A Novel HER3-Targeting Antibody–Drug Conjugate, U3-1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization
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- Yuuri Hashimoto
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Kumiko Koyama
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Yasuki Kamai
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Kenji Hirotani
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Yusuke Ogitani
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Akiko Zembutsu
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Manabu Abe
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Yuki Kaneda
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Naoyuki Maeda
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Yoshinobu Shiose
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Takuma Iguchi
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Tomomichi Ishizaka
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Tsuyoshi Karibe
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Ichiro Hayakawa
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Koji Morita
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Takashi Nakada
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Taisei Nomura
- 2National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
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- Kenichi Wakita
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Takashi Kagari
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Yuki Abe
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Masato Murakami
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Suguru Ueno
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
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- Toshinori Agatsuma
- 1Daiichi Sankyo Co., Ltd., Tokyo, Japan.
抄録
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>HER3 is a compelling target for cancer treatment; however, no HER3-targeted therapy is currently clinically available. Here, we produced U3-1402, an anti-HER3 antibody–drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>In vitro pharmacologic activities and the mechanisms of action of U3-1402 were assessed in several human cancer cell lines. Antitumor activity of U3-1402 was evaluated in xenograft mouse models, including patient-derived xenograft (PDX) models. Safety assessments were also conducted in rats and monkeys.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>U3-1402 showed HER3-specific binding followed by highly efficient cancer cell internalization. Subsequently, U3-1402 was translocated to the lysosome and released its payload DXd. While U3-1402 was able to inhibit HER3-activated signaling similar to its naked antibody patritumab, the cytotoxic activity of U3-1402 in HER3-expressing cells was predominantly mediated by released DXd through DNA damage and apoptosis induction. In xenograft mouse models, U3-1402 exhibited dose-dependent and HER3-dependent antitumor activity. Furthermore, U3-1402 exerted potent antitumor activity against PDX tumors with HER3 expression. Acceptable toxicity was noted in both rats and monkeys.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>U3-1402 demonstrated promising antitumor activity against HER3-expressing tumors with tolerable safety profiles. The activity of U3-1402 was driven by HER3-mediated payload delivery via high internalization into tumor cells.</jats:p> </jats:sec>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 25 (23), 7151-7161, 2019-12-01
American Association for Cancer Research (AACR)
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詳細情報 詳細情報について
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- CRID
- 1360572092702835840
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- ISSN
- 15573265
- 10780432
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- データソース種別
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- Crossref
- KAKEN