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Review
. 2021 Jan-Dec;13(1):1882028.
doi: 10.1080/19420862.2021.1882028.

Coming together at the hinges: Therapeutic prospects of IgG3

Thach H Chu  1 , Edward F Patz Jr  2 , Margaret E Ackerman  1
Affiliations
Review

Coming together at the hinges: Therapeutic prospects of IgG3

Thach H Chu et al. MAbs. 2021 Jan-Dec.

Abstract

The human IgG3 subclass is conspicuously absent among the formats for approved monoclonal antibody therapies and Fc fusion protein biologics. Concern about the potential for rapid degradation, reduced plasma half-life, and increased immunogenicity due to marked variation in allotypes has apparently outweighed the potential advantages of IgG3, which include high affinity for activating Fcγ receptors, effective complement fixation, and a long hinge that appears better suited for low abundance targets. This review aims to highlight distinguishing features of IgG3 and to explore its functional role in the immune response. We present studies of natural immunity and recombinant antibody therapies that elucidate key contributions of IgG3 and discuss historical roadblocks that no longer remain clearly relevant. Collectively, this body of evidence motivates thoughtful reconsideration of the clinical advancement of this distinctive antibody subclass for treatment of human diseases. Abbreviations: ADCC - Antibody-Dependent Cell-mediated CytotoxicityADE - Antibody-dependent enhancementAID - Activation-Induced Cytidine DeaminaseCH - Constant HeavyCHF - Complement factor HCSR - Class Switch RecombinationEM - Electron MicroscopyFab - Fragment, antigen bindingFc - Fragment, crystallizableFcRn - Neonatal Fc ReceptorFcγR - Fc gamma ReceptorHIV - Human Immunodeficiency VirusIg - ImmunoglobulinIgH - Immunoglobulin Heavy chain geneNHP - Non-Human Primate.

Keywords: IgG3; antibody; hinge; immunoglobulin subclass; infectious disease; vaccine.

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Figures

Figure 1.
Figure 1.
Flexibility and other features of human IgG subclasses. Top: Representation of the Fab domain flexibility with respect to the hinge regions of the human IgG subclasses in which positions for Fab domains are represented by spheres in purple and teal. Figure adapted from Hansen et al. with permission. Bottom: Measured values for various physical attributes of IgG3 compared to other human subclasses
Figure 2.
Figure 2.
Sites of amino acid polymorphisms in IgG3 CH2 and CH3 domains. Red amino acids indicate sites of amino acid sequence diversity among G3m allotypes. Brackets indicate recognition footprints of various human Fc receptors
Figure 3.
Figure 3.
Human IgG responses over time and IgH locus arrangement in human, mouse, and rhesus. Top: Schematic of subclass composition over time for human IgG. IgG3 appears early and wanes over time. IgG1 additionally increases early and titer remains high. IgG2 and IgG4 appear later in infection. Affinity increases over time during infection due to somatic hypermutation. Bottom: IGHC locus arrangement across species. Subclass naming convention is based on serum prevalence rather than genetic similarity
See this image and copyright information in PMC

References

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