Monoclonal Antibody Conjugates of Doxorubicin Prepared with Branched Linkers: A Novel Method for Increasing the Potency of Doxorubicin Immunoconjugates

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• 作者：H. Dalton King ; Derek Yurgaitis ; David Willner ; Raymond A. Firestone ; Michael B. Yang ; Shirley J. Lasch ; Karl Erik Hellströ ; m ; and Pamela A. Trail
• 刊名：Bioconjugate Chemistry
• 出版年：1999
• 出版时间：March 1999
• 年：1999
• 卷：10
• 期：2
• 页码：279 - 288
• 全文大小：208K
• 年卷期：v.10,no.2(March 1999)
• ISSN：1520-4812

文摘

Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novelseries of branched hydrazone linkers. Since each linker bound to the mAb carries two DOX molecules,the DOX/mAb molar ratios of these conjugates were approximately 16, twice that of those previouslyprepared with single-chain hydrazone linkers. The conjugates were stable at a physiological pH of 7,but released DOX rapidly at lysosomal pH 5. The branched series of BR96 conjugates demonstratedantigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both aDOX (4-14-fold) and mAb (7-23-fold) basis. The results suggest that, by using the branched linkermethodology, it is possible to significantly reduce the amount of mAb required to achieve antigen-specific cytotoxic activity. In this paper, the synthesis and in vitro biology of branched chainimmunoconjugates are described.