Quantifying molecular specificity in excipient-driven antibody solubilization.

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.