Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4

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...

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Bibliographic Details
Published in:Oncotarget 2015-04, Vol.6 (10), p.7554-7569
Main Authors: Stephenson, Sally-Anne, Douglas, Evelyn L, Mertens-Walker, Inga, Lisle, Jessica E, Maharaj, Mohanan S N, Herington, Adrian C
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - genetics
Antibodies, Monoclonal - pharmacology
Apoptosis
Cell Proliferation
Cysteine - metabolism
Humans
Receptor Protein-Tyrosine Kinases - genetics
Receptor, EphB4 - metabolism
Research Paper
Signal Transduction
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.3199