Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels
Abstract
We have engineered the Fc region of a human immunoglobulin G (IgG) to generate a mutated antibody that modulates the concentrations of endogenous IgGs in vivo. This has been achieved by targeting the activity of the Fc receptor, FcRn, which serves through its IgG salvage function to maintain and regulate IgG concentrations in the body. We show that an IgG whose Fc region was engineered to bind with higher affinity and reduced pH dependence to FcRn potently inhibits FcRn-IgG interactions and induces a rapid decrease of IgG levels in mice. Such FcRn blockers (or 'Abdegs,' for antibodies that enhance IgG degradation) may have uses in reducing IgG levels in antibody-mediated diseases and in inducing the rapid clearance of IgG-toxin or IgG-drug complexes.
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MST-HN IgG Fc is an analog of efgartigimod, a competitive antagonist with weaker affinity and pH-dependent binding to FcRn.
“Another anti-FcRn therapeutic, the Fc fragment MST-HN IgG Fc (an analog of efgartigimod), a competitive antagonist with weaker affinity and pH-dependent binding to FcRn, was included for comparison.”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [21]
MST-HN IgG Fc binds FcRn with higher affinity at acidic pH, such as endosomal pH.
“MST-HN IgG Fc has been shown to bind FcRn with higher affinity at acidic pH, such as that found within endosomes [21].”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [21]
MST-HN IgG Fc uptake is increased at lower pH in HUVECs, consistent with increased affinity at endosomal pH.
“indicating that MST-HN IgG Fc uptake is increased at lower pH in line with increased affinity at endosomal pH [21].”
From The uptake, intracellular trafficking and recycling of FcRn-blocking therapeutics in human endothelial cells in vitro (2026) · cites this paper as [21]
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FcRn: the neonatal Fc receptor comes of age
Roopenian, D. C., & Akilesh, S. (2007) · Nature Reviews Immunology · doi:10.1038/nri2155 · Cited by 2,346 · see citing works
Therapeutic antibodies: successes, limitations and hopes for the future
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Extending Serum Half-life of Albumin by Engineering Neonatal Fc Receptor (FcRn) Binding
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Neonatal Fc receptor – biology and therapeutics
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Sirina, J., D'Hooghe, L. E., Singhvi-Hanns, L. A., Cole, S. L., Shock, A., Holliday, N. D., & Stoddart, L. A. (2026) · Cellular Immunology · doi:10.1016/j.cellimm.2026.105128
- Authors
- Vaccaro, C., Zhou, J., Ober, R. J., & Ward, E. S.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at Dallas (US)
- Corresponding author
- Ward, E Sally
- Venue
- Nature Biotechnology
- Published
- 2005-09-25
- Volume
- 23
- Issue
- 10
- Pages
- 1283-1288
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2061641422
- Cited by
- 407
- References
- 2
- Citations by year
- 2026: 21 · 2025: 29 · 2024: 30 · 2023: 17 · 2022: 30 · 2021: 18 · 2020: 21 · 2019: 16 · 2018: 21 · 2017: 15 · 2016: 15 · 2015: 24 · 2014: 18 · 2013: 17 · 2012: 19
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI039167, R01AI050747, R01AI055556)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- IgG, Fc receptors, neonatal Fc receptor, IgG degradation, antibody-mediated disease, antibody clearance, pH-dependent binding
- MeSH terms
- Animals, Antibodies, Monoclonal, Autoimmune Diseases, Female, Humans, Immunoglobulin G, Immunoglobulin Fc Fragments, Immunotherapy, Receptors, Fc, Recombinant Proteins, Protein Engineering, Histocompatibility Antigens Class I, Mice
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