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

Johnson L, Huseni M, Smyczek T, Lima A, Yeung S, Cheng JH, Molina R, Kan D, De Mazière A, Klumperman J, Kasman I, Zhang Y, Dennis MS, Eastham-Anderson J, Jubb AM, Hwang O, Desai R, Schmidt M, Nannini MA, Barck KH, Carano RA, Forrest WF, Song Q, Chen DS, Naumovski L, Singh M, Ye W, Hegde PS
Source: J Clin Invest
Publication Date: (2013)
Issue: 123(9): 3997-4009
Research Area:
Cells used in publication:
Endothelial, umbilical vein, human (HUVEC)
Species: human
Tissue Origin: vein
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.