Peptabody-EGF: a novel apoptosis inducer targeting ErbB1 receptor overexpressing cancer cells.
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.
Fattah
Omar M
OM
Department of Urology, Urology Research Unit, CHUV, Epalinges, Switzerland.
Cloutier
Sylvain M
SM
Kündig
Christoph
C
Felber
Loyse M
LM
Gygi
Christian M
CM
Jichlinski
Patrice
P
Leisinger
Hans-Jürg
HJ
Gauthier
Eric R
ER
Mach
Jean Pierre
JP
Deperthes
David
D
D000595:Amino Acid Sequence; D017304:Annexin A5 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D008969:Molecular Sequence Data; D015854:Up-Regulation / Q000187:drug effects
D017304:Annexin A5; D000970:Antineoplastic Agents; C514627:peptabody-EGF; D004815:Epidermal Growth Factor; D066246:ErbB Receptors