Isotonic concentrations of excipients control the dimerization rate of a therapeutic immunoglobulin G1 antibody during refrigerated storage based on their rank order of native-state interaction
| Autor: | Younhee Cho, Vladimir Spasojevic, Jon F. Cordia, Douglas D. Banks, Sarah Franc, Sun Jeonghoon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Chemistry Vapor pressure osmometry Equilibrium unfolding Excipient Protein aggregation 030226 pharmacology & pharmacy Biochemistry Dosage form 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Differential scanning calorimetry medicine Native state Biophysics Solubility Molecular Biology medicine.drug |
| Zdroj: | Protein Science. 27:2073-2083 |
| ISSN: | 0961-8368 |
| DOI: | 10.1002/pro.3518 |
| Popis: | Inert co-solutes, or excipients, are often included in protein biologic formulations to adjust the tonicity of liquid dosage forms intended for subcutaneous delivery. Despite the low concentration of their use, many of these excipients alter protein-protein interactions such as dimerization and aggregation rates of high concentration monoclonal antibody (mAb) therapeutics to varying extents during long-term refrigerated clinical storage, challenging the formulation scientist to make informed excipient selections at the earliest stages of development when protein supply and time are often limited. The objectives of this study were to better understand how isotonic concentrations of excipients influence the dimerization rates of a model mAb stored at refrigerated and room temperatures and explore protein sparing biophysical methods capable of predicting this dependence. Despite their prevalence of use in the biopharmaceutical industry, methods for assessing conformational stability such differential scanning calorimetry and isothermal equilibrium unfolding showed little predictive power and we highlight some of the assumptions and technical challenges of their use with mAbs. Conversely, measures of colloidal stability of the native-state such as preferential interaction coefficients measured by vapor pressure osmometry and solubility assessed by polyethylene-glycol induced precipitation correlated reasonably well with the mAb dimerization data and are most consistent with the excipients tested minimizing dimerization by interacting favorably with the residues comprising the protein-protein association interface. |
| Databáze: | OpenAIRE |
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