Abstract C077: GenSci143, a Novel B7-H3 × PSMA Bispecific Antibody-Drug Conjugate (BsADC), Demonstrates Broad-Spectrum Preclinical Antitumor Efficacy with a Favorable Safety Profile

Abstract Introduction: B7-H3 (CD276) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and other solid tumors. Clinical limitations of single-target agents include restricted efficacy in mCRPC monotherapy (e.g., DS-7300a [anti-B7-H3 ADC] and ARX517 [anti-PSMA ADC]), often attributed to tumor heterogeneity and variable target expression. To overcome this, we engineered GenSci143, a bispecific ADC (BsADC) targeting both B7-H3 and PSMA, conjugated to a potent TOP1 inhibitor payload. This dual-targeting strategy aims to enhance efficacy and expand treatable patient populations by simultaneously addressing antigen heterogeneity in mCRPC and other solid tumors. Methods: Target expression was evaluated by immunohistochemistry. In vivo efficacy was assessed across multiple cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models representing prostate cancer (PCa), non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and gastric cancer (GC). Combination potential with enzalutamide (endocrine therapy) was evaluated in a PCa PDX model. Biomarkers associated with therapeutic efficacy were analyzed in PCa PDX models. Pharmacokinetic (PK) and toxicology profiles were characterized in cynomolgus monkeys. Results: In PCa CDX/PDX models with varying B7-H3/PSMA expression, GenSci143 exhibited significantly stronger antitumor activity versus benchmark ADCs DS-7300a and ARX517 analogs. Synergy was observed when combining GenSci143 with enzalutamide in a PCa PDX model. GenSci143 also demonstrated potent efficacy in NSCLC and GC CDX/PDX models. A SLFN11-dependent response pattern was observed in PCa PDX models treated with GenSci143 or DS-7300a, but not ARX517, supporting SLFN11 as a biomarker for TOP1 inhibitor response. PK studies revealed favorable drug exposure with linear kinetics. Repeat-dose toxicity assessments in non-human primates indicated a well-tolerated profile. Conclusion: GenSci143, a dual-targeting B7-H3 × PSMA ADC, achieves superior efficacy over DS-7300a and ARX517 analogs in prostate cancer models with heterogeneous target expression, effectively overcoming limitations of single-target ADCs. Its potent activity across multiple solid tumors (NSCLC, GC) and synergy with endocrine therapy support broader clinical applicability. The association with the SLFN11 biomarker may further optimize patient stratification. These results position GenSci143 as a promising therapeutic modality with enhanced efficacy and expanded patient coverage potential for mCRPC and beyond. Citation Format: Liang Xu, Hui Yi. Lin, Xin Chen, Peng Qi, Nan Shao. Liang, Xuan Ye, Yan Li, Qin Yun. Chen, Chun Qu, Yao Xu, Yu Zhi. Cui, Ming Wei. He, Qiang Wen. Zhai, Fu Li, Long Fang. Yang, John L. Xu, Zhen Xiao. Wang, Zhou Hai. Zhang. GenSci143, a Novel B7-H3 × PSMA Bispecific Antibody-Drug Conjugate (BsADC), Demonstrates Broad-Spectrum Preclinical Antitumor Efficacy with a Favorable Safety Profile [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C077.