These results suggest that the DXd-ADC technology is widely applicable to various target antigens for cancer therapy. In the preclinical setting, the DXd-ADC technology has been effective when applied to target other cancer-associated antigens as well ( 10–12). These features enable the wide therapeutic window of the ADC with high antitumor potency and less systemic toxicity ( 9). The DXd-ADC technology has desirable characteristics for ADC including a highly potent payload (DXd) with a short systemic half-life, a cleavable linker designed to be tumor selective which is stable in circulation, and an average drug-to-antibody ratio (DAR) up to 8 being optimized for each target. Trastuzumab deruxtecan has received an accelerated approval from FDA and PMDA for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (ENHERTU, T-DXd, DS-8201), a novel HER2-directed ADC with this DXd-ADC technology, demonstrated potent antitumor activity with acceptable safety profiles in preclinical models and patients with HER2-positive cancers ( 2, 4–8). Recently, we developed a novel ADC technology platform with a novel DNA topoisomerase I (Topo I) inhibitor, DXd, and a cleavable tetrapeptide-based linker ( 2, 3). These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.ĭato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. 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. Safety profiles were also assessed in rats and cynomolgus monkeys.ĭato-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. 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. 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. Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis.
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