Abstract 10P
Background
Human Cadherin 6 (CDH6) is a single transmembrane protein consisting of 790 amino acids classified into the type 2 cadherin family. Human CDH6 is specifically expressed in the brain and kidneys during the development phase and has been reported to systemically decrease CDH6 expression in the adult body. CDH6 expression is increased specifically in renal cell carcinoma (RCC) and ovarian cancer (OVC). Therefore, CDH6 could be an attractive target for cancer therapy. We created DS-6000a, a CDH6-targeting antibody-drug conjugate (ADC) using an enzymatically cleavable tetrapeptide-based linker, and a high drug-to-antibody ratio (DAR 7 to 8) with a novel DNA topoisomerase I inhibitor (DXd). In this study, the pharmacological activity and the mechanism of action of DS-6000a were evaluated in preclinical in vitro and in vivo models.
Methods
CDH6 expression was assessed by immunohistochemistry and FCM analysis. Induction of DNA damage and apoptosis to tumor cells by DXd released from DS-6000a were assessed by western blot. In vitro cell growth inhibitory and in vivo antitumor activities of DS-6000a were evaluated using CDH6-high and -low RCC and OVC cell lines, xenograft mouse models and patient derived xenograft (PDX) models.
Results
CDH6 is highly expressed in RCC and OVC patient samples. DS-6000a demonstrated in vitro cell growth inhibitory activity in CDH6-high tumor cells, but not in CDH6-low tumor cells. DNA damage and apoptosis were induced in CDH6-high tumor cells after the in vitro treatment with DXd and DS-6000a, but not with isotype control IgG ADC. DS-6000a exhibited strong antitumor activity with tumor regression in CDH6-high cell lines in mouse xenograft models. DS-6000a also showed high efficacy against PDX models.
Conclusions
Based on these preclinical results, DS-6000a could provide a valuable therapy with a potential benefit in CDH6-expressing cancers at the clinical setting.
Clinical trial identification
NCT04707248. First Posted: January 13, 2021.
Editorial acknowledgement
Hirokazu Suzuki, Shotaro Nagase, Chiemi Saito, Motoko Nagata, Yuki Kaneda, Kokichi Honda, Takashi Nakada, Riki Goto, Yusuke Myobatake, Yuki Abe, and Toshinori Agatsuma
Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan; E-mail: suzuki.hirokazu.yc@daiichisankyo.co.jp
Legal entity responsible for the study
Hirokazu Suzuki.
Funding
Has not received any funding.
Disclosure
H. Suzuki, S. Nagase, C. Saito, M. Nagata, Y. Kaneda, K. Honda, Y. Nishiya, T. Honda, T. Nakada, R. Goto, T. Ishizaka, Y. Myobatake, Y.Abe, T. Agatsuma: Financial Interests, Personal, Full Employment: Daiichi Sankyo Co. Ltd., Tokyo, Japan.