ArticlePharmaceutical research2011
Disulfide scrambling in IgG2 monoclonal antibodies: insights from molecular dynamics simulations.
Article in Pharmaceutical research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Efficacy and safety of JMT103 in patients with bone metastases from solid tumors: A randomized Phase Ib clinical trial.International journal of cancer · 2025Trial
- Efficacy and safety of JMT103 in patients with unresectable or surgically-challenging giant cell tumor of bone: a multicenter, phase Ib/II study.Nature communications · 2024Trial
- What's new on giant cell tumor of bone.SICOT-J · 2026Article
- JMT103 versus Non-Denosumab or Denosumab Treatment in Chinese Patients with Unresectable or Surgically Challenging Giant Cell Tumor of Bone: A Propensity Score-Matched Comparison.Cancer medicine · 2025Observational
- Comparing the Hinge-Type Mobility of Natural and Designed Intermolecular Bi-disulfide Domains.Frontiers in chemistry · 2020Article
- Characterizing Thermal Transitions of IgG with Mass Spectrometry.Journal of the American Society for Mass Spectrometry · 2019Article
- Aqueous ionic liquids influence the disulfide bond isoform equilibrium in conotoxin AuIB: a consequence of the Hofmeister effect?Biophysical reviews · 2018Review
- Effects of localized interactions and surface properties on stability of protein-based therapeutics.The Journal of pharmacy and pharmacology · 2018Review
- In-silico prediction of concentration-dependent viscosity curves for monoclonal antibody solutions.mAbs · 2017Article
- Complementary MS methods assist conformational characterization of antibodies with altered S-S bonding networks.Journal of the American Society for Mass Spectrometry · 2013Article
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Authors and funding
3 authors.
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Abstract
purposeTo explore potential non-canonical disulfide linkages feasible in human IgG2 mAbs via molecular dynamics simulations of a model system, Hinge(++).
methodsHinge(++) is derived from the crystal structure of a full-length murine IgG2a antibody by replacing its core hinge region with human IgG2 hinge. Fv and C(H)3 domains were discarded to speed up calculations. Eight independent simulations, grouped in four sets, were performed. In the control set, disulfide bonding is identical to canonical human IgG2 mAb. Different numbers of disulfide bonds were broken in the remaining three sets.
resultsTwo Fabs move towards Fc asymmetrically repeatedly leading to spatial proximity of LC.Cys214 and HC.Cys128 residues in one Fab with Cys residues in the upper hinge region, which could initiate disulfide scrambling. Local dynamics place the eight hinge region Cys residues in a large number of proximal positions which could facilitate non-canonical inter- and intra- heavy chain disulfide linkages in the hinge region.
conclusionConsistent with experimental studies, our simulations indicate inter-chain disulfide linkages in human IgG2 mAbs are degenerate. Potential rational design strategies to devise hinge stabilized human IgG2 mAbs are gleaned.
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