Abstract 2863: TAVO307, a novel ADC targeting CDH17, for the therapy of gastrointestinal cancers

Abstract Background: Gastrointestinal (GI) cancers account for about 28% of all cancers globally, however, the treatment options remain limited partly due to the lack of appropriate cancer targets. Cadherin-17 (CDH17) is a cell adhesion membrane protein predominantly expressed at the tight junctions of intestinal epithelial cells of healthy individuals. However, the aberrant expression of CDH17 in 50-90% of GI tract tumors (including stomach, pancreas, liver/bile duct and colon cancers) is associated with poor prognosis and shorter survival of GI cancer patients. In these tumors, CDH17 interacts with α2β1 integrin to drive the proliferation, adhesion, and metastasis of tumor cells. Such overexpression of CDH17 makes it an attractive target for the developing novel treatments of GI tract cancers. Methods and Results: We discovered an anti-CDH17 antibody with high binding affinity to CDH17 with an EC50 at sub nM range. We prepared an ADC molecule loaded with the anti-mitotic toxin MMAE/MMAF via a lysosomal cleavable dipeptide linker. CDH17-ADC showed potent cytotoxicity (IC50 at sub nM level) to multiple GI and pancreatic cancer cell lines in in vitro cell cytotoxicity assays. In addition, CDH17-MMAE (DAR=4) treatment led to potent tumor growth inhibition (70% to 95% TGI) in multiple CDX and PDX pancreatic, colon, and gastric cancer xenograft models. The mice in the CDH17-MMAE treatment group maintained normal body weight throughout the treatment course without observed toxicity. Conclusions: Targeting CDH17 in GI tract cancers, our lead CDH17-MMAE molecule (TAVO307) showed potent tumor cell cytotoxicity in multiple tumor cell lines in cytotoxicity assays as well as in CDX and PDX tumor models. Further preclinical safety assessment, pharmacokinetics and IND-enabling studies are on-going with the goal to develop TAVO307 as the “best-in-class” ADC molecule for the treatment of colon, gastric, pancreatic and oesophagus cancers with significant unmet medical needs. This antibody can also be applied to alternative targeting modalities. Citation Format: Guangmao Mu, Fulai Zhou, Zhengxia Zha, Sheng Huang, Ying jin, Yuanting Chen, Mark Chiu, Di Zhang. TAVO307, a novel ADC targeting CDH17, for the therapy of gastrointestinal cancers [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 2863.