Abstract 353: Preclinical development of MHB048C: A novel anti-PSMA ADC with a potent topoisomerase I inhibitor

Abstract Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein, is highly and specifically expressed in prostate cancer while showing limited expression in normal tissues. The FDA’s approval of (177) Lu-PSMA-617 has validated PSMA as a therapeutic target for treating metastatic castration-resistant prostate cancer (mCRPC). Here, we present the development and preclinical characterization of MHB048C, a novel PSMA specific antibody-drug conjugate (ADC). MHB048C comprises a human IgG1 antibody against PSMA, conjugated to the SuperTopoiTM payload, a novel DNA topoisomerase I inhibitor that is 3∼5 times more potent than DXd. The drug-antibody ratio is approximately 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. The antibody preferentially binds to the PSMA dimer rather than the monomer, as only dimers display the native conformation. MHB048C showed strong binding affinity in protein and cell-level assays and was efficiently internalized by LNCaP cells, reaching an internalization rate of ∼70% within 1 hour. It exhibited potent cytotoxicity in PSMA-positive prostate cancer cell lines with varying PSMA expression levels and demonstrated significant antitumor activity in an LNCaP FGC prostate cancer xenograft model. In GLP monkey studies, MHB048C exhibited a favorable safety profile with no off-target toxicities. The highest non-severely toxic dose (HNSTD) was determined to be 45 mg/kg Q3W, the maximum dose tested. In conclusion, MHB048C demonstrated potent anti-tumor activity both in vitro and in vivo, along with a favorable safety profile, supporting advancement to clinical development. Citation Format: Yile Chen, Ao Li, Bo Liu, Liyuan Zhu, Xiang Meng, Zhili Yao, Yan Wang, Xialian Weng, Xuefeng Zhu, Shiyu Zhou, Junwei Shi, Guoqing Cao. Preclinical development of MHB048C: A novel anti-PSMA 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 353.