卵巢癌
癌症研究
体内
旁观者效应
医学
癌症
癌细胞
抗体
前列腺癌
生物
内科学
免疫学
生物技术
作者
Hirokazu Suzuki,Shotaro Nagase,Chikara Saito,Atsuko Takatsuka,Motoko Nagata,Kokichi Honda,Yuki Kaneda,Yoshiaki Nishiya,Tomoyo Honda,Tomomichi Ishizaka,Kensuke Nakamura,Takashi Nakada,Yuki Abe,Toshinori Agatsuma
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2024-01-11
标识
DOI:10.1158/1535-7163.mct-23-0287
摘要
Cadherin-6 (CDH6) is expressed in several cancer types, but no CDH6-targeted therapy is currently clinically available. Here, we generated raludotatug deruxtecan (R-DXd; DS-6000), a novel CDH6-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and evaluated its properties, pharmacologic activities, and safety profile. In vitro pharmacologic activities and the mechanisms of action of R-DXd were assessed in serous-type ovarian cancer and renal cell carcinoma cell lines. In vivo pharmacologic activities were evaluated with several human cancer cell lines and patient-derived xenograft mouse models. The safety profile in cynomolgus monkeys was also assessed. R-DXd exhibited CDH6 expression-dependent cell growth-inhibitory activity and induced tumor regression in xenograft models. In this process, R-DXd specifically bound to CDH6, was internalized into cancer cells, and then translocated to the lysosome. The DXd released from R-DXd induced the phosphorylation of Chk1, a DNA damage marker, and cleaved caspase-3, an apoptosis marker, in cancer cells. It was also confirmed that the DXd payload had a bystander effect, passing through the cell membrane and impacting surrounding cells. The safety profile of R-DXd was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. R-DXd demonstrated potent antitumor activity against CDH6-expressing tumors in mice and an acceptable safety profile in monkeys. These findings indicate the potential of R-DXd as a new treatment option for patients with CDH6-expressing serous-type ovarian cancer and renal cell carcinoma in a clinical setting.
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