Abstract 317: Discovery of HDM2017, a CDH17-targeting ADC for colorectal cancers

Abstract Introduction: Cadherin 17 (CDH17) is a cell-to-cell adhesion protein that is a member of the cadherin superfamily. CDH17 is frequently overexpressed in colorectal cancer (CRC), gastric cancer (GC) and pancreas cancer (PC)1. HDM2017 ADC comprises a human monoclonal antibody specifically targeting CDH17 and chemically conjugated to CPT-derivative payloads. HDM2017 is undergoing IND-enabling studies. Methods: In vitro and in vivo preclinical studies were conducted in the discovery of HDM2017 against gastrointestinal cancers. Initial investigations on plasma stability were performed. Exploratory toxicity assessments were carried out in cynomolgus monkeys and rats. Results: HDM2017 demonstrates excellent cell binding activities with CRC and GC cells, with an EC50 ranging between 0.1-1.0nM. Additionally, HDM2017 exhibits strong target-mediated internalization activities, achieving an internalization efficiency of 43-75%. The HDM2017 ADC displays potent expression-dependent in vitro anti-tumor activity in a range of CDH17 expressing tumor cell lines. Treatment with HDM2017 ADC resulted in significant inhibition of tumor growth in xenograft models of CDH17+ human CRC (71∼97% TGI) and GC (71∼90% TGI). HDM2017 ADC exhibited excellent stability in human, monkey, and rat plasma with a drug shedding rate below 0.5%. Toxicity studies primarily revealed payload-related toxicity profile, which supports further development of the ADC molecule. Analysis using CDH17 IHC assay on patient tissues showed detectable expression of CDH17 in 90% (29/29) cases of colorectal cancer, 70% (7/10) cases of gastric cancer and 65% (13/20) cases of pancreas cancer. Conclusion: HDM2017ADC exhibited potent cytotoxicity in vitro and in vivo anti-tumor activity in various gastrointestinal cancer models. The preclinical activity and safety profile warrants further clinical development with biomarker strategy. Overall, the preclinical data presented here suggests that HDM2017 ADC has the potential to provide clinical benefit to gastrointestinal cancer patients. Citation Format: Chen Lin, Yan Xia, Liubin Guo, Yang Chen, Tingyang Wang, Kuan Lu, Hao Pan, Yayun Zhao, Jie Fang, Hongwen Li, Dongzhou Jeffery Liu. Discovery of HDM2017, a CDH17-targeting ADC for colorectal cancers [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 317.