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DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models
B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3–targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377751/ https://www.ncbi.nlm.nih.gov/pubmed/35149548 http://dx.doi.org/10.1158/1535-7163.MCT-21-0554 |
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author | Yamato, Michiko Hasegawa, Jun Maejima, Takanori Hattori, Chiharu Kumagai, Kazuyoshi Watanabe, Akiko Nishiya, Yumi Shibutani, Tomoko Aida, Tetsuo Hayakawa, Ichiro Nakada, Takashi Abe, Yuki Agatsuma, Toshinori |
author_facet | Yamato, Michiko Hasegawa, Jun Maejima, Takanori Hattori, Chiharu Kumagai, Kazuyoshi Watanabe, Akiko Nishiya, Yumi Shibutani, Tomoko Aida, Tetsuo Hayakawa, Ichiro Nakada, Takashi Abe, Yuki Agatsuma, Toshinori |
author_sort | Yamato, Michiko |
collection | PubMed |
description | B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3–targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3–expressing cancer cells, but not that of B7-H3–negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high–B7-H3 tumor xenograft models, including various tumor types of high–B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3–expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3–expressing solid tumors in a clinical setting. |
format | Online Article Text |
id | pubmed-9377751 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-93777512023-01-05 DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models Yamato, Michiko Hasegawa, Jun Maejima, Takanori Hattori, Chiharu Kumagai, Kazuyoshi Watanabe, Akiko Nishiya, Yumi Shibutani, Tomoko Aida, Tetsuo Hayakawa, Ichiro Nakada, Takashi Abe, Yuki Agatsuma, Toshinori Mol Cancer Ther Large Molecule Therapeutics B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3–targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3–expressing cancer cells, but not that of B7-H3–negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high–B7-H3 tumor xenograft models, including various tumor types of high–B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3–expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3–expressing solid tumors in a clinical setting. American Association for Cancer Research 2022-04-01 2022-02-11 /pmc/articles/PMC9377751/ /pubmed/35149548 http://dx.doi.org/10.1158/1535-7163.MCT-21-0554 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Large Molecule Therapeutics Yamato, Michiko Hasegawa, Jun Maejima, Takanori Hattori, Chiharu Kumagai, Kazuyoshi Watanabe, Akiko Nishiya, Yumi Shibutani, Tomoko Aida, Tetsuo Hayakawa, Ichiro Nakada, Takashi Abe, Yuki Agatsuma, Toshinori DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models |
title | DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models |
title_full | DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models |
title_fullStr | DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models |
title_full_unstemmed | DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models |
title_short | DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody–Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models |
title_sort | ds-7300a, a dna topoisomerase i inhibitor, dxd-based antibody–drug conjugate targeting b7-h3, exerts potent antitumor activities in preclinical models |
topic | Large Molecule Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377751/ https://www.ncbi.nlm.nih.gov/pubmed/35149548 http://dx.doi.org/10.1158/1535-7163.MCT-21-0554 |
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