Introduction
 

The neonatal Fc receptor (FcRn) is a heterodimeric protein encoded by the FCGRTgene, consisting of a heavy chain and a light chain (β₂-microglobulin) associated non-covalently. Its heavy chain, structurally similar to MHC class I molecules, comprises a cytoplasmic tail, a transmembrane domain, and three extracellular functional segments (α₁, α₂, α₃). Together with the light chain, these segments form the ligand-binding site for FcRn. FcRn is widely expressed in the body, found in various cell types (e.g., epithelial cells), secondary lymphoid organs (e.g., spleen), and tissues like the placenta.
 

Functions of the FcRn Target
 

1.Mediation of Antibody Recycling:​ Within vascular endothelial cells, the binding of FcRn to IgG is strictly pH-dependent: it binds with high affinity in the acidic endosomal environment (pH 5.0-6.5) and rapidly dissociates in the neutral/alkaline extracellular environment. Through the cycle of "endocytosis-binding-recycling-release," FcRn prevents IgG from being degraded by lysosomes and recycles it back into the bloodstream, thereby significantly prolonging the half-life of IgG.
 

2.Mediation of IgG Transcytosis:​ FcRn is the key protein mediating the transport of IgG across biological barriers. In the placental syncytiotrophoblast, it transports maternal IgG from the maternal to the fetal side via pH-dependent binding and transcytosis, providing passive immunity to the fetus. Similarly, in endothelial/epithelial cells of the respiratory tract, intestines, and the blood-brain barrier, FcRn also mediates transcellular transport, regulating the distribution of antibodies between tissues.
 

3.Enhancement of Antigen Presentation:​ FcRn can utilize its intracellular transport pathway to target internalized IgG-antigen immune complexes (especially large molecular complexes) to processing compartments like lysosomes. Here, antigens are degraded into peptides and loaded onto MHC class II or MHC class I molecules, thereby enhancing cross-presentation of antigens and activating CD4⁺ or CD8⁺ T cell responses, playing a regulatory role in specific inflammatory or immune responses.

 

Applications of FcRn in Disease Pathogenesis and as a Therapeutic Target
 

Autoimmune Diseases:​ Anti-FcRn therapies treat various IgG-mediated autoimmune diseases by blocking FcRn-mediated IgG recycling, thereby accelerating the clearance of pathogenic IgG. To better understand FcRn's pathological role, take myasthenia gravis (MG) as an example. During the pathogenesis of MG, FcRn acts as a key pathological amplifier. As a receptor mediating IgG recycling, FcRn typically protects antibodies from degradation via a pH-dependent mechanism in cells like vascular endothelial cells, significantly extending their half-life. However, pathogenic autoantibodies (e.g., anti-acetylcholine receptor antibodies) produced in MG patients are also indiscriminately recycled and protected by FcRn. This leads to the persistent presence and high titers of autoantibodies in the circulation, resulting in continuous immune attacks on the neuromuscular junction (NMJ), ultimately causing a significant reduction in postsynaptic acetylcholine receptors and structural damage to the synapse, manifesting as the clinical symptoms of myasthenia.
 

Image source: Efgartigimod for Generalized Myasthenia Gravis and Beyond: A Narrative Review of Its Pharmacological Profile, Clinical Utility, and Expanding Applications
 

Main drugs are divided into two categories:
 

·Engineered Fc Fragments:​ For example, Efgartigimod, which is mutated to enhance affinity for FcRn, can significantly and persistently reduce patients' total IgG levels. It has been approved for diseases like MG.
 

·Anti-FcRn Monoclonal Antibodies:​ Such as Nipocalimab and Rozanolixizumab, which bind with high affinity and block FcRn function, showing good efficacy and tolerability in clinical trials for conditions like MG and hemolytic disease of the fetus and newborn.
 

Infectious Diseases:​ Leveraging FcRn's role in mediating IgG transcytosis across mucosal barriers, intranasal vaccines can be designed by fusing viral antigens with the Fc fragment of IgG to induce effective local immune responses in mucosal areas like the respiratory and intestinal tracts, offering a new strategy for mucosal vaccine design. Genetic engineering of the Fc fragment of antiviral neutralizing antibodies (e.g., against HIV, RSV, SARS-CoV-2) to enhance their affinity for FcRn can significantly extend the serum half-life of the antibodies, enhancing efficacy and reducing dosing frequency.
 

Cancer:​ The role of FcRn in cancer is complex, and the relationship between its expression levels and patient prognosis varies by cancer type, suggesting tissue specificity. In tumors with low FcRn expression, the FcRn-mediated albumin recycling pathway can be exploited. Conjugating anticancer drugs to albumin promotes targeted accumulation and retention of the drug at the tumor site (e.g., albumin-bound paclitaxel).
 

Mouse Models
 

FcRn Humanized Mice:​ The mouse's own Fcgrgene is replaced with the human FCGRTgene, enabling the expression of the human FcRn protein. This model is used for accurately predicting the half-life and efficacy of therapeutic antibodies in humans.
 

Fcgrt-KO Mice:​ The Fcgrgene is knocked out in mice, resulting in a complete absence of FcRn protein expression. This model is used for studying the core functions of FcRn, as IgG and albumin lose their protective mechanism, leading to drastically shortened half-lives and significantly reduced plasma concentrations.
 

Fcgrt CKO Mice:​ FcRn is conditionally knocked out in specific tissues or cell types. This model is primarily used to investigate FcRn's transport functions in specific organs (e.g., kidneys, intestines, or placenta) and to evaluate the impact of tissue-specific FcRn deficiency on IgG and albumin metabolism.
 

Supporting Mechanism Research and Drug Development
 

Gene therapy offers hope for common diseases, but its development and validation rely heavily on animal model support. MingCeler Biotech, leveraging its self-developed TurboMice™ technology, has developed multiple disease mouse models. The TurboMice™ technology overcomes the technical challenges of long mouse model generation cycles and low success rates for complex models, enabling editing at almost any target gene locus. Complete homozygous gene-edited mouse models can be prepared directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech​ can customize various FcRn-related mouse models according to client needs, such as FcRn humanized mice, FCGRTKO mice, and FCGRTCKO mice. Inquiries are welcome.
 

References:
 

1.Hu M, Wei S, Zhou W, Wang P. Research progress on neonatal Fc receptor and its application. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Aug 25;50(4):537-544. 10.3724/zdxbyxb-2021-0252. PMID: 34704415; PMCID: PMC8714478.

2.Wyckoff SL, Hudson KE. Targeting the neonatal Fc receptor (FcRn) to treat autoimmune diseases and maternal-fetal immune cytopenias. Transfusion. 2021 May;61(5):1350-1354. doi: 10.1111/trf.16341. Epub 2021 Mar 2. PMID: 33650699; PMCID: PMC8186400.

3.Mansour, G.K.; Alangari, L.; Khosyfan, L.; Alhammad, R.; Hajjar, A.W. Efgartigimod for Generalized Myasthenia Gravis and Beyond: A Narrative Review of Its Pharmacological Profile, Clinical Utility, and Expanding Applications. Biomedicines 2025, 13, 2975. https://doi.org/10.3390/biomedicines13122975.