title: Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4.
abstract: 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.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Sally-Anne
authors.initials: SA
authors.lastname: Stephenson
authors.affiliation: The Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Evelyn L
authors.initials: EL
authors.lastname: Douglas
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Inga
authors.initials: I
authors.lastname: Mertens-Walker
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Lisle
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Mohanan S N
authors.initials: MS
authors.lastname: Maharaj
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Queensland, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Herington
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation; D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D036224:Receptor, EphB4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D020794:Receptor Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D003545:Cysteine
keywords: EphB4; anti-cancer; monoclonal antibody therapy; receptor tyrosine kinase
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