Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy
Leisa Johnson, … , Weilan Ye, Priti S. Hegde
Leisa Johnson, … , Weilan Ye, Priti S. Hegde
Published August 15, 2013
Citation Information: J Clin Invest. 2013;123(9):3997-4009. https://doi.org/10.1172/JCI67892.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 14

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

×

Figure 2

Anti-EGFL7 enhances the activity of anti-VEGF in the RIP-TβAg insulinoma model.

Options: View larger image (or click on image) Download as PowerPoint
Anti-EGFL7 enhances the activity of anti-VEGF in the RIP-TβAg insulinoma...
(A) Representative IF-stained photomicrographs of EGFL7 (red) and the vascular EC membrane marker MECA32 (green) expression in wild-type mouse pancreas (left panel) and in angiogenic islets (middle panel) and invasive carcinomas (right panel) from RIP-TβAg transgenic mice. EGFL7 is present in the perivascular matrix of a subset of blood vessels in normal pancreata and angiogenic islets and in the majority of tumor vessels. (B) Quantitative analysis of microvascular densities in invasive carcinomas after 2 weeks of treatment with IgG2a control anti-ragweed antibody, anti-VEGF (V) (B20-4.1.1), anti-EGFL7 (E) (h18F7), or the combination (VE). All antibodies were dosed via i.p. injection 1 time per week on days 1 and 8. The total number of individual lesions analyzed is indicated below each cohort and originated from 3–5 animals per group, with 1 to 16 tumors per animal. Each dot represents vascular area/tumor area, with mean values ± 95% CI shown. P values were calculated using a mixed-effects model, with the anti-VEGF group serving as the comparator for all other cohorts. *P < 0.05; **P < 0.005; ***P < 0.0005. Please see the Supplemental Methods for additional details. Please note that some or all of the mice from the C, V, and VE (E at 1.5 and 10 mpk) cohorts were used to used to generate additional data presented in Figure 7F and Supplemental Figure 7E.