Electrostatics and viscosity are strongly linked in concentrated antibody solutions

TL;DR

This study investigates how electrostatic interactions influence the viscosity of concentrated antibody solutions, revealing that explicit modeling of charge heterogeneity and long-range Coulomb forces is crucial for accurate predictions.

Contribution

The paper demonstrates that explicit treatment of heterogeneous charges and long-range electrostatics is essential for accurately modeling antibody solution viscosity, advancing the understanding of their rheological behavior.

Findings

Implicit electrostatic models fail to match experimental viscosity data.

Explicit inclusion of counterions and salt ions improves model accuracy.

Transient correlated antibody structures significantly impact viscosity.

Abstract

Monoclonal antibodies are among the most promising therapeutic agents in modern medicine, yet their formulation into high-concentration solutions for subcutaneous self-administration poses a major challenge. A key obstacle is the marked increase in viscosity often observed under these conditions. To gain deeper insights into this phenomenon, coarse-grained models derived from soft matter physics have been widely employed. However, these models have yet to be fully leveraged for analyzing the rheological collective properties of such systems. In this study, using molecular dynamics simulations, we directly compute the antibody solution viscosity by starting from commonly used models in which electrostatic interactions are treated through effective screened Coulomb potentials. We demonstrate that this approach fails to reproduce experimental evidence and we show, by analyzing stress correlations in the system, that it is necessary to treat the heterogeneously charged domains explicitly, also including counterions and salt ions, and to properly account for the long-ranged nature of Coulomb interactions. By thoroughly analyzing the microscopic structure of the system, we further reveal the presence of transient strongly correlated antibodies which would not be present if charges were treated implicitly, thus pointing to a prominent role of electrostatics in determining the increase in viscosity at high concentrations. By taking advantage of our realistic treatment, new approaches can be devised to ensure that antibody solutions exhibit the desired characteristics for their intended broad use and effective deployment.