#2-55E. Neonatal Fc Receptor: A Novel Therapeutic Target for IgG-Mediated Autoimmunity (N Engl J Med, 2025)

How are we advancing the treatment of IgG-mediated autoimmune diseases beyond broad immunosuppression? This comprehensive review, "Neonatal Fc Receptor — Biology and Therapeutics," details the pivotal role of the neonatal Fc receptor (FcRn) as the primary molecule responsible for protecting IgG and albumin from catabolism, thereby maintaining their prolonged plasma half-lives, and regulating IgG transport and immune cell functions. A deep understanding of FcRn biology has catalyzed the emergence of a new therapeutic class: FcRn inhibitors, which function by outcompeting endogenous IgG for FcRn binding and promoting the lysosomal degradation of pathogenic IgG. Crucially, clinical trials demonstrate that FcRn blockade leads to significant reductions in autoantibody levels and substantial clinical benefit in conditions like Myasthenia Gravis (MG) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), securing FDA approvals. However, clinicians must note that in diseases like Immune Thrombocytopenic Purpura (ITP), the correlation between IgG reduction and clinical response is less pronounced, suggesting the involvement of non-FcRn-dependent clearance mechanisms, such as T-cell cytotoxicity or classical FcγRs, which may limit the efficacy of this approach. Comprehending the mechanism of action and varying disease responsiveness of FcRn inhibitors is vital for physicians seeking to optimize treatment strategies and select appropriate patients for this innovative alternative to conventional therapies.

Citation: James B. Bussel, Douglas B. Cines, Richard S. Blumberg. Neonatal Fc Receptor — Biology and Therapeutics. New England Journal of Medicine. 2025. DOI: 10.1056/NEJMra2312718

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