Comparison of Blood-Brain Barrier Transport of Glial-Derived Neurotrophic Factor (GDNF) and an IgG-GDNF Fusion Protein in the Rhesus Monkey
Comparison of Blood-Brain Barrier Transport of Glial-Derived Neurotrophic Factor (GDNF) and an IgG-GDNF Fusion Protein in the Rhesus Monkey
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DOI：
10.1124/dmd.109.028787
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发表时间：
2009-12-01
影响因子：
3.9
通讯作者：
Pardridge, William M.
中科院分区：
文献类型：
--
作者：
Boado, Ruben J.;Pardridge, William M.
胶质源性神经营养因子 (GDNF) 的脑药物开发因缺乏该蛋白穿过血脑屏障 (BBB) 的运输而受到阻碍。通过将神经营养素重新设计为与针对人胰岛素受体 (HIR) 的基因工程单克隆抗体 (MAb) 的融合蛋白，GDNF 跨血脑屏障转运成为可能，该抗体通过内源性胰岛素受体上的血脑屏障。目前的工作旨在比较 GDNF 和 HIR MAb-GDNF 融合蛋白的体内 BBB 转运。由于 HIR MAb 与胰岛素受体结合的物种特异性，本研究在成年恒河猴中进行。测定人 IgG1 的脑摄取量以评估脑血浆容量标记物的摄取量。 GDNF的脑清除率与IgG1的清除率没有差异，这表明GDNF在体内不穿过灵长类动物BBB。相比之下，HIR MAb-GDNF 融合蛋白的 BBB 转运通过胶片和乳剂放射自显影以及毛细管耗竭方法显示。在大脑摄取增加的同时，GDNF 与 HIR MAb 的融合导致肝脏、脾脏和肾脏对 GDNF 的摄取减少。 HIR MAb-GDNF 融合蛋白的施用对血糖控制没有影响。脑摄取参数显示，0.2mg/kg的HIR MAb-GDNF融合蛋白的全身剂量可以使人脑中GDNF的脑浓度增加10倍。
The brain drug development of glial-derived neurotrophic factor (GDNF) is prevented by the lack of transport of this protein across the blood-brain barrier (BBB). GDNF transport across the BBB can be made possible by re-engineering the neurotrophin as a fusion protein with a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR), which crosses the BBB on the endogenous insulin receptor. The present work was designed to compare the BBB transport in vivo of GDNF and the HIR MAb-GDNF fusion protein. Owing to species specificity of HIR MAb binding to the insulin receptor, the present studies were performed in the adult rhesus monkey. The brain uptake of human IgG1 was determined to assess the uptake of a brain plasma volume marker. The brain clearance of GDNF was no different from the clearance of the IgG1, which indicated GDNF does not cross the primate BBB in vivo. In contrast, BBB transport of the HIR MAb-GDNF fusion protein was shown with film and emulsion autoradiography, as well as the capillary depletion method. In parallel with the increased brain uptake, fusion of the GDNF to the HIR MAb resulted in a decrease in the uptake of GDNF by liver, spleen, and kidney. Administration of the HIR MAb-GDNF fusion protein had no effect on glycemic control. The brain uptake parameters show that a systemic dose of the HIR MAb-GDNF fusion protein of 0.2 mg/kg may generate a 10-fold increase in the cerebral concentration of GDNF in the human brain.