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.

Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer

“…Parsatuzumab, a humanized anti‐EGFL7 IgG 1 monoclonal antibody, selectively blocks the interaction between EGFL7 and endothelial cells, thereby potentially inhibiting vascular regrowth and further reducing tumor perfusion after antiangiogenic therapy, such as vascular endothelial growth factor (VEGF) inhibition . In several xenograft and genetically engineered murine tumor models, the addition of anti‐EGFL7 enhanced the antiangiogenesis, tumor growth control, and survival associated with anti‐VEGF monotherapy . Favorable tolerability and evidence of pharmacodynamic modulation and antitumor activity were observed in a phase Ib trial that evaluated parsatuzumab in combination with bevacizumab and bevacizumab/paclitaxel .…”

Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia

“…To evaluate the effects and therapeutic potential of inhibiting EGFL7 in AML, we performed experiments with a commercially available antibody that binds to the EGFL7 protein and inhibits its downstream effects (16). Immunoblotting performed after treatment of patient AML blasts with the anti-EGFL7 antibody showed a decrease in the levels of pAKT (Fig.…”

More than a Scaffold: Extracellular Matrix in Vascular Signaling

“…The matricellular protein CCN2 elicits potent angiogenic activity, and the CCN2-specific humanized antibody FG-3019 inhibits tumor growth and metastasis in pancreatic cancer [146]. Antibodies targeting the ECM-associated protein EGFL7 improve the efficacy of anti-VEGF therapy through induction of EC apoptosis and inhibition of tumor progression in nonsmall cell lung cancer [104]. Finally, different derivatives of antibodies recognizing fibronectin extra-domain B (EDB), as well as large tenascin-C isoforms, have been in use for radioimmunotherapy in different cancers [147].…”

“…The matricellular protein CCN1 promotes EC migration and aberrant neovascularization in pancreatic cancer [103]. EC survival during hypoxic conditions is mediated by a matrix-associated protein EGFL7 [104], while different collagens, which are excessively deposited within the stroma, may control EC proliferation through regulation of ECM stiffness [105,106]. Finally, tenascin-C, which is highly expressed in tumor-derived endothelium [107], regulates multiple aspects of vascular sprouting by instructing EC migration, proliferation, and VEGF expression [108,109].…”