title: BR96 conjugates of highly potent anthracyclines.
abstract: 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 0.03 micrometer and was at least 300-fold more potent than a non-binding IgG-DAPDOX control conjugate.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, 06492-7660, Wallingford, CT, USA. dalton.king@bms.com
authors.forename: H Dalton
authors.initials: HD
authors.lastname: King
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Staab
authors.forename: Kahnie
authors.initials: K
authors.lastname: Pham-Kaplita
authors.forename: Derek
authors.initials: D
authors.lastname: Yurgaitis
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Firestone
authors.forename: Shirley J
authors.initials: SJ
authors.lastname: Lasch
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Trail
mesh_terms: D018943:Anthracyclines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology; D006868:Hydrolysis; D007202:Indicators and Reagents; D007700:Kinetics
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D006835:Hydrazones; D007202:Indicators and Reagents