Targeting the neonatal Fc receptor (FcRn) to treat autoimmune diseases and maternal-fetal immune cytopenias

Abstract

FcRn, a non-classical Fc gamma (γ) receptor (FcγR) with near ubiquitous expression, plays key roles in disease pathogenesis and progression though immunoglobulin G (IgG) transport, IgG recycling, and IgG-immune complex clearance. FcRn function can be inhibited using IgG-based and non-IgG-based antagonists, by exploiting the pH-dependent binding affinity of FcRn for the IgG Fc region. FcRn therapeutics have shown promise in murine models and human clinical trials for autoimmune diseases and maternal-fetal immune cytopenias; they appear safe, well-tolerated, and reduce circulating IgG levels. Compared to traditional therapeutics, inhibiting FcRn has fewer adverse side effects and represents a new approach that is less invasive, time-consuming, and costly.

Keywords: AIHA/drug-induced IHA; HDN; immune thrombocytopenia.

Figure

Inhibiting FcRn can prevent IgG transfer and recycling. FcRn binds the IgG Fc region with high affinity at acidic pH and with low affinity at physiological pH. After IgG internalization, endosomal FcRn binds IgG during acidification, preventing IgG sorting into lysosomes and subsequent degradation. (A) Following IgG internalization at the maternal, apical surface of syncytiotrophoblasts, endosomal acidification, and vesicular transport to the basolateral surface, membrane fusion occurs, and maternal IgG is released into the fetal circulation. (B) Following IgG internalization and endosomal acidification in endothelial cells, IgG is recycled into the circulation after vesicular fusion with the plasma membrane. Inhibiting FcRn function can be achieved with IgG-based and nonIgG-based antagonists, which exploit the pH-dependence of the IgG Fc region binding to FcRn. For example, IgG monoclonal antibody antagonists strongly bind FcRn at acid pH and disrupt IgG-FcRn immune complexes. Of note, it appears these antagonists may have minimal transfer across the placenta or limited recycling capabilities due to their high-affinity FcRn binding at both intracellular and extracellular pH, which prevents release from FcRn. (C) In syncytiotrophoblasts, FcRn antagonists displace bound circulating IgG, and newly liberated IgG is rapidly cleared. (D) A similar process prevents IgG recycling in endothelial cells. Image created with BioRender.com