2025-12-17 ロックフェラー大学
<関連情報>
- https://www.rockefeller.edu/news/38546-new-engineered-derivative-of-a-natural-molecule-could-translate-into-a-powerful-replacement-for-ivig-therapy-for-a-wide-array-of-autoimmune-disorders/
- https://www.science.org/doi/10.1126/science.adv2927
IgGの抗炎症活性は、I型およびII型Fc受容体の共結合によって増強される The anti-inflammatory activity of IgG is enhanced by co-engagement of type I and II Fc receptors
Andrew T. Jones, Alessandra E. Marino, Tetyana Martynyuk, Stylianos Bournazos, and Jeffrey V. Ravetch
Science Published:6 Nov 2025
DOI:https://doi.org/10.1126/science.adv2927
Editor’s summary
Autoimmune diseases can be treated by intravenous immunoglobulin (IVIG), a therapeutic that requires substantial quantities of antibodies to be collected from large numbers of healthy human donors. Based on one proposed mechanism of action for IVIG, Jones et al. produced an antibody tail fragment known as the Fc region and modified it so that it inhibited pathology in mouse modals of autoimmunity with a lower dose than IVIG. This engineered Fc protein was modified by sialylation and contained mutations that increased its interaction with a type I receptor known as FcγRIIB. The interaction between FcγRIIB and another receptor, DC-SIGN, promoted the binding of isolated Fc fragments and antibodies to cells. —Sarah H. Ross
Structured Abstract
INTRODUCTION
Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for a wide variety of inflammatory disorders and autoimmune diseases. The antibodies used for this therapy are prepared by pooling immunoglobulin G (IgG) collected from thousands of human donors. However, the high dose requirements (1 to 2 g/kg), difficulty in administration, high cost, and availability issues have prompted the need to develop a readily available replacement product that is effective at substantially lower doses than IVIG. One pathway implicated in the anti-inflammatory activity of IVIG is dependent on sialylation of the N-linked glycan located in the Fc domain of IgG1, the inhibitory type I IgG Fc receptor (FcγR) FcγRIIB, and the type II Fc receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). In this study, we determined the in vivo anti-inflammatory activity of sialylated IgG1 Fc (sFc) engineered to have enhanced affinity for FcγRIIB, and further characterized the interactions between type I and II Fc receptors.
RATIONALE
Most studies characterizing IVIG in vivo are conducted in murine models expressing endogenous murine FcγRs, which are distinct in function, expression patterns, and affinities for human IgG compared with their human FcγRs. To address this, we characterized the anti-inflammatory activity of IVIG and sFc in FcγR humanized (hFcγR) mice, which recapitulated the expression and function of human FcγRs on the murine background. Furthermore, because FcγRIIB is required to mediate the anti-inflammatory activity of IVIG and sFc, we hypothesized that engineering sFc through mutagenesis to increase its affinity for FcγRIIB would result in a product with substantially enhanced potency compared with IVIG in treating autoimmune diseases.
RESULTS
Using a serum transfer model of arthritis, we demonstrated that both IVIG and wild-type (WT) IgG1 sFc mediated anti-inflammatory activity in hFcγR mice, and this activity was dependent on Fc-sialylation, type I FcγR engagement, and the type II Fc receptor SIGN-R1 (the mouse homolog of DC-SIGN). To determine whether targeting the inhibitory FcγRIIB pathway enhanced the anti-inflammatory activity of sFc, we generated a sialylated version of the V11 Fc variant (V11 sFc), which has a 37-fold enhanced affinity for FcγRIIB compared with WT sFc. Treating mice prophylactically with V11 sFc mediated potent anti-inflammatory activity at a 100 times lower dose (10 mg/kg) compared with IVIG (1 g/kg). Furthermore, a 10 mg/kg dose of V11 sFc was also effective in reducing inflammation in a mouse model of neurological autoimmunity. In addition, we found that the type II FcγR DC-SIGN directly interacted with glycans on FcγRIIB and other type I FcγRs, augmenting the expression and binding capacity of type I FcγRs for sialylated IgG.
CONCLUSION
We propose that type II FcγRs directly interact with type I FcγRs, such as the inhibitory FcγRIIB, to augment their binding to IgG, and that this interaction is critical for mediating the anti-inflammatory activity of IVIG or sialylated IgG. Engineered sialylated IgG with enhanced affinity to FcγRIIB had potent in vivo activity, was effective at substantially lower doses than conventional IVIG therapy, and may serve as the basis for a class of potent anti-inflammatory therapeutics.
Enhancing the anti-inflammatory activity of sialylated IgG.
(A) Intravenous immunoglobulin (IVIG) mediates anti-inflammatory activity at 1 g/kg doses. Fc-engineered sialylated IgG with enhanced affinity for the ITIM-signaling FcγRIIB (V11 sFc) is effective at 10 mg/kg doses, 100 times lower than that of IVIG. (B) The type II FcγR DC-SIGN directly interacts with glycans on FcγRIIB, augmenting its binding and signaling of sialylated IgG. [Figure created using BioRender.com]
Abstract
Intravenous immunoglobulin (IVIG) administered at high doses is used to treat a wide array of autoimmune diseases. Studies in murine models have identified that the anti-inflammatory activity of IVIG is dependent on sialylation of the N-linked glycan on the CH2 domain of immunoglobulin G (IgG), the type I IgG inhibitory Fc receptor FcγRIIB, and the type II Fc receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). We hypothesized that DC-SIGN, a C-type lectin, may directly interact with glycans on FcγRIIB, augmenting its ability to bind sialylated IgG. We found that Fc-engineering sialylated IgG1 to enhance its affinity for FcγRIIB resulted in a molecule that was more potent than IVIG in reducing the inflammatory sequelae of antibody or T cell–mediated autoimmune diseases, providing the basis for a class of potent anti-inflammatory therapeutics.
