Abstract 349: GenSci140, a potential best-in-class FRα-directed biparatopic ADC, for the treatment of platinum-resistant ovarian cancer

Abstract Background: Folate receptor alpha (FRα) is a GPI-anchored cell-surface glycoprotein overexpressed in a variety of solid tumors, including ovarian cancer, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and endometrial cancer. It exhibits limited expression in normal tissues, making it an ideal target for the development of cancer therapy. IMGN853/ELAHERETM, a FRα-directed ADC, has been approved for platinum-resistant epithelial ovarian cancer (PROC) patients with high levels of FRα expression. Despite this advancement, it is estimated that around 60% of PROC patients with medium to low FRα expression do not benefit from this therapy. In addition, occurrence of ocular toxicity has been reported in approximately 40% of patients treated with ELAHERETM. In order to address unmet need in broader patient populations and to minimize toxicity, we developed GenSci140, a novel FRα-directed biparatopic ADC with a potent Topo1 inhibitor payload and a stable but cleavable linker at the drug-to-antibody ratio (DAR) of 6. Materials and Methods: A novel FRα-directed biparatopic antibody was constructed from a monoclonal antibody and a VHH domain antibody to bind with high and low affinity, respectively, to two distinct epitopes on the tumor antigen, and used to generate GenSci140 with our proprietary linker-payload technology. In vitro tumor cell binding and internalization of GenSci140 were characterized by flow cytometry; cytotoxicity and bystander killing activity were assessed in Cell Titer-Glo assay and in luciferase assay, respectively. In vivo anti-tumor efficacy of GenSci140 was assessed in human cancer cell line-derived xenograft (CDX) models in mice, and pharmacokinetic and toxicology profiles were evaluated in cynomolgus monkeys. Results: GenSci140 exhibited significantly stronger in vitro tumor cell binding and more efficient internalization than IMGN853. GenSci140 displayed potent cytotoxicity in FRα-positive tumor cells and effective bystander killing of FRα-negative cells in a FRα+/FRα- tumor cell co-culture system. GenSci140 demonstrated superior in vivo anti-tumor efficacy compared to ELAHERETM and IMGN151 (competitor's next-generation FRα-directed biparatopic ADC product) across a variety of CDX models including ovarian cancer, NSCLC, and TNBC, irrespective of their FRα expression levels. Furthermore, GenSci140 featured a favorable pharmacokinetic profile and was well-tolerated in a non-GLP repeat dose toxicity study in NHPs. Conclusion: These data suggest that GenSci140 could be a more effective and safer treatment option than the current standard of care for 2L PROC, potentially addressing the unmet need of patients with varying levels of FRα expression. Therapeutic potential of this molecule is currently further evaluated in IND-enabling studies. Citation Format: Meihan Li, Fu Li, Yingying Sun, Qiuru Che, Na Dong, Li Tong, Weiming He, Wenqiang Zhai, Peng Qi, Min Zhang, Fanglong Yang, John L. Xu. GenSci140, a potential best-in-class FRα-directed biparatopic ADC, for the treatment of platinum-resistant ovarian 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 349.