Abstract 316: Translational studies of HDM2012, a novel topoisomerase inhibitor ADC targeting MUC17, in patient derived GC, CRC, PDAC tumor models

Introduction: Mucin-17 (MUC17) is a transmembrane glycoprotein, expressed on the apical membrane of normal gastrointestinal mucosal epithelial cells, play important roles in preventing infection at mucosal surfaces1-2. MUC17 is a promising target for ADC development due to its highly expressed in gastric, colon and pancreatic cancers, but limit normal organs expression. Methods: HDM2012 is a MUC17 targeting ADC, consisting of a topoisomerase inhibitor via a cleavable liker with average drug antibody ratio (DAR) 8. The efficacy and safety of HDM2012 was tested in patient derived xenograft (PDX) models and monkeys, respectively. Results: HDM2012 showed target dependent anti-tumor activity and by-stander effect in vitro. HDM2012 exhibits good efficacy in PDX and CDX models. In gastric PDX models, HDM2012 demonstrated dose dependent efficacy, with TGI (tumor growth inhibition) value of 82-93%, regardless of prior Ironitecan and Top-I ADC treatment. In heavily pre-treated colon cancer PDX models, HDM2012 induced prolonged tumor regression, with TGI value of 94.6%. Furthermore, in MUC17 low expression pancreatic PDX models, HDM2012 could induce sustained tumor regression, with TGI value of 91.5%. In exploratory toxicology study, HDM2012 is well tolerated by cynomolgus monkeys at 45 mpk. Conclusion: Here, we reporting a novel ADC product HDM2012 targeting MUC17, is a potential therapeutic approach for MUC17 positive GC, CRC, PDAC cancer treatment. All the experiment data indicated HDM2012 may be a promising candidate for GI cancer treatment. Reference: 1. Gum JR, et al. Biochem Biophys Res Commun.2002;291:466-475. 2. Van Putten JPM, et al. J Innate Immun. 2017;9:281-299. Citation Format: Qinyu Shu, Zhaofeng Qin, Shengxing Zhao, Yang Chen, Kuan Lu, Qian Zhang, Liubin Guo, Qingli Wei, Hao Pan, Yan Xia, Hongwen Li, Dongzhou Jeffery Liu. Translational studies of HDM2012, a novel topoisomerase inhibitor ADC targeting MUC17, in patient derived GC, CRC, PDAC tumor models [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 316.