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一种抗 PCSK9 抗体在他汀类药物的基础上降低 LDL-胆固醇，并抑制肝细胞 SREBP 调节的基因。

An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes.

机构信息

Department of Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065, USA.

出版信息

Int J Biol Sci. 2012;8(3):310-27. doi: 10.7150/ijbs.3524. Epub 2012 Feb 9.

DOI:10.7150/ijbs.3524
PMID:22355267
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3282994/
Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target for treating coronary heart disease. We report a novel antibody 1B20 that binds to PCSK9 with sub-nanomolar affinity and antagonizes PCSK9 function in-vitro. In CETP/LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (≥ 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody. In addition, 1B20 induces increases in total plasma antibody-bound PCSK9 levels and decreases in liver mRNA levels of SREBP-regulated genes PCSK9 and LDLR, with a time course that parallels decreases in plasma LDL-cholesterol (LDL-C). Consistent with this observation in mice, in statin-responsive human primary hepatocytes, 1B20 lowers PCSK9 and LDLR mRNA levels and raises serum steady-state levels of antibody-bound PCSK9. In addition, mRNA levels of several SREBP regulated genes involved in cholesterol and fatty-acid synthesis including ACSS2, FDPS, IDI1, MVD, HMGCR, and CYP51A1 were decreased significantly with antibody treatment of primary human hepatocytes. In rhesus monkeys, subcutaneous (SC) dosing of 1B20 dose-dependently induces robust LDL-C lowering (maximal ~70%), which is correlated with increases in target engagement and total antibody-bound PCSK9 levels. Importantly, a combination of 1B20 and Simvastatin in dyslipidemic rhesus monkeys reduced LDL-C more than either agent alone, consistent with a mechanism of action that predicts additive effects of anti-PCSK9 agents with statins. Our results suggest that antibodies targeting PCSK9 could provide patients powerful LDL lowering efficacy on top of statins, and lower cardiovascular risk.

摘要

前蛋白转化酶枯草溶菌素 9（PCSK9）是治疗冠心病的有前途的治疗靶点。我们报告了一种新型抗体 1B20，它以亚纳摩尔亲和力结合 PCSK9，并在体外拮抗 PCSK9 功能。在 CETP/LDLR-半小鼠中，两次连续剂量的 1B20，间隔 14 天，以 3 或 10mpk 给药，诱导 LDL-胆固醇（7-14 天内降低≥25%）的剂量依赖性降低，与抗体对 PCSK9 的占据程度密切相关。此外，1B20 诱导总血浆抗体结合 PCSK9 水平升高和 SREBP 调节基因 PCSK9 和 LDLR 的肝 mRNA 水平降低，与血浆 LDL-胆固醇（LDL-C）的降低呈时间相关性。与小鼠中的这一观察结果一致，在他汀类药物反应性人原代肝细胞中，1B20 降低 PCSK9 和 LDLR mRNA 水平，并提高血清中抗体结合 PCSK9 的稳态水平。此外，几种 SREBP 调节基因的 mRNA 水平，包括参与胆固醇和脂肪酸合成的 ACSS2、FDPS、IDI1、MVD、HMGCR 和 CYP51A1，在用原代人肝细胞进行抗体治疗时显著降低。在恒河猴中，1B20 的皮下（SC）给药剂量依赖性地诱导强烈的 LDL-C 降低（最大约 70%），这与靶标结合增加和总抗体结合 PCSK9 水平相关。重要的是，1B20 与辛伐他汀在血脂异常恒河猴中的联合应用降低 LDL-C 的效果超过单独使用任何一种药物，这与预测抗 PCSK9 药物与他汀类药物联合使用的作用机制一致。我们的结果表明，针对 PCSK9 的抗体可以在他汀类药物的基础上为患者提供强大的 LDL 降低疗效，并降低心血管风险。

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J Lipid Res. 2011 Jan;52(1):78-86. doi: 10.1194/jlr.M011445. Epub 2010 Oct 19.
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