title: ZD2767, an improved system for antibody-directed enzyme prodrug therapy that results in tumor regressions in colorectal tumor xenografts.
abstract: ZD2767 represents an improved version of antibody-directed enzyme prodrug therapy. It consists of a conjugate of the F(ab')2 A5B7 antibody fragment and carboxypeptidase G2 (CPG2) and a prodrug, 4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl L-glutamic acid. The IC50 of the prodrug against LoVo colorectal tumor cells was 47 microM, and cleavage by CPG2 released the potent bis-iodo phenol mustard drug (IC50 = 0.34 microM). The drug killed both proliferating and quiescent LoVo cells. Administration of the ZD2767 conjugate to nude mice bearing LoVo colorectal xenografts resulted in approximately 1% of injected ZD2767 conjugate localizing/g of tumor after 72 h, and blood and normal tissue levels of the conjugate were 10-50-fold lower. A single round of therapy involving the administration of the prodrug 72 h after the conjugate to athymic mice bearing established LoVo xenografts resulted in approximately 50% of the tumors undergoing complete regressions, tumor growth delays greater than 30 days, and little toxicity (as judged by body-weight loss). Similar studies using a control antibody-CPG2 conjugate that does not bind to LoVo tumor cells resulted in a growth delay of less than 5 days, confirming the tumor specificity of this approach. These studies demonstrate the potential of ZD2767 for the treatment of colorectal cancer.
authors.affiliation: Cancer, Metabolism, and Endocrine Research Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: D C
authors.initials: DC
authors.lastname: Blakey
authors.forename: P J
authors.initials: PJ
authors.lastname: Burke
authors.forename: D H
authors.initials: DH
authors.lastname: Davies
authors.forename: R I
authors.initials: RI
authors.lastname: Dowell
authors.forename: S J
authors.initials: SJ
authors.lastname: East
authors.forename: K P
authors.initials: KP
authors.lastname: Eckersley
authors.forename: J E
authors.initials: JE
authors.lastname: Fitton
authors.forename: J
authors.initials: J
authors.lastname: McDaid
authors.forename: R G
authors.initials: RG
authors.lastname: Melton
authors.forename: I A
authors.initials: IA
authors.lastname: Niculescu-Duvaz
authors.forename: P E
authors.initials: PE
authors.lastname: Pinder
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: A F
authors.initials: AF
authors.lastname: Wright
authors.forename: C J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage*; D014183:Transplantation, Heterologous; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D018906:Antineoplastic Agents, Alkylating; D000922:Immunotoxins; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C097602:ZD 2767; D011623:gamma-Glutamyl Hydrolase