Abstract Antibody-drug conjugate (ADC) has rapidly transformed the treatment landscape for solid tumors; however, due to heterogeneity in target antigen expression, suboptimal efficacy and emergence of acquired resistance present significant challenges to the development of curative ADCs for cancers. Here, we report the preclinical evaluation of GenSci143, a novel B7-H3 × PSMA-directed bispecific ADC (BsADC), designed to overcome tumor antigen heterogeneity-associated drug resistance for the treatment of metastatic castration-resistant prostate cancer (mCRPC). GenSci143 comprises a highly active topoisomerase 1 inhibitor payload conjugated to a dual-targeting antibody via a plasma-stable linker to minimize off-target toxicity. Gene profiling analysis reveals high co-expression of B7-H3 and PSMA in prostate cancer (PCa), laying the biological basis of dual targeting strategy. In vitro, GenSci143 exhibited strong binding, efficient internalization, and potent cytotoxicity against PCa cells expressing either or both target antigens, as well as a robust bystander killing effect, outperformed single-target benchmark ADCs that are currently in clinical development. In multiple cancer cell line-derived and patient-derived xenograft (CDX/PDX) models of PCa, GenSci143 induced profound tumor regression and demonstrated superior antitumor activity vs. competitor ADCs. Furthermore, GenSci143 displayed excellent plasma stability and favorable pharmacokinetic properties in non-human primates. The compelling preclinical efficacy across cancer models with varying levels of target antigen expression and its exceptional plasma stability support the translational relevance of GenSci143. These results indicate that GenSci143 is a promising therapeutic candidate for castration resistant PCa and potentially other malignancies, warranting its further clinical development.
Xu et al. (Fri,) studied this question.