Influence of the dissociation rate constant on the intra-tumor distribution of antibody-drug conjugate against tissue factor

Ryo Tsumura, Shino Manabe, Hiroki Takashima, Yoshikatsu Koga, Masahiro Yasunaga, Yasuhiro Matsumura

研究成果: Article査読

30 被引用数 (Scopus)

抄録

Antibody-drug conjugates (ADCs) are currently considered to be promising agents for cancer therapy. However, especially in solid tumors, the uneven distribution of ADCs would decrease their efficacy in clinical studies. We suggest that in addition to optimizing ADC components, such as the linker structure and anticancer agent, it is necessary to consider the distribution of the ADC within tumor tissue. In this study, we established three kinds of anti–tissue factor (TF) ADCs: 1849ADC with a low kd, 444ADC with an intermediate kd, and 1084ADC with a high kd. All three of the anti-TF ADCs exhibited almost the same in vitro cytotoxicity and pharmacological and biochemical characteristics, although the binding kinetics parameters differed. In vivo, all ADCs exerted equivalent antitumor effects against small BxPC3 tumors. However, on larger BxPC3 tumors, 1084ADC (higher kd) exerted higher antitumor activity than 1849ADC (lower kd). Furthermore, immunofluorescence staining indicated that 1084ADC was distributed throughout the whole tumor, whereas 1849ADC was mainly localized close to tumor vessels. We conclude that the ADC with a higher kd increased the antitumor effect of because it penetrated and distributed evenly throughout the entire solid tumor. These findings highlight the importance of the kd of a mAb in ADC design.

本文言語English
ページ(範囲)49-56
ページ数8
ジャーナルJournal of Controlled Release
284
DOI
出版ステータスPublished - 2018 8月 28
外部発表はい

ASJC Scopus subject areas

  • 薬科学

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