BR96 conjugates of highly potent anthracyclines

The 6-maleimidocaproylhydrazone derivatives of highly potent antitumor agents 5-Diacetoxypentyldoxorubicin and Morpholinodoxorubicin were synthesized and conjugated to monoclonal antibody BR96 and control IgG. Immunoconjugate molar ratios were generally 7.5–8.5, and dimer aggregate levels were low. The linkers released parent drug at lysosomal pH 5, while they remained stable at neutral pH. BR96 conjugates were highly potent and antigen specific in vitro. The BR96–DAPDOX conjugate demonstrated an IC50 of 0.03μm and was at least 300-fold more potent than a non-binding IgG–DAPDOX control conjugate.