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.
Highlights
Human intravenous immune globulin (IVIg) is a biological product obtained by pooling polyclonal IgG from thousands of healthy donors
We demonstrate that therapeutic human IgG1 antibodies can suppress angiogenesis in a target-independent manner via FcγRI,[5] a high-affinity receptor for IgG1.6–8 we tested whether IVIg, which is composed of ~ 60% IgG1, possessed similar anti-angiogenic properties
We tested the effect of IVIg in the following five different mouse models of angiogenesis: laser-induced choroidal angiogenesis, a model of neovascular age-related macular degeneration (AMD),[15,16] suture-induced corneal angiogenesis,[10,11] hind limb ischemia induced by femoral artery ligation[11,13] and a syngeneic mouse fibrosarcoma tumor model,[17] all in wild-type mice, as well as a human xenograft model of colorectal carcinoma in nude mice.[18]
Summary
Human intravenous immune globulin (IVIg) is a biological product obtained by pooling polyclonal IgG from thousands of healthy donors. It is approved for the treatment of numerous primary immunodeficiencies.[1] It is widely used in an ‘off-label’ manner to treat a wide range of dermatological, neurological, inflammatory and transplantation-related diseases. The biological actions of IVIg have been attributed both to the polyclonal specificities of the antibodies therein[2] and to immunomodulatory or anti-inflammatory effects driven by their IgG Fc regions.[3,4] In a companion paper, we demonstrate that therapeutic human IgG1 antibodies can suppress angiogenesis in a target-independent manner via FcγRI,[5] a high-affinity receptor for IgG1.6–8 we tested whether IVIg, which is composed of ~ 60% IgG1, possessed similar anti-angiogenic properties
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