Targeting FcRn: A New Frontier in Precision Therapy for IgG-Mediated Autoimmune Disorders

 

 

Autoimmune diseases affect millions of people worldwide and arise when the immune system mistakenly attacks the body's own tissues. In many of these disorders, pathogenic Immunoglobulin G (IgG) autoantibodies drive chronic inflammation and tissue damage. Conditions such as Myasthenia gravis, Immune thrombocytopenia (ITP), Pemphigus, and Chronic inflammatory demyelinating polyneuropathy (CIDP) are classic examples of IgG-mediated autoimmune diseases.

The neonatal Fc receptor (FcRn) is expressed in several tissues such as vascular endothelial cells, liver, kidneys and immune cells. FcRn was first identified as a mediator of transplacental transport of maternal antibodies to the foetus, but is now recognised as an important regulator of IgG homeostasis. FcRn protects IgG antibodies from intracellular degradation by a highly efficient recycling mechanism. After uptake of IgG molecules by cells they are transported into acidic endosomes where protonation of histidine residues in the Fc region leads to a high affinity binding to FcRn. The bound antibodies are recycled to the cell surface and released into the bloodstream at neutral pH rather than being degraded in lysosomes.

Fig 1. Mechanism of action of FcRn inhibitors. (Zhu et al., 2025)

This recycling pathway, which is pH dependent, extends the half-life of IgG antibodies to ~21 days. While important to maintaining protective immunity, it also prolongs the survival of pathogenic autoantibodies involved in autoimmune disease.

FcRn inhibitors are engineered monoclonal antibodies or modified Fc fragments that block the interaction between FcRn and IgG. They block IgG recycling, leading to degradation of antibodies in lysosomes, which quickly reduces circulating IgG levels including pathogenic autoantibodies. This in turn reduces antibody-mediated tissue damage and clinical improvement is observed. Unlike traditional immunosuppressants, FcRn inhibitors specifically block the FcRn–IgG pathway, maintaining much of the immune system’s normal function.

FcRn inhibitor clinical development has moved forward rapidly. The first FcRn inhibitor approved for generalised myasthenia gravis (gMG) was Efgartigimod, an engineered IgG1 Fc fragment. Another therapy approved for myasthenia gravis, Rozanolixizumab, a humanised anti-FcRn monoclonal antibody, has demonstrated significant clinical benefit in generalised Myasthenia gravis. A wide range of other options, such as ALXN1830, Nipocalimab, and Batoclimab, are presently being evaluated clinically. Numerous IgG-mediated conditions, such as Neuromyelitis optica spectrum illness, Rheumatoid arthritis, Thyroid eye disease, Sjögren's syndrome, and Haemolytic disease of the foetus and infant, are being studied for these treatments.

Compared to conventional treatments, FcRn inhibitors provide a number of benefits. They have a quicker onset of effect than many B-cell-targeted treatments, accomplish sustained IgG reduction without the need for repeated plasma exchange procedures, and specifically lower pathogenic IgG antibodies without generally impairing immune cell function. By successfully lowering all IgG subclasses, they may also provide benefits in IgG4-mediated disorders. With continuous efforts to refine dosing regimens and assess long-term safety, FcRn inhibitors are being investigated in an increasing variety of autoimmune diseases.

REFERENCE:

Zhu, Lina, Lanjun Li, and Jun Wu. "FcRn inhibitors: Transformative advances and significant impacts on IgG-mediated autoimmune diseases." Autoimmunity Reviews 24.3 (2025): 103719.

Patel, Dhavalkumar D., and James B. Bussel. "Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention." Journal of Allergy and Clinical Immunology 146.3 (2020): 467-478. 

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