title: Human IgG1 antibodies suppress angiogenesis in a target-independent manner.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kim
authors.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.
authors.forename: Takeshi
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authors.lastname: Mizutani
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Yasuma
authors.affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tudisco
authors.affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; Bio-Ker, MultiMedica Group, Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cicatiello
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Ana
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authors.lastname: Bastos-Carvalho
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Nagaraj
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authors.lastname: Kerur
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Yoshio
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authors.lastname: Hirano
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Judit Z
authors.initials: JZ
authors.lastname: Baffi
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Shengjian
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Tetsuhiro
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authors.lastname: Yasuma
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Parthasarathy
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authors.lastname: Arpitha
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fowler
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Wright
authors.affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Apicella
authors.affiliation: Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Greco
authors.affiliation: Department of Advanced Biomedical Sciences, University of Naples 'Federico II', Naples, Italy; CEINGE-Biotecnologie Avanzate, s.c.a.r.l., Naples, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Brunetti
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.
authors.forename: Menotti
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authors.lastname: Ruvo
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Sandomenico
authors.affiliation: Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Nozaki
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ijima
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ogura
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Terasaki
authors.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.
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.affiliation: Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeanette Hw
authors.initials: JH
authors.lastname: Leusen
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.affiliation: Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Michael R
authors.initials: MR
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authors.affiliation: Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Armour
authors.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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bruhns
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J Sjef
authors.initials: JS
authors.lastname: Verbeek
authors.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.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy; IRCCS MultiMedica, Milano, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: De Falco
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA; Department of Physiology, University of Kentucky, Lexington, KY, USA.
authors.forename: Jayakrishna
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authors.lastname: Ambati