(6-Maleimidocaproyl)hydrazone of doxorubicin--a new derivative for the preparation of immunoconjugates of doxorubicin

Bioconjug Chem. Nov-Dec 1993;4(6):521-7. doi: 10.1021/bc00024a015.

Abstract

The (6-maleimidocaproyl)hydrazone of doxorubicin was synthesized and conjugated to several mAbs, including chimeric BR96, via a Michael addition reaction to thiol-containing mAbs. DTT reduction of disulfides present in the mAb was a reliable and general method for generating a consistent number of reactive SH groups. The conjugates, after purification by Bio-Beads, were free of unreacted linker and/or doxorubicin. All conjugates released doxorubicin under acidic conditions that mimic the lysosomal environment, while they were relatively stable at neutral pH. BR96 conjugates showed antigen-specific cytotoxicity.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / immunology
  • Animals
  • Antibodies, Monoclonal / metabolism
  • Cross-Linking Reagents / chemical synthesis*
  • Cross-Linking Reagents / chemistry
  • Dithiothreitol / chemistry
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / chemical synthesis
  • Doxorubicin / chemistry
  • Doxorubicin / metabolism
  • Doxorubicin / toxicity*
  • Drug Stability
  • Epitopes
  • Humans
  • Hydrazones / chemical synthesis*
  • Hydrazones / chemistry
  • Immunotoxins / chemistry*
  • Immunotoxins / metabolism
  • Immunotoxins / toxicity*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Mice
  • Oxidation-Reduction
  • Sulfhydryl Compounds / chemistry

Substances

  • Antibodies, Monoclonal
  • Cross-Linking Reagents
  • Epitopes
  • Hydrazones
  • Immunotoxins
  • Sulfhydryl Compounds
  • doxorubicin(6-maleimidocaproyl)hydrazone
  • Doxorubicin
  • Dithiothreitol