Datopotamab deruxtecan, a novel TROP2-tareting antibody-drug conjugate with a topoisomerase I inhibitor payload, shows preclinical activity against primary and metastatic uterine and ovarian TROP2 over-expressing carcinosarcoma
Uterine and ovarian carcinosarcomas (CS) are rare gynecologic tumors with a high recurrence rate and poor prognosis. Datopotamab-deruxtecan (Dato-DXd) is a novel antibody-drug-conjugate (ADC) targeting TROP2. We evaluated the preclinical activity of Dato-DXd in vitro against primary and metastatic CS cell lines with various TROP2 expression and in vivo against CS xenografts in mice. TROP2 expression was determined using flow-cytometry. Cells were treated with Dato-DXd and a control ADC (CTL ADC) to evaluate IC TROP2 expressing CS cell lines were highly sensitive to killing induced by Dato-DXd. In contrast, low-expressing CS cell lines had no significant difference in cell cytotoxicity. Dato-DXd induced ADCC in the presence of peripheral blood lymphocytes from healthy donors. When TROP2-negative cells were admixed with TROP2-overexpressing cells, a significant bystander effect with Dato-DXd was appreciated. In vivo, mouse xenografts overexpressing TROP2 treated with Dato-DXd demonstrated tumor growth suppression and longer overall survival compared to CTL ADC-treated xenografts. Dato-DXd is active against primary and metastatic uterine and ovarian CS overexpressing TROP2 in vitro and in vivo. Our preclinical results warrant future clinical trials for patients with advanced/recurrent gynecologic CS resistant to chemotherapy.