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.