Abstract 4723: Development and preclinical activity of BSI-721, a novel antibody-drug conjugate (ADC) targeting cadherin 17 (CDH17) in gastrointestinal cancers

Abstract Background: Cadherin 17 (CDH17) is a cell adhesion protein that belongs to the cadherin superfamily. CDH17 is highly restricted to tight junctions in normal gastrointestinal (GI) tissues. In contrast, CDH17 is frequently overexpressed and becomes accessible to targeted therapeutics in several GI malignancies, including colorectal, gastric, pancreatic, and esophageal cancers. This differential expression profile makes CDH17 a promising therapeutic target for antibody-based therapeutics, including ADCs. Here, we described the development and preclinical activity of BSI-721, a novel ADC that combines a fully humanized anti-CDH17 monoclonal antibody (mAb) with monomethyl auristatin E (MMAE) via a cleavable peptide linker. Methods: The anti-CDH17 mAb was generated from AceMouse™ mice immunized with 293T cells overexpressing human full-length CDH17 and purified CDH17 extracellular domain recombinant protein, sequentially. Binding affinity of the anti-CDH17 mAb was assessed by surface plasmon resonance and flow cytometry. CDH17 expression as cell surface density on cancer cells was determined by quantitative flow cytometry. The anti-CDH17 mAb was conjugated to MMAE via a protease-cleavable valine-citrulline linker. Cytotoxicity of BSI-721 was evaluated in cell lines with varying endogenous expression levels of CDH17. In vivo, efficacy of BSI-721 was assessed in CDH17-high gastric and CDH17-moderate/low pancreatic CDX models. Results: The anti-CDH17 mAb showed strong binding affinity to both human and cynomolgus monkey CDH17 and cell lines with varying expression levels of CDH17. HIC-HPLC analysis revealed that MMAE was conjugated to the anti-CDH17 mAb in a drug-to-antibody ratio (DAR) of 4 with a high yield of (among which, more than 50% conjugates carrying a DAR of 4). BSI-721 exhibited potent cytotoxicity against cell lines with varying expression levels of CDH17 (subnanomolar IC50). In CDH17-high gastric cancer model (SNU-5), treatment with BSI-721 resulted in significant tumor regression (with achievement of partial response) and tumor growth inhibition (TGI). BSI-721 also demonstrated a significant TGI in CDH17-moderate/low pancreatic cancer model (AsPC1). Additionally, candidate antibodies have been identified with potential to be developed into immunohistochemistry (IHC) companion diagnostic assay. Conclusion: These data highlight the potential of BSI-721 as an effective targeted therapy for GI malignancies with varying expression levels of CDH17. Further, pharmacokinetics, toxicity, and IND-enabling studies of BSI-721 are underway. Citation Format: Xiaoyao Hao, Jingyu Liu, hongyan li, jun li, jialong wang, Hui-Han Hu, frank liu, mingjiu chen, Qun Lv. Development and preclinical activity of BSI-721, a novel antibody-drug conjugate (ADC) targeting cadherin 17 (CDH17) in 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 4723.