Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy.
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.
Genentech Inc., South San Francisco, California 94080, USA. johnson.leisa@gene.com
Leisa
L
Johnson
Mahrukh
M
Huseni
Tanya
T
Smyczek
Anthony
A
Lima
Stacey
S
Yeung
Jason H
JH
Cheng
Rafael
R
Molina
David
D
Kan
Ann
A
De Mazière
Judith
J
Klumperman
Ian
I
Kasman
Yin
Y
Zhang
Mark S
MS
Dennis
Jeffrey
J
Eastham-Anderson
Adrian M
AM
Jubb
Olivia
O
Hwang
Rupal
R
Desai
Maike
M
Schmidt
Michelle A
MA
Nannini
Kai H
KH
Barck
Richard A D
RA
Carano
William F
WF
Forrest
Qinghua
Q
Song
Daniel S
DS
Chen
Louie
L
Naumovski
Mallika
M
Singh
Weilan
W
Ye
Priti S
PS
Hegde
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D017209:Apoptosis; D000068258:Bevacizumab; D002135:Calcium-Binding Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D066255:EGF Family of Proteins; D016228:Endothelial Growth Factors / Q000276:immunology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007340:Insulinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C527877:EGFL7 protein, human; D016228:Endothelial Growth Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab