Application Notes

Analysis of formulation-dependent colloidal and conformational stability of monoclonal antibodies

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1 Unfolding and Aggregation of mAbs Application Note NT-PR-005 Analysis of formulation-dependent colloidal and conformational stability of monoclonal antibodies Franziska Söltl 1 , Jonathan Derix 1 , Patrick Garidel 2 , Michaela Blech 2 and Dennis Breitsprecher 1 1 NanoTemper Technologies GmbH, Munich, Germany 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Global Bioprocess & Pharmaceutical Development, Global Formulation Development, Biberach, Germany Abstract The growing number of biological drugs such as monoclonal antibodies (mAbs), as well as the wealth of heterogeneity between mAb variants requires a thorough development process to maximize mAbs compliance with regulation. Therefore, biophysical analytical methods are required already at early stages of the development process to guide and streamline further antibody processing and to predict antibody developability. In this case study, we demonstrate how the Prometheus NT.48 can be used to predict long- term mAb stability in a formulation screen by simultaneous quantification of both, conformational and colloidal stability of biologicals in thermal gradients. Introduction Monoclonal antibodies (mAbs) constitute the majority of therapeutic biologicals today. Owed to their high specificity and potency, they are used to treat a number of diseases, ranging from different cancer types to autoimmune defects. Novel protein engineering approaches lead to a growing number of therapeutic mAbs, which can additionally be modified to be bispecific, conjugated with other biologicals or modified with small molecule drugs. The conformational and colloidal stability of antibodies are key parameters to predict their stability and also developability, since they affect the long-term storage stability which is critical for Figure 1: Relation between conformational and colloidal stability of antibodies. (A) Equilibrium and non-equilibrium states between folded and unfolded antibodies and aggregates. (B) Schematic plot showing the consequence of strong aggregation of the unfolded state. Irreversible aggregation leads to an accumulation of aggregates over time, eventually resulting in complete aggregation of the mAb. (C) Schematic representation of directed unfolding and aggregation of antibodies in a thermal gradient.

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