The
epidermal growth factor receptor (EGFR) plays a central role in cell life by controlling processes such as growth or proliferation. This receptor is commonly overexpressed in a number of epithelial
malignancies and its upregulation is often associated with an aggressive phenotype of the
tumor. Thus, targeting of EGFR represents a very promising challenge in oncology, and
antibodies raised against this receptor have been investigated as potential
antitumor agents. Various putative mechanisms of action were proposed for such
antibodies, including decreased proliferation, induction of apoptosis, stimulation of the immunological response against targeted
cancer cells or combinations thereof. We report here the development of an alternative high affinity molecule that is directed against EGFR. Production of this pentameric
protein, named
peptabody-EGF, includes expression in a bacterial expression system and subsequent refolding and multimerization of peptabody monomers. The
protein complex contains 5 human
EGF ligand domains, which confer specific binding towards the extracellular portion of EGFR. Receptor binding of the
peptabody-EGF had a strong antiproliferative effect on different
cancer cell lines overexpressing EGFR. However, cells expressing constitutive levels of the target receptor were barely affected.
Peptabody-EGF treated
cancer cells exhibited typical characteristics of apoptosis, which was found to be induced within 30 min after the addition of the
peptabody-EGF. In vitro experiments demonstrated a significantly higher binding activity for
peptabody-EGF than for the therapeutic monoclonal EGFR antibody Mab-425. Furthermore, the antitumor action provoked by the
peptabody-EGF was greatly superior than antibody mediated effects when tested on EGFR overexpressing
cancer cell lines. These findings suggest a potential application of this high affinity molecule as a novel tool for anti-EGFR
therapy.