PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate

阿利罗库单抗 载脂蛋白B PCSK9 可欣 化学 脂蛋白 低密度脂蛋白受体 内分泌学 分解代谢 内科学 低密度脂蛋白 胆固醇 生物化学 生物 医学 载脂蛋白A1 新陈代谢
作者
Mikaël Croyal,Thi-Thu-Trang Tran,Rose Hélène Blanchard,Jean-Christophe Le Bail,Elise F. Villard,Bruno Poirier,Audrey Aguesse,Stéphanie Billon‐Crossouard,Stéphane Ramin‐Mangata,Valentin Blanchard,Brice Nativel,Kévin Chemello,Ilya Khantalin,Aurélie Thedrez,Philip Janiak,Michel Krempf,Christophe Boixel,Gilles Lambert,Etienne Guillot
出处
期刊:Clinical Science [Portland Press]
卷期号:132 (10): 1075-1083 被引量:42
标识
DOI:10.1042/cs20180040
摘要

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivo. Six nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [2H3]-leucine was assessed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (−28%), LDL-C (−67%), Lp(a) (−56%), apolipoprotein B100 (apoB100) (−53%), and apo(a) (−53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (−42%), but not significantly that of apoB100, compared with IgG1, respectively. In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.
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