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Evaluating the Effects of Hinge Flexibility on the Solution Structure of Antibodies at Concentrated Conditions.
- Source :
-
Journal of pharmaceutical sciences [J Pharm Sci] 2019 May; Vol. 108 (5), pp. 1663-1674. Date of Electronic Publication: 2018 Dec 26. - Publication Year :
- 2019
-
Abstract
- Employing 2 different coarse-grained models, we evaluated the effect of intramolecular domain-domain distances and hinge flexibility on the general solution structure of monoclonal antibodies (mAbs), within the context of protein-protein steric repulsion. These models explicitly account for the hinge region, and represent antibodies at either domain or subdomain levels (i.e., 4-bead and 7-bead representations, respectively). Additionally, different levels of mAb flexibility are also considered. When evaluating mAbs as rigid structures, analysis of small-angle scattering profiles showed that changes in the relative internal distances between Fc and Fab domains significantly alter the local arrangement of neighboring molecules, as well as the molecular packing of the concentrated mAb solutions. Likewise, enabling hinge flexibility in either of the mAb models led to qualitatively similar results, where flexibility increases the spatial molecular arrangement at elevated concentrations. This occurs because fluctuations in mAb quaternary structure are modulated by the close proximity between molecules at elevated concentrations (>50 mg mL <superscript>-1</superscript> ), yielding an increased molecular packing and osmotic compressibility. However, our results also showed that the mechanism behind this synergy between flexibility and packing strongly depends on both the level of structural detail and the number of degrees-of-freedom considered in the coarse-grained model.<br /> (Copyright © 2019 American Pharmacists Association®. All rights reserved.)
- Subjects :
- Scattering, Small Angle
Antibodies, Monoclonal chemistry
Solutions chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-6017
- Volume :
- 108
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of pharmaceutical sciences
- Publication Type :
- Academic Journal
- Accession number :
- 30593783
- Full Text :
- https://doi.org/10.1016/j.xphs.2018.12.013