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.