YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
誌上シンポジウム
トポイソメラーゼI阻害剤を搭載した新規ADC技術開発
我妻 利紀
著者情報
ジャーナル フリー

2017 年 137 巻 5 号 p. 545-550

詳細
抄録

 Antibody-drug conjugates (ADCs) selectively deliver large amounts of antitumor drugs to tumor tissue and show significant antitumor effects with a wide therapeutic window. We developed a new linker-drug technology platform with an exatecan derivative, which is a highly potent topoisomerase I inhibitor. The major advantages of the technology are: 1) high and homogeneous drug-to-antibody ratio (DAR) availability; 2) potent antitumor activity in conjunction with bystander killing; 3) few safety concerns because of the stable linker limiting release of free drug; and 4) a wide application to therapeutic antibodies. Using this linker-drug technology, we generated an anti-HER2 ADC, namely DS-8201a. DS-8201a, in which almost all eight cysteine residues of the antibody are bound to drug, was effective against trastuzumab DM1 (T-DM1)-insensitive patient-derived xenograft (PDX) models with high HER2 expression and also demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression. DS-8201a was well tolerated in rats and monkeys following repeated administration. These results suggest that DS-8201a may be efficacious in a broader population of HER2-positive cancer patients and also confirm the importance of this new class of novel topoisomerase I inhibitor-based ADC technology.

著者関連情報
© 2017 The Pharmaceutical Society of Japan
前の記事 次の記事
feedback
Top