BR96 conjugates of highly potent anthracyclines

Bioorg Med Chem Lett. 2003 Jul 7;13(13):2119-22. doi: 10.1016/s0960-894x(03)00375-5.

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.

MeSH terms

  • Anthracyclines / chemical synthesis*
  • Anthracyclines / pharmacology*
  • Antibiotics, Antineoplastic / chemical synthesis*
  • Antibiotics, Antineoplastic / pharmacology*
  • Antibodies, Monoclonal / chemistry*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Hydrazones / chemical synthesis
  • Hydrazones / pharmacology
  • Hydrolysis
  • Indicators and Reagents
  • Kinetics

Substances

  • Anthracyclines
  • Antibiotics, Antineoplastic
  • Antibodies, Monoclonal
  • Hydrazones
  • Indicators and Reagents