Trophoblast
cell surface antigen 2 (TROP2) is highly expressed on various epithelial
tumors and correlates with poor prognosis. We developed the novel TROP2-directed
antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent
DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human
cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into
tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing
tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft
tumors, but neither isotype control
IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with
tumor regression in several TROP2-expressing xenograft
tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing
tumors by efficient payload delivery into
tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing
tumors in the clinical setting.