Potent TRIM21 and complement-dependent intracellular antiviral immunity requires the IgG3 hinge

Abstract

Humans have four IgG antibody subclasses that selectively or differentially engage immune effector molecules to protect against infections. Although IgG1 has been studied in detail and is the subclass of most approved antibody therapeutics, increasing evidence indicates that IgG3 is associated with enhanced protection against pathogens. Here, we report that IgG3 has superior capacity to mediate intracellular antiviral immunity compared with the other subclasses due to its uniquely extended and flexible hinge region, which facilitates improved recruitment of the cytosolic Fc receptor TRIM21, independently of Fc binding affinity. TRIM21 may also synergize with complement C1/C4-mediated lysosomal degradation via capsid inactivation. We demonstrate that this process is potentiated by IgG3 in a hinge-dependent manner. Our findings reveal differences in how the four IgG subclasses mediate intracellular immunity, knowledge that may guide IgG subclass selection and engineering of antiviral antibodies for prophylaxis and therapy.

A new dawn for monoclonal antibodies against antimicrobial resistant bacteria

“…However, with the main aim of increasing the efficacy of therapeutic mAbs against bacterial targets, many efforts were recently made. Progresses in the field include machine and deep learning approaches for structural prediction (Jumper et al, 2021 ), the design computational design of antibody nanocages (Divine et al, 2021 ), the implementation of mAb immunomodulatory activities through the engineering of the IgG hinge region (Foss et al, 2022 ), the development of nucleic acid-encoded monoclonal antibodies (Schlake et al, 2019 ) and the hetero-oligomerization of therapeutic antibodies (Oostindie et al, 2022 ) ( Figure 1C ). Herein, we discussed novel approaches that show great potential in the fight against AMR.…”

“…HINGEneering: Recent studies have demonstrated that the molecular engineering of the hinge region is a valuable tool to modulate the functionality of IgG antibodies (Foss et al, 2022 ; Orr et al, 2022 ). IgG3 is a very potent immunoglobulin, which can trigger different effector functions, including complement activation, antibody-mediated phagocytosis and antibody-mediated cellular toxicity (Damelang et al, 2019 ).…”

“…In their study, Foss and colleagues have demonstrated that the more extended IgG3 hinge region associates with enhanced intracellular antiviral immunity compared to the other IgG subclasses. This process occurs via the tripartite motif containing 21 (Trim21) Fc receptor, an intracellular detection system for opsonized pathogens that have evaded lysosomal degradation (Foss et al, 2022 ). Although Trim21 binds specifically to the Heavy chain constant domain CH2-CH3 and not to the mAb hinge region, a substitution of the IgG3 hinge through molecular engineering to the other IgG subclasses boosted the Trim21 activation, leading to pathogen clearance.…”

“…Although Trim21 binds specifically to the Heavy chain constant domain CH2-CH3 and not to the mAb hinge region, a substitution of the IgG3 hinge through molecular engineering to the other IgG subclasses boosted the Trim21 activation, leading to pathogen clearance. Moreover, the IgG3 hinge-engineering onto the IgG1 subclass increases complement deposition upon pathogen opsonization (Foss et al, 2022 ). To date, IgG3 has not been the choice of interest for marketed mAbs because of concerns about its short half-life and increased immunogenicity, however, substituting the IgG3 hinge region into the IgG1 structure may overcome these limitations and it is a promising approach to developing future antibody therapeutics (Chu et al, 2021 ; Werner and Nimmerjahn, 2022 ).…”

Epstein–Barr virus infection, B‐cell dysfunction and other risk factors converge in gut‐associated lymphoid tissue to drive the immunopathogenesis of multiple sclerosis: a hypothesis

“… 101 , 102 The latter mechanism would likely be augmented by an IgG antibody response generated from CD11c + /T‐bet + MBCs as they are skewed towards IgG3, as well as IgG1, production. 103 , 104 , 105 IgG3 binds more avidly to cell‐surface FcγRs than other IgG subclasses 106 and also elicits an antiviral response by binding to the intra‐cellular Fc receptor TRIM21, 107 which when bound by immune complexes in DCs, promotes antigen cross‐presentation and stimulation of CD8 + T cells. 108 Furthermore, in murine models of SLE, CD11c + /T‐bet + MBCs cause aberrant differentiation of Tfh cells resulting in impaired affinity maturation of antibody responses.…”