Abstract LB222: Preclinical characterization of IBI3010, a FRα targeting biparatopic antibody-drug conjugate (ADC), for the treatment of FRα expressing tumors

Abstract Folate Receptor alpha (FRα) is a validated target that is overexpressed in multiple cancers with unmet medical need, including ovarian, lung and breast cancers, while restricted expression in normal tissues. Although mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate (ADC) with a microtubule inhibitor, has been approved from the FDA for the treatment of FRα-expressing platinum-resistant ovarian cancer. There is still a large proportion of patients who do not respond to treatment, especially those with low FRα expression. We have developed a next-generation anti-FRα ADC, IBI3010, which consists of an FRα-targeting biparatopic antibody that is conjugated to a novel topoisomerase I inhibitor, NT1, with a homogeneous drug-to-antibody ratio of 8 (DAR8). Here, we describe the key pharmacological experiments, in vivo efficacy and results from the good laboratory practice (GLP) toxicology studies. In vitro studies have shown that the biparatopic antibody exhibits higher binding and internalization in tumor cells. IBI3010 shows comparable or better cytotoxicity to IMGN853 in various FRα expressing cancer cell lines. In addition, IBI3010 has superior in vitro bystander effect compared to IMGN853. In vivo efficacy was evaluated in various cell line-derived xenograft models with different FRα expression levels. IBI3010 exhibits superior antitumor activity to IMGN853, especially in the FRα low-expression models. In the GLP toxicology study, IBI3010 was tolerated in cynomolgus monkeys at all dose levels, with the highest dose of 60 mg/kg, defined as the highest non-severely toxic dose (HNSTD). Our findings support the clinical development of IBI3010 to evaluate its potential as an ADC therapeutic for FRα-expressing solid tumors. Citation Format: Bo Wang, Jiakai Xing, Shuaixiang Zhou, Weiwei Wu, Min Wu, Rongmei Zuo, Chenchen Zhu, Menghui Zhao, Li Li, Chengjie Cai, Nan Gao, Zhihai Wu, Ninghuan Li, Zeyu Liu, Jinling Xu, Bingliang Chen, Kaijie He. Preclinical characterization of IBI3010, a FRα targeting biparatopic antibody-drug conjugate (ADC), for the treatment of FRα expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB222.