Antitumor effects of an antibody-carboxypeptidase G2 conjugate in combination with a benzoic acid mustard prodrug.
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.
Blakey
D C
DC
ICI Pharmaceuticals, Macclesfield, Cheshire.
Valcaccia
B E
BE
East
S
S
Wright
A F
AF
Boyle
F T
FT
Springer
C J
CJ
Burke
P J
PJ
Melton
R G
RG
Bagshawe
K D
KD
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*
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