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: Sally-Anne Stephenson, Evelyn L Douglas, Inga Mertens-Walker, Jessica E Lisle, Mohanan S N Maharaj, Adrian C Herington
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 10 Pg. 7554-69 (Apr 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25831049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Receptor Protein-Tyrosine Kinases
• Receptor, EphB4
• Cysteine

Topics

• Antibodies, Monoclonal (genetics, pharmacology)
• Apoptosis
• Cell Proliferation
• Cysteine (metabolism)
• Humans
• Receptor Protein-Tyrosine Kinases (genetics)
• Receptor, EphB4 (metabolism)
• Signal Transduction