Monoclonal antibody conjugates of doxorubicin prepared with branched linkers: A novel method for increasing the potency of doxorubicin immunoconjugates

Bioconjug Chem. Mar-Apr 1999;10(2):279-88. doi: 10.1021/bc980100i.

Abstract

Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novel series of branched hydrazone linkers. Since each linker bound to the mAb carries two DOX molecules, the DOX/mAb molar ratios of these conjugates were approximately 16, twice that of those previously prepared with single-chain hydrazone linkers. The conjugates were stable at a physiological pH of 7, but released DOX rapidly at lysosomal pH 5. The branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a DOX (4-14-fold) and mAb (7-23-fold) basis. The results suggest that, by using the branched linker methodology, it is possible to significantly reduce the amount of mAb required to achieve antigen-specific cytotoxic activity. In this paper, the synthesis and in vitro biology of branched chain immunoconjugates are described.

MeSH terms

  • Animals
  • Antibodies, Monoclonal* / metabolism
  • Antibodies, Monoclonal* / pharmacokinetics
  • Cell Survival / drug effects
  • Doxorubicin* / pharmacokinetics
  • Doxorubicin* / toxicity
  • Humans
  • Hydrazones
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Immunoconjugates* / chemistry
  • Immunoconjugates* / pharmacokinetics
  • Immunoconjugates* / toxicity
  • Immunoglobulin G / metabolism
  • Indicators and Reagents
  • Kinetics
  • Lung Neoplasms
  • Lysosomes / metabolism
  • Mice
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Hydrazones
  • Immunoconjugates
  • Immunoglobulin G
  • Indicators and Reagents
  • Doxorubicin