Polymeric human Fc-fusion proteins with modified effector functions
Open accessAbstract
The success of Fc-fusion bio-therapeutics has spurred the development of other Fc-fusion products for treating and/or vaccinating against a range of diseases. We describe a method to modulate their function by converting them into well-defined stable polymers. This strategy resulted in cylindrical hexameric structures revealed by tapping mode atomic force microscopy (AFM). Polymeric Fc-fusions were significantly less immunogenic than their dimeric or monomeric counterparts, a result partly owing to their reduced ability to interact with critical Fc-receptors. However, in the absence of the fusion partner, polymeric IgG1-Fc molecules were capable of binding selectively to FcγRs, with significantly increased affinity owing to their increased valency, suggesting that these reagents may prove of immediate utility in the development of well-defined replacements for intravenous immunoglobulin (IVIG) therapy. Overall, these findings establish an effective IgG Fc-fusion based polymeric platform with which the therapeutic and vaccination applications of Fc-fusion immune-complexes can now be explored.
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The hexameric IgG-Fc fusion with an additional N-glycosylation site in the IgM-tailpiece has increased FcγR binding affinity.
“The hexameric IgG-Fc fusion, with its additional N-glycosylation site in the IgM-tailpiece, was shown to have increased FcγR binding affinity, which suggested the potential for developing this strategy to replace intravenous immunoglobulin G (IVIG) therapy with a well-defined and more homogeneous biotherapeutic product.”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [118]
The Results (‘Binding to FcγRs’; page not provided) report higher FcγR affinity for hexameric IgG1-Fc without the fused antigen, and the Discussion proposes these polymers as potential well-defined replacements for IVIG. The same Results section says the antigen-bearing hexamer bound poorly to FcγRs. Our copy describes adding an IgM tailpiece but does not establish the claimed additional N-glycosylation site. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPolymeric recombinant IgGs have been generated by insertion of a C-terminal IgM-tailpiece and modifications to Cys residues involved in multimerisation, generating multimeric forms with increased valency for therapeutic and vaccine applications.
“With regards to multimerisation scaffolds, polymeric recombinant IgGs have been generated by the insertion of a C-terminal IgM-tailpiece and modifications to Cys residues involved in multimerisation, to generate multimeric forms with increased valency for therapeutic and vaccine applications [118].”
From Glycoengineering Chinese hamster ovary cells: a short history (2021) · cites this paper as [118]
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- Authors
- Mekhaiel, D. N. A., Czajkowsky, D. M., Andersen, J. T., Shi, J., El-Faham, M., Doenhoff, M., McIntosh, R. S., Sandlie, I., He, J., Hu, J., Shao, Z., & Pleass, R. J.
- Affiliations
- Liverpool School of Tropical Medicine (GB)
- Shanghai Jiao Tong University (CN)
- Oslo University Hospital (NO)
- University of Nottingham (GB)
- University of Oslo (NO)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Pleass, Richard J.
- ORCID
- Venue
- Scientific Reports
- Published
- 2011-10-19
- Volume
- 1
- Issue
- 1
- Pages
- 124-124
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC3216605
- OpenAlex
- W2093483949
- Cited by
- 85
- References
- 60
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 12 · 2019: 6 · 2018: 4 · 2017: 10 · 2016: 6 · 2015: 5 · 2014: 4 · 2013: 2 · 2012: 1
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- LSTM Online Archive (Liverpool School of Tropical Medicine) (submittedVersion, cc-by-nc-sa)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-sa)
- Funders
- National Institute for Health and Care Research
- University of Oxford
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality
- Norges Forskningsråd (179573/V40, 179573)
- Medical Research Council
- Helse Sør-Øst RHF (179573/V40, 39375)
- Fellowships for Young International Scientists
- National Key Research and Development Program of China (2007CB936000)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- Fc fusion protein, IgG1, Fc receptor binding, Fc gamma receptor, immunogenicity, valence, intravenous immunoglobulin replacement, immune complexes, biologic therapy, vaccination
- MeSH terms
- Animals, B-Lymphocytes, Base Sequence, Biological Therapy, Complement System Proteins, Female, Humans, Immunoglobulin G, Immunization, Immunoglobulin Fc Fragments, Malaria, Mice, Inbred BALB C, Models, Molecular, Plasmodium berghei, Protein Binding, Receptors, Fc, Recombinant Fusion Proteins, Histocompatibility Antigens Class I, Receptors, IgG, DNA Primers, Mice, Protein Multimerization
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