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PCSK9 inhibition with alirocumab reduces lipoprotein (a) levels in non-human primates by lowering apolipoprotein (a) production rate.

著者 Croyal M , Tran TT , Blanchard RH , Lebail JC , Villard EF , Poirier B , Aguesse A , Billon-Crossouard S , Ramin-Mangata S , Blanchard V , Nativel B , Chemello K , Khantalin I , Thedrez A , Janiak P , Krempf M , Boixel C , Lambert G , Guillot E
Clin Sci (Lond).2018 May 03 ; ():.
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Therapeutic antibodies targeting 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 non-human 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 hours. 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 (FCR) 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.
PMID: 29724769 [PubMed - as supplied by publisher]
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