Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass
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In the accompanying report ( Wypych, J., Li, M., Guo, A., Zhang, Z., Martinez, T., Allen, M. J., Fodor, S., Kelner, D. N., Flynn, G. C., Liu, Y. D., Bondarenko, P. V., Ricci, M. S., Dillon, T. M., and Balland, A. (2008) J. Biol. Chem. 283, 16194-16205 ), we have identified that the human IgG2 subclass exists as an ensemble of distinct isoforms, designated IgG2-A, -B, and -A/B, which differ by the disulfide connectivity at the hinge region. In this report, we studied the structural and functional properties of the IgG2 disulfide isoforms and compared them to IgG1. Human monoclonal IgG1 and IgG2 antibodies were designed with identical antigen binding regions, specific to interleukin-1 cell surface receptor type 1. In vitro biological activity measurements showed an increased activity of the IgG1 relative to the IgG2 in blocking interleukin-1beta ligand from binding to the receptor, suggesting that some of the IgG2 isoforms had lower activity. Under reduction-oxidation conditions, the IgG2 disulfide isoforms converted to IgG2-A when 1 m guanidine was used, whereas IgG2-B was enriched in the absence of guanidine. The relative potency of the antibodies in cell-based assays was: IgG1 > IgG2-A > IgG2 >> IgG2-B. This difference correlated with an increased hydrodynamic radius of IgG2-A relative to IgG2-B, as shown by biophysical characterization. The enrichment of disulfide isoforms and activity studies were extended to additional IgG2 monoclonal antibodies with various antigen targets. All IgG2 antibodies displayed the same disulfide conversion, but only a subset showed activity differences between IgG2-A and IgG2-B. Additionally, the distribution of isoforms was influenced by the light chain type, with IgG2lambda composed mostly of IgG2-A. Based on crystal structure analysis, we propose that IgG2 disulfide exchange is caused by the close proximity of several cysteine residues at the hinge and the reactivity of tandem cysteines within the hinge. Furthermore, the IgG2 isoforms were shown to interconvert in whole blood or a "blood-like" environment, thereby suggesting that the in vivo activity of human IgG2 may be dependent on the distribution of isoforms.
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The relative flexibility of the IgG hinge region differs as IgG3 > IgG1 > IgG4 > IgG2.
“The relative flexibility differs as follows: lgG3 > lgG1 > lgG4 > lgG2 (71).”
From Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy (2017) · cites this paper as [71]
The Structural Heterogeneity section compares the hinge structures of IgG1 and IgG2, and the Discussion describes flexibility differences among IgG2 isoforms. Neither gives a hinge-flexibility ranking across IgG3, IgG1, IgG4, and IgG2. Searches for that ranking and for IgG4 in relation to hinge flexibility found no supporting passage in our copy; page numbers were unavailable. (LLM, conf=0.74)
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- Authors
- Dillon, T. M., Ricci, M. S., Vezina, C., Flynn, G. C., Liu, Y. D., Rehder, D. S., Plant, M., Henkle, B., Li, Y., Deechongkit, S., Varnum, B., Wypych, J., Balland, A., & Bondarenko, P. V.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Dillon, Thomas M.
- Bondarenko, Pavel V.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 283
- Issue
- 23
- Pages
- 16206-16215
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3259628
- OpenAlex
- W2004290717
- Cited by
- 291
- References
- 34
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 8 · 2023: 10 · 2022: 8 · 2021: 15 · 2020: 19 · 2019: 15 · 2018: 22 · 2017: 18 · 2016: 20 · 2015: 24 · 2014: 19 · 2013: 19 · 2012: 22
- FWCI
- 14.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- hinge region, disulfide exchange, monoclonal antibodies, IL1R1, IL-1β, hydrodynamic radius, antibody structure
- MeSH terms
- Disulfides, Humans, Immunoglobulin G, Immunoglobulin lambda-Chains, Oxidation-Reduction, Structure-Activity Relationship, Crystallography, X-Ray, Protein Isoforms, Protein Structure, Quaternary
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