Abstract 2877: MRG007, a cadherin 17-targeted, glycan-linked, exatecan-based antibody-drug conjugate, demonstrated potent anti-tumor activity and a good safety profile in preclinical studies

Abstract Background: Colorectal cancer (CRC) is the one of the most challenging cancers with unmet medical needs. Cadherin 17 (CDH17) is a membranous cell adhesion molecule. It is frequently overexpressed in CRC and several other gastrointestinal (GI) cancers, with limited expression in normal intestinal tissue and pancreatic duct. The differential expression profile in tumor versus normal tissue makes it an attractive target for antibody-drug conjugate (ADC) in GI cancers, particularly CRC. MRG007 is a CDH17-targeting ADC consisting of a novel humanized IgG1 antibody site-specifically conjugated with the cytotoxin Exatecan using Synaffix’s GlycoConnectTM technology with a well-balanced DAR value. This differentiated drug design will potentially improve anti-tumor efficacy and broaden the therapeutic window. Materials and Methods: The biological activity and safety profile of MRG007 were investigated in a series of preclinical studies, including (1) binding ability to CDH17 expressed on GI cancer cells as well as rhesus CDH17 evaluated by flow cytometry; (2) internalization rate in GI cancer cells evaluated by pHAb Reactive Dye labeling; (3) in vitro cytotoxicity against a panel of GI cancer cell lines; (4) anti-tumor activity evaluated in several GI cancer cell line-derived xenograft (CDX) and CRC patient-derived xenograft (PDX) mouse models with different levels of CDH17 expression; (5) plasma stability evaluated in human, rhesus, rat and mouse plasma; (6) an exploratory pharmacokinetic (PK) and toxicology study in rhesus monkey. Results: MRG007, the CDH17-targeting ADC, and its antibody moiety showed strong binding activity to CDH17 expressed on a panel of GI cancer cell lines. Similar binding potency to both human and rhesus monkey CDH17 makes rhesus monkey suitable for toxicological evaluation. Rapid internalization of MRG007 was observed in a panel of CDH17-expressing GI cancer cells, and MRG007 maintained comparable internalization efficiency to the naked antibody. MRG007 demonstrated efficient and CDH17-dependent cytotoxic activity in a panel of GI cancer cells expressing varying levels of CDH17. MRG007 exhibited a robust and dose-dependent tumor growth inhibition in multiple GI cancer CDX and CRC PDX mouse models with varying levels of CDH17 expression, which was significantly better than GGFG-DXd DAR8 ADC conjugated with the same naked antibody. Remarkable stability of MRG007 was shown in the plasma of various species tested with minimal payload release and stable DAR value. MRG007 demonstrated a favorable PK and safety profile with good tolerability in the exploratory toxicology study. Conclusion: Overall, the preclinical study results suggest that MRG007 is a differentiated and potent ADC drug candidate for the treatment of CDH17-expressing cancers in clinical trials. Citation Format: Peng Zeng, Qi Wu, Yongjun An, Yili Feng, Yanchun Wang, Shoujia Liu, Deliang Li, Feifei Cui, Lei Fang. MRG007, a cadherin 17-targeted, glycan-linked, exatecan-based antibody-drug conjugate, demonstrated potent anti-tumor activity and a good safety profile in preclinical studies [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 2877.