Human Anti-Human PCSK9 (Evolocumab) Monoclonal Antibody, clone Evolocumab [Biosimilar] Functional Grade

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine proprotein found in apoptotic cerebellar neurons. PCSK9 is the ninth member of the proprotein convertase family. Studies have found that it is expressed in many tissues and organs in the body, with higher expression concentrations in the liver, kidney, brain and small intestine. The main function of PCSK9 is to bind to the low-density lipoprotein receptor (LDLR) in hepatocytes and direct the low-density lipoprotein receptor-low-density lipoprotein cholesterol (LDL-C) complex to lysosomes for degradation. Surface recycling prevents the uptake of LDL-C by stem cells, thereby regulating lipid metabolism. Circulating PCSK9 levels have been shown to predict the risk of cardiovascular disease in patients aged 60 years and without prevalent cardiovascular disease, independent of established risk factors. PCSK9 levels are considered a predictor of carotid atherosclerosis.

Figure 1. Mechanism action of anti-PCSK9 monoclonal antibody (mAb) and statins. (Sources: Sobati S, et al. 2020)

In the human body, serum cholesterol levels are mainly determined by three metabolic pathways, namely, dietary cholesterol intake, cholesterol synthesis, and cholesterol degradation in the body. PCSK9 can increase liver degradation of low-density lipoprotein, thereby reducing the liver's ability to clear low-density lipoprotein, leading to hypercholesterolemia. Low-density lipoprotein cholesterol (LDL-C) is a pathogenic factor and major therapeutic target for atherosclerotic cardiovascular disease (ASCVD). Studies have found that reduced LDL-C levels are associated with a reduction in stroke, myocardial infarction, unstable angina, and myocardial revascularization. As a junction for cholesterol metabolism, PCSK9 has been shown to negatively regulate transintestinal cholesterol excretion (Tice), a pathway for cholesterol metabolism, and thus the role of PCSK9 in the pathogenesis of dyslipidemia has attracted more interest. Although most of the current research on PCSK9 focuses on its local function in regulating LDL levels in the liver, some studies have shown that PCSK9 is also expressed in other cells and tissues, including all cellular components of the vascular wall, especially endothelial cells and smooth muscle cells, which are two cells that regulate the function of the vascular wall. In addition, it is also present in inflammatory cells such as macrophages. Macrophages are the precursors of lipid-rich foam cells in atherosclerosis, and studies have shown that the metaplasia of smooth muscle cells may also produce macrophage-like foam cells. Therefore, in addition to its well-known regulatory effect on liver LDLR, PCSK9 may also have a pro-atherosclerotic effect, and elevated PCSK9 levels are an independent risk factor for atherosclerosis. Neuronal apoptosis occurs extensively during the development of the central nervous system. However, abnormal regulation of apoptosis may occur, leading to the development of neurodegenerative diseases such as Alzheimer's disease (AD). Studies have shown that neurodegenerative changes may be due to the fact that cholesterol and its metabolites in the brain may participate in the pathological process of nervous system lesions. In addition, the study found that after excluding the influence of relevant confounding factors such as age, gender, and smoking history, low plasma cholesterol levels may be a risk factor for the onset of Parkinson's disease (PD). In the brain, PCSK9 has been shown to promote neuronal apoptosis by activating the Bcl-2/Bax/caspase3 signaling pathway. An animal experiment showed that the expression of PCSK9 and BACE1 in the brain of mice fed a high-fat diet increased, leading to the production of Aβ and brain cell apoptosis. A recent study also found that the level of PCSK9 in the cerebrospinal fluid (CSF) of AD patients was higher than that of non-AD patients, indicating that there is a pathophysiological connection between PCSK9 and AD, and PCSK9 may play a role in AD by activating lipid accumulation, apoptosis, and the production of amyloid proteins in the brain. In addition, the study found that after excluding the influence of relevant confounding factors such as age, gender, and smoking history, low plasma cholesterol levels may be a risk factor for the onset of Parkinson's disease (PD). In the brain, PCSK9 has been shown to promote neuronal apoptosis by activating the Bcl-2/Bax/caspase3 signaling pathway. An animal experiment showed that the expression of PCSK9 and BACE1 in the brain of mice fed a high-fat diet increased, leading to the production of Aβ and brain cell apoptosis. A recent study also found that the level of PCSK9 in the cerebrospinal fluid (CSF) of AD patients was higher than that of non-AD patients, indicating that there is a pathophysiological connection between PCSK9 and AD, and PCSK9 may play a role in AD by activating lipid accumulation, apoptosis, and the production of amyloid proteins in the brain.

Inhibition of PCSK9 expression in the blood can increase the number of LDLR on the cell surface and increase the cellular uptake of LDL-C, becoming a new lipid-lowering strategy. Lipid-lowering therapy with traditional statins is the cornerstone of treatment for familial hypercholesterolemia and can reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in these patients. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have recently been shown to be effective and safe drugs for the treatment of familial hypercholesterolemia. In addition, a recent meta-analysis study showed that PCSK9 inhibitors have greater benefits than statins in lowering LDL cholesterol in patients with hypercholesterolemia. In addition to the recognized cholesterol-lowering effects, the use of clinically approved monoclonal antibodies to inhibit PCSK9 in patients with hypercholesterolemia can also affect the distribution of HDL cholesterol subclasses, especially in patients who are not concurrently treated with the PCSK9 inhibitor Ezetimibe.

NARC1
Proprotein Convertase 9
NARC-1
FH3