title: Antitumor effects of an antibody-carboxypeptidase G2 conjugate in combination with a benzoic acid mustard prodrug.
abstract: The F(ab')2 fragment of the antitumor monoclonal antibody, A5B7, was covalently linked to the bacterial enzyme carboxypeptidase G2 (CPG2). The resulting conjugate was used in combination with a prodrug of a benzoic acid mustard alkylating agent to treat human colon tumor xenografts in a two-step targeting strategy, antibody-directed enzyme prodrug therapy (ADEPT). The prodrug, 4-[(2-chloroethyl) (2-mesyloxyethyl)amino]-benzoyl-L-glutamic acid is rapidly converted by CPG2 to a drug that is at least 15x more toxic in vitro against LS174T colorectal tumor cells than the prodrug. Optimal tumor/blood ratios of the A5B7-CPG2 were achieved 72 h after administration of the conjugate to athymic mice bearing established LS174T tumor xenografts. Significant antitumor activity was seen in LS174T tumor-bearing mice treated with the conjugate followed 3 d later by the prodrug. In contrast, prodrug, conjugate, or active drug alone did not result in any antitumor activity in this tumor model. These studies demonstrate the advantage of a two-step ADEPT system for the treatment of colorectal cancer.
authors.affiliation: ICI Pharmaceuticals, Macclesfield, Cheshire.
authors.forename: D C
authors.initials: DC
authors.lastname: Blakey
authors.forename: B E
authors.initials: BE
authors.lastname: Valcaccia
authors.forename: S
authors.initials: S
authors.lastname: East
authors.forename: A F
authors.initials: AF
authors.lastname: Wright
authors.forename: F T
authors.initials: FT
authors.lastname: Boyle
authors.forename: C J
authors.initials: CJ
authors.lastname: Springer
authors.forename: P J
authors.initials: PJ
authors.lastname: Burke
authors.forename: R G
authors.initials: RG
authors.lastname: Melton
authors.forename: K D
authors.initials: KD
authors.lastname: Bagshawe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use*; D019817:Benzoic Acid; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D003601:Cytotoxicity Tests, Immunologic; D004359:Drug Therapy, Combination; D005260:Female; D005971:Glutamates / Q000494:pharmacology*; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009150:Mustard Compounds / Q000627:therapeutic use*; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D011355:Prodrugs / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D001565:Benzoates; D005971:Glutamates; D000922:Immunotoxins; D009150:Mustard Compounds; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C092575:4-((2-chloroethyl) (2-mesyloxyethyl)amino)benzoic acid; C092574:4-((2-chloroethyl)(2-mesyloxyethyl)amino)benzoylglutamic acid; D019817:Benzoic Acid; D011623:gamma-Glutamyl Hydrolase