Immunoglobulin G Fc Research Articles

Altered Spike Immunoglobulin G Fc N-Linked Glycans Are Associated With Hyperinflammatory State in Adult Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome in Children.

Severe coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome (MIS-C) are characterized by excessive inflammatory cytokines/chemokines. In adults, disease severity is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G (IgG) Fc afucosylation, which induces proinflammatory cytokine secretion from innate immune cells. This study aimed to define spike IgG Fc glycosylation following SARS-CoV-2 infection in adults and children and following SARS-CoV-2 vaccination in adults and the relationships between glycan modifications and cytokines/chemokines. We analyzed longitudinal (n = 146) and cross-sectional (n = 49) serum/plasma samples from adult and pediatric COVID-19 patients, MIS-C patients, adult vaccinees, and adult and pediatric controls. We developed methods for characterizing bulk and spike IgG Fc glycosylation by capillary electrophoresis and measured levels of 10 inflammatory cytokines/chemokines by multiplexed enzyme-linked immunosorbent assay. Spike IgG was more afucosylated than bulk IgG during acute adult COVID-19 and MIS-C. We observed an opposite trend following vaccination, but it was not significant. Spike IgG was more galactosylated and sialylated and less bisected than bulk IgG during adult COVID-19, with similar trends observed during pediatric COVID-19/MIS-C and following SARS-CoV-2 vaccination. Spike IgG glycosylation changed with time following adult COVID-19 or vaccination. Afucosylated spike IgG exhibited inverse and positive correlations with inflammatory markers in MIS-C and following vaccination, respectively; galactosylated and sialylated spike IgG inversely correlated with proinflammatory cytokines in adult COVID-19 and MIS-C; and bisected spike IgG positively correlated with inflammatory cytokines/chemokines in multiple groups. We identified previously undescribed relationships between spike IgG glycan modifications and inflammatory cytokines/chemokines that expand our understanding of IgG glycosylation changes that may impact COVID-19 and MIS-C immunopathology.

Neutrophil Depletion Changes the N-Glycosylation Pattern of IgG in Experimental Murine Sepsis.

Sepsis is a life-threatening condition with a rising disease burden worldwide. It is a multifactorial disease and is defined as a dysregulated host response to infection. Neutrophils have been shown to be involved in the pathogenesis of sepsis by exacerbating inflammation. However, the exact effector mechanism of action still remains a mystery. Changes in the glycosylation pattern of the immunoglobulin G (IgG) Fc region are described for several diseases including meningococcal sepsis. In this study, we investigated the possible contribution of neutrophils and neutrophil implication, potentially related to degranulation or neutrophil extracellular trap (NET) formation in changing the IgG Fc N-glycosylation pattern in a murine sepsis model. We have measured the serum level of cytokines/chemokines and immunoglobulins, the serum activity of neutrophil elastase (NE), and analyzed the IgG Fc glycosylation pattern by Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (LC-ESI-MS) and Lectin enzyme-linked immunosorbent assay (ELISA). We observed an increased activity of NE- and neutrophil-associated cytokines such as keratinocyte chemoattractant (KC) with the development of sepsis. Regarding the IgG Fc N-glycosylation, we observed an increase in fucosylation and α1,3-galactosylation and a decrease for sialyation. Interestingly, these changes were not uniform for all IgG subclasses. After depletion of neutrophils, we saw a change in the exposure of fucose and α2,6-linked sialic acid during the time course of our experimental sepsis model. In conclusion, neutrophils can influence changes in the IgG glycosylation pattern in experimental sepsis.

A Thioether‐Bridging Surface Modification of Polymeric Microspheres Offers Nonbiological Protein A‐Mimetic Affinity for IgG

AbstractSurface modification of polymeric materials to control their interaction with proteins has been studied extensively, leading to widespread bio‐applications. However, the development of nonbiological, smart polymer surfaces, mimicking the recognition ability of biomolecules, remains a challenge. The present study presents a thioether‐bridging surface modification of polymeric microspheres as a new approach for mimicking protein A affinity for immunoglobulin G (IgG). The bridge‐modified surface is created through an epoxide linking reaction of porous polymeric microspheres with potassium thioacetate in a 2:1 molar ratio, acting as a protein A ligand, which is essential for industrial IgG purification. This surface exhibits buffer responsiveness and selective high‐affinity binding to the IgG Fc region. Remarkably, a comparison among the binding behaviors of a series of thioether‐modified microspheres indicates that bridging structures composed of β,β′‐dihydroxysulfide play a predominant role in IgG recognition. This straightforward approach can lead to the development of economical and practical nonbiological alternatives to protein A‐conjugated materials, providing solutions for various applications such as biosensors and site‐specific reagents utilizing the affinity of the IgG Fc region. The improved understanding of protein interactions at bridged/non‐bridged interfaces can be valuable in various applications such as implant materials and biomaterials.

IgG sialylation occurs in B cells pre antibody secretion.

Sialic acids as terminal sugar residues on cell surface or secreted proteins have many functional roles. In particular, the presence or absence of α2,6-linked sialic acid residues at the immunoglobulin G (IgG) Fc fragment can switch IgG effector functions from pro- to anti-inflammatory activity. IgG glycosylation is considered to take place inside the plasma blast/plasma cell while the molecule travels through the endoplasmic reticulum and Golgi apparatus before being secreted. However, more recent studies have suggested that IgG sialylation may occur predominantly post-antibody secretion. To what extent this extracellular IgG sialylation process contributes to overall IgG sialylation remains unclear, however. By generating bone marrow chimeric mice with a B cell-specific deletion of ST6Gal1, the key enzyme required for IgG sialylation, we now show that sialylation of the IgG Fc fragment exclusively occurs within B cells pre-IgG secretion. We further demonstrate that B cells expressing ST6Gal1 have a developmental advantage over B cells lacking ST6Gal1 expression and thus dominate the plasma cell pool and the resulting serum IgG population in mouse models in which both ST6Gal1-sufficient and -deficient B cells are present.

GlYcoLISA: antigen-specific and subclass-specific IgG Fc glycosylation analysis based on an immunosorbent assay with an LC-MS readout.

Immunoglobulin G (IgG) fragment crystallizable (Fc) glycosylation modulates effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Consequently, assessing IgG Fc glycosylation is important for understanding the role of antibodies in infectious, alloimmune and autoimmune diseases. GlYcoLISA determines the Fc glycosylation of antigen-specific IgG by an immunosorbent assay with a liquid chromatography-mass spectrometry (LC-MS) readout. Detection of antigen-specific IgG glycosylation in a subclass- and site-specific manner is realized by LC-MS-based glycopeptide analysis after proteolytic cleavage. GlYcoLISA addresses challenges related to the low abundance of specific IgG and the high background of total IgG by using well-established immunosorbent assays for purifying antibodies of the desired specificity using immobilized antigen. Alternative methods with sufficient glycan resolution lack these important specificities. GlYcoLISA is performed in a 96-well plate format, and the analysis of 160 samples takes ~5 d, with 1 d for sample preparation, 2 d of LC-MS measurement and 2 d for partially automated data processing. GlYcoLISA requires expertise in LC-MS operation and data processing.

Chimerism of avian IgY-scFv and truncated IgG-Fc: A novel strategy in cross-species antibody generation and enhancement.

Chicken single-chain fragment variable (IgY-scFv) is a functional fragment and an emerging development in genetically engineered antibodies with a wide range of biomedical applications. However, scFvs have considerably shorter serum half-life due to the absence of antibody Fc region compared with the full-length antibody, and usually requires continuous intravenous administration for efficacy. A promising approach to overcome this limitation is to fuse scFv with immunoglobulin G (IgG) Fc region, for better recognition and mediation by the neonatal Fc receptor (FcRn) in the host. In this study, engineered mammalian ΔFc domains (CH2, CH3, and intact Fc region) were fused with anti-canine parvovirus-like particles avian IgY-scFv to produce chimeric antibodies and expressed in the HEK293 cell expression system. The obtained scFv-CH2, scFv-CH3, and scFv-Fc can bind with antigen specifically and dose-dependently. Surface plasmon resonance investigation confirmed that scFv-CH2, scFv-CH3, and scFv-Fc had different degrees of binding to FcRn, with scFv-Fc showing the highest affinity. scFv-Fc had a significantly longer half-life in mice compared with the unfused scFv. The identified ΔFcs are promising for the development of engineered Fc-based therapeutic antibodies and proteins with longer half-lives. The avian IgY-scFv-mammalian IgG Fc region opens up new avenues for antibody engineering, and it is a novel strategy to enhance the rapid development and screening of functional antibodies in veterinary and human medicine.

The solution structure of the unbound IgG Fc receptor CD64 resembles its crystal structure: Implications for function.

FcγRI (CD64) is the only high-affinity Fcγ receptor found on monocytes, macrophages, eosinophils, neutrophils and dendritic cells. It binds immunoglobulin G (IgG) antibody-antigen complexes at its Fc region to trigger key immune responses. CD64 contains three immunoglobulin-fold extracellular domains (D1, D2 and D3) and a membrane-spanning region. Despite the importance of CD64, no solution structure for this is known to date. To investigate this, we used analytical ultracentrifugation, small-angle X-ray scattering, and atomistic modelling. Analytical ultracentrifugation revealed that CD64 was monomeric with a sedimentation coefficient s020,w of 2.53 S, together with some dimer. Small-angle X-ray scattering showed that its radius of gyration RG was 3.3-3.4 nm and increased at higher concentrations to indicate low dimerization. Monte Carlo modelling implemented in the SASSIE-web package generated 279,162 physically-realistic trial CD64 structures. From these, the scattering best-fit models at the lowest measured concentrations that minimised dimers revealed that the D1, D2 and D3 domains were structurally similar to those seen in three CD64 crystal structures, but showed previously unreported flexibility between D1, D2 and D3. Despite the limitations of the scattering data, the superimposition of the CD64 solution structures onto crystal structures of the IgG Fc-CD64 complex showed that the CD64 domains do not sterically clash with the IgG Fc region, i.e. the solution structure of CD64 was sufficiently compact to allow IgG to bind to its high-affinity Fcγ receptor. This improved understanding may result in novel approaches to inhibit CD64 function, and opens the way for the solution study of the full-length CD64-IgG complex.

Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates

Immunoglobulin G (IgG) antibodies coordinate immune effector responses by interacting with effector cells via fragment crystallizable γ (Fcγ) receptors. The IgG Fc domain directs effector responses through subclass and glycosylation variation. Although each Fc variant has been extensively characterized in isolation, during immune responses, IgG is almost always produced in Fc mixtures. How this influences effector responses has not been examined. Here, we measure Fcγ receptor binding to mixed Fc immune complexes. Binding of these mixtures falls along a continuum between pure cases and quantitatively matches a mechanistic model, except for several low-affinity interactions mostly involving IgG2. We find that the binding model provides refined estimates of their affinities. Finally, we demonstrate that the model predicts effector cell-elicited platelet depletion in humanized mice. Contrary to previous views, IgG2 exhibits appreciable binding through avidity, though it is insufficient to induce effector responses. Overall, this work demonstrates a quantitative framework for modeling mixed IgG Fc-effector cell regulation.

Synthetic nanobodies as tools to distinguish IgG Fc glycoforms

Protein glycosylation is a crucial mediator of biological functions and is tightly regulated in health and disease. However, interrogating complex protein glycoforms is challenging, as current lectin tools are limited by cross-reactivity while mass spectrometry typically requires biochemical purification and isolation of the target protein. Here, we describe a method to identify and characterize a class of nanobodies that can distinguish glycoforms without reactivity to off-target glycoproteins or glycans. We apply this technology to immunoglobulin G (IgG) Fc glycoforms and define nanobodies that specifically recognize either IgG lacking its core-fucose or IgG bearing terminal sialic acid residues. By adapting these tools to standard biochemical methods, we can clinically stratify dengue virus and SARS-CoV-2 infected individuals based on their IgG glycan profile, selectively disrupt IgG-Fcγ receptor binding both in vitro and in vivo, and interrogate the B cell receptor (BCR) glycan structure on living cells. Ultimately, we provide a strategy for the development of reagents to identify and manipulate IgG Fc glycoforms.

An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodies

The pH-selective interaction between the immunoglobulin G (IgG) fragment crystallizable region (Fc region) and the neonatal Fc receptor (FcRn) is critical for prolonging the circulating half-lives of IgG molecules through intracellular trafficking and recycling. By using directed evolution, we successfully identified Fc mutations that improve the pH-dependent binding of human FcRn and prolong the serum persistence of a model IgG antibody and an Fc-fusion protein. Strikingly, trastuzumab-PFc29 and aflibercept-PFc29, a model therapeutic IgG antibody and an Fc-fusion protein, respectively, when combined with our engineered Fc (Q311R/M428L), both exhibited significantly higher serum half-lives in human FcRn transgenic mice than their counterparts with wild-type Fc. Moreover, in a cynomolgus monkey model, trastuzumab-PFc29 displayed a superior pharmacokinetic profile to that of both trastuzumab-YTE and trastuzumab-LS, which contain the well-validated serum half-life extension Fcs YTE (M252Y/S254T/T256E) and LS (M428L/N434S), respectively. Furthermore, the introduction of two identified mutations of PFc29 (Q311R/M428L) into the model antibodies enhanced both complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity activity, which are triggered by the association between IgG Fc and Fc binding ligands and are critical for clearing cancer cells. In addition, the effector functions could be turned off by combining the two mutations of PFc29 with effector function-silencing mutations, but the antibodies maintained their excellent pH-dependent human FcRn binding profile. We expect our Fc variants to be an excellent tool for enhancing the pharmacokinetic profiles and potencies of various therapeutic antibodies and Fc-fusion proteins.

Distinct Longitudinal Changes in Immunoglobulin G N-Glycosylation Associate with Therapy Response in Chronic Inflammatory Diseases.

Immunosuppressants and biologicals are widely used therapeutics for various chronic inflammatory diseases (CID). To gain more detailed insight into their downstream effects, we examined their impact on serum immunoglobulin G (IgG) glycosylation. We analyzed IgG subclass-specific fragment crystallizable (Fc) N-glycosylation in patients suffering from various CID using the LC-MS approach. Firstly, we compared IgG Fc N-glycosylation between 128 CID patients and 204 healthy controls. Our results replicated previously observed CID-related decrease in IgG Fc galactosylation (adjusted p-value range 1.70 × 10−2–5.95 × 10−22) and sialylation (adjusted p-value range 1.85 × 10−2–1.71 × 10−18). Secondly, to assess changes in IgG Fc N-glycosylation associated with therapy and remission status, we compared 139 CID patients receiving either azathioprine, infliximab, or vedolizumab therapy. We observed an increase in IgG Fc galactosylation (adjusted p-value range 1.98 × 10−2–1.30 × 10−15) and sialylation (adjusted p-value range 3.28 × 10−6–4.34 × 10−18) during the treatment. Furthermore, patients who reached remission displayed increased Fc galactosylation levels (p-value range 2.25 × 10−2–5.44 × 10−3) in comparison to patients with active disease. In conclusion, the alterations in IgG Fc glycosylation and the fact these changes are even more pronounced in patients who achieved remission, suggest modulation of IgG inflammatory potential associated with CID therapy.

IgG subclasses in New World Monkeys: an issue for debate?

Immunoglobulin G (IgG) is an essential antibody in adaptive immunity; a differential expansion of the gene encoding the Fc region (IGHG) of this antibody has been observed in mammals. Like humans, animal biomedical models, such as mice and macaques, have four functional genes encoding 4 IgG subclasses; however, the data for New World monkeys (NWM) seems contentious. Some publications argue for the existence of a single-copy gene for IgG Fc; however, a recent paper has suggested the presence of IgG subclasses in some NWM species. Here, we evaluated the genetic distances and phylogenetic relationships in NWM to assess the presence of IgG subclasses using the sequences of IGHG genes from 13 NWM species recovered from genomic data and lab PCR and cloning-based procedures available in GenBank. The results show that several sequences do not cluster into the expected taxon, probably due to cross-contamination during laboratory procedures, and consequently, they appear to be wrongly assigned. Additionally, several sequences reported as subclasses were shown to be 100% identical in the CH domains. The data presented here suggests that there is not enough evidence to establish the presence of IgG subclasses in NWM.

IgG targeting distinct seasonal coronavirus- conserved SARS-CoV-2 spike subdomains correlates with differential COVID-19 disease outcomes.

Despite SARS-CoV-2 being a “novel” virus, early detection of anti-spike IgG in severe COVID-19 patients may be caused by the amplification of humoral memory responses against seasonal coronaviruses. Here, we examine this phenomenon by characterizing anti-spike IgG responses in non-hospitalized convalescent individuals across a spectrum of COVID-19 severity. We observe that disease severity positively correlates with anti-spike IgG levels, IgG cross-reactivity against other betacoronaviruses (β-CoVs), and FcγR activation. Analysis of IgG targeting β-CoV-conserved and non-conserved immunodominant epitopes within the SARS-CoV-2 spike protein revealed epitope-specific relationships: IgG targeting the conserved heptad repeat (HR) 2 region significantly correlates with milder disease, while targeting the conserved S2′FP region correlates with more severe disease. Furthermore, a lower HR2-to-S2′FP IgG-binding ratio correlates with greater disease severity, with ICU-hospitalized COVID-19 patients showing the lowest HR2/S2′FP ratios. These findings suggest that HR2/S2′FP IgG profiles may predict disease severity and offer insight into protective versus deleterious humoral recall responses.

Evaluation of HSV-2 gE Binding to IgG-Fc and Application for Vaccine Development.

Glycoprotein E (gE) and glycoprotein I (gI) are expressed as a heterodimer on the surface of Herpes simplex virus (HSV). Glycoprotein E binds Fc domain of immunoglobulin G (IgG) and inhibits activities mediated by the IgG Fc domain, contributing to immune evasion by HSV. It has been reported that HSV type 1 gE (gE-1) is capable of binding IgG Fc as a monomer and in a heterodimeric complex with gI, with the heterodimer having 50- to100-fold greater affinity for Fc than gE alone. We report the production of both a soluble form of HSV type 2 gE (gE-2) and a soluble HSV-2 gE/gI heterodimer (gE-2/gI-2). Characterization of soluble gE-2 by surface plasmon resonance (SPR) demonstrates that it is incapable of binding human IgG or the IgG Fc domain. Co-expression with HSV-2 gI (gI-2) and purification of the gE-2/gI-2 heterodimer enable gE-2 to bind human IgG through its Fc domain. We hypothesize that functional epitopes of wildtype gE-2 may be masked by plasma IgG Fc and affect the immunogenicity of the gE-2/gI-2 heterodimer as a vaccine antigen. A series of gE-2 mutations within the surface-exposed Fc:gE-2 interface was designed, and gE-2 mutants were co-expressed with gI-2. Evaluation of twelve gE-2 mutant heterodimers by SPR assay identified nine gE-2 mutations which abrogated or reduced Fc binding while maintaining heterodimer formation with gI. Vaccinating rabbits with the four most Fc-binding deficient gE-2/gI-2 heterodimers elicited comparable anti-heterodimer binding antibody titers and statistically significantly higher serum neutralization antibody levels than wildtype heterodimers. Taken together, these data support the concept of rational antigen design for improved vaccine candidates.

Baseline IgG-Fc N-glycosylation profile is associated with long-term outcome in a cohort of early inflammatory arthritis patients

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease for which prediction of long-term prognosis from disease’s outset is not clinically feasible. The importance of immunoglobulin G (IgG) and its Fc N-glycosylation in inflammation is well-known and studies described its relevance for several autoimmune diseases, including RA. Herein we assessed the association between IgG N-glycoforms and disease prognosis at 2 years in an early inflammatory arthritis cohort.MethodsSera from 118 patients with early inflammatory arthritis naïve to treatment sampled at baseline were used to obtain IgG Fc glycopeptides, which were then analyzed in a subclass-specific manner by liquid chromatography coupled to mass spectrometry (LC-MS). Patients were prospectively followed and a favorable prognosis at 2 years was assessed by a combined index as remission or low disease activity (DAS28 < 3.2) and normal functionality (HAQ ≤ 0.25) while on treatment with conventional synthetic DMARDs and never used biologic DMARDs.ResultsWe observed a significant association between high levels of IgG2/3 Fc galactosylation (effect 0.627 and adjusted p value 0.036 for the fully galactosylated glycoform H5N4F1; effect −0.551 and adjusted p value 0.04963 for the agalactosylated H3N4F1) and favorable outcome after 2 years of treatment. The inclusion of IgG glycoprofiling in a multivariate analysis to predict the outcome (with HAQ, DAS28, RF, and ACPA included in the model) did not improve the prognostic performance of the model.ConclusionPending confirmation of these findings in larger cohorts, IgG glycosylation levels could be used as a prognostic marker in early arthritis, to overcome the limitations of the current prognostic tools.

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes

Glucose-responsive oral insulin delivery platform for one treatment a day in diabetes

High-throughput rat immunoglobulin G N-glycosylation profiling revealed subclass-specific changes associated with chronic stress

Immunoglobulin G (IgG) glycosylation corresponds well with immune system changes, so it can potentially be used as a biomarker for the consequences of chronic stress such as low-grade inflammation and enhanced immunosenescence in older animals. Here we present a high-throughput glycoproteomic workflow, including IgG enrichment, HILIC glycopeptide purification, and nano-LC-MS analysis of tryptic glycopeptides applied for the analysis of rat IgG. A cohort of 80 animals was exposed to seven stressors in a customized chronic stress protocol with blood and tissue sampling in three timepoints. Young female rats experienced an increase in agalactosylated glycoforms on IgG2a and IgG2c accompanied by a decrease in monogalactosylation. Among old females, increased galactosylation was observed in the IgG2b subclass, pointing to an anti-inflammatory activity of IgG. Additionally, IgG Fc N-glycosylation patterns in Sprague Dawley rats were analyzed, quantified, and reported for the first time. Our findings emphasize age-, sex- and subclass-dependent differences in IgG glycosylation related to chronic stress exposure, confirming the relevance of newly developed methods for further research in glycobiology of rodent immune response. SignificanceIn this study, we showed that a high-throughput streamlined methodology based on protein L 96-well monolithic plates for efficient rat IgG immunoaffinity enrichment from blood plasma, paired with appropriate tryptic glycopeptide preparation, HILIC-SPE enrichment, and nano-LC-MS methods was suitable for quick processing of large sample sets. We report a subclass-specific profiling and changes in rat IgG Fc galactosylation and adrenal gland immunohistochemistry of male and female animals exposed to a customized chronic stress protocol.

Serum and Plasma Immunoglobulin G Fc N-Glycosylation Is Stable during Storage.

Immunoglobulin G (IgG) glycosylation is studied in biological samples to develop clinical markers for precision medicine, for example, in autoimmune diseases and oncology. Inappropriate storage of proteins, lipids, or metabolites can lead to degradation or modification of biomolecular features, which can have a strong negative impact on accuracy and precision of clinical omics studies. Regarding the preservation of IgG glycosylation, the range of appropriate storage conditions and time frame is understudied. Therefore, we investigated the effect of storage on IgG Fc N-glycosylation in the commonly analyzed biofluids, serum and plasma. Short-term storage and accelerated storage stability were tested by incubating samples from three healthy donors under stress conditions of up to 50 °C for 2 weeks using −80 °C for 2 weeks as the reference condition. All tested IgG glycosylation features—sialylation, galactosylation, bisection, and fucosylation—remained unchanged up to room temperature as well as during multiple freeze–thaw cycles and exposure to light. Only when subjected to 37 °C or 50 °C for 2 weeks, galactosylation and sialylation subtly changed. Therefore, clinical IgG glycosylation analysis does not rely as heavily on mild serum and plasma storage conditions and timely analysis as many other omics analyses.

Targeting the neonatal Fc receptor (FcRn) to treat autoimmune diseases and maternal-fetal immune cytopenias.

FcRn, a non-classical Fc gamma (γ) receptor (FcγR) with near ubiquitous expression, plays key roles in disease pathogenesis and progression though immunoglobulin G (IgG) transport, IgG recycling, and IgG-immune complex clearance. FcRn function can be inhibited using IgG-based and non-IgG-based antagonists, by exploiting the pH-dependent binding affinity of FcRn for the IgG Fc region. FcRn therapeutics have shown promise in murine models and human clinical trials for autoimmune diseases and maternal-fetal immune cytopenias; they appear safe, well-tolerated, and reduce circulating IgG levels. Compared to traditional therapeutics, inhibiting FcRn has fewer adverse side effects and represents a new approach that is less invasive, time-consuming, and costly.

Broad-Spectrum Anti-coronavirus Vaccines and Therapeutics to Combat the Current COVID-19 Pandemic and Future Coronavirus Disease Outbreaks.

While the COVID-19 pandemic caused by SARS-CoV-2 is continuing, it may become worse in the coming winter months with a high potential for the emergence and spread of escape variants of SARS-CoV-2. SARS-related CoVs (SARSr-CoVs) from bats may also cause outbreaks of emerging coronavirus diseases in the future. These predictions call for the development of broad-spectrum anti-coronavirus vaccines and therapeutics to combat the current COVID-19 pandemic and future emerging coronavirus disease epidemics. In this review, we describe advances and challenges in the development of broad-spectrum vaccines and neutralizing antibodies against lineage B betacoronaviruses (β-CoV-Bs), including SARS-CoV-2, SARS-CoV, and SARSr-CoVs, as well as peptide-based pan-CoV fusion inhibitors and their potential in the prevention and treatment of COVID-19 and other human coronavirus infections.