Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors

The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose–response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose–response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight^{^−0.25} (AS by W^{^−0.25}) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors. Graphical Abstract: [Figure not available: see fulltext.].