Biophysical Determinants for the Viscosity of Concentrated Monoclonal Antibody Solutions

Abstract

Monoclonal antibodies (mAbs) are particularly relevant for therapeutics due to their high specificity and versatility, and mAb-based drugs are hence used to treat numerous diseases. The increased patient compliance of self-administration motivates the formulation of products for subcutaneous (SC) administration. The associated challenge is to formulate highly concentrated antibody solutions to achieve a significant therapeutic effect, while limiting their viscosity and preserving their physicochemical stability. Protein−protein interactions (PPIs) are in fact the root cause of several potential problems concerning the stability, manufacturability, and delivery of a drug product. The understanding of macroscopic viscosity requires an in-depth knowledge on protein diffusion, PPIs, and self-association/aggregation. Here, we study the self-diffusion of different mAbs of the IgG1 subtype in aqueous solution as a function of the concentration and temperature by quasi-elastic neutron scattering (QENS). QENS allows us to probe the short-time self-diffusion of the molecules and therefore to determine the hydrodynamic mAb cluster size and to gain information on the internal mAb dynamics. Small-angle neutron scattering (SANS) is jointly employed to probe structural details and to understand the nature and intensity of PPIs. Complementary information is provided by molecular dynamics (MD) simulations and viscometry, thus obtaining a comprehensive picture of mAb diffusion.

Elucidation of the Reversible Self-Association Interface of a Diabody–Interleukin Fusion Protein Using Hydrogen-Exchange Mass Spectrometry and In Silico Modeling

“…Given the complex charge-variant profile of FP-1 discussed above, we posit that the asymmetric surface charge on the diabody and the IL-22 domains result in attractive long-range electrostatic interactions between surfaces with complementary charge distribution. This is consistent with previously reported results, demonstrating the role of electrostatic interactions in driving self-association and high viscosity in mAbs via cluster formation . Once in close proximity, short-range hydrophobic interactions become entropically favored and can lead to the formation of FP-1 dimers via the solvent-exposed loops of the V L domain.…”

Possible Approaches to Studying the Influence of Magnetic Fields and Mechanical Effects on the Physicochemical Properties of Aqueous IgG Colloids

“…This observation is in good agreement with known data; it was previously shown that the minimum IgG concentration detectable with viscometry is ~0.1 mg/mL [38]. It should be noted that the viscosity of colloids depends not only on concentration, but also on temperature [39], pH [40], ionic strength, cation-anion environment [41], and the like [42][43][44]. Progress in viscometry research can be found in a literature review [45].…”

Introducing the Molecular Pharmaceutics Special Issue on Industrial Drug Delivery─In Silico to Bedside

“…To this end, overcoming the often steep viscosity increase as a function of concentration is key to fitting the dose into a pen injector. Mosca et al provided key insights into the biophysical root causes of this phenomenon in this article series.…”