Effective preclinical activity of datopotamab deruxtecan (Dato-DXd), an ADC targeting trophoblast cell-surface antigen 2 (TROP2), against primary cervical carcinoma cell lines and xenografts

Abstract

Background: Cervical cancer is one of the most prevalent and deadly cancers worldwide. Here we demonstrate the preclinical pharmacology of Dato-DXd, a TROP2-targeting antibody-drug conjugate (ADC), against primary cervical cancer cell lines and xenografts. Methods: Primary cervical cancer cell lines with differential TROP2 expression were identified by flow cytometry. Tumor cell death was evaluated at serial dilutions of Dato-DXd in TROP2-expressing and non-expressing cell lines. CSFE-incubated lines were evaluated for the ability of Dato-DXd to induce bystander killing after admixing TROP2-expressing tumor cells with non-expressing tumor cells. Dato-DXd-induced apoptosis was evaluated using phosphorylated H2AX. Antibody-directed cellular cytotoxicity (ADCC) was evaluated using a standard 4-h 51Cr assay. Finally, the in vivo anti-tumor activity of Dato-DXd was assessed in TROP2-expressing cervical cancer mouse models. Results: 67 % (4/6) of primary cervical cancer cell lines showed high expression of TROP2. Dato-DXd was highly effective in inducing tumor cell death in TROP2-expressing cell lines (CVX4 and CVX8) while no killing was induced against TROP2 non-expressing cell lines (ADX2). When TROP2+ tumor cells (CVX4) were co-cultured with TROP2 negative tumor cells (ADX2) in the presence of Dato-DXd, significant bystander activity was noted against ADX2 cells. Dato-DXd exposure increased phosphorylated H2AX, a marker of apoptosis, and induced significant levels of ADCC in TROP2-expressing models. In vivo, Dato-DXd was effective in tumor growth suppression and the median overall survival was unreached by day 50 in mice harboring TROP2+ xenografts. Conclusion: Dato-DXd demonstrated remarkable preclinical activity against TROP2-expressing primary cervical cancer cell lines and xenografts. Clinical evaluation of Dato-DXd is warranted in advanced/recurrent cervical cancer patients.