Understanding the relationship between biotherapeutic protein stability and solid-liquid interfacial shear in constant region mutants of IgG1 and IgG4.
Bottom Line: Five variants of IgG1 and IgG4 antibodies were created using combinations of two discrete triple amino acid sequence mutations denoted TM and YTE.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.
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
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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).
Affiliation: The Advanced Centre for Biochemical Engineering, University College London, Torrington Place, London, WC1E 7JE, UK; MedImmune, Granta Park, Cambridge, CB21 6GH, UK.