FcRn augments induction of tissue factor activity by IgG-containing immune complexes.

Thromboembolism complicates disorders caused by immunoglobulin G (IgG)-containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization, and propagation of coagulation by ICs, is mediated through Fcγ receptor IIa (FcγRIIa); however, the involvement of other receptors has not been investigated in detail. The neonatal Fc receptor (FcRn) that mediates IgG and albumin recycling also participates in cellular responses to IgG-containing ICs. Here we asked whether FcRn is also involved in the induction of TF-dependent factor Xa (FXa) activity by IgG-containing ICs by THP-1 monocytic cells and human monocytes. Induction of FXa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), ß-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(α)-Rh(D) antibodies that mediate hemolysis in vivo was inhibited by a humanized monoclonal antibody (mAb) that blocks IgG binding to human FcRn. IgG-containing ICs that bind to FcγR and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an α-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human FcγRIIa was expressed as a transgene. These data implicate FcRn in TF-dependent FXa activity induced by soluble and cell-associated IgG-containing ICs. Antibodies to FcRn, now in clinical trials in warm autoimmune hemolytic anemia to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism.

Safety, Tolerability, and Activity of ALXN1830 Targeting the Neonatal Fc Receptor in Chronic Pemphigus.

Pemphigus is a debilitating IgG-mediated autoimmune disease requiring better tolerated, more targeted, and rapid onset therapies. ALXN1830 is a humanized IgG4 antibody that blocks neonatal Fc receptor interactions with IgG. A multicenter, open-label safety and tolerability phase 1b/2 trial (NCT03075904) was conducted in North America from July 2017 to January 2019 and included patients aged ≥18 years with a confirmed diagnosis of pemphigus (vulgaris or foliaceus) and active disease. Dosing included five weekly intravenous doses of ALXN1830 (10 mg/kg) and follow-up through day 112 (study termination). Pharmacokinetics, pharmacodynamics, safety, and efficacy, as evaluated by determining the change in the median pemphigus disease area index, were determined. In this pilot study of eight patients, five weekly infusions of ALXN1830 produced a rapid improvement in the pemphigus disease area index score within 14 days of the first dose. Pemphigus disease area index improvement increased further together with reductions in IgG, circulating immune complexes of IgG, and anti-desmoglein antibodies without affecting albumin, IgM, IgA, or C-reactive protein levels. ALXN1830 was well-tolerated, with headache as the most common adverse event. This study reveals the importance of neonatal Fc receptor in the biology of pemphigus and the potential for use of ALXN1830 in pemphigus treatment.