| Hazard Information | Back Directory | [Clinical Use]
Human IgG1 monoclonal antibody:
Treatment of primary hypercholesterolaemia / mixed
dyslipidaemia | [Enzyme inhibitor]
This humanized anti-PCSK9 monoclonal antibody (MW = 146 kDa; CAS
1245916-14-6), developed as REGN727 (Regeneron Pharmaceuticals) and
SAR236553 and Praluent? in cooperation with Sanofi, inhibits
atherosclerosis, improves plaque morphology, and enhances statin effects
. Its target, Pro-protein Convertase Subtilisin/Kexin type 9 (or
PCSK9), is a secreted pro-protein convertase. Inhibition of PCSK9
increases hepatic Low-Density Lipoprotein Receptors (LDLRs), thereby
enhancing hepatic LDL clearance. PCSK9 undergoes autocatalytic
processing of its pro-domain within the endoplasmic reticulum, and its
e inhibitory pro-peptide segment remains associated with it following
subsequent secretion. PCSK9 phosphorylation at Ser-47 in its pro-peptide
and Ser-688 in its C-terminal domain by a Golgi casein kinase-like protein
kinase appears to stabilize secreted PCSK9. The level of circulating PCSK9
appears to be inversely related to blood HDL levels, and it is
understandable that cholesterol-lowering statins have the effect of
increasing PCSK9 gene expression as well as the circulating level of
PCSK9. Alirocumab binds to circulating PCSK9, blocking the latter’s
action on surface LDLR. Alirocumab dose-dependently decreases plasma
lipids and atherosclerosis progression, and it enhances the beneficial effects
of atorvastatin in ApoE3-Leiden transgenic mice. | [Drug interactions]
Potentially hazardous interactions with other drugs
Live vaccines: risk of generalised infections - avoid. | [Metabolism]
As alirocumab is a protein it is expected to degrade
to small peptides and individual amino acids. At low
concentrations, the elimination is mainly through
saturable binding to target (PCSK9), while at higher
concentrations the elimination is largely through a nonsaturable proteolytic pathway. |
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