Abstract 5469: Preclinical safety and efficacy of SOT109, an antibody-drug conjugate targeting cadherin 17 (CDH17) for the treatment of colorectal and other gastrointestinal tract tumors

Abstract Background: Colorectal cancer is the third most prevalent type of cancer, with an incidence of nearly 2 million new cases annually, and ranks as the second leading cause of cancer mortality worldwide. CDH17 is a single-pass transmembrane glycoprotein involved in calcium-dependent cell-cell adhesion and epithelial homeostasis regulation. In normal physiology, CDH17 is predominantly localized on the lateral surfaces of intestinal and pancreatic ductal epithelial cells​. However, it is frequently overexpressed and aberrantly localized in gastrointestinal tumors including colorectal, gastric, pancreatic and gastroesophageal carcinomas. We have developed SOT109, a proprietary CDH17 targeting exatecan-based antibody-drug conjugate (ADC) and evaluated its preclinical safety and efficacy. Results: Immunohistochemical staining of patient tumor and healthy tissue microarrays confirmed CDH17 expression in normal tissues including the colon, stomach and small intestine, with pronounced expression in colorectal, gastric, and gastroesophageal junction tumors, consistent with previously published literature. SOT109 candidates were generated from a fully human CDH17 monoclonal antibody conjugated via a hydrophobic linker to exatecan, a cytotoxic topoisomerase I inhibitor payload. Candidates were selected by rigorous screening for optimal binding epitopes and affinity, together with binding, internalization, and cytotoxicity in vitro. SOT109 candidates demonstrated specific binding to CDH17 and selective internalization and killing of target-positive cancer cells. Lead candidates underwent evaluation in several preclinical in vivo mouse tumor models, including cell-derived and patient-derived xenografts. Treatment with SOT109 resulted in profound and sustained tumor regressions. The doses tested in these studies were well tolerated in mice, with no dose-limiting toxicities observed. Subsequent studies in non-human primates revealed a favorable pharmacokinetic and safety profile. Summary: SOT109 targets the overexpressed tumor antigen CDH17 and exhibits potent anti-tumor efficacy coupled with a clean safety profile in preclinical models of colorectal carcinoma. These data suggest that SOT109 holds significant potential as a therapeutic candidate for patients with gastrointestinal malignancies and supports the further clinical development of SOT109. Citation Format: Nataliia Kalynovska, Diana Hudecz, Matous Hrdinka, Ilona Prochazkova, Eliska Kohelova, Lenka Palova Jelinkova, Filip Jaburek, Tomas Zimmermann, Lukas Fojtik, Irena Adkins, Sarka Stehlikova, Amy Jensen-Smith, Radek Spisek, Martin Steegmaier. Preclinical safety and efficacy of SOT109, an antibody-drug conjugate targeting cadherin 17 (CDH17) for the treatment of colorectal and other gastrointestinal tract tumors [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 5469.