Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies Using Human Intravenous Clearance or Antibody Isoelectric Point.

There has been an increasing trend towards subcutaneous (SC) delivery of fusion proteins and monoclonal antibodies (mAbs) 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 due to a lack of reliable in vitro and preclinical in vivo predictive models. In this study, we explored the relationships between human SC bioavailability and physicochemical or pharmacokinetic properties of 19 Fc- or albumin-fusion proteins and 98 monoclonal antibodies. An inverse linear correlation was observed between human SC bioavailability and intravenous clearance (CL) or isoelectric point (pI). Multivariate regression models were developed using intravenous CL and pI of a training set (N = 59) as independent variables. The predictive models of mAbs were validated with an independent test set (N = 33). Two linear regression models resulted in 24 (73%) and 27 (82%) among 33 predictions within 0.8- to 1.2-fold deviations. Due to the small sample size of dataset, regression model validation was not conducted for fusion proteins. Overall, this study demonstrated that CL- and pI-based multivariate regression models could be used to predict human SC bioavailability of mAbs.