Overcoming multidrug resistance in gastrointestinal cancers with a CDH17-targeted ADC conjugated to a DNA topoisomerase inhibitor.

Abstract

Cadherin 17 (CDH17) has emerged as a promising target for gastrointestinal (GI) cancers, which are often complicated by multidrug resistance (MDR) and recurrence. In this study, we developed 7MW4911, a CDH17-targeted antibody-drug conjugate (ADC) that incorporates a topoisomerase inhibitor MF-6 (Topi MF-6) payload linked via a cleavable linker, designed specifically to address MDR in GI cancers. 7MW4911 exhibited high specificity for CDH17-expressing cancer cells and potent cytotoxicity in vitro. In preclinical models, including patient-derived xenografts (PDXs) with distinct mutations, 7MW4911 achieved tumor growth inhibition ranging from 71% to 99%. Remarkably, 7MW4911 outperformed monomethyl auristatin E (MMAE)-based and Deruxtecan (DXd)-based ADCs in MDR models, highlighting its effectiveness against drug-resistant cancer phenotypes. Additionally, 7MW4911 showed favorable pharmacokinetics and a highest non-severely toxic dose (HNSTD) exceeding 20 mg/kg in cynomolgus monkeys, underscoring its promising safety profile. Together, these findings position 7MW4911 as a promising ADC candidate capable of enhancing therapeutic outcomes in GI cancers.