Protein formulations at high concentrations (&gt;200 mg/ml), particularly of monoclonal antibodies, are strongly desired for subcutaneous drug delivery for the treatment of many diseases, including cancer and autoimmune diseases. However, at high concentrations, attractive hydrophobic and electrostatic protein-protein interactions (PPI) can cause the formation of protein networks that drastically raise the solution viscosity and also produce irreversible aggregates. Herein, we demonstrate the effects of various classes of small molecule co-solutes on the viscosity and stability of concentrated mAb solutions formed by filtration techniques. For the mAbs studied, significant improvements in viscosity and stability are seen for co-solutes, such as arginine, histidine and imidazole, that contain both a formal charge and a functional group that preferentially interacts with hydrophobic residues. These co-solutes likely disrupt protein networks by weakening attractive hydrophobic and electrostatic PPI. In contrast, electrolytes without a hydrophobic region (such as lysine and inorganic salts) as well as uncharged co-solutes (such as alanine and trehalose) did not improve protein stability or viscosity. The viscosity of the protein solutions were measured by capillary rheometry,  the stability by size exclusion chromatography after accelerated storage and the interactions by turbidimetry and dynamic light scattering to obtain the diffusion interaction parameter, k<sub>D</sub>.

Effects of small molecule co-solutes on the viscosity and stability of highly concentrated solutions of monoclonal antibodies

251st National Meeting (2016)

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