Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy

J Clin Invest. 2013 Sep;123(9):3997-4009. doi: 10.1172/JCI67892. Epub 2013 Aug 15.


Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antibodies / pharmacology*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Apoptosis*
  • Bevacizumab
  • Calcium-Binding Proteins
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Clinical Trials, Phase I as Topic
  • EGF Family of Proteins
  • Endothelial Growth Factors / immunology*
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / physiology
  • Humans
  • Insulinoma / blood supply
  • Insulinoma / drug therapy
  • Insulinoma / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Neoplastic Cells, Circulating / drug effects
  • Neoplastic Cells, Circulating / metabolism
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Tumor Burden / drug effects
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / physiology
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Antibodies
  • Antibodies, Monoclonal, Humanized
  • Calcium-Binding Proteins
  • EGF Family of Proteins
  • EGFL7 protein, human
  • Endothelial Growth Factors
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Bevacizumab