Unveiling the intra-tumor fate of trastuzumab deruxtecan in a xenograft model to support its mechanism of action.

Autor: Nagai Y; Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. Electronic address: nagai.youko.fx@daiichisankyo.co.jp., Oitate M; Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan., Shibayama T; Quantitative Clinical Pharmacology, Daiichi Sankyo Co., Ltd., Tokyo, Japan., Takakusa H; Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan., Watanabe N; Precision Medicine Function, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Jazyk: angličtina
Zdroj: Drug metabolism and pharmacokinetics [Drug Metab Pharmacokinet] 2024 Jun; Vol. 56, pp. 101001. Date of Electronic Publication: 2024 Jan 23.
DOI: 10.1016/j.dmpk.2024.101001
Abstrakt: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate used for cancer treatment comprising an anti-human epidermal growth factor receptor type 2 (HER2) antibody and the topoisomerase I inhibitor DXd. The present study investigated the intratumor fate of T-DXd. Fluorescence-labeled T-DXd was found to accumulate in tumors of HER2-positive tumor xenograft mice and was observed to be distributed within lysosomes of in vitro tumor cells in accordance with their HER2 expression. DXd was released by cysteine proteases, including cathepsins, in lysosomal fractions in vitro in response to the pH. Tumor slices obtained from HER2-positive tumor xenograft mice treated with T-DXd were examined by semi-quantitative and three-dimensional immunohistochemical assays using phosphor-integrated dots, which visualized DXd-related signals in the nucleus, the site of topoisomerase I inhibition. In addition, based on the data showing the antibody component of T-DXd barely distributed in the nucleus, it was suggested that the DXd-related signals detected in the nucleus were predominantly derived from free DXd. These observations help support the mode of action of T-DXd from the perspective of drug disposition.
(© 2024 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.)
Databáze: MEDLINE
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