In the present report, two formulation strategies, based on different aggregation models, were compared for their ability to quickly predict which excipients (cosolutes) would minimize the aggregation rate of an immunoglobulin G1 monoclonal antibody (mAb-1) stored for long term at refrigerated and room temperatures. The first formulation strategy assumed that a conformational change to an aggregation-prone intermediate state was necessary to initiate the association process and the second formulation strategy assumed that protein self-association was instead controlled by the solubility of the native state. The results of these studies indicate that the stabilizing effect of excipients formulated at isotonic concentrations is derived from their ability to solubilize the native state, not by the increase of protein conformational stability induced by their presence. The degree the excipients solvate the native state was determined from the apparent transfer free energy of the native state from water into each of the excipients. These values for mAb-1 and two additional therapeutic antibodies correlated well to their long-term 4°C and room temperature aggregation data and were calculated using only the literature values for the apparent transfer free energies of the amino acids into the various excipients and the three-dimensional models of the antibodies.
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