An Unaddressed Scientific Need: Predicting Human Bioavailability of Subcutaneously Administered Fc-Fusion Proteins and Monoclonal Antibodies

There has been an increasing trend towards subcutaneous (SC) delivery of therapeutic proteins in recent years versus intravenous (IV) administration. The prediction of bioavailability is one of the major barriers in clinical translation of SC administered therapeutic proteins. Although monkeys and minipigs outperform other animal model, no animal model is acceptable for a reliable prediction of human bioavailability of SC administered proteins. In this study, we collected human SC bioavailability of 98 monoclonal antibodies and 19 Fc-fused proteins. We explored the relationships between SC bioavailability and physicochemical properties (hydrophobicity and electric charges of Fv, Fab and Fc domains, isoelectric point, and FcRn binding affinity). Furthermore, we explored the potential relationships between SC bioavailability and the dose of therapeutic proteins and human systemic clearance. The established relationships can be used to roughly estimate the SC bioavailability of Fc-fused proteins.