Biomedical Engineering Reference
In-Depth Information
therapeutic anti-HIV TSAO (non-nucleoside reverse transcriptase inhibitors)
molecules via an amide bond specifically cleaved by DP4, Garcia-Apricio et al.
demonstrated the eciency of DP4 at releasing a pharmacological active
compound upon proteolytic cleavage and suggested the possibility of altering
the half-life of the drug/prodrug by modifying the di- or tetra-peptide moi-
ety. 271,272 Aggarwal et al. identified a consensus sequence for FAP endopepti-
dase cleavage for use in the development of cytotoxic prodrugs. 273 This led to
the development of FAP selective peptide 'protoxins' in which the FAP selective
peptide is incorporated into the activation domain of a cytotoxic protein or
peptide rather than being directly linked to the activated toxin itself. 274 LeBeau
et al. demonstrated the feasibility of this approach with the generation of a FAP
selective 'promelittin' toxin that was eciently cleaved by FAP, releasing the
active cytoltic melittin resulting in site directed toxicity to FAP expressing
cells. 274 The anti-tumor effect of these protoxins was also demonstrated by
direct injection of the promelittin into human-prostate and breast-cancer
xenografts resulting in an increase in tumor necrosis and reduced tumor size. 274
These exciting results show promise for the future development of clinically
validated prodrugs targeting drugs to sites where DP4 or FAP are expressed for
treatment of systemic diseases such as HIV or FAP selective tumors.
1.7.2 Targeting Non-Enzymatic Function
Non-enzymatic functions of DP4 and FAP contribute to their involvement in
cell adhesion and migration, thus providing an additional therapeutic pathway
in the treatment of cancer progression. Targeting non-enzymatic functions for
treatment of disease by blocking protein-binding interactions has its diculties.
In the case of immunotherapy targeting of proteases, there is the added benefit
of directly blocking the enzymatic activity of the enzyme or altering its con-
formation so that substrate entry is blocked. However, mAbs are not guar-
anteed to block the numerous protein-binding sites of a protein and hence have
to be developed with the specific aim in mind of blocking a single protein-
protein interaction. There are also a number of issues regarding administering
an antibody and its stability within the human body once exposed to the mileu
of proteases that are present in vivo. Antibodies targeting FAP for immu-
notherapy have been discussed above, but note should be given as to their
potential to disrupt binding/interactions of FAP to extracellular matrix pro-
teins, uPAR, and even DP4. It may be possible that DP4 forms tetrameric
structures between adjacent cells that might participate in the adhesion and
growth of tumors within certain cancers. Future work may demonstrate the use
of antibodies to block such interactions. Studies demonstrating the ecacy of
immunotargeting DP4 have been demonstrated.
Binding of soluble anti-DP4 mAb has been shown to inhibit the growth of
human renal carcinoma cells (RCC) in vitro and in vivo, demonstrating its
potential clinical use for the treatment of DP4-positive RCC. 275 In a similar
study, Inamoto et al. demonstrated the effectiveness of humanized anti-DP4 in
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