(463d) Colloidal-Scale Modeling of Monoclonal Antibodies: Aggregation and Rheological Properties for Therapeutic Use

Monoclonal antibodies (mAbs) are a powerful platform for a wide range of therapeutics for treating rheumatoid arthritis, multiple sclerosis, cancers, and COVID, among others. Subcutaneous injection of mAb solutions have a significantly lower burden of treatment for patients relative to intravenous administration and thus helps ensure medication adherence. One long-standing challenge in subcutaneous delivery of therapeutic mAbs is the high concentration necessary for efficacy in one injection. The high concentration and colloidal-scale interactions between mAbs can lead to formation of large aggregates that in turn drive up viscosity dramatically, sometimes making pressure-driven injection intractable. We employ colloidal-scale modeling of mAbs in a large-scale dynamic simulation to study aggregation and to predict and engineer bulk rheological properties of mAb solutions. Utilizing LAMMPS, we model individual proteins as colloids with patchy and bumpy surfaces endowed with attractive and repulsive properties. We identify assembly morphology and structure and connect it to the strength of interaction potential and patchy surface morphology. By tuning these parameters, we identify elements of a phase diagram showing equilibrium and non-equilibrium behavior including cluster, networks and gels. We characterize microscopic changes in the aggregating structure by tracking particle positions, coordination numbers, and bond dynamics and correlate these with the resulting mesoscale structure and macroscopic properties. These predictions offer potential therapeutic strategies to steer assembled structures towards specific morphologies.