Abstract A105: MC003: ADoTope, a first-in-class dual-payload bi-epitope combination chemoimmunotherapy antibody drug conjugate (ADC) targeting Folate Receptor Alpha (FRa) in platinum-resistant epithelial ovarian cancer

Abstract Background Folate receptor alpha (FRα) is expressed on the surface of nearly 80% of epithelial ovarian cancers (EOC), including recurrent disease, providing a compelling rationale for the development of antibody-drug conjugates (ADCs) targeting this antigen. 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. 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. Citation Format: Seah H. Lim, Hailiang Zheng, Pei Pei Zhong. MC003: ADoTope, a first-in-class dual-payload bi-epitope combination chemoimmunotherapy antibody drug conjugate (ADC) targeting Folate Receptor Alpha (FRa) in platinum-resistant epithelial ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A105.