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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; (2014) Understanding the Relationship Between Biotherapeutic Protein Stability and Solid-Liquid Interfacial Shear in Constant Region Mutants of IgG1 and IgG4. J Pharm Sci , 103 (2) pp. 437-444. 10.1002/jps.23822. Green open access

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Abstract

Relative stability of therapeutic antibody candidates is currently evaluated primarily through their response to thermal degradation, yet this technique is not always predictive of stability in manufacture, shipping, and storage. A rotating disk shear device is proposed that produces defined shear conditions at a known solid-liquid interface to measure stability in this environment. Five variants of IgG1 and IgG4 antibodies were created using combinations of two discrete triple amino acid sequence mutations denoted TM and YTE. Antibodies were ranked for stability based on shear device output (protein decay coefficient, PDC), and compared with accelerated thermal stability data and the melting temperature of the CH2 domain (Tm 1) from differential scanning calorimetry to investigate technique complimentarity. 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. © 2013 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Type: Article
Title: Understanding the Relationship Between Biotherapeutic Protein Stability and Solid-Liquid Interfacial Shear in Constant Region Mutants of IgG1 and IgG4.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/jps.23822
Publisher version: http://dx.doi.org/10.1002/jps.23822
Additional information: © 2013 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: IgG antibody, biopharmaceuticals characterization, calorimetry (DSC), in silico modeling, molecular modeling, protein aggregation, protein structure, thermal analysis
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/1419242
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