Insulin Receptor Antibody-Iduronate 2-Sulfatase Fusion Protein: Pharmacokinetics, Anti-Drug Antibody, and Safety Pharmacology in Rhesus Monkeys
Insulin Receptor Antibody-Iduronate 2-Sulfatase Fusion Protein: Pharmacokinetics, Anti-Drug Antibody, and Safety Pharmacology in Rhesus Monkeys
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DOI：
10.1002/bit.25289
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发表时间：
2014-11-01
影响因子：
3.8
通讯作者：
Pardridge, William M.
中科院分区：
文献类型：
--
作者：
Boado, Ruben J.;Hui, Eric Ka-Wai;Pardridge, William M.
II型粘多糖沉积症（MPS）由编码溶酶体酶艾杜糖醛酸2-硫酸酯酶（IDS）的基因突变引起。大多数MPSII病例影响大脑。然而，使用重组IDS的酶替代疗法不治疗脑，因为IDS是不穿过血脑屏障（BBB）的大分子药物。为了能够穿透血脑屏障，IDS已被重新设计为IgG-IDS融合蛋白，其中IgG结构域是针对人胰岛素受体（HIR）的单克隆抗体（MAb）。HIRMAb通过内源性BBB胰岛素受体上的受体介导的转运穿过BBB，并且融合蛋白的HIRMAb结构域充当分子特洛伊木马以将融合的IDS从血液运送到脑中。本研究报告了HIRMAb-IDS融合蛋白的首次安全性药理学和药代动力学研究。将幼年雄性恒河猴每周静脉内（IV）输注0、3、10或30 mg/kg的HIRMAb-IDS融合蛋白，持续26周。融合蛋白的血浆清除率遵循线性药代动力学曲线，其与免疫反应性HIRMAb-IDS融合蛋白的血浆浓度的测量或血浆IDS酶活性的测定等效。每月监测抗药抗体（ADA）滴度，ADA应答主要针对融合蛋白HIRMAb结构域的可变区。研究期间未观察到输注相关反应或免疫应答的临床体征。一组安全药理学、临床化学和组织组织病理学显示没有不良事件的迹象，并且证明了用3-30 mg/kg每周IV输注剂量的HIRMAb-IDS融合蛋白长期治疗灵长类动物的安全性特征。(C)2014 Wiley Periodicals，Inc.
Mucopolysaccharidosis (MPS) Type II is caused by mutations in the gene encoding the lysosomal enzyme, iduronate 2-sulfatase (IDS). The majority of MPSII cases affect the brain. However, enzyme replacement therapy with recombinant IDS does not treat the brain, because IDS is a large molecule drug that does not cross the blood-brain barrier (BBB). To enable BBB penetration, IDS has been re-engineered as an IgG-IDS fusion protein, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, and the HIRMAb domain of the fusion protein acts as a molecular Trojan horse to ferry the fused IDS into brain from blood. The present study reports on the first safety pharmacology and pharmacokinetics study of the HIRMAb-IDS fusion protein. Juvenile male Rhesus monkeys were infused intravenously (IV) weekly for 26 weeks with 0, 3, 10, or 30 mg/kg of the HIRMAb-IDS fusion protein. The plasma clearance of the fusion protein followed a linear pharmacokinetics profile, which was equivalent either with measurements of the plasma concentration of immunoreactive HIRMAb-IDS fusion protein, or with assays of plasma IDS enzyme activity. Anti-drug antibody (ADA) titers were monitored monthly, and the ADA response was primarily directed against the variable region of the HIRMAb domain of the fusion protein. No infusion related reactions or clinical signs of immune response were observed during the course of the study. A battery of safety pharmacology, clinical chemistry, and tissue histopathology showed no signs of adverse events, and demonstrate the safety profile of chronic treatment of primates with 3-30 mg/kg weekly IV infusion doses of the HIRMAb-IDS fusion protein. (C) 2014 Wiley Periodicals, Inc.