Expression of the antibody-drug conjugate targets TROP2, CLDN6, B7-H3, and DLL3 in mesonephric-like adenocarcinoma of the female genital tract

OBJECTIVE: Mesonephric-like adenocarcinoma (MLA) of the endometrium and ovary is a rare and aggressive malignancy with limited treatment options. Antibody-drug conjugates (ADCs) targeting cell-surface proteins such as TROP2, CLDN6, B7-H3, and DLL3 are emerging therapies in gynecologic cancers; however, their expression has never been systematically investigated in MLA. This study aimed to characterize the expression of these potential therapeutic targets in MLA. METHODS: Immunohistochemical staining for TROP2, CLDN6, B7-H3, and DLL3 was performed in a cohort of 22 MLAs (11 endometrial and 11 ovarian). H-scores (range 0-300) were calculated to quantify expression levels for each biomarker. RESULTS: B7-H3 was universally expressed in all 22 cases (100%), often at high levels, with a median H-score of 140 (range: 20-245). TROP2 was also expressed in all cases (22/22; 100%) but with lower overall scores (median H-score 95, range: 37.5-210). CLDN6 expression was observed in most tumors (21/22; 95.5%) with variable intensity (median H-score 66.3, range 0-175). In contrast, DLL3 was largely negative, with minimal staining in a small subset of cases (3/12, 25%; median H-score of 0 (range: 0-17)). CONCLUSIONS: MLAs consistently express B7-H3, TROP2, and CLDN6, identifying them as highly promising therapeutic targets for ADC-based therapies, but this may require biomarker informed eligibility screening. DLL3 is unlikely to be a useful therapeutic target in this aggressive histotype. These findings expand the biomarker landscape in MLA and provide a rationale for clinical investigation of ADCs in this setting.