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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.
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Research Article Oncology Article has an altmetric score of 14

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

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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

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Figure 4

Combination of anti-EGFL7 plus anti-VEGF inhibits the growth of xenografted H1299 NSCLC tumors.

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Combination of anti-EGFL7 plus anti-VEGF inhibits the growth of xenograf...
(A) Four groups of mice (10 each) were treated with the indicated antibodies. Individual tumor growth curves from mice harboring established tumors and dosed i.p. with control anti-ragweed (10 mpk, 1 time per week), anti-EGFL7 m18F7 (10 mpk, 2 times per week), anti-VEGF B20-4.1 (10 mpk, 1 time per week), or the combination of m18F7 plus B20-4.1. All treatments were dosed until tumors reached 1000 mm3, and the study was terminated on day 86. Tumors that reached end point before day 86 were continuously plotted at the end point volume of 1000 mm3 (black dots at the top). (B) Due to variable growth patterns, tumor growth was compared across treatments using an AUC measurement between days 0 and 86. Smaller AUC values represent slower growth. Tumors treated with combination therapy grew significantly more slowly than tumors in all other treatment cohorts, whereas tumors treated with either anti-EGFL7 or anti-VEGF monotherapy grew at a rate comparable to that of control. (C) The number of days each animal stayed on the study is another parameter reflecting tumor growth rates, as animals were taken off the study when their tumors reached 1000 mm3. Animals treated with the combination therapy stayed on study significantly longer than all other groups. The mean ± SEM is depicted. P values were calculated by unpaired, 2-tailed Student’s t test. *P < 0.05.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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