Highly concentrated (&gt; 200 mg/mL) monoclonal antibody (mAb) formulations with low viscosities are strongly desired for subcutaneous drug delivery for the treatment of diseases such as cancer. Small-molecule co-solutes such as arginine and various electrolytes have in some cases been shown to greatly reduce the viscosity of concentrated mAbs. However, the mechanism by which co-solutes modify mAb viscosity is not well understood. Herein, we investigate the effects of several amino acids and inorganic ionic co-solutes on the viscosity of mAbs up to 250 mg/mL. We relate the viscosities to measurable changes in the mAb structure and protein-protein interactions (PPI) in order to develop a hierarchical understanding of the co-solute effects on the mAb behavior. We demonstrate that the viscosity reduction is correlated with the disruption of mAb network formation, as probed by static light scattering, dynamic light scattering and rheology. We also show that the changes in the scale and strength of the mAb network are correlated with modification of the PPI strength at short to long length scales, as revealed by small-angle X-ray scattering. Finally, we demonstrate that these changes in the PPI and viscosity are a function of the co-solute structure.

Effect of co-solutes on viscosity and structure of highly concentrated monoclonal antibodies

253rd National Meeting (2017)

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