Quantifying molecular specificity in excipient-driven antibody solubilization
TL;DR
It is shown that excipient-mediated solubilization of therapeutic antibodies is markedly molecularly specific, and the integration of high-throughput experimentation with molecular feature analysis offers a foundation for improving the understanding and prediction of antibody-specific formulation behavior.
Abstract
ABSTRACT Excipients are widely used to suppress the self-association of therapeutic proteins, yet their mechanisms of action are not well understood and often assumed to be nonspecific. Here we show that excipient-mediated solubilization of therapeutic antibodies is markedly molecularly specific. Using a high-throughput combinatorial droplet microfluidic platform, we systematically quantify the effects of common pharmaceutical excipients across a diverse panel of monoclonal antibodies (mAbs). Although all studied excipients enhance solubility, their effects can vary significantly between antibodies, spanning dynamic ranges from approximately 7-fold to over 200-fold. Integrating experimental solubilization measurements with sequence- and structure-derived molecular descriptors, we identify interpretable physicochemical determinants underlying excipient responses; for example, the histidine effect is strongly dependent on mAb dipole moment. Our findings reveal trends that highlight the molecular specificity and complexity of antibody–excipient interactions, as well as the limitations of purely generic formulation rules. Overall, this study provides a quantitative framework for analyzing excipient effects across diverse antibodies and supports the development of predictive approaches for rational formulation design. The integration of high-throughput experimentation with molecular feature analysis offers a foundation for improving our understanding and prediction of antibody-specific formulation behavior.
