ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys
ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys
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DOI：
10.1194/jlr.m054890
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发表时间：
2015-07-01
影响因子：
6.5
通讯作者：
Gromada, Jesper
中科院分区：
文献类型：
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作者：
Gusarova, Viktoria;Alexa, Corey A.;Gromada, Jesper
血管生成素样蛋白3（ANGPTL 3）是一种仅在肝脏中合成的循环蛋白，其抑制LPL和内皮脂肪酶（EL），这些酶水解血浆脂蛋白中的TG和磷脂。在这里，我们描述了一种以高亲和力结合ANGPTL 3的全人源单克隆抗体（REGN 1500）的开发和测试。REGN 1500在体外逆转ANGPTL 3诱导的LPL活性抑制。对血脂正常的C57 Bl/6小鼠静脉给予REGN 1500可增加LPL活性，并使血浆TG水平降低>= 50%。对血脂异常C57 Bl/6小鼠长期给予REGN 1500 8周可降低TG、LDL-胆固醇（LDL-C）和HDL-胆固醇（HDL-C）的循环血浆水平，而肝脏、脂肪或心脏TG含量无任何变化。在EL基因敲除小鼠中的研究显示，REGN 1500通过EL依赖性机制降低血清HDL-C。最后，对血脂异常食蟹猴单次给予REGN 1500导致血浆TG、非HDL-C和HDLC快速显著降低。即使在基线血浆TG大于400 mg/dl的猴中，REGN 1500也使血浆TG水平正常化。总的来说，这些数据表明，使用REGN 1500中和ANGPTL 3可降低血脂异常小鼠和猴的血脂，因此为治疗高脂血症患者提供了潜在的治疗剂。
Angiopoietin-like protein 3 (ANGPTL3) is a circulating protein synthesized exclusively in the liver that inhibits LPL and endothelial lipase (EL), enzymes that hydrolyze TGs and phospholipids in plasma lipoproteins. Here we describe the development and testing of a fully human monoclonal antibody (REGN1500) that binds ANGPTL3 with high affinity. REGN1500 reversed ANGPTL3-induced inhibition of LPL activity in vitro. Intravenous administration of REGN1500 to normolipidemic C57Bl/6 mice increased LPL activity and decreased plasma TG levels by >= 50%. Chronic administration of REGN1500 to dyslipidemic C57Bl/6 mice for 8 weeks reduced circulating plasma levels of TG, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) without any changes in liver, adipose, or heart TG contents. Studies in EL knockout mice revealed that REGN1500 reduced serum HDL-C through an EL-dependent mechanism. Finally, administration of a single dose of REGN1500 to dyslipidemic cynomolgus monkeys caused a rapid and pronounced decrease in plasma TG, nonHDL-C, and HDLC. REGN1500 normalized plasma TG levels even in monkeys with a baseline plasma TG greater than 400 mg/dl. Collectively, these data demonstrate that neutralization of ANGPTL3 using REGN1500 reduces plasma lipids in dyslipidemic mice and monkeys, and thus provides a potential therapeutic agent for treatment of patients with hyperlipidemia.