BR96 conjugates of highly potent anthracyclines

• Published in: Bioorganic & medicinal chemistry letters 2003-07, Vol.13 (13), p.2119-2122
• Main Authors: King, H.Dalton, Staab, Andrew J., Pham-Kaplita, Kahnie, Yurgaitis, Derek, Firestone, Raymond A., Lasch, Shirley J., Trail, Pamela A.
• Format: Article
• Language: English
• Subjects: Anthracyclines - chemical synthesis; Anthracyclines - pharmacology; Antibiotics, Antineoplastic - chemical synthesis; Antibiotics, Antineoplastic - pharmacology; Antibodies, Monoclonal - chemistry; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Drug Screening Assays, Antitumor; General aspects; Humans; Hydrazones - chemical synthesis; Hydrazones - pharmacology; Hydrolysis; Indicators and Reagents; Kinetics; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00375-5

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 IC 50 of 0.03μm and was at least 300-fold more potent than a non-binding IgG–DAPDOX control conjugate. BR96 conjugates of the highly potent antitumor agents 5-diacetoxypentyldoxorubicin and morpholinodoxorubicin were synthesized and found to be highly potent and antigen specific in vitro.