Effect of Size on Solid Tumor Disposition of Protein Therapeutics

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Zhe LiDhaval K Shah

Abstract

In this study, we evaluated the effect of size on tumor disposition of protein therapeutics, including the plasma and tumor pharmacokinetics (PK) of trastuzumab (∼150 kDa), FcRn-nonbinding trastuzumab (∼150 kDa), F(ab)2 fragment of trastuzumab (∼100 kDa), Fab fragment of trastuzumab (∼50 kDa), and trastuzumab scFv (∼27 kDa) in both antigen (i.e., HER2)-overexpressing (N87) and antigen-nonexpressing (MDA-MB-468) tumor-bearing mice. The observed data were used to develop the maximum tumor uptake versus molecular weight and tumor-to-plasma area under the curve (AUC) ratio versus molecular weight relationships. Comparison of the PK of different sizes of FcRn nonbinding molecules in target-expressing tumor showed 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 were also used to validate a systems PK model for tumor disposition of different-sized protein therapeutics. The PK model was able to predict a priori the PK of all five molecules in both tumor types reasonably well (within 2- to 3-fold). In addition, the model captured the bell-shaped relationships observed between maximum tumor uptake and mol...Continue Reading

References

Sep 10, 2005·Nature Biotechnology·Philipp Holliger, Peter J Hudson
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Mar 23, 2012·Nature Reviews. Cancer·Andrew M ScottLloyd J Old
Jul 7, 2017·Pharmaceutical Research·Zhe LiDhaval K Shah
Feb 8, 2019·Immunotherapy·Kanta TsumotoMasahiro Tomita

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