RT Journal Article
SR Electronic
T1 Effect of Size on Solid Tumor Disposition of Protein Therapeutics
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.087809
DO 10.1124/dmd.119.087809
A1 Zhe Li
A1 Yingyi Li
A1 Hsuan-Ping Chang
A1 Hsueh-Yuan Chang
A1 Leiming Guo
A1 Dhaval K Shah
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/08/06/dmd.119.087809.abstract
AB Here we have evaluated the effect of size on tumor disposition of protein therapeutics. Plasma and tumor PK of trastuzumab (~150 kDa), FcRn non-binding trastuzumab (~150 kDa), F(ab)2 fragment of trastuzumab (~100 kDa), Fab fragment of trastuzumab (~50 kDa), and trastuzumab scFv (~27 kDa) was evaluated in antigen (i.e. HER2) overexpressing (N87) and antigen non-expressing (MDA-MB-468) tumor bearing mice. The observed data was used to develop 'maximum tumor uptake vs. molecular weight' and 'tumor-to-plasma AUC ratio vs. molecular weight' relationships. When comparing the PK of different size FcRn non-binding molecules in target expressing tumor, it was found that ~100 kDa is an optimal size to achieve maximum tumor uptake and ~50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio of protein therapeutics. The PK data was also used to validate a systems pharmacokinetics (PK) model for tumor disposition of different size protein therapeutics. It was found that the PK model was able to a priori predict the PK of all five molecules in both tumor types reasonably well (within 2-3 fold). In addition, the model was also able to capture the 'bell-shaped' relationships observed between maximum tumor uptake and molecular weight, and tumor-to-plasma AUC ratio and molecular weight. As such, our results provide an unprecedented insight into the effect of size and target engagement on tumor PK of protein therapeutics. Our results also provide further validation of the tumor disposition model, which can be used to support discovery, development, and preclinical-to-clinical translation of different size protein therapeutics.SIGNIFICANCE STATEMENT This manuscript highlights the importance of molecular size and target engagement on tumor disposition of protein therapeutics. Our results suggest that ~100 kDa is an optimal size to achieve maximum tumor uptake and ~50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio for non-FcRn binding targeted protein therapeutics. We also demonstrate that systems pharmacokinetics model developed to characterize tumor disposition of protein therapeutics can a priori predict the disposition of different size protein therapeutics in target expressing and target non-expressing solid tumors.