Multi-omic profiling reveals antibody-drug conjugate targetability in ovarian cancer

Abstract

Abstract Antibody-drug conjugates (ADCs) require high and homogeneous target expression for optimal efficacy, yet the spatial, temporal, and cellular heterogeneity of clinically approved ADC targets in high-grade serous ovarian cancer (HGSC) remains incompletely defined. We analyzed bulk RNA-sequencing, single-cell RNA-sequencing, and whole-genome sequencing data from 867 samples across 304 patients enrolled in the real-world DECIDER cohort to systematically evaluate 11 approved ADC targets. FOLR1, TACSTD2 , and ERBB2 emerged as highly expressed candidates. Inter-patient variability exceeded intra-patient heterogeneity, which further decreased following neoadjuvant chemotherapy. Target expression was highly concordant across anatomical sites and largely stable from diagnosis to relapse. Single-cell RNA-sequencing results revealed that TACSTD2 and FOLR1 showed the most frequent cancer cell-restricted expression. In rare cases of gene amplification, ERBB2 and F3 emerged as potential targets alongside TACSTD2 and FOLR1 . Overall, 80% of patients displayed homogeneous expression of at least one actionable target, with frequent co-expression of TACSTD2 and FOLR1 . These findings indicate that ADC target expression in HGSC is broadly stable across space and time and support the prioritization and strategic integration of TACSTD2 - and FOLR1 -directed ADCs in this disease.