Abstract 2868: Preclinical evaluation of LM-350: An innovative anti-CDH17 antibody drug conjugate for gastrointestinal cancer therapy

Abstract Background: Cadherin 17 (CDH17) is a membrane cell adhesion protein selectively expressed in gastrointestinal cancers, including colorectal (CRC), gastric (GC), and pancreatic cancers (PC). Its expression in normal intestinal epithelial cells is limited. LM-350, a CDH17-targeted antibody-drug conjugate (ADC), is composed of a humanized monoclonal antibody (LM-150) conjugated to the next-generation topoisomerase I inhibitor LDX2 via a cleavable linker, with a drug-antibody ratio of 8. Methods: Target binding activity, specificity, and cross-species reactivity of LM-350 was evaluated by flow cytometry. Internalization was evaluated using an acidic pH-sensitive dye, with fluorescence signal detection via flow cytometry. Cytotoxicity and bystander effects were evaluated using the CellTiter-Glo luminescent cell viability assay. In vivo anti-tumor activity of LM-350 was evaluated in CDH17-positive CRC and GC cell line-derived xenografts (CDX) and patient-derived xenografts (PDX). Immunohistochemistry was used to assess CDH17 expression in tumor tissues. Results: LM-350 demonstrated concentration-dependent binding to CDH17-expressing human CRC and GC cells, with EC50 values ranging from 0.13 to 0.94 nM, which was comparable to the un-conjugated monoclonal antibody LM-150. LM-150 exhibited high specificity and binding affinity to monkey CDH17 but not to rodent CDH17. In addition, LM-350 induced concentration and time dependent cellular internalization and potent cytotoxic effects in CDH17-positive cells. In vivo, LM-350 treatment at doses of 3 or 6 mg/kg significantly inhibited or regressed tumor growth in multiple CRC and GC xenograft models, with tumor growth inhibition rates ranging from 70% to 129%. Conclusion: The novel ADC LM-350 targeting CDH17 exhibited potent anti-tumor activity in vitro and in CRC and GC xenograft models. LM-350 demonstrated high therapeutic potential in CDH17-positive gastrointestinal cancers, particularly in CRC and GC. Citation Format: Wentao Huang, Jin Li, Xia Qin, Da Fei, Runsheng Li. Preclinical evaluation of LM-350: An innovative anti-CDH17 antibody drug conjugate for gastrointestinal cancer therapy [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 2868.