| Autor: |
Toshinori Agatsuma, Suguru Ueno, Masato Murakami, Yuki Abe, Takashi Kagari, Kenichi Wakita, Taisei Nomura, Takashi Nakada, Koji Morita, Ichiro Hayakawa, Tsuyoshi Karibe, Tomomichi Ishizaka, Takuma Iguchi, Yoshinobu Shiose, Naoyuki Maeda, Yuki Kaneda, Manabu Abe, Akiko Zembutsu, Yusuke Ogitani, Kenji Hirotani, Yasuki Kamai, Kumiko Koyama, Yuuri Hashimoto |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6527970.v1 |
| Popis: |
Purpose: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.Experimental Design: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.Results: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.Conclusions: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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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