Data from Raludotatug Deruxtecan, a CDH6-Targeting Antibody–Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models

• DOI: 10.1158/1535-7163.c.7104454.v1
• Publication Date: 2024-03-04T21:06:48Z
• Authors: Hirokazu Suzuki; Shotaro Nagase; Chiemi Saito; Atsuko Takatsuka; Motoko Nagata; Kokichi Honda; Yuki Kaneda; Yumi Nishiya; Tomoyo Honda; Tomomichi Ishizaka; Kensuke Nakamura; Takashi Nakada; Yuki Abe; Toshinori Agatsuma
• Keywords: Conjugate; Antibody-drug conjugate

<div>Abstract<p>Cadherin-6 (CDH6) is expressed in several cancer types, but no CDH6-targeted therapy currently clinically available. Here, we generated raludotatug deruxtecan (R-DXd; DS-6000), a novel CDH6-targeting antibody–drug conjugate with potent DNA topoisomerase I inhibitor, and evaluated its properties, pharmacologic activities, safety profile. <i>In vitro</i> activities the mechanisms of action R-DXd were assessed serous-type ovarian renal cell carcinoma lines. vivo</i> human lines patient-derived xenograft mouse models. The profile cynomolgus monkeys was also assessed. exhibited CDH6 expression-dependent growth-inhibitory activity induced tumor regression In this process, specifically bound to CDH6, internalized into cells, then translocated lysosome. DXd released from phosphorylation Chk1, damage marker, cleaved caspase-3, an apoptosis cells. It confirmed that payload had bystander effect, passing through membrane impacting surrounding favorable highest non-severely toxic dose 30 mg/kg monkeys. demonstrated antitumor against CDH6-expressing tumors mice acceptable These findings indicate potential as new treatment option for patients clinical setting.</p></div>