Abstract 6173: Preclinical studies of BB-1712: A B7H3-targeting eribulin-containing ADC with the potential to overcome resistance to DNA topoisomerase I inhibitor-containing ADCs

Abstract B7-H3, a member of the B7 family of proteins, is overexpressed in various solid tumors, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), while exhibiting minimal expression in healthy tissues. This unique expression profile positions B7-H3 as a promising target for antibody-drug conjugates (ADCs). Multiple B7H3-targeting ADCs are currently being tested in different stages of clinical trials and several of them have reported antitumor activities in heavily treated patients. In this study, we introduce BB-1712, a novel B7-H3-targeting ADC that incorporates eribulin as its cytotoxic payload, with the potential to treat patients not sensitive to ADCs containing DNA topoisomerase I inhibitors as payload toxin such as DS-7300a. BB-1712 was designed to leverage eribulin's distinct mechanism of action, which effectively inhibits tumor growth through multiple mode of actions including promotion of apoptosis, tumor microenvironment modulation, immunogenic cell death and bystander killing. We conducted extensive preclinical evaluations of BB-1712, focusing on its in vitro cytotoxicity and in vivo tumor inhibitory activities against a range of B7-H3-expressing cancer cell lines and xenograft models.Our results demonstrated that BB-1712 exhibited binding activity to B7-H3-positive cell lines similarly to that of Infinatamab, and displayed potent cytotoxic effects across multiple human cancer models, including non-small cell lung cancer, breast cancer, gastric cancer and small cell lung cancer cell lines. In xenograft studies, BB-1712 achieved significant tumor regression at well-tolerated doses without obvious toxicity. Notably, BB-1712 effectively overcame resistance to DS-7300a in both SCLC and NSCLC models previously treated with this agent. Pharmacokinetic and toxicology assessments in non-human primates revealed a favorable safety profile for BB-1712 at clinically relevant dosages and administration schedules.In summary, our findings suggest that BB-1712 has promising preclinical efficacy and safety profiles as well as the potential to circumvent resistance mechanisms associated with current therapies. These results support the advancement of BB-1712 into clinical trials for patients with B7-H3-expressing solid tumors. Citation Format: Yang Wang, Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Qi Zhang, Ziping Wei, Yuhong Zhou. Preclinical studies of BB-1712: A B7H3-targeting eribulin-containing ADC with the potential to overcome resistance to DNA topoisomerase I inhibitor-containing ADCs [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 6173.