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Breaking the Aggregation of the Monoclonal Antibody Bevacizumab (Avastin®) by Dexamethasone Phosphate: Insights from Molecular Modelling and Asymmetrical Flow Field-Flow Fractionation.
MedLine Citation:
PMID:  23412914     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PURPOSE: To investigate the mechanism behind the aggregation breaking properties of dexamethasone phosphate and related corticosteroids on the IgG1 antibody bevacizumab (Avastin®). METHODS: An in silico 3D dimer model is developed to identify the bevacizumab-bevacizumab interface, and different corticosteroids are docked onto the model to distinguish preferred binding sites. In silico predictions are validated by in vitro stability studies, where the antibody is stressed in presence or absence of each corticosteroid and formed aggregates are quantified by asymmetrical flow field-flow fractionation. RESULTS: The dimer model features one close crystal contact area: Lys445 on the Fc region interacts with one Fab arm of the second bevacizumab. Docking reveals an interaction between the phosphate group of dexamethasone phosphate and Lys445, while the rest of the molecule is hindering dimer formation. Predictions are confirmed in vitro, demonstrating that dexamethasone phosphate and betamethasone phosphate partly prevent antibody aggregation, whereas triamcinolone acetonide phosphate does not. CONCLUSIONS: Results suggest that bevacizumab monomers follow a specific mechanism to form dimers in which a protein-protein interaction hotspot can be distinguished. The dimer formation can be hindered by corticosteroids in a specific way. This approach allows a simple way to stabilize IgG1 antibodies.
Authors:
Marieke Veurink; Yvonne Westermaier; Robert Gurny; Leonardo Scapozza
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-2-15
Journal Detail:
Title:  Pharmaceutical research     Volume:  -     ISSN:  1573-904X     ISO Abbreviation:  Pharm. Res.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-2-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
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