Biomedical Engineering Reference
In-Depth Information
23
ANTIBODY-DIRECTED ENZYME PRODRUG
THERAPY (ADEPT)
S
URINDER
K. S
HARMA
Research Department of Oncology, University College London, London, UK
23.1 Introduction
23.2 The components
23.3 Adept systems with carboxypeptidase G2 (CPG2)
23.4 Fusion proteins
23.5 Immunogenicity
23.6 Conclusions and future outlook
Acknowledgments
References
but only one system has progressed to clinical trials.
Although preclinical studies provide valuable information,
it is only through clinical studies that the real challenges can
be identified. These need to be addressed when developing
new ADEPT systems for cancer.
The aim of ADEPT is to restrict the cytotoxic action of the
drug to tumors only. Although the idea may appear simple, its
successful application requires multidisciplinary approach
and an understanding of all the parameters involved.
23.2 THE COMPONENTS
23.1
INTRODUCTION
23.2.1 The Target
Ideally, the target molecule should be unique to the surface
membrane of cancer cells. Such targets are available for only
certain types of cancer at present. In so far as a potential
target has some normal tissue expression, it should not be on
a vital or irreplaceable organ. It is also desirable that the
targeted molecule should not internalize the antibody-
enzyme conjugate since this would obviously result in
inactivation of the enzyme, whereas one enzyme molecule
remaining on the cell surface may convert many prodrug
molecules into cytotoxic agents. The target molecule should
be expressed on a high proportion of the cancer cells but as is
well-known marker antigens are not invariably expressed on
all the cells of epithelial cancers. It may be noted that one of
the virtues of the ADEPT approach is that by generating
small toxic drugs unmarked cells are as vulnerable as those
expressing the marker antigen. It may also be supposed that
secretion of the target antigen into extracellular space and
into the blood would prevent an antibody-enzyme conjugate
from localizing at tumor sites. However, this does not appear
Antibody-enzyme conjugates were first reported in the early
1970s [1] but it was not until 1987 that it was suggested [2]
that these could be used in combination with prodrugs.
This led to the development of what is known as
antibody-directed enzyme prodrug therapy or ADEPT.
ADEPT (Figure 23.1) is a selective form of chemotherapy
where an antibody directed at a tumor-associated antigen is
used to deliver a unique enzyme to tumor sites [3,4]. After
localization of enzyme in the tumor and clearance from
blood, a nontoxic prodrug is given with the expectation that
it would be converted, by the enzyme, to a potent cytotoxic
drug at tumor sites. The enzyme provides an amplification
effect as one enzyme can convert many prodrug molecules
generating higher concentration of the drug within tumors.
The drug is generated extracellularly and being a small
molecule can diffuse throughout the tumor killing antigen
positive as well as the antigen negative cell, thus providing a
by-stander effect [5]. Many preclinical studies [reviewed in
References 6-8] have confirmed feasibility of this approach
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