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

Abstract

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.

• Authors: Leisa Johnson, Mahrukh Huseni, Tanya Smyczek, Anthony Lima, Stacey Yeung, Jason H Cheng, Rafael Molina, David Kan, Ann De Mazière, Judith Klumperman, Ian Kasman, Yin Zhang, Mark S Dennis, Jeffrey Eastham-Anderson, Adrian M Jubb, Olivia Hwang, Rupal Desai, Maike Schmidt, Michelle A Nannini, Kai H Barck, Richard A D Carano, William F Forrest, Qinghua Song, Daniel S Chen, Louie Naumovski, Mallika Singh, Weilan Ye, Priti S Hegde
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 9 Pg. 3997-4009 (Sep 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23945239 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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