| Autor: |
Miki Yamaguchi, Reiko Kamei, Ken Sakurai, Tsuyoshi Karibe, Satoru Yasuda, Michiko Kitamura, Daisuke Okajima, Toshinori Agatsuma, Shu Takahashi, Tetsuo Aida, Sumie Muramatsu, Tomomichi Fujitani, Junko Yamaguchi, Hirofumi Hamada, Yutaka Noguchi, Takashi Nakada, Tomoyo Honda, Takanori Maejima, Masato Murakami, Tomoko Shibutani, Riki Goto, Yuki Abe, Tadashi Toki |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Molecular cancer therapeutics. 20(12) |
| ISSN: |
1538-8514 |
| Popis: |
Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody–drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models. The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys. Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable. Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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