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Antibody-directed enzyme prodrug therapy: efficacy and mechanism of action in colorectal carcinoma.

Authors
  • Napier, M P
  • Sharma, S K
  • Springer, C J
  • Bagshawe, K D
  • Green, A J
  • Martin, J
  • Stribbling, S M
  • Cushen, N
  • O'Malley, D
  • Begent, R H
Type
Published Article
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Date
Mar 01, 2000
Volume
6
Issue
3
Pages
765–772
Identifiers
PMID: 10741695
Source
Medline
License
Unknown

Abstract

In antibody-directed enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i.v. and localizes in the tumor. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibody-directed enzyme prodrug therapy with A5B7 F(ab')2 antibody to carcinoembryonic antigen conjugated to carboxypeptidase G2 (CPG2). A galactosylated antibody directed against the active site of CPG2 (SB43-gal) was given to clear and inactivate circulating enzyme. A benzoic acid mustard-glutamate prodrug was given when plasma enzyme levels had fallen to a predetermined safe level, and this was converted by CPG2 in the tumor into a cytotoxic form. Enzyme levels derived from quantitative gamma camera imaging and from direct measurements in plasma and tumor biopsies showed that the median tumor:plasma ratio of enzyme exceeded 10000:1 at the time of prodrug administration. Enzyme concentrations in the tumor (median, 0.47 units g(-1)) were sufficient to generate cytotoxic levels of active drug. The concentration of prodrug needed for optimal conversion (Km) of 3 microM was achieved. Prodrug conversion to drug was shown by finding detectable levels of drug in plasma. There was evidence of tumor response; one patient had a partial response, and six patients had stable disease for a median of 4 months after previous tumor progression (one of these six had a tumor marker response). Manageable neutropenia and thrombocytopenia occurred. Conditions for effective antitumor therapy were met, and there was evidence of tumor response in colorectal cancer.

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