Antibody directed enzyme prodrug therapy (ADEPT): clinical report.
Following an extensive series of studies in nude mice with human xenografts a pilot scale clinical trial of antibody directed enzyme prodrug therapy has been initiated. The principle is to activate a relatively inert prodrug to an active cytotoxin by a tumour located enzyme. In the first stage of the study a prodrug para-N-(mono-2-chloroethyl monomesyl)-aminobenzoyl glutamic acid was administered to six patients with advanced colorectal cancer in a dose escalating protocol. Nausea and vomiting occurred as the only discernible toxic effect at the higher dose levels. Three of these patients and two other patients with advanced disease have proceeded to the second stage of the study in which an antibody-enzyme conjugate was given IV, followed after 36-48 h by a galactosylated anti-enzyme antibody. When plasma enzyme levels had become undetectable the patients received multiple doses of the prodrug. At the lower doses toxicity was minimal as were clinical responses. Two patients received higher doses which resulted in myelosuppression and temporary regression of advanced disease. No complications resulted from administration of the antibody-enzyme complex or enzyme inactivating antibody. The myelosuppression is attributable to the relatively long half-life of the active drug formed from the prodrug used in the present study.
Bagshawe
K D
KD
Department of Medical Oncology, Charing Cross and Westminster Medical School, London.
Sharma
S K
SK
Springer
C J
CJ
Antoniw
P
P
Boden
J A
JA
Rogers
G T
GT
Burke
P J
PJ
Melton
R G
RG
Sherwood
R F
RF
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D006063:Chorionic Gonadotropin / Q000276:immunology; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005971:Glutamates / Q000008:administration & dosage*; D006801:Humans; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage*; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006063:Chorionic Gonadotropin; D005971:Glutamates; C074509:N-(mono-2-chloroethylmonomethyl)aminobenzoyl glutamic acid; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; D011623:gamma-Glutamyl Hydrolase