Biomedical Engineering Reference
In-Depth Information
peptidyl-chloromethyl ketones that inhibit FAP but not DPP-4. Two inhibitors
were synthesized, both mimicking an endopeptidase substrate, and both were
found to inhibit FAP enzyme activity in a dose-dependent and irreversible
manner. A similar study focused on the FAP dipeptide substrate specificity and
identified the N-acyl-Gly-Pro motif for inhibitor design. 148
A further detailed analysis of the substrate specificity of FAP using synthetic
peptide libraries has also been carried out to provide an insight into the
importance of residues around the cleavage site to aid in the design of selective
FAP inhibitors. 150 A substrate analog inhibitor was investigated which inhib-
ited FAP with a K i of 54 mM but did not inhibit DPP-4, even at 2 mM. It was
hypothesized that Arg-xxx-Gly-Pro, where xxx represents a linker of
amino acids in length, may be useful for FAP-specific inhibitor design. 150
Further examination of this compound and another recently reported FAP
inhibitor that inhibits FAP and a related enzyme, prolyl endopeptidase
(PEP), 155 may be useful in developing FAP-selective inhibitors for in vivo use.
B Alternative Strategies for Targeting FAP
In addition to the potential use of FAP inhibitors in tumor therapy, other
approaches exploiting FAP are being investigated. A monoclonal anti-FAP
antibody, F19, has been studied in targeting metastatic colon cancer. 135 This
showed FAP to be highly expressed in primary and metastatic colorectal car-
cinomas but had limited expression in normal adult tissue. However, while the
humanized version of this antibody proved to be safe and well tolerated, it was
demonstrated to be non-inhibitory and showed limited clinical ecacy. 156,157
Humanized monoclonal antibodies to FAP might be used for targeting tumors
or for activation of endogenous anti-tumoral mechanisms. 136 Bispecific anti-
bodies directed against FAP and the T-cell receptor component CD3 target
cytotoxic effector cells to FAP-expressing cells. 137,158
Immunotherapies targeting FAP have shown some promise. FAP-targeted
DNA vaccines have successfully suppressed primary tumor cell growth and
metastasis of multidrug-resistant murine colon and breast carcinoma by T-cell-
mediated killing of FAP-positive tumor-associated fibroblasts. 159 In immu-
notherapy, tumor growth was inhibited in mice vaccinated against FAP using
melanoma, carcinoma, and lymphoma models, and the FAP-vaccinated mice
remained viable and appeared healthy. 160
FAP-specific prodrugs, whereby cleavage of the prodrug by FAP results in a
cytotoxic product, is an excellent approach because it strategically utilises the
unique FAP enzyme specificity and restricted expression pattern. Specifically
killing FAP-positive tumor stromal cells may yield greater biological ecacy
than inhibitors owing to fewer bystander effects. Melittin, a well-characterized
cytolytic peptide from the venom of the honeybee, Apis millifera, has been
modified into a FAP-specific protoxin that is eciently activated by FAP and
selectively toxic to FAP-expressing cell lines. 161 Intratumoral injection with a
FAP-activated protoxin produced significant cell lysis and growth inhibition of
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