Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation
Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation
Antibodies can mediate immune recruitment or clearance of immune complexes through the interaction of their Fc domain with cellular Fc receptors. Clustering of antibodies is a key step in generating sufficient avidity for efficacious receptor recognition. However, Fc receptors may be saturated with prevailing, endogenous serum immunoglobulin and this raises the threshold by which cellular receptors can be productively engaged. Here, we review the factors controlling serum IgG levels in both healthy and disease states, and discuss how the presence of endogenous IgG is encoded into the functional activation thresholds for low- and high-affinity Fc receptors. We discuss the circumstances where antibody engineering can help overcome these physiological limitations of therapeutic antibodies. Finally, we discuss how the pharmacological control of Fc receptor saturation by endogenous IgG is emerging as a feasible mechanism for the enhancement of antibody therapeutics.
Antibody structure, Effector functions, Fc, Fc receptors, Glycosylation, Immunoglobulin, Therapeutic antibodies
Bauer-Smith, Hannah
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Sudol, Abigail S.L.
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Beers, Stephen A.
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Crispin, Max
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November 2023
Bauer-Smith, Hannah
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Sudol, Abigail S.L.
edd31bca-5f7f-4c17-9f50-b76cadb3a311
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Bauer-Smith, Hannah, Sudol, Abigail S.L., Beers, Stephen A. and Crispin, Max
(2023)
Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 1867 (11), [130448].
(doi:10.1016/j.bbagen.2023.130448).
Abstract
Antibodies can mediate immune recruitment or clearance of immune complexes through the interaction of their Fc domain with cellular Fc receptors. Clustering of antibodies is a key step in generating sufficient avidity for efficacious receptor recognition. However, Fc receptors may be saturated with prevailing, endogenous serum immunoglobulin and this raises the threshold by which cellular receptors can be productively engaged. Here, we review the factors controlling serum IgG levels in both healthy and disease states, and discuss how the presence of endogenous IgG is encoded into the functional activation thresholds for low- and high-affinity Fc receptors. We discuss the circumstances where antibody engineering can help overcome these physiological limitations of therapeutic antibodies. Finally, we discuss how the pharmacological control of Fc receptor saturation by endogenous IgG is emerging as a feasible mechanism for the enhancement of antibody therapeutics.
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Accepted/In Press date: 23 August 2023
e-pub ahead of print date: 29 August 2023
Published date: November 2023
Additional Information:
Funding Information:
We thank Sally Ward for critically reading the manuscript. M.C. gratefully acknowledges Chris Scanlan and Mark Wormald for stimulating discussions on competition effects. The review was supported by Against Breast Cancer ( www.againstbreastcancer.org ; H.S., A.S.L.S., S.B. and M.C.), Cancer Research UK (CRUK A24721; S.B.) and the United States National Institute of Health (NIH 1U01AI148153-01; S.B.). We are particularly grateful to employees of Cisco Ltd. who supported the Against Breast Cancer studentship to H.S. A further studentship to A.S.L.S. was provided by the School of Biological Sciences, University of Southampton. M.C. is a Supernumerary Fellow of Oriel College, Oxford, UK, and Professor Adjunct within the Department of Microbiology & Immunology, Scripps Research, La Jolla, USA.
Funding Information:
S.A.B. has acted as a consultant for a number of biotechs and receives institutional support for grants and patents from BioInvent. M.C. has acted as a consultant for a number of biotechs and legal firms and is a named inventor on a patent application describing “Combined therapeutic use of antibodies and endoglycosidases” (WO2013110946A1) which was acquired by Hansa Biopharma.
Publisher Copyright:
© 2023
Keywords:
Antibody structure, Effector functions, Fc, Fc receptors, Glycosylation, Immunoglobulin, Therapeutic antibodies
Identifiers
Local EPrints ID: 482194
URI: http://eprints.soton.ac.uk/id/eprint/482194
ISSN: 0304-4165
PURE UUID: fe3c1f4b-f661-42df-98bf-9c21810e0560
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Date deposited: 21 Sep 2023 16:32
Last modified: 27 Mar 2024 02:56
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Author:
Hannah Bauer-Smith
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