Pharmacokinetics and Brain Uptake of an IgG-TNF Decoy Receptor Fusion Protein Following Intravenous, Intraperitoneal, and Subcutaneous Administration in Mice
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- 作者：Rachita K. Sumbria ; Qing-Hui Zhou ; Eric Ka-Wai Hui ; Jeff Zhiqiang Lu ; Ruben J. Boado ; William M. Pardridge
- 刊名：Molecular Pharmaceutics
- 出版年：2013
- 出版时间：April 1, 2013
- 年：2013
- 卷：10
- 期：4
- 页码：1425-1431
- 全文大小：274K
- 年卷期：v.10,no.4(April 1, 2013)
- ISSN：1543-8392
文摘
Tumor necrosis factor (TNF)-伪 is a proinflammatory cytokine active in the brain. Etanercept, the TNF decoy receptor (TNFR), does not cross the blood鈥揵rain barrier (BBB). The TNFR was re-engineered for BBB penetration as a fusion protein with a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb domain of the fusion protein acts as a molecular Trojan horse and mediates transport via the endogenous BBB TfR. To support future chronic treatment of mouse models of neural disease with daily administration of the cTfRMAb-TNFR fusion protein, a series of pharmacokinetics and brain uptake studies in the mouse was performed. The cTfRMAb-TNFR fusion protein was radiolabeled and injected into mice via the intravenous, intraperitoneal (IP), or subcutaneous (SQ) routes of administration at doses ranging from 0.35 to 10 mg/kg. The distribution of the fusion protein into plasma following the IP or SQ routes was enhanced by increasing the injection dose from 3 to 10 mg/kg. The fusion protein demonstrated long circulation times with high metabolic stability following the IP or SQ routes of injection. The IP or SQ routes produced concentrations of the cTfRMAb-TNFR fusion protein in the brain that exceed by 20- to 50-fold the concentration of TNF伪 in pathologic conditions of the brain. The SQ injection is the preferred route of administration, as the level of cTfRMAb fusion protein produced in the brain is comparable to that generated with intravenous injection, and at a much lower plasma area under the concentration curve of the fusion protein as compared to IP administration.