| Téléchargement | - Voir la version finale : Binding symmetry and surface flexibility mediate antibody self-association (PDF, 4.9 Mio)
- Voir les données supplémentaires : Binding symmetry and surface flexibility mediate antibody self-association (PDF, 11.8 Mio)
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| DOI | Trouver le DOI : https://doi.org/10.1080/19420862.2019.1632114 |
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| Auteur | Rechercher : Schrag, Joseph D.1; Rechercher : Picard, Marie-ÈveIdentifiant ORCID : https://orcid.org/0000-0002-4316-2830; Rechercher : Gaudreault, Francis1Identifiant ORCID : https://orcid.org/0000-0001-5656-3118; Rechercher : Gagnon, Louis-Patrick1Identifiant ORCID : https://orcid.org/0000-0001-7417-866X; Rechercher : Baardsnes, Jason1Identifiant ORCID : https://orcid.org/0000-0001-5587-3034; Rechercher : Manenda, Mahder S.Identifiant ORCID : https://orcid.org/0000-0002-8640-5556; Rechercher : Sheff, Joey1Identifiant ORCID : https://orcid.org/0000-0002-9269-6863; Rechercher : Deprez, Christophe1Identifiant ORCID : https://orcid.org/0000-0003-2687-3144; Rechercher : Baptista, Cassio1; Rechercher : Hogues, Hervé1; Rechercher : Kelly, John F.1; Rechercher : Purisima, Enrico O.1; Rechercher : Shi, RongIdentifiant ORCID : https://orcid.org/0000-0001-8494-900X; Rechercher : Sulea, Traian1Identifiant ORCID : https://orcid.org/0000-0001-5301-8261 |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Format | Texte, Article |
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| Sujet | aggregation; native folding; single point mutation; structure-aggregation relationship; prediction method |
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| Résumé | Solution stability is an important factor in the optimization of engineered biotherapeutic candidates such as monoclonal antibodies because of its possible effects on manufacturability, pharmacology, efficacy and safety. A detailed atomic understanding of the mechanisms governing self-association of natively folded protein monomers is required to devise predictive tools to guide screening and re-engineering along the drug development pipeline. We investigated pairs of affinity-matured full-size antibodies and observed drastically different propensities to aggregate from variants differing by a single amino-acid. Biophysical testing showed that antigen-binding fragments (Fabs) from the aggregating antibodies also reversibly associated with equilibrium dissociation constants in the low-micromolar range. Crystal structures (PDB accession codes 6MXR, 6MXS, 6MY4, 6MY5) and bottom-up hydrogen-exchange mass spectrometry revealed that Fab self-association occurs in a symmetric mode that involves the antigen complementarity-determining regions. Subtle local conformational changes incurred upon point mutation of monomeric variants foster formation of complementary polar interactions and hydrophobic contacts to generate a dimeric Fab interface. Testing of popular in silico tools generally indicated low reliabilities for predicting the aggregation propensities observed. A structure-aggregation data set is provided here in order to stimulate further improvements of in silico tools for prediction of native aggregation. Incorporation of intermolecular docking, conformational flexibility, and short-range packing interactions may all be necessary features of the ideal algorithm. |
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| Date de publication | 2019-07-19 |
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| Maison d’édition | Taylor & Francis |
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| Licence | |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Numéro du CNRC | NRC-HHT_53508 |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | 0c949240-61b0-4677-8818-225315b4f12a |
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| Enregistrement créé | 2020-11-27 |
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| Enregistrement modifié | 2021-01-08 |
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