Aggregation Propensity: Characterization of Monoclonal Antibody Stability

Abstract

The study of aggregation propensity of a monoclonal antibody (mAb) and its sensitivity to applied stresses is believed to correlate with the overall stability of the mAb. As such, the aggregation propensity under various stresses can be used to develop a unique aggregation metric to rank order a panel of mAbs based on their stability. Often in a drug discovery campaign, multiple mAbs may imbue the desired in vivo efficacy, at which point identification of the most developable mAb becomes an important factor to decide on a single candidate for further development. This study focuses on the assessment of the stability of a panel of mAbs, by defining their propensity for aggregation along the native and non-native aggregation pathways. Kosmotrope based solubility evaluates a mAb’s colloidal stability, or propensity for native aggregation, while differential scanning fluorescence reports conformational stability, or propensity for non-native aggregation. By combining the conformational and colloidal stability metrics, an overall aggregation propensity profile can be generated for a mAb. To parse out further information on stability, the mAb panel was exposed to a series of stresses, which mimic stresses a mAb based drug would be exposed to during manufacturing and storage. After exposure to stress, the mAb panel was then monitored for change in apparent colloidal and conformational stability. There was no variation in the stability metrics measured, as a function of stress. However, observed precipitation denoted differential sensitivity to the stresses. Combining observational data with the stability metrics measured, allowed for rank ordering of aggregation propensity, and overall stability.