文摘
The anticancer drug doxorubicin (DOX) has been linked to chimeric BR96, an internalizing monoclonalantibody that binds to a Lewisy-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.
