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: Banks DD; Department of Biologics Drug Product Development, Celgene Corp, 10300 Campus Point Drive Suite 100, San Diego, California, 92121., Cordia JF; Department of Biologics Drug Product Development, Celgene Corp, 10300 Campus Point Drive Suite 100, San Diego, California, 92121., Spasojevic V; Department of Biologics Drug Product Development, Celgene Corp, 10300 Campus Point Drive Suite 100, San Diego, California, 92121., Sun J; Department of Biotherapeutics, Celgene Corp, 10300 Campus Point Drive Suite 100, San Diego, California, 92121., Franc S; Department of Biologics Drug Product Development, Celgene Corp, 10300 Campus Point Drive Suite 100, San Diego, California, 92121., Cho Y; Department of Biologics Drug Product Development, Celgene Corp, 10300 Campus Point Drive Suite 100, San Diego, California, 92121.
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2018 Dec; Vol. 27 (12), pp. 2073-2083.
DOI: 10.1002/pro.3518
Abstrakt: 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.
(© 2018 The Protein Society.)
Databáze: MEDLINE
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