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  Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility

Orr, C. M., Fisher, H., Yu, X., Chan, C.-H.-T., Gao, Y., Duriez, P. J., et al. (2022). Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility. Science Immunology, 7(73): eabm3723. doi:10.1126/sciimmunol.abm3723.

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Supplementary Materials: Figs. S1 to S5, Tables S1 to S3 (.pdf); Data file S1 (.xlsx); MDAR Reproducibility Checklist (.pdf)
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https://doi.org/10.1126/sciimmunol.abm3723 (Verlagsversion)
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 Urheber:
Orr, C. M.1, 2, 3, 4, Autor
Fisher, H.1, 2, Autor
Yu, X.2, Autor
Chan, C. H.-T.2, Autor
Gao, Y.3, 5, 6, Autor           
Duriez, P. J.2, 7, Autor
Booth, S. G.2, Autor
Elliott, I.1, 2, 8, Autor
Inzhelevskaya, T.2, Autor
Mockridge, I.2, Autor
Penfold, C. A.2, Autor
Wagner, A.4, Autor
Glennie, M. J.2, Autor
White, A. L.2, 9, Autor
Essex, J. W.8, 10, Autor
Pearson, A. R.3, 5, Autor
Cragg, M. S.2, 10, Autor
Tews, I.1, 10, Autor
Affiliations:
1University of Southampton, Biological Sciences, ou_persistent22              
2University of Southampton, Centre for Cancer Immunology, ou_persistent22              
3Hamburg Centre for Ultrafast Imaging CFEL, ou_persistent22              
4Diamond Light Source, ou_persistent22              
5Institute for Nanostructure and Solid State Physics, ou_persistent22              
6International Max Planck Research School for Ultrafast Imaging & Structural Dynamics (IMPRS-UFAST), Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_2266714              
7University of Southampton, CRUK Protein Core Facility, ou_persistent22              
8University of Southampton, School of Chemistry, ou_persistent22              
9UCB Pharma, ou_persistent22              
10University of Southampton, Institute for Life Sciences, ou_persistent22              

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 Zusammenfassung: Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural “switch” affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.

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Sprache(n): eng - English
 Datum: 2022-03-182021-09-132022-05-202022-07-08
 Publikationsstatus: Online veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1126/sciimmunol.abm3723
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Titel: Science Immunology
  Kurztitel : Sci Immunol.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Washington, DC : American Association for the Advancement of Science
Seiten: - Band / Heft: 7 (73) Artikelnummer: eabm3723 Start- / Endseite: - Identifikator: ISSN: 2470-9468
CoNE: https://pure.mpg.de/cone/journals/resource/2470-9468