Abstract 4543: A novel CDH17-targeted radioligand therapy overcomes resistance to microtubule and topoisomerase I inhibitor ADCs and achieves potent efficacy in GI-tract tumors

Abstract CDH17 (Cadherin 17) is a single-pass transmembrane protein that is highly and widely expressed in adenocarcinomas of the colon, stomach, and pancreas, as well as in subsets of ovarian and lung cancers. Here, we describe the development of a CDH17-targeted antibody-drug and a radioligand conjugate, their in vivo efficacy across a large panel of GI-tract PDX tumors, and the pharmacokinetic and safety profiles in non-human primates. A fully human monoclonal antibody against CDH17 was generated and conjugated to Deruxtecan at a DAR of 8 (CO-ADC-010). CO-ADC-010 demonstrated rapid internalization and potent CDH17-dependent cytotoxicity, along with favorable plasma stability, pharmacokinetics, and manufacturability. In a large-scale in vivo efficacy study, CO-ADC-010 achieved >90% tumor growth inhibition (TGI) in 80% of tested PDX models. This performance significantly surpassed a comparator ADC carrying MMAE at DAR 4, which showed a similar TGI in only 33% of models, suggesting better suitability of topoisomerase-based payloads for CDH17-directed delivery. In non-human primates, a single-dose exploratory toxicology study of CO-ADC-010 at 10, 30, and 45 mg/kg revealed no target-related toxicities at any dose, with all clinical and pathological findings deemed mild and reversible.Despite strong initial responses to CO-ADC-010, many tumors relapsed over prolonged treatment due to acquired resistance to the payload, while CDH17 expression was not altered. To overcome the limitations of the de novo and acquired resistance to the ADC treatments, we also developed a CDH17-targeted radioligand therapy (RLT) using the same antibody scaffold. We demonstrate that CDH17-targeted RLT shows broad and durable responses across the PDX panel, including full activity in models refractory to Deruxtecan-based ADCs, demonstrating the superiority of RLT in these indications in overcoming drug resistance and achieving durable responses. These data collectively support CDH17-targeted RLT as a promising therapeutic approach for CDH17-positive gastrointestinal malignancies. Citation Format: Abdul Mondal, Garima Kaushik, Marina Bell, Maxwell Hilbert, Arnab Mukharjee, Dennis Beckford, Paul Heverly, Michael Ritchie, Kakajan Komurov. A novel CDH17-targeted radioligand therapy overcomes resistance to microtubule and topoisomerase I inhibitor ADCs and achieves potent efficacy in GI-tract tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4543.