Biodistribution of an antibody-enzyme conjugate for antibody-directed enzyme prodrug therapy in nude mice bearing a human colon adenocarcinoma xenograft.
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.
Stribbling
S M
SM
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
Martin
J
J
Pedley
R B
RB
Boden
J A
JA
Sharma
S K
SK
Springer
C J
CJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005971:Glutamates / Q000627:therapeutic use*; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D051379:Mice; D008819:Mice, Nude; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D011623:gamma-Glutamyl Hydrolase / Q000493:pharmacokinetics*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D005971:Glutamates; D018796:Immunoconjugates; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C092574:4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid; D011623:gamma-Glutamyl Hydrolase