Molecularly specific solubilization of therapeutic antibodies

Understanding the effects of formulation excipients on protein solubility is a key part of physical chemistry and pharmaceutical sciences. While excipients are routinely employed to reduce the self-association of biologic drugs, their mechanisms of action remain poorly understood and are often assumed to be broadly nonspecific. Using a high-throughput combinatorial droplet microfluidic platform, we systematically survey and quantify how common pharmaceutical excipients affect the solubility of a diverse panel of therapeutic monoclonal antibodies (mAbs). We show that, while excipients are generally solubilizing, their effects vary substantially across different mAbs, with excipient-specific solubilization scores spanning dynamic ranges of approximately 7-fold to >200-fold across the antibody panel. Histidine, arginine and sodium chloride, in particular, engage in interactions characterized by unique molecular specificity, whereas sucrose effects are largely governed by nonspecific, solvent-mediated interactions. Correlating excipient performance with dynamical mAb molecular features from solvated full-length homology models allows us to dissect and quantify the relative contributions of molecular features governing excipient-mediated solubilization. We envision this new physicochemical understanding lays the groundwork for rational excipient selection and bespoke formulation design, with direct implications for accelerating protein therapeutic development for preclinical scenarios.