Computational Screening for mAb Colloidal Stability with Coarse-Grained, Molecular-Scale Simulations.

Monoclonal antibodies (mAbs) are an important modality of protein therapeutics with broad applications for numerous diseases. However, colloidal instabilities occurring at high protein concentrations can limit the ability to develop stable, high-concentration liquid dosage forms that are required for patient-centric, device-mediated products. Therefore, it is advantageous to identify colloidally stable mAbs early in the discovery process to ensure that they are selected for development. Experimental screening for colloidal stability can be time- and resource-consuming and is most feasible at the later stages of drug development due to material requirements. Alternatively, computational approaches have emerging potential to provide efficient screening and focus developmental efforts on mAbs with the greatest developability potential, while providing mechanistic relationships for colloidal instability. In this work, coarse-grained, molecular-scale models were fine-tuned to screen for colloidal stability at amino-acid resolution. This model parameterization provides a framework to screen for mAb self-interactions and extrapolate to bulk solution behavior. This approach was applied to a wide array of mAbs under multiple buffer conditions, demonstrating the utility of the presented computational approach to augment early candidate screening and later formulation strategies for protein therapeutics.