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Background Folate receptor alpha (FRα) is expressed on the surface of nearly 80% of epithelial ovarian cancers (EOC), including recurrent disease. It is, therefore, a good target for antibody-drug conjugates (ADCs). This is particularly relevant in the platinum-resistant setting, where treatment options remain limited. While the FDA has approved mirvetuximab soravtansine for platinum-resistant ovarian cancer, its clinical performance underscores a persistent unmet need in this highly refractory population. Importantly, the approval is restricted to patients whose tumors demonstrate FRα expression in ≥75% of cells, limiting eligibility to approximately 35–40% of platinum-resistant patients.Methods A panel of human antibodies targeting FRα was isolated from a human phage display library. Using biolayer interferometry (BLI), we identified a pair of antibodies, designated Clone 65 and Clone 91, that bind to two distinct, non-overlapping epitopes on FRα. Clone 65 was conjugated to gemcitabine, a nucleotide analog, and Clone 91 to exatecan, a topoisomerase I inhibitor, both via enzyme-sensitive linkers. The resulting ADCs exhibited an average drug-to-antibody ratio (DAR) of 8. Both the naked antibodies and their corresponding ADCs were used in subsequent experiments.Results The ADoTope antibodies consist of a pair of fully human, high-affinity IgG1 monoclonal antibodies, each recognizing a distinct, non-overlapping epitope on FRα ( figure 1). We first demonstrated that the naked forms of Clone 65 and Clone 91, which comprise the ADoTope antibody pair, mediated potent antitumor activity via in vitro antibody-dependent cellular cytotoxicity (ADCC). However, similar to mirvetuximab soravtansine, they did not elicit significant complement-dependent cytotoxicity (CDC).To assess the therapeutic advantage of a dual-payload strategy, the ADC MC003 was evaluated in vitro against its corresponding single-payload ADCs in the platinum-resistant ovarian cancer cell line SKOV3. MC003 exhibited greater potency than the individual ADCs, including mirvetuximab soravtansine, supporting the enhanced tumor-killing efficacy of the dual-payload format. In vivo studies using SCID mice bearing SKOV3 xenografts further confirmed that MC003, administered on a molar/kg basis, achieved superior tumor growth inhibition and outperformed mirvetuximab soravtansine. Our data highlights the therapeutic potential and tolerability of this dual-payload ADC.Conclusions The ADoTope platform not only functionally increases the antigen copy number and potentially broads the serviceable market, it also allows for dual-payload conjugation to enhance cytotoxicity and reduce the risk for resistance. Our data provides preclinical support for the ADoTope platform and justifies advancing MC003 to further development for platinum-resistant ovarian cancer treatment. MC003 is currently in IND-enabling stage of development.Ethics Approval All animal experiments were carried out under the Sanyou Biopharmaceuticals Laboratory Animal Ethics Committee.Abstract 995 Figure 1