Developing a molecular interaction-based toolkit for a soft matter physics driven approach to the formulation of future antibody-based drugs

Monoclonal antibodies (mAbs) are engineered proteins that can serve as substitute antibodies in the immune system, attracting enormous attention from pharmaceutical industry and fundamental biophysics due to their potential in e.g. cancer treatment.However, their use in concentrated formulations is often severely limited due to i. high turbidity and ii. high viscosity.

There is currently no established approach to understand the origin of this behaviour or to predict it from low concentration data and mAb molecular structure.Based on preliminary experiments we speculate that both originate from the presence of larger clusters, with turbidity linked to large-scale density fluctuations induced by an underlying liquid-liquid phase separation and high viscosity arising from transient clusters caused by (patchy) attractions between mAbs.We propose to establish methods based primarily on Small Angle X-ray Scattering to detect and distinguish between attraction-induced clusters and near-critical fluctuations.

We use Light Scattering, microrheology and Neutron Spin Echo to characterise structural and dynamic properties over the required length and time scales.

Combining experiments with theories and simulations for interacting, self-assembling mAbs will then allow to develop a quantitative understanding of the link between molecular structure, interaction potential, thermodynamic stability, cluster size distribution and viscosity of mAbs as a function of key solution parameters.