Abstract 351: Preclinical development of MHB009C: A novel anti-B7-H4 ADC with a potent topoisomerase I inhibitor

Abstract B7-H4, a member of B7 family, is a transmembrane protein that inhibits T cell immunity. It is overexpressed in various malignancies, including breast, ovarian, and endometrial cancers, as well as cholangiocarcinoma, where it has been associated with tumor progression and poor patient outcomes. Antibody-drug conjugates (ADC) targeting B7-H4 have demonstrated promising clinical activity. Here, we present the development and preclinical characterization of MHB009C, a novel B7-H4 ADC. MHB009C comprises a human IgG1 antibody against B7-H4, conjugated to the SuperTopoiTM payload, a novel DNA topoisomerase I inhibitor that is 3∼5 times more potent than DXd, with a drug-antibody ratio of ∼4.0. Fc function was silenced to minimize nonspecific ADC uptake, and the linker was designed to enhance hydrophilicity and prevent the retro-Michael reaction, improving plasma stability. MHB009C demonstrated strong binding affinity to B7-H4 and was efficiently internalized by SK-BR-3 cells. It exhibited potent cytotoxicity in B7-H4-positive breast cancer cell lines and showed significant antitumor activity in an MX-1 breast cancer xenograft model. GLP study in monkeys revealed a favorable safety profile with no off-target toxicities, and the highest non-severely toxic dose (HNSTD) was determined to be 30 mg/kg Q3W, the maximum dose tested. In conclusion, MHB009C demonstrated potent anti-tumor activity both in vitro and in vivo, along with a favorable safety profile, supporting further clinical development. Citation Format: Liyuan Zhu, Bo Liu, Yile Chen, Xiang Meng, Ao Li, Li Liu, Zhili Yao, Yan Wang, Xialian Weng, Xuefeng Zhu, Yang Liu, Shiyu Zhou, Junwei Shi, Guoqing Cao. Preclinical development of MHB009C: A novel anti-B7-H4 ADC with a potent topoisomerase I inhibitor [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 351.