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.
|Journal||Signal Transduction and Targeted Therapy|
|State||Published - 2016|
Bibliographical noteFunding Information:
We thank TS Khurana, S Bondada, K Ambati, AM Rao and GS Rao for discussions; L Toll, GR Pattison R King, L Xu, M McConnell, C Payne, D Robertson, G Botzet, A Uiettenbogaard, E Lindroos and the Institute of Genetics and Biophysics animal house and integrated microscopy facilities for technical assistance. JA was supported by US National Institutes of Health (NIH) grants DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238 and R01EY024068, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, Foundation Fighting Blindness Individual Investigator Research Award, Harrington Discovery Institute Scholar-Innovator Award, Carl Marshall Reeves Foundation, John Templeton Foundation, Dr E Vernon Smith and Eloise C Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant; SDeF by AIRC (Associazione Italiana Ricerca sul Cancro) grant IG11420 and Italian Ministry for Scientific Research, project PON01_01434; BJF and SB by NIH T32HL091812 and UL1RR033173; YH by Alcon Research Award; AB-C by the Programme for Advanced Medical Education (sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal) and Bayer Global Ophthalmology Research Award; YH by Alcon Japan Research award; NK by Beckman Initiative for Macular Research and NIH K99/R00EY024336; CBW by International Retinal Research Foundation; BDG by American Heart Association and International Retinal Research Foundation; BKA by NIH R01EY017182 and R01EY017950, VA Merit Award and Department of Defense; and OV by Ministry of Health, Czech Republic—conceptual development of research organization (Institute for Clinical and Experimental Medicine—IKEM, IN 00023001).
JA is a co-founder of iVeena Holdings, iVeena Pharmaceuticals, iVeena Delivery Systems and Inflammasome Therapeutics, and has received honoraria from Allergan and research funding from Olix Pharmaceuticals unrelated to this work. JA and SDeF are named as inventors on patent applications filed by the University of Kentucky relating to the technology described in this work.
© 2016 West China Hospital, Sichuan University.
ASJC Scopus subject areas
- Cancer Research