(228ef) Modeling the Aggregation and Oxidation of Therapeutic Proteins

Therapeutic proteins are the most rapidly growing class of pharmaceuticals for use in diverse clinical settings including cancer, chronic inflammatory diseases and infectious diseases. However, these proteins tend to degrade due to several mechanisms such as aggregation and oxidation during production, formulation or storage. This degradation can reduce their biological activity or cause immunological response in the patients. Here we discuss in silico molecular modeling tools to assess the risk of degradation from aggregation and oxidation, and to identify the regions of the protein responsible for them. Aggregation is assessed using Spatial-Aggregation-Propensity (SAP) model which identifies the hydrophobic patches on the protein that are prone to aggregation. Oxidation of methionine residues is assessed using molecular simulation models based on solvent accessible area and 2-shell water coordination number. We apply these models on several model proteins and therapeutic candidates and demonstrate that they are highly accurate based on comparison with experimental data. These models aid in assessing the risk of protein degradation early on in the drug development cycle and enable further protein engineering to improve stability.