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Review
. 2021 Mar 17;22(6):3048.
doi: 10.3390/ijms22063048.

In Translation: FcRn across the Therapeutic Spectrum

Timothy Qi  1 , Yanguang Cao  1
Affiliations
Review

In Translation: FcRn across the Therapeutic Spectrum

Timothy Qi et al. Int J Mol Sci. .

Abstract

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.

Keywords: Fc-fusion protein; immune complex; immunoglobulin G; monoclonal antibody; neonatal Fc receptor; pharmacokinetics; physiologically-based pharmacokinetic modeling.

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Conflict of interest statement

T.Q. owns equity in Humanigen, a clinical-stage biopharmaceutical company.

Figures

Figure 1
Figure 1
Simplified representation of intracellular IgG salvage by FcRn. (1) Uptake of IgG and other circulating factors by macropinocytosis. (2) Acidification of the early endocytic vesicle and delivery to the sorting endosome. (3) Titration of His residues in the IgG Fc region enables saturable binding to FcRn in a 1:2 complex. Other FcRn substrates, such as albumin, are not depicted for simplicity. (4) Recycling endosomes return FcRn-IgG complexes to the cell surface(s), where a shift toward a more neutral pH reduces binding affinity. IgG is then released. (5) FcRn is rapidly retrieved from the plasma membrane, resulting in a low surface-resident pool. (6) IgG molecules not salvaged by FcRn remain soluble and are delivered by late endosomes (not shown) to lysosomes, where they are degraded.
Figure 2
Figure 2
FcRn-mediated effects on IgG disposition across the human body. Generally, endothelial cells mediate recycling, whereas epithelial and parenchymal cells mediate transcytosis. (1) In the eye, epithelial and endothelial cells recycle and transcytose intravitreally administered IgG. (2) Endothelial cells of the blood-brain barrier and blood-cerebrospinal barrier (not depicted) purportedly recycle IgG and mediate its efflux from the brain parenchyma. (3) FcRn in the liver protects IgG from excretion into the bile and is central to albumin synthesis and excretion (not depicted). (4) FcRn mediates absorption of IgG and Fc-bearing therapeutics in the lower and upper respiratory tracts. (5) Bidirectional IgG transcytosis potentiates antimicrobial immunity in the intestinal lumen and immune priming in the lamina propria. (6) The glomerular basement membrane is protected from IgG accumulation by FcRn-mediated recycling as well as transcytosis into the urine. Proximal tubule epithelial cells later reabsorb IgG via FcRn-mediated transcytosis (not depicted). (7) FcRn mediates bidirectional transcytosis of IgG in the uterine and vaginal epithelium, contributing to in situ pathogen neutralization and immunity. (8) Placental FcRn is expressed in the syncytiotrophoblast, where it facilitates the transfer of IgG from mother to child. Transferred IgG is then maintained by placental-fetal endothelial cells via FcRn-mediated recycling. (9) A bespoke trafficking role for FcRn in the skin has not been characterized. However, FcRn expression in keratinocytes can lead to pemphigus vulgaris by promoting the endocytosis of autoreactive IgG. (10) The majority of FcRn-mediated recycling is attributable to endothelial and bone-marrow derived cells, especially those of monocytic origins.
Figure 3
Figure 3
FcRn roles in effector function, antigen presentation, and maturation of immune cells. (1) FcRn is critical to phagocytosis. Studies in neutrophils and macrophages suggest opsonized Ag cross-links FcγR on the cell surface, leading to endocytosis and tripartite binding with FcRn. (2) Antigen-presenting cells process and present Ag to potentiate adaptive immune responses. Multimeric immune complexes are endocytosed via FcγR cross-linking and relayed to FcRn upon endosome acidification. FcRn directs the multimers toward lysosomes, where they are degraded. Ags, however, are transferred to MHC class II molecules and presented on the cell surface. Some subpopulations capable of cross-presentation on MHC class I molecules also use FcRn to protect Ag from phagosomal degradation (not depicted). (3) FcRn-mediated transcytosis of immune complexes in the gut and placenta portends generation of immunosuppressive Treg populations. (4) FcRn deficiency impairs NK maturation through unknown mechanisms, suggesting a role in antitumor immunity.
Figure 4
Figure 4
Antigen clearance by recycling and sweeping antibodies. (1) Recycling antibodies enter the cell through nonspecific pinocytosis. By design, recycling antibodies possess pH-dependent antigen affinity. Upon endosome acidification, antigen is released and subsequently degraded in lysosomes, whereas recycling antibodies are rescued by FcRn. The recycling antibody is then exocytosed and free to repeatedly engage additional antigen targets. (2) Sweeping antibodies contain pH-agnostic Fc domains and can bind FcRn at physiologic pH, triggering receptor-mediated endocytosis. Like recycling antibodies, sweeping antibodies possess pH-dependent antigen affinity and follow the same intracellular trafficking patterns. However, sweeping antibodies do not unbind FcRn upon exocytosis, instead lingering at the cell surface. They are subsequently capable of triggering their own endocytosis upon engagement of additional antigen targets.
Figure 5
Figure 5
Administration of exogenous IgG saturates FcRn and enhances clearance of endogenous IgG. Competition for FcRn binding reduces the proportion of endogenous IgG protected from intracellular degradation. In autoimmune settings, this may enhance the clearance of pathogenic IgG.
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