PCSK9: a convertase that coordinates LDL catabolism.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(12)60771-5.pdf

Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels ≈2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR−/− mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.

https://www.pnas.org/content/pnas/106/24/9820.full.pdf

A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(12)61771-1.pdf

Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study

Atherosclerosis is a life-long illness that begins with risk factors, which in turn contribute to the development of subclinical disease, followed by the establishment of overt cardiovascular disease (CVD) Thrombotic-occlusive complications of atherosclerosis are among the most widespread and costly health problems Oxidized low-density lipoprotein (OxLDL) plays an important role in atherogenesis by promoting an inflammatory environment and lipid deposition in the arterial wall As cardiovascular events occur in individuals without common risk factors, there is a need for additional tools that may help in CVD risk assessment and management The use of biomarkers has improved diagnostic, therapeutic and prognostic outcome in cardiovascular medicine This review elaborates on the value of circulating OxLDL as a biomarker of CVD Three enzyme-linked immunosorbent assays (4E6, DLH3 and E06) using murine monoclonal antibodies for determination of OxLDL blood levels have been developed However, none of these assays are currently approved for routine clinical practice We identified studies investigating OxLDL in CVD (measured by 4E6, DLH3 or E06 assay) by searching the PubMed database Circulating OxLDL was found to be associated with all stages of atherosclerosis, from early atherogenesis to hypertension, coronary and peripheral arterial disease, acute coronary syndromes and ischemic cerebral infarction The results of studies investigating the usefulness of OxLDL for CVD prediction were also summarized Furthermore, OxLDL was found to be associated with pathologic conditions linked to CVD, including diabetes mellitus, obesity and metabolic syndrome (MetS) In addition, we have addressed the mechanisms by which OxLDL promotes atherogenesis, and the effects of antiatherogenic treatments on circulating OxLDL Finally, we highlight the evidence suggesting that lipoprotein (a) [Lp(a)] is the preferential carrier of oxidized phospholipids (OxPL) in human plasma A strong association between OxPL/apoB level (representing the content of OxPL on apolipoprotein B-100 particles, measured by E06 assay) and Lp(a) has been determined

Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases.

Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis

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Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis