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: D C Blakey, P J Burke, D H Davies, R I Dowell, S J East, K P Eckersley, J E Fitton, J McDaid, R G Melton, I A Niculescu-Duvaz, P E Pinder, S K Sharma, A F Wright, C J Springer
• Journal: Cancer research (Cancer Res) Vol. 56 Issue 14 Pg. 3287-92 (Jul 15 1996) ISSN: 0008-5472 [Print] United States
• PMID: 8764123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neoplasm
• Antineoplastic Agents, Alkylating
• Immunotoxins
• Nitrogen Mustard Compounds
• Prodrugs
• ZD 2767
• gamma-Glutamyl Hydrolase

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Neoplasm (therapeutic use)
• Antineoplastic Agents, Alkylating (administration & dosage)
• Colorectal Neoplasms (drug therapy)
• Female
• Humans
• Immunotoxins (administration & dosage)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Nitrogen Mustard Compounds (administration & dosage)
• Prodrugs (administration & dosage)
• Transplantation, Heterologous
• gamma-Glutamyl Hydrolase (metabolism)