Molecularly specific solubilization of therapeutic antibodies

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Abstract
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.
Funding Information
  • European Research Council (101001615)

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