Human IgG1 antibodies suppress angiogenesis in a target-independent manner.
Identifieur interne : 002415 ( PubMed/Curation ); précédent : 002414; suivant : 002416Human IgG1 antibodies suppress angiogenesis in a target-independent manner.
Auteurs : Sasha Bogdanovich [États-Unis] ; Younghee Kim [États-Unis] ; Takeshi Mizutani [Japon] ; Reo Yasuma [Japon] ; Laura Tudisco [Italie] ; Valeria Cicatiello [Italie] ; Ana Bastos-Carvalho [États-Unis] ; Nagaraj Kerur [États-Unis] ; Yoshio Hirano [États-Unis] ; Judit Z. Baffi [États-Unis] ; Valeria Tarallo [Italie] ; Shengjian Li [États-Unis] ; Tetsuhiro Yasuma [États-Unis] ; Parthasarathy Arpitha [États-Unis] ; Benjamin J. Fowler [États-Unis] ; Charles B. Wright [États-Unis] ; Ivana Apicella [Italie] ; Adelaide Greco [Italie] ; Arturo Brunetti [Italie] ; Menotti Ruvo [Italie] ; Annamaria Sandomenico [Italie] ; Miho Nozaki [Japon] ; Ryo Ijima [Japon] ; Hiroki Kaneko [Japon] ; Yuichiro Ogura [Japon] ; Hiroko Terasaki [Japon] ; Balamurali K. Ambati [États-Unis] ; Jeanette Hw Leusen [Pays-Bas] ; Wallace Y. Langdon [Australie] ; Michael R. Clark [Royaume-Uni] ; Kathryn L. Armour [Royaume-Uni] ; Pierre Bruhns [France] ; J Sjef Verbeek [Pays-Bas] ; Bradley D. Gelfand [États-Unis] ; Sandro De Falco [Italie] ; Jayakrishna Ambati [États-Unis]Source :
- Signal transduction and targeted therapy [ 2095-9907 ]
Abstract
Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.
DOI: 10.1038/sigtrans.2015.1
PubMed: 26918197
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Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Yasuma, Reo" sort="Yasuma, Reo" uniqKey="Yasuma R" first="Reo" last="Yasuma">Reo Yasuma</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Tudisco, Laura" sort="Tudisco, Laura" uniqKey="Tudisco L" first="Laura" last="Tudisco">Laura Tudisco</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Cicatiello, Valeria" sort="Cicatiello, Valeria" uniqKey="Cicatiello V" first="Valeria" last="Cicatiello">Valeria Cicatiello</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Bastos Carvalho, Ana" sort="Bastos Carvalho, Ana" uniqKey="Bastos Carvalho A" first="Ana" last="Bastos-Carvalho">Ana Bastos-Carvalho</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Kerur, Nagaraj" sort="Kerur, Nagaraj" uniqKey="Kerur N" first="Nagaraj" last="Kerur">Nagaraj Kerur</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Hirano, Yoshio" sort="Hirano, Yoshio" uniqKey="Hirano Y" first="Yoshio" last="Hirano">Yoshio Hirano</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z" last="Baffi">Judit Z. Baffi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Tarallo, Valeria" sort="Tarallo, Valeria" uniqKey="Tarallo V" first="Valeria" last="Tarallo">Valeria Tarallo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Li, Shengjian" sort="Li, Shengjian" uniqKey="Li S" first="Shengjian" last="Li">Shengjian Li</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Yasuma, Tetsuhiro" sort="Yasuma, Tetsuhiro" uniqKey="Yasuma T" first="Tetsuhiro" last="Yasuma">Tetsuhiro Yasuma</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Arpitha, Parthasarathy" sort="Arpitha, Parthasarathy" uniqKey="Arpitha P" first="Parthasarathy" last="Arpitha">Parthasarathy Arpitha</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Fowler, Benjamin J" sort="Fowler, Benjamin J" uniqKey="Fowler B" first="Benjamin J" last="Fowler">Benjamin J. Fowler</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Wright, Charles B" sort="Wright, Charles B" uniqKey="Wright C" first="Charles B" last="Wright">Charles B. Wright</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Apicella, Ivana" sort="Apicella, Ivana" uniqKey="Apicella I" first="Ivana" last="Apicella">Ivana Apicella</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Greco, Adelaide" sort="Greco, Adelaide" uniqKey="Greco A" first="Adelaide" last="Greco">Adelaide Greco</name><affiliation wicri:level="1"><nlm:affiliation>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples</wicri:regionArea></affiliation></author><author><name sortKey="Brunetti, Arturo" sort="Brunetti, Arturo" uniqKey="Brunetti A" first="Arturo" last="Brunetti">Arturo Brunetti</name><affiliation wicri:level="1"><nlm:affiliation>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples</wicri:regionArea></affiliation></author><author><name sortKey="Ruvo, Menotti" sort="Ruvo, Menotti" uniqKey="Ruvo M" first="Menotti" last="Ruvo">Menotti Ruvo</name><affiliation wicri:level="1"><nlm:affiliation>Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Biostrutture e Bioimmagini, CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Sandomenico, Annamaria" sort="Sandomenico, Annamaria" uniqKey="Sandomenico A" first="Annamaria" last="Sandomenico">Annamaria Sandomenico</name><affiliation wicri:level="1"><nlm:affiliation>Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Biostrutture e Bioimmagini, CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Nozaki, Miho" sort="Nozaki, Miho" uniqKey="Nozaki M" first="Miho" last="Nozaki">Miho Nozaki</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Ijima, Ryo" sort="Ijima, Ryo" uniqKey="Ijima R" first="Ryo" last="Ijima">Ryo Ijima</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Kaneko, Hiroki" sort="Kaneko, Hiroki" uniqKey="Kaneko H" first="Hiroki" last="Kaneko">Hiroki Kaneko</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Ogura, Yuichiro" sort="Ogura, Yuichiro" uniqKey="Ogura Y" first="Yuichiro" last="Ogura">Yuichiro Ogura</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Terasaki, Hiroko" sort="Terasaki, Hiroko" uniqKey="Terasaki H" first="Hiroko" last="Terasaki">Hiroko Terasaki</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K" last="Ambati">Balamurali K. Ambati</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT</wicri:regionArea></affiliation></author><author><name sortKey="Leusen, Jeanette Hw" sort="Leusen, Jeanette Hw" uniqKey="Leusen J" first="Jeanette Hw" last="Leusen">Jeanette Hw Leusen</name><affiliation wicri:level="1"><nlm:affiliation>Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht</wicri:regionArea></affiliation></author><author><name sortKey="Langdon, Wallace Y" sort="Langdon, Wallace Y" uniqKey="Langdon W" first="Wallace Y" last="Langdon">Wallace Y. Langdon</name><affiliation wicri:level="1"><nlm:affiliation>School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA</wicri:regionArea></affiliation></author><author><name sortKey="Clark, Michael R" sort="Clark, Michael R" uniqKey="Clark M" first="Michael R" last="Clark">Michael R. Clark</name><affiliation wicri:level="1"><nlm:affiliation>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge</wicri:regionArea></affiliation></author><author><name sortKey="Armour, Kathryn L" sort="Armour, Kathryn L" uniqKey="Armour K" first="Kathryn L" last="Armour">Kathryn L. Armour</name><affiliation wicri:level="1"><nlm:affiliation>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge</wicri:regionArea></affiliation></author><author><name sortKey="Bruhns, Pierre" sort="Bruhns, Pierre" uniqKey="Bruhns P" first="Pierre" last="Bruhns">Pierre Bruhns</name><affiliation wicri:level="1"><nlm:affiliation>Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1222, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1222, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Verbeek, J Sjef" sort="Verbeek, J Sjef" uniqKey="Verbeek J" first="J Sjef" last="Verbeek">J Sjef Verbeek</name><affiliation wicri:level="1"><nlm:affiliation>Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Gelfand, Bradley D" sort="Gelfand, Bradley D" uniqKey="Gelfand B" first="Bradley D" last="Gelfand">Bradley D. Gelfand</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="De Falco, Sandro" sort="De Falco, Sandro" uniqKey="De Falco S" first="Sandro" last="De Falco">Sandro De Falco</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; IRCCS MultiMedica, Milano, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; IRCCS MultiMedica, Milano</wicri:regionArea></affiliation></author><author><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="????"><PubDate><MedlineDate>2016</MedlineDate></PubDate></date><idno type="RBID">pubmed:26918197</idno><idno type="pmid">26918197</idno><idno type="doi">10.1038/sigtrans.2015.1</idno><idno type="wicri:Area/PubMed/Corpus">002462</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002462</idno><idno type="wicri:Area/PubMed/Curation">002415</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002415</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Human IgG1 antibodies suppress angiogenesis in a target-independent manner.</title><author><name sortKey="Bogdanovich, Sasha" sort="Bogdanovich, Sasha" uniqKey="Bogdanovich S" first="Sasha" last="Bogdanovich">Sasha Bogdanovich</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Younghee" sort="Kim, Younghee" uniqKey="Kim Y" first="Younghee" last="Kim">Younghee Kim</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Mizutani, Takeshi" sort="Mizutani, Takeshi" uniqKey="Mizutani T" first="Takeshi" last="Mizutani">Takeshi Mizutani</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Yasuma, Reo" sort="Yasuma, Reo" uniqKey="Yasuma R" first="Reo" last="Yasuma">Reo Yasuma</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Tudisco, Laura" sort="Tudisco, Laura" uniqKey="Tudisco L" first="Laura" last="Tudisco">Laura Tudisco</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Cicatiello, Valeria" sort="Cicatiello, Valeria" uniqKey="Cicatiello V" first="Valeria" last="Cicatiello">Valeria Cicatiello</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Bastos Carvalho, Ana" sort="Bastos Carvalho, Ana" uniqKey="Bastos Carvalho A" first="Ana" last="Bastos-Carvalho">Ana Bastos-Carvalho</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Kerur, Nagaraj" sort="Kerur, Nagaraj" uniqKey="Kerur N" first="Nagaraj" last="Kerur">Nagaraj Kerur</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Hirano, Yoshio" sort="Hirano, Yoshio" uniqKey="Hirano Y" first="Yoshio" last="Hirano">Yoshio Hirano</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z" last="Baffi">Judit Z. Baffi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Tarallo, Valeria" sort="Tarallo, Valeria" uniqKey="Tarallo V" first="Valeria" last="Tarallo">Valeria Tarallo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Li, Shengjian" sort="Li, Shengjian" uniqKey="Li S" first="Shengjian" last="Li">Shengjian Li</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Yasuma, Tetsuhiro" sort="Yasuma, Tetsuhiro" uniqKey="Yasuma T" first="Tetsuhiro" last="Yasuma">Tetsuhiro Yasuma</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Arpitha, Parthasarathy" sort="Arpitha, Parthasarathy" uniqKey="Arpitha P" first="Parthasarathy" last="Arpitha">Parthasarathy Arpitha</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Fowler, Benjamin J" sort="Fowler, Benjamin J" uniqKey="Fowler B" first="Benjamin J" last="Fowler">Benjamin J. Fowler</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Wright, Charles B" sort="Wright, Charles B" uniqKey="Wright C" first="Charles B" last="Wright">Charles B. Wright</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="Apicella, Ivana" sort="Apicella, Ivana" uniqKey="Apicella I" first="Ivana" last="Apicella">Ivana Apicella</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Greco, Adelaide" sort="Greco, Adelaide" uniqKey="Greco A" first="Adelaide" last="Greco">Adelaide Greco</name><affiliation wicri:level="1"><nlm:affiliation>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples</wicri:regionArea></affiliation></author><author><name sortKey="Brunetti, Arturo" sort="Brunetti, Arturo" uniqKey="Brunetti A" first="Arturo" last="Brunetti">Arturo Brunetti</name><affiliation wicri:level="1"><nlm:affiliation>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples</wicri:regionArea></affiliation></author><author><name sortKey="Ruvo, Menotti" sort="Ruvo, Menotti" uniqKey="Ruvo M" first="Menotti" last="Ruvo">Menotti Ruvo</name><affiliation wicri:level="1"><nlm:affiliation>Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Biostrutture e Bioimmagini, CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Sandomenico, Annamaria" sort="Sandomenico, Annamaria" uniqKey="Sandomenico A" first="Annamaria" last="Sandomenico">Annamaria Sandomenico</name><affiliation wicri:level="1"><nlm:affiliation>Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Biostrutture e Bioimmagini, CNR, Naples</wicri:regionArea></affiliation></author><author><name sortKey="Nozaki, Miho" sort="Nozaki, Miho" uniqKey="Nozaki M" first="Miho" last="Nozaki">Miho Nozaki</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Ijima, Ryo" sort="Ijima, Ryo" uniqKey="Ijima R" first="Ryo" last="Ijima">Ryo Ijima</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Kaneko, Hiroki" sort="Kaneko, Hiroki" uniqKey="Kaneko H" first="Hiroki" last="Kaneko">Hiroki Kaneko</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Ogura, Yuichiro" sort="Ogura, Yuichiro" uniqKey="Ogura Y" first="Yuichiro" last="Ogura">Yuichiro Ogura</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Terasaki, Hiroko" sort="Terasaki, Hiroko" uniqKey="Terasaki H" first="Hiroko" last="Terasaki">Hiroko Terasaki</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya</wicri:regionArea></affiliation></author><author><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K" last="Ambati">Balamurali K. Ambati</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT</wicri:regionArea></affiliation></author><author><name sortKey="Leusen, Jeanette Hw" sort="Leusen, Jeanette Hw" uniqKey="Leusen J" first="Jeanette Hw" last="Leusen">Jeanette Hw Leusen</name><affiliation wicri:level="1"><nlm:affiliation>Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht</wicri:regionArea></affiliation></author><author><name sortKey="Langdon, Wallace Y" sort="Langdon, Wallace Y" uniqKey="Langdon W" first="Wallace Y" last="Langdon">Wallace Y. Langdon</name><affiliation wicri:level="1"><nlm:affiliation>School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA</wicri:regionArea></affiliation></author><author><name sortKey="Clark, Michael R" sort="Clark, Michael R" uniqKey="Clark M" first="Michael R" last="Clark">Michael R. Clark</name><affiliation wicri:level="1"><nlm:affiliation>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge</wicri:regionArea></affiliation></author><author><name sortKey="Armour, Kathryn L" sort="Armour, Kathryn L" uniqKey="Armour K" first="Kathryn L" last="Armour">Kathryn L. Armour</name><affiliation wicri:level="1"><nlm:affiliation>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge</wicri:regionArea></affiliation></author><author><name sortKey="Bruhns, Pierre" sort="Bruhns, Pierre" uniqKey="Bruhns P" first="Pierre" last="Bruhns">Pierre Bruhns</name><affiliation wicri:level="1"><nlm:affiliation>Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1222, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1222, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Verbeek, J Sjef" sort="Verbeek, J Sjef" uniqKey="Verbeek J" first="J Sjef" last="Verbeek">J Sjef Verbeek</name><affiliation wicri:level="1"><nlm:affiliation>Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Leiden University Medical Center, Leiden</wicri:regionArea></affiliation></author><author><name sortKey="Gelfand, Bradley D" sort="Gelfand, Bradley D" uniqKey="Gelfand B" first="Bradley D" last="Gelfand">Bradley D. Gelfand</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author><author><name sortKey="De Falco, Sandro" sort="De Falco, Sandro" uniqKey="De Falco S" first="Sandro" last="De Falco">Sandro De Falco</name><affiliation wicri:level="1"><nlm:affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; IRCCS MultiMedica, Milano, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; IRCCS MultiMedica, Milano</wicri:regionArea></affiliation></author><author><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY</wicri:regionArea></affiliation></author></analytic><series><title level="j">Signal transduction and targeted therapy</title><idno type="ISSN">2095-9907</idno></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">26918197</PMID><DateCreated><Year>2016</Year><Month>02</Month><Day>26</Day></DateCreated><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">2095-9907</ISSN><JournalIssue CitedMedium="Print"><Volume>1</Volume><PubDate><MedlineDate>2016</MedlineDate></PubDate></JournalIssue><Title>Signal transduction and targeted therapy</Title><ISOAbbreviation>Signal Transduct Target Ther</ISOAbbreviation></Journal><ArticleTitle>Human IgG1 antibodies suppress angiogenesis in a target-independent manner.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">15001</ELocationID><Abstract><AbstractText>Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bogdanovich</LastName><ForeName>Sasha</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kim</LastName><ForeName>Younghee</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mizutani</LastName><ForeName>Takeshi</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yasuma</LastName><ForeName>Reo</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tudisco</LastName><ForeName>Laura</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cicatiello</LastName><ForeName>Valeria</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bastos-Carvalho</LastName><ForeName>Ana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kerur</LastName><ForeName>Nagaraj</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hirano</LastName><ForeName>Yoshio</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baffi</LastName><ForeName>Judit Z</ForeName><Initials>JZ</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tarallo</LastName><ForeName>Valeria</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Shengjian</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yasuma</LastName><ForeName>Tetsuhiro</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arpitha</LastName><ForeName>Parthasarathy</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fowler</LastName><ForeName>Benjamin J</ForeName><Initials>BJ</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wright</LastName><ForeName>Charles B</ForeName><Initials>CB</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Apicella</LastName><ForeName>Ivana</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Greco</LastName><ForeName>Adelaide</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brunetti</LastName><ForeName>Arturo</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ruvo</LastName><ForeName>Menotti</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sandomenico</LastName><ForeName>Annamaria</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nozaki</LastName><ForeName>Miho</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ijima</LastName><ForeName>Ryo</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kaneko</LastName><ForeName>Hiroki</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ogura</LastName><ForeName>Yuichiro</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Terasaki</LastName><ForeName>Hiroko</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ambati</LastName><ForeName>Balamurali K</ForeName><Initials>BK</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leusen</LastName><ForeName>Jeanette Hw</ForeName><Initials>JH</Initials><AffiliationInfo><Affiliation>Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Langdon</LastName><ForeName>Wallace Y</ForeName><Initials>WY</Initials><AffiliationInfo><Affiliation>School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Clark</LastName><ForeName>Michael R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Armour</LastName><ForeName>Kathryn L</ForeName><Initials>KL</Initials><AffiliationInfo><Affiliation>Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bruhns</LastName><ForeName>Pierre</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Immunology, Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1222, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Verbeek</LastName><ForeName>J Sjef</ForeName><Initials>JS</Initials><AffiliationInfo><Affiliation>Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gelfand</LastName><ForeName>Bradley D</ForeName><Initials>BD</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Falco</LastName><ForeName>Sandro</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; IRCCS MultiMedica, Milano, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ambati</LastName><ForeName>Jayakrishna</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 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HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Curation/RBID.i -Sk "pubmed:26918197" \
| HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd \
| NlmPubMed2Wicri -a AustralieFrV1
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