Abstract 5466: 7MW4911, a novel cadherin 17-targeting ADC, demonstrates potent efficacy in preclinical models of gastrointestinal cancers

Abstract Background: Cadherin 17 (CDH17), a member of the 7D-cadherin superfamily, is critically involved in intercellular adhesion, tissue integrity, and intestinal peptide transport. It is predominantly expressed on the basolateral membrane of intestinal and pancreatic ductal epithelial cells, with minimal expression in non-gastrointestinal (GI) tissues. Overexpression of CDH17 is strongly associated with tumor progression and metastasis in colorectal, gastric, and pancreatic cancers, making it an attractive target for therapeutic intervention. Here, we report the development of 7MW4911, a novel ADC designed to selectively target CDH17-positive tumors while sparing normal tissues. Methods: CDH17 expression as a therapeutic target was validated using comprehensive omics analyses. An anti-CDH17 specific mAb Mab0727 was generated using Mabwell’s integrated novel antibody discovery system. The ADC 7MW4911 was constructed by conjugating Mab0727 to the proprietary payload MF-6 via a cleavable linker, achieving a drug-to-antibody ratio (DAR) of 4 using site-specific inter-chain disulfide bond conjugation technology. Binding affinity, internalization, and cytotoxicity of 7MW4911 were evaluated in CDH17-positive GI cancer cell lines. Efficacy was further assessed in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Pharmacokinetics and safety were studied in cynomolgus monkeys. Results: Immunohistochemistry (IHC) analysis confirmed CDH17 as a highly specific target, with expression observed in 100% (110/110) of colorectal, 77% (110/142) of gastric, and 55% (58/105) of pancreatic cancer samples. 7MW4911 demonstrated strong binding, efficient internalization, and potent cytotoxicity in CDH17-positive cell lines. In vivo, 7MW4911 showed substantial tumor growth inhibition (TGI), with TGI ranging from 29-97% in nine colorectal CDX models, 56-95% in three gastric models, and 81% in one pancreatic model. In PDX models, TGI ranged from 71-99% across nine colorectal and one gastric model. Importantly, 7MW4911 outperformed MMAE-based ADCs in multidrug-resistant CDX and PDX models. Pharmacokinetic studies in cynomolgus monkeys demonstrated a favorable safety profile, with a maximum tolerated dose exceeding 20 mg/kg and minimal off-target toxicity. Conclusions 7MW4911 demonstrated exceptional preclinical efficacy, including robust activity against multidrug-resistant cancers, along with a strong safety profile. These findings highlight its potential as a transformative therapeutic candidate for CDH17-positive GI cancers, addressing significant unmet needs in oncology. Citation Format: Rui Wang, Peng Fang, Wei Zhou, Cuicui Guo, Xiaoding Tan, Hai Wu, Xun Gui. 7MW4911, a novel cadherin 17-targeting ADC, demonstrates potent efficacy in preclinical models of gastrointestinal 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 5466.