Abstract LB057: Pre-clinical characterization of IBI343, a site-specifically conjugated anti-Claundin18.2 ADC, for treating solid tumors

Abstract Claudin18.2 is important for the formation and function of tight junctions between cells in epithelial tissues. Normally expressed only in gastric mucosa, Claudin18.2 is overexpressed in multiple types of solid tumors, including gastric, pancreatic, breast and colon cancers. Despite being a well-established tumor-associated antigen, the clinical value and feasibility of targeting Claudin18.2 by various modalities are yet-to-be fully demonstrated. IBI343 is a fully humanized anti-Claudin18.2 monoclonal antibody conjugated to Exatecan via site-specific glycol-conjugation with an average drug-to-antibody ratio (DAR) of 3.6. IBI343 showed robust antigen-specific in vitro cytotoxicity in cancer cell lines with varying levels of Claudin18.2 expression. In addition, due to the cleavable linker design and high hydrophilicity of the payload, IBI343 demonstrated potent bystander killing effects in vitro. The glycan-based conjugation technology leads to enhanced stability of the conjugated linker-payload and the entire ADC molecule, which results in superior pharmacokinetics. IBI343 showed potent in vivo anti-tumor efficacy with complete tumor regressions in multiple xenograft models. Furthermore, it demonstrated strong in vitro and in vivo synergistic effects with various anti-cancer agents, including immune checkpoint blockers and DNA damage repair pathway inhibitors. IBI343 displayed good safety profile in monkey GLP toxicology study (HNSTD = 30 mg/kg). These pre-clinical findings show that IBI343 is a promising anti-cancer agent with large therapeutic window, and support clinical exploration of IBI343 in patients with Claudin18.2-expressing tumors. A companion late-breaking abstract of clinical phase 1 study results (NCT05458219) will also be presented in AACR 2024. Citation Format: Shuaixiang Zhou, Xiong Yao, Jian Guan, Keke Fei, Jia Lu, Weiwei Wu, Yang Liu, Tianyu Zhu, Zhuangguang Liao, Shi Chen, Bingliang Chen, Kaijie He. Pre-clinical characterization of IBI343, a site-specifically conjugated anti-Claundin18.2 ADC, for treating solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB057.