Preclinical activity of Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate targeting TROP2, in poorly differentiated endometrial carcinomas

Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC) targeting trophoblast antigen-2 (TROP2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver DXd, a potent topoisomerase I inhibitor. We evaluated TROP2 expression in primary endometrial cancer (EC) cell lines and the activity of Dato-DXd against EC cell lines with different TROP2 expression in vitro and in vivo. TROP2 expression was assessed in nine primary tumor cell lines by flow cytometry. Cell viability after exposure to Dato-DXd was evaluated using flow cytometry-based assays to calculate the half-maximal inhibitory concentration (IC50). Bystander effect assay assessed the viability of TROP2-negative cells when co-cultured with high TROP2-expressing cells. Fluorescent anti-phosphorylated-histone H2AX antibody was used to demonstrate dsDNA breaks. Antibody-dependent cell cytotoxicity (ADCC) was tested in vitro using 4-hour chromium-release assays. In vivo activity of Dato-DXd was evaluated against TROP2-positive EC xenografts. 78% (7/9) of the primary EC cell lines expressed TROP2. EC cell lines expressing TROP2 were significantly more sensitive to Dato-DXd compared to control ADC. Dato-DXd-exposed, TROP2-positive EC demonstrated increased dsDNA breaks compared with non-binding conjugate exposure. Dato-DXd mediated ADCC against TROP2-positive cell lines and induced significant bystander killing of TROP2-negative tumors when admixed with TROP2-positive tumors. In vivo, injection of Dato-DXd was well tolerated and demonstrated impressive tumor growth inhibition against chemotherapy-resistant poorly differentiated EC xenografts (p<0.0001). In conclusion, Dato-DXd is a novel ADC with remarkable preclinical activity against poorly differentiated EC cell lines overexpressing TROP2. Clinical trials with Dato-DXd in recurrent endometrial cancer patients are warranted.