MGT-1143, a novel CDH17-targeting ADC for gastrointestinal cancers

Background: Pan-gastrointestinal cancers represent a heterogeneous group of malignancies arising from the gastrointestinal tract, including esophageal, gastric, pancreatic, and colorectal cancers, which collectively contribute to a major global cancer burden and mortality. Cadherin-17 (CDH17), a Ca²⁺-dependent adhesion molecule, is overexpressed across multiple GI cancers and has been associated with poor prognosis. Here, we report the development and preclinical evaluation of MGT-1143, a novel Exatecan-based ADC that integrates a fully humanized anti-CDH17 monoclonal antibody (mAb) with Marigold's proprietary linker platform. MGT-1143 is currently undergoing IND-enabling studies. Methods: The preclinical activity of MGT-1143 was assessed through a series of in vitro and in vivo studies to characterize its pharmacological and safety profiles. Binding affinity, cross-species reactivity, and target specificity of MGT-1143 were evaluated using ELISA and flow cytometry. Antibody internalization was determined by flow cytometry, while cytotoxicity was assessed using the CellTiter-Glo luminescent viability assay. In vivo anti-tumor efficacy was evaluated in CDH17-positive cell line-derived xenograft (CDX) models. Results: The MGT-1143 antibody exhibited high target specificity with no detectable cross-reactivity toward other cadherin family members. MGT-1143 demonstrated strong binding affinity and rapid internalization in CDH17-expressing cells, resulting in potent cytotoxicity across multiple CDH17-positive cell lines. Furthermore, MGT-1143 induced robust and dose-dependent anti-tumor activity in xenograft mouse models expressing varying levels of CDH17, confirming its target-dependent efficacy. Conclusions: Collectively, the preclinical data support the continued development of MGT-1143 as a promising therapeutic candidate for the treatment of CDH17-positive gastrointestinal cancers. Ongoing IND-enabling studies will further define its safety and translational potential.