Monoclonal antibody conjugates of doxorubicin prepared with branched linkers:: A novel method for increasing the potency of doxorubicin immunoconjugates

被引:62
作者
King, HD
Yurgaitis, D
Willner, D
Firestone, RA
Yang, MB
Lasch, SJ
Hellström, KE
Trail, PA
机构
[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Wallingford, CT 06492 USA
[2] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA
[3] Bristol Myers Squibb Pharmaceut Res Inst, Seattle, WA 98121 USA
关键词
D O I
10.1021/bc980100i
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novel series 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 previously prepared 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 demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a DOX (4-14-fold) and mAb (7-23-fold) basis. The results suggest that, by using the branched linker methodology, 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 chain immunoconjugates are described.
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页码:279 / 288
页数:10
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