title: Intravenous immune globulin suppresses angiogenesis in mice and humans.
abstract: Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~ 60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.
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; 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: Takeshi
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics-CNR, Naples, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tudisco
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; 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: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirano
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
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
authors.initials: T
authors.lastname: Yasuma
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: 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. ar.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. ar.l., Naples, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Brunetti
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: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sevim Barbasso
authors.initials: SB
authors.lastname: Helmers
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.affiliation: Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague 4, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Viklicky
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: 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: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Bastos-Carvalho
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
authors.initials: J
authors.lastname: Ambati