Pharmacokinetics and brain uptake of an IgG-TNF decoy receptor fusion protein following intravenous, intraperitoneal, and subcutaneous administration in mice.
Pharmacokinetics and brain uptake of an IgG-TNF decoy receptor fusion protein following intravenous, intraperitoneal, and subcutaneous administration in mice.
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小鼠静脉内、腹膜内和皮下给药后 IgG-TNF 诱饵受体融合蛋白的药代动力学和脑摄取。
DOI：
10.1021/mp400004a
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发表时间：
2013
影响因子：
4.9
通讯作者：
Pardridge,WilliamM
中科院分区：
文献类型：
--
作者：
Sumbria,RachitaK;Zhou,Qing-Hui;Hui,EricKa-Wai;Lu,JeffZhiqiang;Boado,RubenJ;Pardridge,WilliamM
肿瘤坏死因子(TNF)-α是一种在大脑中活跃的促炎细胞因子。依那西普，TNF诱饵受体（TNFR），不能穿过血脑屏障（BBB）。将该TNFR与小鼠转铁蛋白受体（TfR）嵌合单克隆抗体（mAb）进行融合，使其能够穿透血脑屏障，该融合蛋白被命名为cTfRMAb-TNFR。融合蛋白的cTfRMAb结构域作为分子特洛伊木马，介导内源性血脑屏障TfR的转运。为了支持未来通过每日给药cTfRMAb-TNFR融合蛋白对神经疾病小鼠模型的慢性治疗，在小鼠中进行了一系列的药代动力学和脑摄取研究。cTfRMAb-TNFR融合蛋白被放射性标记，并通过静脉、腹腔（IP）或皮下（SQ）给药途径注射到小鼠体内，剂量范围为0.35至10 mg/kg。将注射剂量从3 mg/kg增加到10 mg/kg，可增强融合蛋白沿IP或SQ途径进入血浆的分布。融合蛋白在IP或SQ注射途径下表现出长循环时间和高代谢稳定性。IP或SQ途径在脑内产生的cTfRMAb-TNFR融合蛋白浓度超过脑病理条件下TNFα浓度的20- 50倍。SQ注射是首选的给药途径，因为脑内产生的cTfRMAb融合蛋白水平与静脉注射产生的水平相当，并且与IP给药相比，融合蛋白浓度曲线下的血浆区域要小得多。
Tumor necrosis factor (TNF)-α is a proinflammatory cytokine active in the brain. Etanercept, the TNF decoy receptor (TNFR), does not cross the blood–brain 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 TNFα 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.