The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Cytokines in the pathogenesis of rheumatoid arthritis
McInnes, I. B., & Schett, G. A. (2007) · Nature reviews. Immunology · doi:10.1038/nri2094 · Cited by 2,575
The Impact of Glycosylation on the Biological Function and Structure of Human Immunoglobulins
Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M., & Dwek, R. A. (2006) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141702 · Cited by 1,354
Post-translational modifications in the context of therapeutic proteins
Walsh, G., & Jefferis, R. (2006) · Nature Biotechnology · doi:10.1038/nbt1252 · Cited by 1,007
Crystal Structure of a Neutralizing Human IgG Against HIV-1: A Template for Vaccine Design
Saphire, E. O., Parren, P. W. H. I., Pantophlet, R. A., Zwick, M. B., Morris, G. M., Rudd, P. M., Dwek, R. A., Stanfield, R. L., Burton, D. R., & Wilson, I. A. (2001) · Science · doi:10.1126/science.1061692 · Cited by 959
Downstream processing of monoclonal antibodies—Application of platform approaches
Shukla, A. A., Hubbard, B. R., Tressel, T., Guhan, S., & Low, D. K. R. (2007) · Journal of Chromatography B · doi:10.1016/j.jchromb.2006.09.026 · Cited by 900
Probing conformational changes in proteins by mass spectrometry
Chowdhury, S. K., Katta, V., & Chait, B. T. (1990) · Journal of the American Chemical Society · doi:10.1021/ja00180a074 · Cited by 652
Disulfide bonds as switches for protein function.
Hogg, P. (2003) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/s0968-0004(03)00057-4 · Cited by 581
Therapeutic antibodies for human diseases at the dawn of the twenty-first century
Brekke, O. H., & Sandlie, I. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd984 · Cited by 572
Heterogeneity of Monoclonal Antibodies
Liu, H., Gaza‐Bulseco, G., Faldu, D., Chumsae, C. M., & Sun, J. (2007) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.21180 · Cited by 505
Advances in refolding of proteins produced in E. coli
Lilie, H., Schwarz, E., & Rudolph, R. (1998) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(98)80035-9 · Cited by 477
Immunoglobulin G: Functional sites
Burton, D. R. (1985) · Molecular Immunology · doi:10.1016/0161-5890(85)90151-8 · Cited by 433
Guerne, P. A., Carson, D. A., & Lotz, M. (1990) · The Journal of Immunology · doi:10.4049/jimmunol.144.2.499 · Cited by 365
Schmidt, B., Ho, L., & Hogg, P. J. (2006) · Biochemistry · doi:10.1021/bi0603064 · Cited by 342
Jefferis, R. (2007) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.7.9.1401 · Cited by 301
Human IgG2 Antibodies Display Disulfide-mediated Structural Isoforms
Wypych, J., Li, M., Guo, A., Zhang, Z., Martinez, T., Allen, M. J., Fodor, S., Kelner, D. N., Flynn, G. C., Liu, D., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709987200 · Cited by 286
Self-citationStructural Comparison of Fucosylated and Nonfucosylated Fc Fragments of Human Immunoglobulin G1
Matsumiya, S., Yamaguchi, Y., Saito, J., Nagano, M., Sasakawa, H., Otaki, S., Satoh, M., Shitara, K., & Kato, K. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.02.034 · Cited by 279
Canfield, S. M., & Morrison, S. L. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.173.6.1483 · Cited by 266
Contrasting IgG structures reveal extreme asymmetry and flexibility.
Saphire, E., Stanfield, R., Maxcrispin, M., Parren, P., Rudd, P., Dwek, R., Burton, D., & Wilson, I. A. G. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00244-9 · Cited by 249
Conformations of disulfide bridges in proteins
Srinivasan, N., Sowdhamini, R., Ramakrishnan, C., & Balaram, P. (1990) · International journal of peptide & protein research · doi:10.1111/j.1399-3011.1990.tb00958.x · Cited by 196
Dillon, T. M., Bondarenko, P. V., Rehder, D. S., Pipes, G. D., Kleemann, G. R., & Speed, M. A. (2006) · Journal of Chromatography A · doi:10.1016/j.chroma.2006.01.016 · Cited by 189
Self-citationSowdhamini, R., Srinivasan, N., Shoichet, B. K., Santi, D. V., Ramakrishnan, C., & Balaram, P. (1989) · Protein Engineering Design and Selection · doi:10.1093/protein/3.2.95 · Cited by 188
Immunoglobulins: Structural Studies of Immunoglobulin G
Frangione, B., Milstein, C., & Pink, J. R. L. (1969) · Nature · doi:10.1038/221145a0 · Cited by 176
Heterogeneity of recombinant antibodies: linking structure to function.
Harris, R. (2005) · PubMed · Cited by 141
Chaderjian, W. B., Chin, E. T., Harris, R. J., & Etcheverry, T. (2005) · Biotechnology Progress · doi:10.1021/bp0497029 · Cited by 118
Dillon, T. M., Bondarenko, P. V., & Ricci, M. S. (2004) · Journal of Chromatography A · doi:10.1016/j.chroma.2004.08.058 · Cited by 91
Self-citationBlood glutathione and cysteine changes in cardiovascular disease
Mills, B. J., Weiss, M. M., Lang, C. A., Liu, M. C., & Ziegler, C. H. (2000) · Journal of Laboratory and Clinical Medicine · doi:10.1067/mlc.2000.105976 · Cited by 87
Banks, D. D., Gadgil, H. S., Pipes, G. D., Bondarenko, P. V., Hobbs, V., Scavezze, J. L., Kim, J., Jiang, X., Mukku, V. R., & Dillon, T. M. (2007) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.21014 · Cited by 83
Self-citationBeenhouwer, D. O., Yoo, E. M., Lai, C. W., Rocha, M. A., & Morrison, S. L. (2007) · Infection and Immunity · doi:10.1128/iai.01161-06 · Cited by 77
Influence of the Isotype of the Light Chain on the Properties of IgG
Montaño, R. F., & Morrison, S. L. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.1.224 · Cited by 63
Plasma Cysteine Deficiency and Decreased Reduction of Nitrososulfamethoxazole with HIV Infection
Naisbitt, D. J., Vilar, F. J., Stalford, A. C., Wilkins, E. G. L., Pirmohamed, M., & Park, B. K. (2000) · AIDS Research and Human Retroviruses · doi:10.1089/088922200750054657 · Cited by 59
Plasma cystine concentration and redox state in aging and physical exercise
Hildebrandt, W., Kinscherf, R., Hauer, K. A., Holm, E., & Dröge, W. (2002) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(02)00013-1 · Cited by 57
Gorgani, N. N., Parish, C. R., & Altin, J. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.29633 · Cited by 40
Structure-based Stability Engineering of the Mouse IgG1 Fab Fragment by Modifying Constant Domains
Teerinen, T., Valjakka, J., Rouvinen, J., & Takkinen, K. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.06.073 · Cited by 25
Brekke, O. H., Bremnes, B., Sandin, R., Aase, A., Michaelsen, T. E., & Sandlie, I. (1993) · Molecular Immunology · doi:10.1016/0161-5890(93)90103-i · Cited by 8
Research works printed but not linked: 3
- Liu, H., Gaza-Bulseco, G., Faldu, D., Chumsae, C., and Sun, J. (2008) J. Pharm. Sci., in press
- Harris, 2005, Dev. Biol. (Basel), 122, 117
- Dillon, 2004, J. Chromatogr. A, 1053, 299, 10.1016/S0021-9673(04)01410-4 · DOI
Cited by
Sorted by citations
IgG Subclasses and Allotypes: From Structure to Effector Functions
Vidarsson, G., Dekkers, G., & Rispens, T. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00520 · Cited by 2,667
Stability of Protein Pharmaceuticals: An Update
Manning, M. C., Chou, D. K., Murphy, B. M., Payne, R. W., & Katayama, D. S. (2010) · Pharmaceutical Research · doi:10.1007/s11095-009-0045-6 · Cited by 1,140
Strategies and challenges for the next generation of therapeutic antibodies
Beck, A., Wurch, T., Bailly, C., & Corvaı̈a, N. (2010) · Nature reviews. Immunology · doi:10.1038/nri2747 · Cited by 868
Disulfide bond structures of IgG molecules
Liu, H., & May, K. M. L. (2012) · mAbs · doi:10.4161/mabs.4.1.18347 · Cited by 487
Khawli, L. A., Goswami, S., Hutchinson, R., Glover, Z. K., Yang, J., Wang, X., Yao, Z., Sreedhara, A., Cano, T., Tesar, D. B., et al. (2010) · mAbs · doi:10.4161/mabs.2.6.13333 · Cited by 437
Metadata
- 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
- Life Sciences › Immunology and Microbiology › Immunology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
