Abstract 343: GenSci143, a novel B7-H3×PSMA bispecific and potential best-in-class ADC, for the treatment of metastatic castration-resistant prostate cancer

Abstract Background: PCa is the most common cancer among men worldwide. Once patients have progressed to castration resistance, treatment options become scarce, leaving a substantial unmet need in the mCRPC settings. Both B7-H3 and PSMA are tumor-associated antigens that exhibit high levels of expression in PCa, and dual targeting of them with a single agent represents a promising therapeutic approach to the treatment of mCRPC. We developed GenSci143, a novel B7-H3×PSMA-directed bispecific ADC comprised of a bispecific antibody against B7-H3 and PSMA, a highly stable but cleavable linker, and a potent topoisomerase 1 inhibitor payload. Potential of GenSci143 as a novel targeted cancer therapy is currently evaluated in preclinical studies. Methods: Membrane expression of B7-H3 and PSMA in tissue microarrays of PCa biopsies was examined by immunohistochemistry analysis. Cell surface levels of B7-H3 and PSMA in PCa cell lines were quantified by flow cytometry using Quantibrite beads. Binding affinity of GenSci143 to B7-H3- and/or PSMA-expressing tumor cells was also determined using flow cytometry. To assess internalization, cells were treated with pHrodoTM-labelled antibodies, and fluorescence intensity was recorded. In vitro cytotoxic effect of GenSci143 on PCa cell lines was evaluated using a Luminescent Cell Viability assay. In vivo anti-tumor activity of GenSci143 was assessed in CDX models of PCa and compared to that of the DS-7300 and ARX517 analogs. Results: B7-H3 and PSMA were highly co-expressed in PCa tissues (N=102), lending strong support to our dual-targeting therapeutic approach for mCRPC. GenSci143 showed strong in vitro binding, internalization, and cytotoxicity in tumor cells expressing either B7-H3 or PSMA or both TAAs. In human CDX models of PCa in mice, GenSci143 effectively induced tumor regression across different expression levels of B7-H3 and PSMA and demonstrated superior anti-tumor efficacy versus the DS-7300 and ARX517 analogs. Moreover, GenSci143 showed much better in vitro plasma stability than DS-7300. Following intravenous injection at 10 mg/kg in cynomolgus monkeys, GenSci143 exhibited a favorable pharmacokinetic profile, with serum concentration of free payload lower than 1.0 ng/mL at any time examined. In a pilot non-GLP repeat dose toxicity study in cynomolgus monkeys, GenSci143 was well tolerated, demonstrating a significantly higher therapeutic index than DS-7300 based on PK-PD modeling and simulation. Conclusion: These results suggest that GenSci143 has the potential to become an effective therapeutic option for mCRPC patients and support its further evaluation in IND-enabling studies. Citation Format: Yao Xu, Fu Li, Zhiyu Cui, Hongmei Xie, Wei Yan, Yan Li, Weiming He, Wenqiang Zhai, Fanglong Yang, John L. Xu. GenSci143, a novel B7-H3×PSMA bispecific and potential best-in-class ADC, for the treatment of metastatic castration-resistant prostate cancer [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 343.