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Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
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Novel EphB4 monoclonal antibodies modulate angiogenesis and inhibit tumor growth

Valery Krasnoperov1, S Ram Kumar, Eric Ley

  • 1Vasgene Thereapeutics Inc., Los Angeles, CA, USA.

The American Journal of Pathology
|February 6, 2010
PubMed

Insights

Two new monoclonal antibodies targeting EphB4 receptor tyrosine kinase inhibit tumor growth and angiogenesis. These antibodies offer distinct mechanisms for cancer therapy, with one combination therapy showing enhanced antitumor activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • EphB4 receptor tyrosine kinase and EphrinB2 ligand are crucial for blood vessel formation and maturation.
  • Their interaction is vital for angiogenesis, vessel maturation, and pericyte recruitment.
  • EphB4 is frequently overexpressed in epithelial cancers, promoting tumor cell survival.

Purpose of the Study:

  • To develop and characterize novel anti-EphB4 monoclonal antibodies for cancer therapy.
  • To investigate the distinct mechanisms by which these antibodies inhibit tumor angiogenesis and growth.
  • To evaluate the therapeutic potential of these antibodies, alone and in combination with bevacizumab.

Main Methods:

  • Development of two anti-EphB4 monoclonal antibodies (MAb131 and MAb47).
  • In vitro assessment of endothelial tube formation and in vivo evaluation in human tumor xenograft models.
  • Analysis of antibody binding domains, EphB4 receptor levels, and combination therapy efficacy with bevacizumab.

Main Results:

  • MAb131 targets fibronectin-like domain 1, inducing human EphB4 degradation and inhibiting human endothelial tube formation and tumor growth.
  • MAb47 targets fibronectin-like domain 2, inhibiting angiogenesis and tumor growth in both EphB4-positive and negative xenografts without altering receptor levels.
  • Combination of MAb47 and bevacizumab demonstrated enhanced antitumor activity and induced tumor regression.
  • Humanized antibodies hAb47 and hAb131 retained efficacy in preclinical models of primary tumor development and metastasis.

Conclusions:

  • Anti-EphB4 monoclonal antibodies represent a promising therapeutic strategy for inhibiting tumor angiogenesis and growth.
  • Distinct antibody mechanisms, including receptor degradation and direct inhibition of angiogenesis, offer versatile therapeutic options.
  • Combination therapy with MAb47 and bevacizumab shows significant potential for enhanced antitumor efficacy and tumor regression.

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