Despite carrying extremely low LDL-C levels, these subjects are healthy, fertile, and have normal cognitive functions

Despite carrying extremely low LDL-C levels, these subjects are healthy, fertile, and have normal cognitive functions.1618Subjects with more common PCSK9 loss-of-function mutations14have reduced LDL-C levels and CVD risk.15,19These observations combined have provided the rationale for a safe and effective use of PCSK9 inhibitors to reduce LDL-C level and CVD risk. Currently, statins are the most widely prescribed lipid-lowering drugs.20Statins reduce LDL-C levels by inhibiting HMG-CoA reductase (also known as 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, or HMGCR), the rate-limiting step in cholesterol synthesis.21The depletion of the intracellular cholesterol pool increases LDLR transcription, which in turn favors LDL clearance.22LDLR upregulation under cellular cholesterol-depletion state is mediated by sterol regulatory element-binding protein 2 (SREBP2)-dependent mechanisms. in the past decade. Two companies have recently received the approval for their anti-PCSK9 mAbs by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Regeneron/Sanofi, Belotecan hydrochloride with alirocumab (commercial name PRALUENT) and, Amgen with evolocumab (commercial name Repatha). The introduction of anti-PCSK9 mAbs will provide an alternative therapeutic strategy to address many of the unmet needs of current lipid-lowering therapies, such as inability to achieve goal LDL-C level, or intolerance and aversion to statins. This review will focus on the kinetics of PCSK9, pharmacokinetics and pharmacodynamics of anti-PCSK9 mAbs, and recent data linking PCSK9 and anti-PCSK9 mAbs to cardiovascular events. Moreover, it will highlight the unanswered questions that still need to be addressed in order to understand the physiologic function, kinetics, and dynamics of PCSK9. Keywords:PCSK9, LDLR, monoclonal antibodies, pharmacokinetics, cardiovascular risk == Introduction == Pro-protein convertase subtilisin/kexin type 9 (PCSK9) plays a fundamental role in low-density lipoprotein (LDL) metabolism through the post-transcriptional regulation of LDL receptor (LDLR).13PCSK9 is mainly produced by the liver, intestine, and kidney and is synthesized as a precursor of 75 kDa, which undergoes autocatalytic cleavage in the endoplasmic reticulum to form the mature, secreted heterodimer. Once secreted, PCSK9 circulates in the plasma compartment in two different molecular forms, the 62 kDa form, which is the most active47and predominantly present on LDL,810and a 55 kDa form (produced by cleavage of the mature PCSK9 by furin), which is considered to be Belotecan hydrochloride less active47and is mainly present in the apolipoprotein B (apoB)-free plasma compartment.11Mature PCSK9 directly binds the epidermal growth factor-like repeat A (EGF-A) domain of LDLR and acts as a chaperone, targeting LDLR toward intracellular degradation through an endosomal/lysosomal route.12One study also suggested that PCSK9 might directly influence LDLR degradation intracellularly, preventing LDLR from reaching the cell surface.2 Gain-of-function mutations in PCSK9 account for 1%3% of the individuals with familial hypercholesterolemia (FH) and are associated with early onset of cardiovascular diseases (CVDs).13On the contrary, PCSK9 loss-of-function mutations reduce LDL-cholesterol (LDL-C) levels and significantly decrease CVD risk.14,15A few individuals with no detectable levels of PCSK9 in plasma have been identified. Despite carrying extremely low LDL-C levels, these subjects are healthy, fertile, and have normal cognitive functions.1618Subjects with more common PCSK9 loss-of-function mutations14have reduced LDL-C levels and CVD risk.15,19These observations combined have provided the rationale for a safe and effective use of PCSK9 inhibitors to reduce LDL-C level and CVD risk. Currently, statins are the most widely prescribed lipid-lowering drugs.20Statins reduce LDL-C levels by inhibiting HMG-CoA reductase (also known as 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, or HMGCR), the rate-limiting step in cholesterol synthesis.21The depletion of the intracellular cholesterol pool increases LDLR transcription, which in turn favors LDL clearance.22LDLR upregulation under cellular cholesterol-depletion state is mediated by sterol regulatory element-binding protein 2 (SREBP2)-dependent mechanisms. Surprisingly, SREBP2 is also responsible for the regulation of PCSK9 expression.23Thus, statin-mediated upregulation of PCSK9 should limit the LDL-C-lowering effect of these drugs.24 The current dogma (cholesterol hypothesis) is that the effect of lowering LDL-C on CVD risk is Belotecan hydrochloride independent of the mechanism by which LDL-C is lowered.25PCSK9 inhibition using monoclonal antibodies (mAbs) may help reach the goal of LDL-C reduction and may improve CVD risk in hypercholesterolemic individuals as either monotherapy or in addition to statins. The recently published results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) confirmed that the administration of lipid-lowering agents such as ezetimibe on top of statins further reduced LDL-C levels and the CVD event rate compared to monotherapy.26These data provide an encouraging platform for the likelihood that agents that act through LDL-lowering mechanisms other than HMGCR will also have cardiovascular (CV) benefits. mAbs directed toward PCSK9 have shown their efficacy in reducing LDL-C levels, and a detailed summary of the phase III clinical trials with alirocumab (Odissey program), evolocumab (Proficio program) and bococizumab (Spire program) has been recently reviewed in another publication27by the authors of the current review and others.28,29However, despite the efficacy of PCSK9 antibodies on LDL-C reduction and their excellent safety profile,30three central questions related to their effect and mechanism of action remain unanswered: 1) Is the effect of the blocking antibody evident within Rabbit Polyclonal to EDG2 minutes from injection? This question is triggered by the knowledge that whereas the PCSK9-LDLR complex is formed in only a few minutes, degradation of LDLR instead takes several hours; 2) What are the pharmacokinetic and pharmacodynamic characteristics of the antibodyantigen (AbAg) complex? This question is triggered by the knowledge that a portion of the AbAg complex will reside on lipoproteins, which may direct clearance of the immune complex via unique pathways; 3) Do PCSK9 mAbs reduce atherosclerotic plaque burden and CVD events? This question is triggered by the knowledge that inhibiting PCSK9 not only drives.