Abstract 2884: Development of antibody drug conjugates targeting MUC16 in ovarian cancer subtypes

Abstract Background: Ovarian cancer (OC) remains a formidable challenge due to limited treatment options and inevitable development of multidrug resistance. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic modality, particularly for cancers with high unmet needs such as ovarian cancer (OC). MUC16, also known as CA125, is a high-molecular-weight glycoprotein overexpressed in ovarian cancer, serving as a biomarker for diagnosis and monitoring while contributing to tumor progression and immune evasion. Our laboratory previously identified 4H11, an antibody that preferentially binds to the retained (ectodomain) portion of MUC16. To exploit this target, we have systematically evaluated a panel of ADC payloads and linkers, including Auristatins (MMAE, MMAF), Camptothecin (SN-38), Maytansinoids, Calicheamicin, Nemorubicin, and Belotecan, conjugated to our proprietary antibody 4H11. Given the heterogeneity of OC, we investigated the efficacy of these ADCs across various subtypes, including high-grade serous ovarian carcinoma (HGSOC) and patient derived organoids. Methods: ADCs were synthesized by conjugating 4H11 to different payloads via established linker chemistries. The resulting ADCs were characterized for drug-to-antibody ratio (DAR) and stability. In vitro cytotoxicity was assessed using a panel of OC cell lines and patient-derived organoids representing multiple subtypes. Dose-response curves were generated to evaluate IC50 values, and selectivity for antigen-positive cells was confirmed. Additionally, we analyzed differential sensitivity among subtypes to identify the most effective payload and ADC formulation. Results: All ADCs demonstrated high stability and target specificity in vitro. Notably, ADCs with maytansinoids exhibited superior potency across HGSOC and other subtypes, achieving sub-nanomolar IC50 values in MUC16-positive cell lines. However, nemorubicin-conjugated ADCs showed enhanced efficacy in certain non-HGSOC subtypes, suggesting subtype-specific vulnerability. In organoid models, ADC efficacy closely mirrored cell line data, highlighting the translational potential of these findings. Importantly, payload and linker selection significantly impacted ADC performance, with maytansinoids yielding the best overall therapeutic index across of broad spectrum of OC histologic subtypes. Conclusion: The retained portion of MUC16 is a viable target for ADC development. The maytansinoid conjugates emerged as leading candidates for further preclinical evaluation and potential clinical development based on their broad spectrum of activity against multiple histological subtypes. Our findings further underscore preferential susceptibility of different OC histologic subtypes to different ADC payloads. Citation Format: Mengyao Xu, Bo Rueda, David Spriggs, Yeku Oladapo. Development of antibody drug conjugates targeting MUC16 in ovarian cancer subtypes [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 2884.