Recapitulation of IVIG Anti-Inflammatory Activity with a Recombinant IgG Fc

TLDR

High‑dose IVIG from pooled plasma is known to exert anti‑inflammatory effects, but the precise mechanism remains unclear because of IVIG heterogeneity, although recent work shows that sialylation of the IgG Fc N‑linked glycan is essential for activity. The study aims to define the glycan requirements for anti‑inflammatory activity and engineer a recombinant, sialylated IgG1 Fc with superior potency. The authors mapped the glycan determinants of Fc sialylation and used this knowledge to design a recombinant IgG1 Fc fragment that is fully sialylated and highly potent. The resulting recombinant Fc precisely identifies the active component of IVIG and provides a template for developing a more potent, readily available IVIG substitute.

Abstract

It is well established that high doses of monomeric immunoglobulin G (IgG) purified from pooled human plasma [intravenous immunoglobulin (IVIG)] confer anti-inflammatory activity in a variety of autoimmune settings. However, exactly how those effects are mediated is not clear because of the heterogeneity of IVIG. Recent studies have demonstrated that the anti-inflammatory activity of IgG is completely dependent on sialylation of the N-linked glycan of the IgG Fc fragment. Here we determine the precise glycan requirements for this anti-inflammatory activity, allowing us to engineer an appropriate IgG1 Fc fragment, and thus generate a fully recombinant, sialylated IgG1 Fc with greatly enhanced potency. This therapeutic molecule precisely defines the biologically active component of IVIG and helps guide development of an IVIG replacement with improved activity and availability.