AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys.
AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys.
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DOI：
10.1016/j.jbiotec.2009.08.019
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发表时间：
2009-10-26
影响因子：
4.1
通讯作者：
Pardridge, William M.
中科院分区：
文献类型：
--
作者：
Boado, Ruben J.;Hui, Eric K. -W.;Lu, Jeff Zhiqiang;Pardridge, William M.
由于酶缺乏穿过血脑屏障（BBB）的运输，酶替代疗法对大脑无效。重组蛋白（例如溶酶体酶、艾杜糖醛酸酶）可以穿透人类血脑屏障，将蛋白质重新设计为 IgG 融合蛋白，其中 IgG 部分靶向内源性血脑屏障转运系统。 IgG 充当分子特洛伊木马，将融合蛋白运送到大脑中。 AGT-181是人艾杜糖醛酸酶和针对人胰岛素受体的嵌合单克隆抗体的基因工程融合蛋白。成年恒河猴重复静脉注射 0.2-20 mg/kg 剂量的 AGT-181。慢性AGT-181给药在任何剂量下都没有产生毒性，器官组织学没有变化，血浆或脑脊液葡萄糖没有变化，也没有明显的免疫反应。根据血浆免疫反应性 AGT-181 或血浆艾杜糖醛酸酶活性的测量，AGT-181 被迅速从血浆中去除。血浆药代动力学分析显示其具有较高的全身分布容积和与小分子相当的清除率。安全药理学研究为 AGT-181 未来药物开发奠定了基础，作为治疗 Hurler 综合征大脑的新方法。
Enzyme replacement therapy is not effective for the brain, owing to the lack of transport of the enzyme across the blood-brain barrier (BBB). Recombinant proteins such as the lysosomal enzyme, iduronidase, can penetrate the human BBB, following the re-engineering of the protein as an IgG fusion protein, where the IgG moiety targets an endogenous BBB transport system. The IgG acts as a molecular Trojan horse to ferry the fused protein into brain. AGT-181 is a genetically engineered fusion protein of human iduronidase and a chimeric monoclonal antibody against the human insulin receptor. Adult Rhesus monkeys were administered repeat intravenous doses of AGT-181 ranging from 0.2–20 mg/kg. Chronic AGT-181 dosing resulted in no toxicity at any dose, no changes in organ histology, no change in plasma or cerebrospinal fluid glucose, and no significant immune response. AGT-181 was rapidly removed from plasma, based on measurements of either plasma immunoreactive AGT-181 or plasma iduronidase enzyme activity. Plasma pharmacokinetics analysis showed a high systemic volume of distribution, and a clearance rate comparable to a small molecule. The safety pharmacology studies provide the basis for future drug development of AGT-181 as a new therapeutic approach to treatment of the brain in Hurler’s syndrome.
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DOI：
10.1073/pnas.88.21.9695
发表时间：
1991-11-01
影响因子：
11.1
作者：
SCOTT, HS;ANSON, DS;HOPWOOD, JJ
通讯作者：
HOPWOOD, JJ
影响因子：
2
作者：
Tsukimura, Takahiro;Tajima, Youichi;Sakuraba, Hitoshi
通讯作者：
Sakuraba, Hitoshi
影响因子：
4.2
作者：
Wraith, JE
通讯作者：
Wraith, JE
影响因子：
3.8
作者：
Boado, Ruben J.;Zhang, Yufeng;Pardridge, William M.
通讯作者：
Pardridge, William M.
影响因子：
3.7
作者：
Pardridge, William M.;Boado, Ruben J.
通讯作者：
Boado, Ruben J.