Biophysical Determinants for the Viscosity of Concentrated Monoclonal Antibody Solutions

Monoclonal antibodies (mAbs) are particularly relevantfor therapeuticsdue to their high specificity and versatility, and mAb-based drugsare hence used to treat numerous diseases. The increased patient complianceof self-administration motivates the formulation of products for subcutaneous(SC) administration. The associated challenge is to formulate highlyconcentrated antibody solutions to achieve a significant therapeuticeffect, while limiting their viscosity and preserving their physicochemicalstability. Protein-protein interactions (PPIs) are in factthe root cause of several potential problems concerning the stability,manufacturability, and delivery of a drug product. The understandingof macroscopic viscosity requires an in-depth knowledge on proteindiffusion, PPIs, and self-association/aggregation. Here, we studythe self-diffusion of different mAbs of the IgG1 subtype in aqueoussolution as a function of the concentration and temperature by quasi-elasticneutron scattering (QENS). QENS allows us to probe the short-timeself-diffusion of the molecules and therefore to determine the hydrodynamicmAb cluster size and to gain information on the internal mAb dynamics.Small-angle neutron scattering (SANS) is jointly employed to probestructural details and to understand the nature and intensity ofPPIs. Complementary information is provided by molecular dynamics(MD) simulations and viscometry, thus obtaining a comprehensive pictureof mAb diffusion.

Automated summary

Monoclonal antibodies (mAbs) are widely used for therapeutic purposes due to their high specificity and versatility. In this study, the self-diffusion of different mAbs was investigated using quasi-elastic neutron scattering (QENS) and small-angle neutron scattering (SANS) techniques. The results provide insights into the hydrodynamic properties, protein-protein interactions (PPIs), and internal dynamics of mAbs. This comprehensive understanding is crucial for formulating highly concentrated antibody solutions with optimal therapeutic effects.