Antibody-directed Enzyme Prodrug Therapy: Efficacy and Mechanism of Action in Colorectal Carcinoma
2000
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
( K m ) of 3 μm 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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