Two formulation strategies, based on different aggregation models, were compared for their ability to predict which co-solutes would minimize the aggregation rate of an IgG1 monoclonal antibody (mAb-1) stored long term at refrigerated and room temperatures. These studies indicate that the stabilizing effect of co-solutes formulated at isotonic concentrations is derived from their ability to solubilize the native state ensemble, not by the increase of protein conformational stability induced by their presence. The degree the co-solutes solvate the native state was estimated from the apparent transfer free energy of the native state from water into each of the co-solutes. These values for mAb-1 and two additional mAbs correlated well to their long term 4 �C and room temperature aggregation data and were calculated using only the apparent transfer free energies of the amino acid side-chains and peptide backbone unit into the various co-solutes and the three-dimensional models of the antibodies.

Native-state solubility and transfer free energy as predictive tools for selecting co-solutes to include in protein formulation development

245th National Meeting (2013)

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