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

作者：Johnson Leisa^*; Huseni Mahrukh; Smyczek Tanya; Lima Anthony; Yeung Stacey; Cheng Jason H; Molina Rafael; Kan David; De Maziere Ann; Klumperman Judith; Kasman Ian; Zhang Yin; Dennis Mark S; Eastham Anderson Jeffrey; Jubb Adrian M; Hwang Olivia; Desai Rupal; Schmidt Maike; Nannini Michelle A; Barck Kai H; Carano Richard A D; Forrest William F; Song Qinghua; Chen Daniel S; Naumovski Louie; Singh Mallika; Ye Weilan; Hegde Priti S

来源：Journal of Clinical Investigation, 2013, 123(9): 3997-4009.

DOI：10.1172/JCI67892

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.

• 出版日期2013-9