Abstract 352: Preclinical development of MHB042C: A next-generation anti-c-Met ADC conjugating VHH-Fc fusion protein with a novel topoisomerase I inhibitor

Abstract c-MET, a receptor tyrosine kinase encoded by the MET proto-oncogene, is widely expressed in various solid tumors. Antibody-drug conjugates (ADC) targeting c-Met have shown promising clinical activity in patients with high c-MET expression, yet the therapeutic benefit remains limited for those with moderate or low expression levels. Here, we present the development and preclinical characterization of MHB042C, a next-generation anti-c-Met ADC. Unlike conventional monoclonal antibody (mAb), MHB042C utilizes a humanized VHH targeting c-Met, fused with human IgG1 Fc to deliver the cytotoxic payload. The smaller VHH-Fc fusion protein offers higher potential for tumor tissue penetration compared to traditional mAb. This unique configuration streamlines the conjugation process, achieving a uniform drug-to-antibody ratio (DAR) of 4. Additionally, Fc function was silenced to minimize nonspecific ADC uptake. The payload, SuperTopoiTM, a novel DNA topoisomerase I inhibitor, was 3 to 5 times more potent than DXd. The linker was designed to enhance hydrophilicity and to resist the retro-Michael reaction, thereby improving plasma stability. In preclinical assays, MHB042C demonstrated stronger cellular binding than competitor antibodies, reaching an internalization rate of approximately 60% in Hs746t cells within one hour. MHB042C exhibited potent cytotoxicity across c-Met-positive cancer cell lines and showed marked antitumor activity in an EBC-1 Squamous NSCLC xenograft model. GLP study in monkeys revealed a favorable safety profile with no off-target toxicities. The highest non-severely toxic dose (HNSTD) was determined to be 15 mg/kg Q3W, the maximum dose tested. In conclusion, MHB042C demonstrated potent antitumor activity both in vitro and in vivo, along with a favorable safety profile, supporting advancement to clinical development. Citation Format: Bo Liu, Liyuan Zhu, 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 MHB042C: A next-generation anti-c-Met ADC conjugating VHH-Fc fusion protein with a novel 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 352.