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 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. (See also Evolocumab)
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.
