Biodistribution of an antibody-enzyme conjugate for antibody-directed enzyme prodrug therapy in nude mice bearing a human colon adenocarcinoma xenograft

Cancer Chemother Pharmacol. 1997;40(4):277-84. doi: 10.1007/s002800050659.


The enzyme carboxypeptidase G2 (CPG2) can be targeted to tumors by antibodies and used to activate prodrugs in a treatment called antibody-directed enzyme prodrug therapy (ADEPT). Different doses of CPG2 conjugated to the anti-CEA antibody A5B7 were administered i.v. to nude mice bearing the LS174T human colon adenocarcinoma xenograft, and the biodistribution of conjugate activity 48 and 72 h later was determined using a novel high-performance liquid chromatography (HPLC) method. Conjugate doses of 2,500 and 625 U/kg gave tumor enzyme levels of 0.5-0.6 U/g. Lower doses of 300 and 150 U/kg gave tumor enzyme levels of 0.1-0.3 U/g. Intriguingly, the best tumor:blood ratio of conjugate activity at both 48 and 72 h was achieved after administration of the 625-U/kg dose, not the 2,500-U/kg dose. After 48 h this ratio was 3.8, whereas after 72 h the value was 5.5. This conjugate dose also gave the greatest tumor:tissue ratios in all other tissues examined. After 72 h the tumor:colon ratio was 105, whereas the tumor:kidney ratio was 36. In ADEPT, to obtain maximal tumor damage to LS174T xenografts in nude mice with minimal systemic toxicity using the A5B7-CPG2 conjugate, prodrug should therefore be administered at least 72 h after a conjugate dose of 625 U/kg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism*
  • Animals
  • Antibodies, Monoclonal / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Carcinoembryonic Antigen / immunology
  • Chromatography, High Pressure Liquid
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism*
  • Female
  • Glutamates / therapeutic use*
  • Immunoconjugates / pharmacokinetics*
  • Mice
  • Mice, Nude
  • Nitrogen Mustard Compounds / therapeutic use*
  • Prodrugs / therapeutic use*
  • Tissue Distribution
  • Transplantation, Heterologous
  • gamma-Glutamyl Hydrolase / pharmacokinetics*


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Carcinoembryonic Antigen
  • Glutamates
  • Immunoconjugates
  • Nitrogen Mustard Compounds
  • Prodrugs
  • 4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid
  • gamma-Glutamyl Hydrolase