Abstract 1764: MC003: A novel bi-epitope, dual-payload, fixed-combination chemoimmunotherapy antibody drug conjugate for the treatment of folate receptor alpha-expressing ovarian cancer

Abstract Background: Folate receptor alpha (FRα) is overexpressed in approximately 80% of epithelial ovarian cancers (EOC), but with limited expression in most normal tissues. FRα is, therefore, an ideal therapeutic target for antibody drug conjugates (ADCs). In patients with platinum-resistant ovarian cancer, where treatment options are scarce and outcomes remain dismal, FRα-targeted ADCs have emerged as a promising approach. To enhance therapeutic efficacy and overcome drug resistance, we developed a novel bi-epitope, dual-payload FRα-targeted ADC, designated MC003 (ADoTope FRα ADC), and evaluated its preclinical pharmacology, efficacy, and safety profile. Methods: A panel of fully human monoclonal antibodies specific for FRα was isolated from a human v-gene phage display library. Through biolayer interferometry (BLI), two high-affinity antibodies, Clone 65 and Clone 91, were identified to bind distinct, non-overlapping epitopes on FRα with comparable KD values. Clone 65 was conjugated to gemcitabine, a nucleoside analog, and Clone 91 to exatecan, a potent topoisomerase I inhibitor, both via enzyme-cleavable linkers. Each ADC achieved an average drug-to-antibody ratio (DAR) of approximately 8. The fixed 1:1 combination of the two ADCs constituted MC003, representing the ADoTope dual-payload format. Results: Both Clone 65 and Clone 91, in their unconjugated forms, demonstrated robust antibody-dependent cellular cytotoxicity (ADCC) against FRα-positive SKOV3 ovarian cancer cells but lacked complement-dependent cytotoxicity (CDC). When conjugated, MC003 exhibited markedly enhanced cytotoxic potency in vitro compared to either single-payload ADC, indicating synergistic antitumor activity. In SCID mice bearing established SKOV3 xenografts, MC003 achieved superior tumor growth suppression relative to mirvetuximab soravtansine, a clinically approved FRα ADC. Histological analysis revealed increased intratumoral CD8+ T-cell infiltration, dendritic cell maturation, and upregulation of MMP9, suggesting immune activation within the tumor microenvironment. Single-dose toxicology studies in Sprague Dawley rats and cynomolgus monkeys demonstrated that MC003 was well tolerated up to 20 mg/kg—approximately 6.5-fold above the pharmacologically active dose—with no evidence of bone marrow suppression, hepatotoxicity, or nephrotoxicity. Conclusions: ADoTope enhances FRα targeting by simultaneously engaging two distinct epitopes, effectively functionally increasing the antigen density and enabling the co-delivery of mechanistically distinct cytotoxic payloads. MC003 also mediates efficient ADCC and induces immune activation. These preclinical findings support the advancement of MC003 into IND-enabling studies as the next-generation therapeutic for platinum-resistant ovarian cancer. Citation Format: Seah H. Lim, Hailiang Zheng, Peipei Zhong. MC003: A novel bi-epitope, dual-payload, fixed-combination chemoimmunotherapy antibody drug conjugate for the treatment of folate receptor alpha-expressing ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1764.