointestinal cancer therapy [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 2876.