Antibodies | N-Glycosylation of Antibodies: Biological Effects During Infections and Therapeutic Applications

This systematic review summarizes the roles of antibody N-glycosylation in infections and therapies, with a focus on its effects on Fc receptor binding, complement activation, and neutralization capacity against viruses/bacteria. The article also discusses how infections and vaccinations influence antibody glycosylation profiles, providing important insights for disease stage diagnosis and optimization of therapeutic monoclonal antibodies.

Literature Overview
This article, 'N-Glycosylation of Antibodies: Biological Effects During Infections and Therapeutic Applications', published in the journal Antibodies, systematically reviews the biological functions of antibody N-glycosylation and its roles during infections and therapeutic applications. The article highlights that N-glycosylation of antibodies affects their effector functions, such as ADCC, complement activation, and cytokine release. Moreover, following different infections (e.g., tuberculosis, dengue, influenza, and SARS-CoV-2) and after vaccination, significant changes occur in the glycosylation profiles of antibodies, which can be used to assess infection stages and vaccine efficacy.

Background Knowledge
Antibodies (immunoglobulins) are key effector molecules of humoral immunity, and their functions are not only dependent on antigen-binding sites but also deeply influenced by N-glycosylation modifications. N-glycosylation at the conserved Asn297 site in the antibody constant region, particularly in IgG, plays a critical role in antibody conformation, stability, and interactions with Fc receptors (FcγR) and complement C1q. Infections and vaccinations dynamically alter antibody glycosylation profiles, such as reduced fucosylation and increased sialylation, which in turn influence inflammatory or immunomodulatory functions. The pharmacokinetics and safety of therapeutic monoclonal antibodies are also closely related to their N-glycan structures. Therefore, understanding the regulatory mechanisms of antibody glycosylation is essential for both infection immunology and monoclonal antibody development.

Research Methods and Experiments
This review systematically analyzed N-glycosylation sites and common glycan types across different antibody isotypes (IgG, IgA, IgM, IgD, IgE) through a comprehensive literature review. Using infection and vaccination models, the study assessed how glycosylation modifications influence Fc receptor binding, complement activation, and neutralization of pathogens. The article also summarized dynamic changes in antibody glycosylation profiles under different disease conditions (e.g., tuberculosis, COVID-19, dengue) and vaccine platforms (e.g., mRNA, adenovirus vector vaccines), and validated their correlations with disease progression and vaccine immunogenicity using clinical data.

Key Conclusions and Perspectives

• N-glycosylation of IgG, especially at the Asn297 site, dynamically changes during infections and after vaccination, which affects its binding to FcγR, thereby modulating ADCC and inflammatory cytokine release.
• In tuberculosis patients, low galactosylation and high fucosylation of IgG are associated with disease activity, while cytokines such as interferon-γ regulate the expression of glycosylation-related enzymes.
• SARS-CoV-2 infection reduces mannose content in IgM but increases sialylation, thereby enhancing its pro-inflammatory effects and activating the complement system.
• Vaccination can induce high sialylation and fucosylation in IgG, affecting its binding to inhibitory receptors such as FcγRIIb, which in turn influences the formation of humoral immune memory.
• The N-glycosylation site of IgA, such as Asn459, plays a dual role in mucosal immunity by either independently blocking pathogen binding or regulating immune responses through FcαRI, contributing to pathogen neutralization.

Conclusion
This article provides a comprehensive summary of the roles of antibody N-glycosylation during infections and in therapeutic applications, highlighting the functional versatility of glycosylation profiles in modulating Fc receptor binding, complement activation, and pathogen neutralization. Changes in antibody glycosylation patterns across multiple infection models correlate with disease severity and vaccine-induced immune responses, suggesting their potential use in disease diagnostics and therapeutic optimization. Looking ahead, combining glycomic analyses with antibody engineering may further improve the functional specificity and safety of therapeutic antibodies, offering new strategies for infection immunology and tumor-targeted therapies.

AbTrimmer

View Tool Details

Antibody drug developability risk assessment and druggability analysis are critical steps in the drug discovery pipeline, aiming to identify promising clinical candidates early in the development process while mitigating potential risks. Building upon previous work (TAP tool), we developed AbTrimmer, a computational tool that evaluates antibody drug development risks based on multiple biophysical parameters, including Patches of Surface Hydrophobicity (PSH), Patches of Surface Positive Charge (PPC), Patches of Surface Negative Charge (PNC), Structural Fv charge symmetry parameter (SFvCSP), and aggregation scores. By precisely quantifying antibody features such as hydrophobicity and charge distribution, and comparing against clinically validated or marketed therapeutic antibodies, AbTrimmer enables comprehensive risk assessment of antibody molecules.