Anti-tumour effects of an antibody-carboxypeptidase G2 conjugate in combination with phenol mustard prodrugs.
ADEPT is an antibody-based targeting strategy for the treatment of cancer. We have developed two new prodrugs, 4-[N,N-bis(2-chloroethyl)amino]-phenoxycarbonyl-L- glutamic acid (PGP) and (S)-2-[N-[4-[N,N-bis(2-chloroethyl)amino]- phenoxycarbonyl]amino]-4-(5-tetrazoyl)butyric acid (PTP), which are cleaved by the bacterial enzyme CPG2 to release the 4-[N,N-bis(2-chloroethyl)amino] phenol drug. In vitro, both prodrugs are approximately 100- to 200-fold less potent than the parent drug (1 h IC50 = 1.4 microM) in LoVo colorectal tumour cells. These prodrugs have been evaluated for utility in ADEPT when used in combination with a conjugate of CPG2 and the F(ab')2 fragment of the anti-CEA monoclonal antibody, A5B7. The conjugate was shown to localise specifically to established LoVo tumour xenografts growing in nude mice and optimal tumour-normal tissue ratios were achieved after 72 h. Administration of either prodrug, at doses which cause 6-8% body weight loss, 72 h after administration of the A5B7-CPG2 conjugate to the LoVo tumour-bearing mice resulted in tumour regressions and growth delays of 14-28 days. The PTP prodrug in combination with a high dose of conjugate (10 mg kg-1) gave the best anti-tumour activity despite being a 10-fold worse substrate for CPG2 than PGP. Prodrug alone, active drug alone or prodrug in combination with a non-specific conjugate had minimal anti-tumour activity in this tumour model.
Blakey
D C
DC
Cancer Research Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
Davies
D H
DH
Dowell
R I
RI
East
S J
SJ
Burke
P J
PJ
Sharma
S K
SK
Springer
C J
CJ
Mauger
A B
AB
Melton
R G
RG
D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000008:administration & dosage* / Q000378:metabolism; D001711:Biotransformation; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011549:Pseudomonas / Q000201:enzymology; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage* / Q000378:metabolism
C096843:(4-(N,N-bis(2-chloroethyl)amino)phenoxycarbonyl)glutamic acid; C096846:2-(N-(4-(N,N-bis(2-chloroethyl)amino)phenoxycarbonyl)amino)-4-(5-tetrazolyl)butyric acid; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D018906:Antineoplastic Agents, Alkylating; D001426:Bacterial Proteins; D002272:Carcinoembryonic Antigen; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D011355:Prodrugs; C000929:hydroxyaniline mustard; D000816:Aniline Mustard; D011623:gamma-Glutamyl Hydrolase