Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4
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Sally-Anne Stephenson1,2,3, Evelyn L. Douglas4, Inga Mertens-Walker1,2,3, Jessica E. Lisle1,2,3, Mohanan S.N. Maharaj1,2,3, Adrian C. Herington1,2,3
1Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia
2Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia
3Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
4The Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia
Sally-Anne Stephenson, e-mail: firstname.lastname@example.org
Keywords: EphB4, receptor tyrosine kinase, monoclonal antibody therapy, anti-cancer
Received: January 19, 2015 Accepted: January 23, 2015 Published: March 25, 2015
EphB4 is a membrane-bound receptor tyrosine kinase (RTK) commonly over-produced by many epithelial cancers but with low to no expression in most normal adult tissues. EphB4 over-production promotes ligand-independent signaling pathways that increase cancer cell viability and stimulate migration and invasion. Several studies have shown that normal ligand-dependent signaling is tumour suppressive and therefore novel therapeutics which block the tumour promoting ligand-independent signaling and/or stimulate tumour suppressive ligand-dependent signaling will find application in the treatment of cancer. An EphB4-specific polyclonal antibody, targeting a region of 200 amino acids in the extracellular portion of EphB4, showed potent in vitro anti-cancer effects measured by an increase in apoptosis and a decrease in anchorage independent growth. Peptide exclusion was used to identify the epitope targeted by this antibody within the cysteine-rich region of the EphB4 protein, a sequence defined as a potential ligand interacting interface. Addition of antibody to cancer cells resulted in phosphorylation and subsequent degradation of the EphB4 protein, suggesting a mechanism that is ligand mimetic and tumour suppressive. A monoclonal antibody which specifically targets this identified extracellular epitope of EphB4 significantly reduced breast cancer xenograft growth in vivo confirming that EphB4 is a useful target for ligand-mimicking antibody-based anti-cancer therapies.
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