Abstract 830: Combined a B7-H3-targeting antibody-drug conjugate, 7MW3711, and PARP inhibitors synergistically potentiates the antitumor activity in B7-H3-positive cancers

Abstract Introduction: B7-H3, an attractive target for antibody drug conjugate, is overexpressed in multiple tumors. Overexpression of B7-H3 in tumor cells frequently correlates with fewer tumor-infiltrating lymphocytes, faster cancer progression, and poor clinical outcome in several malignancies. Preliminary evidence revealed PARP inhibitors (PARPi) and B7-H3-directed antibody-drug conjugate (ADC) as two practical approaches to overcome chemoresistance in solid cancers. Thus, synthetic lethality exploitation by an anti-B7-H3 ADC plus PARPi might be a promising strategy in solid tumor models. Here, we investigated the activity of 7MW3711, a B7-H3-directed ADC bearing a novel isomerase I inhibitor (TOP1i) payload, alone and in combination with PARPi, in preclinical models to evaluate the potential for future clinical application. Method: 7MW3711 was evaluated in vitro and vivo efficacy with or without PARPi (Olaparib or AZD5305). In vitro, human cancer cell lines were treated with 7MW3711 and two PARPi to determine the effect on anti-proliferative effects, double-stranded DNA breaks, and cell-cycle arrest. In vivo, mice bearing ovarian and SCLC tumor xenografts were treated with the combination of 7MW3711 and PARPi. Results: Evaluation of the drug resistance ability in cell lines expressing P-gp revealed 7MW3711 exhibited > 3-fold more potent than DS7300 (B7-H3-directed DXd ADC), indicating that 7MW3711 has a lower efflux efficiency in drug-resistant strains. 7MW3711 combined use of PARPi synergistically potentiated the inhibitory effects of 7MW3711 on the growth of B7-H3-positive cancer cells, inducing DNA damage and apoptosis. The highest level of double-stranded DNA breaks was observed in cells treated with combination which can be determined in the upregulation of γ-H2AX protein. Combination increased both G2/M phase-arrested cells and S-phase cells, reduced G1-phase, indicating that most proliferating cells were arrested. Combining 7MW3711 with olaparib or AZD5305 produced significant antitumor effects and survival benefit above that achieved with monotherapy in various B7-H3-positive solid tumor xenografts. Collectively, our results demonstrate the synergistic antitumor activity of combining 7MW3711 with PARPi, suggesting that DNA damage-repair inhibitors in combination with B7-H3-targeted ADCs is a promising approach for treating B7-H3-positive malignancies. Conclusion: These data provide evidence for the potential utility of 7MW3711 combination with PARPi for treatment of B7-H3-expressing tumors and support the rationale for further clinical studies. Citation Format: Xiaowei Cen, Peng Fang, Yueyue Yang, Dongan Yu, Yueqin Yao, Fei Mei, Xueying Li, Meng You, Yiyan Zhang, Long Yin, Xiaowei Sun, Xiaoding Tan, Wei Zhou, Hai Wu. Combined a B7-H3-targeting antibody-drug conjugate, 7MW3711, and PARP inhibitors synergistically potentiates the antitumor activity in B7-H3-positive cancers [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 830.