Synthesis and antitumor activity of the immunoconjugate BR96-Dox

BR96-Dox is an immunoconjugate (IC) in which doxorubicin (8 equivalents) is linked via an acid-labile hydrazone to the chimeric MAb BR96. It binds to a modified Le(y) Ag on tumor cells: which then internalize it via endocytosis into lysosomes. There, the acidic milieu hydrolyzes the hydrazone link, releasing free Dox. In vivo, it is more active and less toxic than untargeted Dox, producing complete remissions and many cures of subcutaneous human breast, lung and colon tumors, as well as disseminated lung tumors. In vivo, only BR96(+) and not BR96(-) tumors respond, and ICs with nonbinding Abs are inactive.