Biomedical Engineering Reference
In-Depth Information Targeting FAP
Due to the highly restricted and specific expression of FAP, particularly within
tumor stroma, FAP is clinically interesting as a target for immunotherapy in
the treatment of cancer and non-invasive bio-imaging. Clinical trials aimed at
directly targeting the enzymatic activity of FAP with Val-boroPro (Talabostat;
PT-100), an amino boronic dipeptide inhibitor of DPs, for the treatment of
solid tumors managed to reach phase II studies but failed to demonstrate
clinical e cacy. 261 Val-boroPro had previously shown promise in the in vivo
reduction in tumour growth in mice, 262 but the direct inhibition of FAP by this
compound is unlikely. Due to the strict specificity of FAPs endopeptidase
activity, FAP selective inhibitors have been developed 263 but are yet to be used
in clinical studies. Clinical trials involving immunotherapy targeting of FAP for
the treatment of colon cancer and non-small cell lung cancers have also reached
phase II studies but failed due to a lack of ecacy. 264-267 Immunotherapy
targeting FAP may inhibit both enzymatic activities and extracellular matrix
interactions of FAP. It appears that FAP shows more promise as a biomarker
and target for non-invasive imaging of tumours or for use as site-directed
targeted cancer radiotherapy as being developed by Molecular Insight Phar-
maceuticals. 268 Currently immunoconjugate therapy utilizing a novel FAP
antibody-maytansinoid conjugate, monoclonal antibody (mAb) FAP5-DM1, is
being explored as a treatment option in epithelial cancers. 269 Maytansinoid is
an immunotoxic substance that enters into cancer cells, blocking their growth
upon binding of the antibody to the cell surface. Preliminary studies in mouse
xenograft models of lung, pancreas, head, and neck cancers demonstrated long-
lasting inhibition of tumor growth and tumor rejection upon immunoconjugate
treatment with mAb FAP5-DM1 with no adverse side-effects. 269 Loeffer et al.
constructed an oral DNA vaccine targeting FAP, suppressing tumor growth
and metastasis in FAP-vaccinated mice and increasing their uptake of che-
motherapeutics. 270 Mice vaccinated against FAP also displayed decreased
collagen type I expression, a physiological substrate of FAP that can contribute
to decreased chemotherapeutic drug uptake in tumors and play a role in reg-
ulating tumor sensitivity. 270 Effects of this treatment were reported to be from a
CD8 1 T cell-mediated anti-FAP immune response. Targeting DP4 and FAP for Prodrug Development
The ubiquitous distribution of DP4 in the human body coupled with its rare
ability to selectively cleave the post-proline bond of N-terminal dipeptides
makes it a suitable target for the development of prodrugs where systemic drug
delivery is required, such as blood disorders including human immunodeficiency
virus (HIV). In contrast, the strict specificity of FAP endopeptidase activity and
highly specific expression in cancer and at sites of tissue remodeling make it a
valuable pro drug target for the delivery of site-specific treatment. Practicality in
utilizing the enzymatic activity of DP4 or FAP in the development of prodrugs
has been demonstrated. Using a specific di- or tetra-peptide linked to
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