Cathepsin B-Labile Dipeptide Linkers for Lysosomal Release of Doxorubicin from Internalizing Immunoconjugates: Model Studies of Enzymatic Drug Release and Antigen-Specific In Vitro Anticancer Activity

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• 作者：Gene M. Dubowchik ; Raymond A. Firestone ; Linda Padilla ; David Willner ; Sandra J. Hofstead ; Kathleen Mosure ; Jay O. Knipe ; Shirley J. Lasch ; and Pamela A. Trail
• 刊名：Bioconjugate Chemistry
• 出版年：2002
• 出版时间：July 2002
• 年：2002
• 卷：13
• 期：4
• 页码：855 - 869
• 全文大小：189K
• 年卷期：v.13,no.4(July 2002)
• ISSN：1520-4812

文摘

The anticancer drug doxorubicin (DOX) has been linked to chimeric BR96, an internalizing monoclonalantibody that binds to a Lewis^y-related, tumor-associated antigen, through two lysosomally cleavabledipeptides, Phe-Lys and Val-Cit, giving immunoconjugates 72 and 73. A self-immolative p-aminobenzyloxycarbonyl (PABC) spacer between the dipeptides and the DOX was required for rapid andquantitative generation of free drug. DOX release from model substrate Z-Phe-Lys-PABC-DOX 49was 30-fold faster than from Z-Val-Cit-PABC-DOX 42 with the cysteine protease cathepsin B alone,but rates were identical in a rat liver lysosomal preparation suggesting the participation of morethan one enzyme. Conjugates 72 and 73 showed rapid and near quantitative drug release withcathepsin B and in a lysosomal preparation, while demonstrating excellent stability in human plasma.Against tumor cell lines with varying levels of BR96 expression, both conjugates showed potent,antigen-specific cytotoxic activity, suggesting that they will be effective in delivering DOX selectivelyto antigen-expressing carcinomas.