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Polyol-Induced Increases in Thermal Stability of Antibodies by DSC

Aggregation of proteins has been an intense area of study largely due to the growth of the biotechnology industry. As protein therapeutics are developed, aggregation must be monitored and reduced as it can potentially cause immunogenicity1 as well as a possible decrease in activity.2,3 One of the ways aggregation is controlled is through the use of osmolytes as excipients.4 Many excipients have been shown to induce stability through preferential exclusion. A particular subclass of these molecules includes polyols and carbohydrates.5,6 Polyols are typically added to protein formulations in order to increase tonicity and improve stability.

The addition of polyol osmolytes has been shown to prevent aggregation, retain activity, inhibit chemical degradation, enhance the refolding of proteins,7 and increase the thermal stability of proteins.4-6,8-11 It has been shown that the more hydroxyl groups on the carbon chain of the polyol, the greater the thermodynamic stability that can be induced. This has been attributed to an entropic effect where the polyol is excluded from the surface of the protein. The polyol has a greater impact on the waterpeptide interactions than it does on the interactions with the nonpolar groups that are exposed when the protein is denatured.12

To date, no systematic study has been performed using multiple proteins to address whether different stereoisomers of a polyol would induce more or less thermal stability on a protein. The goal of the study was to understand how the size of a polyol and orientation of the hydroxyl group influence the amount of thermal stability that could be induced upon seven monoclonal antibodies of different isotypes. In order to monitor thermal stability, differential scanning calorimetry (DSC) has been employed. DSC has been used to monitor the unfolding of proteins due to heat denaturation in order to study the unfolding of the domains of an antibody,13 monitor thermal reversibility,14-16 and screen formulations for excipients. 17,18