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Understanding the relationship between biotherapeutic protein stability and solid-liquid interfacial shear in constant region mutants of IgG1 and IgG4.

Tavakoli-Keshe R, Phillips JJ, Turner R, Bracewell DG - J Pharm Sci (2013)

Bottom Line: Results suggest that the techniques are orthogonal, with thermal methods based on intramolecular interaction and shear device stability based on localized unfolding revealing less stable regions that drive aggregation.Molecular modeling shows the modifications' effects on the antibody structures and indicates a possible role for Fc conformation and Fab-Fc docking in determining suspended protein stability.The data introduce the PDC value as an orthogonal stability indicator, complementary to traditional thermal methods, allowing lead antibody selection based on a more full understanding of process stability.

View Article: PubMed Central - PubMed

Affiliation: The Advanced Centre for Biochemical Engineering, University College London, Torrington Place, London, WC1E 7JE, UK; MedImmune, Granta Park, Cambridge, CB21 6GH, UK.

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Diagram representing comparability of thermal degradation and interfacial shear-induced aggregation for determining relative stability. The thermal degradation route is based on work on nonnative protein aggregation by Roberts and co-workers,41,42 whereas the interfacial route builds upon this background with work by Biddlecombe et al.28
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fig01: Diagram representing comparability of thermal degradation and interfacial shear-induced aggregation for determining relative stability. The thermal degradation route is based on work on nonnative protein aggregation by Roberts and co-workers,41,42 whereas the interfacial route builds upon this background with work by Biddlecombe et al.28

Mentions: In this study, the effects of controlled antibody modifications TM39 and YTE40 on a drug candidate's secondary and tertiary structures and overall charge were evaluated. By using the solid–liquid interfacial shear device, the relative stability of protein candidates was measured. This technique was compared with melting temperature (Tm) data from DSC and the results from a 4-week accelerated stability study at 40°C to give relative stability based on thermal parameters. This comparison could be used to determine whether the shear device method could be used as an orthogonal method for lead antibody screening (Fig. 1).


Understanding the relationship between biotherapeutic protein stability and solid-liquid interfacial shear in constant region mutants of IgG1 and IgG4.

Tavakoli-Keshe R, Phillips JJ, Turner R, Bracewell DG - J Pharm Sci (2013)

Diagram representing comparability of thermal degradation and interfacial shear-induced aggregation for determining relative stability. The thermal degradation route is based on work on nonnative protein aggregation by Roberts and co-workers,41,42 whereas the interfacial route builds upon this background with work by Biddlecombe et al.28
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263191&req=5

fig01: Diagram representing comparability of thermal degradation and interfacial shear-induced aggregation for determining relative stability. The thermal degradation route is based on work on nonnative protein aggregation by Roberts and co-workers,41,42 whereas the interfacial route builds upon this background with work by Biddlecombe et al.28
Mentions: In this study, the effects of controlled antibody modifications TM39 and YTE40 on a drug candidate's secondary and tertiary structures and overall charge were evaluated. By using the solid–liquid interfacial shear device, the relative stability of protein candidates was measured. This technique was compared with melting temperature (Tm) data from DSC and the results from a 4-week accelerated stability study at 40°C to give relative stability based on thermal parameters. This comparison could be used to determine whether the shear device method could be used as an orthogonal method for lead antibody screening (Fig. 1).

Bottom Line: Results suggest that the techniques are orthogonal, with thermal methods based on intramolecular interaction and shear device stability based on localized unfolding revealing less stable regions that drive aggregation.Molecular modeling shows the modifications' effects on the antibody structures and indicates a possible role for Fc conformation and Fab-Fc docking in determining suspended protein stability.The data introduce the PDC value as an orthogonal stability indicator, complementary to traditional thermal methods, allowing lead antibody selection based on a more full understanding of process stability.

View Article: PubMed Central - PubMed

Affiliation: The Advanced Centre for Biochemical Engineering, University College London, Torrington Place, London, WC1E 7JE, UK; MedImmune, Granta Park, Cambridge, CB21 6GH, UK.

Show MeSH
Related in: MedlinePlus