Anti-EGFL7 antibody enhances the antiangiogenic and antitumor activity of anti-VEGF therapy.

  • Major finding: Anti-EGFL7 antibodies enhance the antiangiogenic and antitumor activity of anti-VEGF therapy.

  • Mechanism: EGFL7 promotes endothelial cell adhesion and survival under anti-VEGF therapy-induced stresses.

  • Impact: Circulating progenitor cells represent a biomarker of anti-EGFL7 activity in mice and patients.

Prolonged treatment with VEGF-targeted therapies such as the monoclonal antibody bevacizumab has been shown to inhibit the growth of various solid tumors and to provide increased survival benefit. Suppression of tumor angiogenesis generates a nutrient- and oxygen-deprived microenvironment, suggesting that inhibition of factors that promote endothelial cell survival under these stress conditions may enhance the long-term efficacy of anti-VEGF therapy. Johnson and colleagues found that EGF-like domain 7 (EGFL7), an extracellular matrix–associated protein expressed by tumor blood vessels, protected endothelial cells from apoptosis in response to hypoxia or nutrient deficiency. Treatment with anti-EGFL7 antibodies inhibited EGFL7-stimulated endothelial cell adhesion and survival in vitro and augmented the antiangiogenic activity of anti-VEGF antibody in xenograft tumor models, resulting in a greater reduction in microvascular density and enhanced suppression of tumor growth. Furthermore, anti-EGFL7 improved the durability and efficacy of anti-VEGF therapy in a genetically engineered mouse model of non–small cell lung cancer, in which tumor blood vessels express EGFL7 in the context of the autochthonous microenvironment; this enhanced antitumor effect was dose dependent and was associated with prolonged progression-free survival and overall survival. To enable assessment of anti-EGFL7 activity, the authors characterized a population of human CD34+ circulating progenitor cells (CPC) in the peripheral blood that expressed high levels of EGFL7 mRNA compared with circulating endothelial cells and were capable of differentiating into endothelial cells. Anti-EGFL7 treatment specifically reduced the number of CPCs in preclinical mouse models as well as in patients from a phase I clinical trial examining anti-EGFL7 as a single agent or in combination with bevacizumab. This integrated preclinical and clinical analysis suggests a pharmacodynamic biomarker for anti-EGFL7 response and defines an optimal dose for future clinical trials of anti-EGFL7.

Johnson L, Huseni M, Smyczek T, Lima A, Yeung S, Cheng JH, et al. Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy. J Clin Invest 2013;123:3997–4009.

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