Antibody-directed enzyme prodrug therapy: a promising approach for a selective treatment of cancer based on prodrugs and monoclonal antibodies

Chem Biol Drug Des. 2009 Sep;74(3):205-11. doi: 10.1111/j.1747-0285.2009.00856.x. Epub 2009 Jul 29.


The antibody-directed enzyme prodrug therapy allows a selective liberation of cytotoxic agents from non-toxic prodrugs in cancerous tissue by targeted antibody-enzyme conjugates. We have developed a series of novel glycosidic prodrugs based on the natural antibiotic CC-1065 and the duocarmycins, which are up to 4800 times less toxic than the drugs liberated from these prodrugs in the presence of the activating enzyme (e.g., beta-D-galactosidase). Furthermore, the drugs show very high cytotoxicities with IC(50) values of as low as 4.5 pm. In this report, we summarize our recent results on the development and biological evaluation of these novel third-generation prodrugs with higher water solubility, higher difference in cytotoxicity between the prodrugs and the corresponding drugs and improved cytotoxicity of the drugs as compared with previous compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism*
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • Drug Design
  • Duocarmycins
  • Glycosides / chemistry
  • Humans
  • Indoles / toxicity
  • Neoplasms / drug therapy*
  • Prodrugs / chemistry*
  • Prodrugs / toxicity
  • Pyrroles / toxicity
  • Stereoisomerism
  • beta-Galactosidase / chemistry
  • beta-Galactosidase / metabolism*


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Duocarmycins
  • Glycosides
  • Indoles
  • Prodrugs
  • Pyrroles
  • duocarmycin SA
  • CC 1065
  • beta-Galactosidase