Abstract 3140: BL-M05D1, a novel claudin 18.2-targeting ADC, demonstrates specific potent anti-tumor efficacy in preclinical evaluation

Abstract Claudin 18. 2, is a member of the tight junction protein family, and an isoform of claudin18. It is therapeutically targeted in cancer due to its limited expression in normal tissue and prevalent expression in a variety of human carcinomas. To develop a promising therapeutic anti-tumor agent, we generated BL-M05D1, an anti-Claudin 18. 2-Ed-04 ADC. It is comprised of a novel, specific monoclonal antibody against Claudin 18. 2 (5103F3), having a wt Fc that can mediate ADCC and CDC in vitro. BL-M05D1 is composed of (5103F3), a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04). The novel Ed-04 is a derivative of the alkaloid camptothecin and mediates cell cycle arrest at the S phase and subsequent apoptosis. BL-M05D1 achieves a high drug-to-antibody-ratio (DAR=8) with a highly stable linker and is readily internalized and trafficked to lysosomal cellular compartments. The antitumor efficacy of BL-M05D1 was evaluated in xenograft tumor models. BL-M05D1 exhibited strong tumor inhibition capacity toward the human gastric cancer cell MKN-45-Claudin18. 2 (#C11D) xenograft model, and human pancreatic cancer cell Patu8988s-Claudin18. 2 (#C7G) xenograft model. In summary, these studies suggest BL-M05D1, a novel Claudin 18. 2-targeting ADC, is potentially efficacious in the treatment of Claudin 18. 2-expressing carcinomas. The clinical phase I is being undertaken to evaluate safety, dosing and observations of preliminary signs of efficacy. Citation Format: Weili Wan, Kelcey Dinkel, Austin Sanford, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Ruigang Li, Jahan Salar Khalili, Xiao Sa, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M05D1, a novel claudin 18. 2-targeting ADC, demonstrates specific potent anti-tumor efficacy in preclinical evaluation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3140.