Highly concentrated (&gt; 200 mg/mL) monoclonal antibody (mAb) formulations with low viscosities and high stability 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 protein-protein interactions (PPI), structure, and self-association behavior as assessed through small-volume high-throughput techniques such as dynamic light scattering (DLS) and static light scattering (SLS). We interpret the mAb diffusion and light scattering behavior in the context of thermodynamic and hydrodynamic interactions, in order to develop a predictive fundamental understanding of co-solute effects on the mAb viscosity and stability. We demonstrate that the viscosity reduction is correlated with the disruption of mAb self-association and attractive PPI, as directly probed by SLS and DLS. Finally, we demonstrate that these changes in the PPI and viscosity are a function of the co-solute structure.<br/>

Understanding co-solutes effects on viscosity and protein interactions in highly concentrated monoclonal antibodies through protein structure and dynamics

255th National Meeting (2018)

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