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New developments in atherosclerosis: clinical potential of PCSK9 inhibition.

Giunzioni I, Tavori H - Vasc Health Risk Manag (2015)

Bottom Line: In contrast, loss-of-function mutations of PCSK9 result in increased surface LDLR and improved LDL-C clearance.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, with alirocumab (commercial name--PRALUENT(®)) and, Amgen with evolocumab (commercial name--Repatha™).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.

View Article: PubMed Central - PubMed

Affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.

ABSTRACT
Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted 692-amino acid protein that binds surface low-density lipoprotein (LDL) receptor (LDLR) and targets it toward lysosomal degradation. As a consequence, the number of LDLRs at the cell surface is decreased, and LDL-cholesterol (LDL-C) clearance is reduced, a phenomenon that is magnified by gain-of-function mutations of PCSK9. In contrast, loss-of-function mutations of PCSK9 result in increased surface LDLR and improved LDL-C clearance. This provides the rationale for targeting PCSK9 in hypercholesterolemic subjects as a means to lower LDL-C levels. Monoclonal antibodies (mAbs) against PCSK9 that block its interaction with the LDLR have been developed 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, 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.

No MeSH data available.


Related in: MedlinePlus

Mechanism of action and clearance for PCSK9 and anti-PCSK9 antibodies.Notes: (A) Mechanism of LDL internalization by LDLR. Once LDL binds to LDLR it invaginates and is internalized into coated endocytic vesicles that form endosomes. LDL dissociates from LDLR, and LDLR is recycled on the cell surface. The entire cycle takes 10–15 minutes. (B) PCSK9 (unbound PCSK9 or LDL-bound PCSK9) directly binds the EGF-A domain of LDLR and targets LDLR toward intracellular degradation through an endosomal/lysosomal route. PCSK9 half-life in plasma is approximately 5 minutes. It is unknown whether the kinetics of unbound PCSK9 or LDL-bound PCSK9 differ. (C) IgG elimination. IgG internalization is mediated by fluid phase pinocytosis or receptor mediated endocytosis, followed by intracellular degradation of the IgG in the lysosome. A significant fraction of IgG is not targeted toward lysosomal degradation, but is redirected to the cell surface and released into the plasma through a process mediated by FcRn. (D) PCSK9-mAbs complex elimination. The elimination is presumably mediated by PCSK9 through a mechanism similar to PCSK9-mediated degradation of LDLR (degradation through endosomal/lysosomal route). However, a clear mechanism has not been described.Abbreviations: LDL, low-density lipoprotein; LDLR, LDL receptor; mAbs, monoclonal antibodies; IgG, immunoglobulin G; PCSK9, pro-protein convertase subtilisin/kexin type 9; FcRn, neonatal Fc receptor.
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f1-vhrm-11-493: Mechanism of action and clearance for PCSK9 and anti-PCSK9 antibodies.Notes: (A) Mechanism of LDL internalization by LDLR. Once LDL binds to LDLR it invaginates and is internalized into coated endocytic vesicles that form endosomes. LDL dissociates from LDLR, and LDLR is recycled on the cell surface. The entire cycle takes 10–15 minutes. (B) PCSK9 (unbound PCSK9 or LDL-bound PCSK9) directly binds the EGF-A domain of LDLR and targets LDLR toward intracellular degradation through an endosomal/lysosomal route. PCSK9 half-life in plasma is approximately 5 minutes. It is unknown whether the kinetics of unbound PCSK9 or LDL-bound PCSK9 differ. (C) IgG elimination. IgG internalization is mediated by fluid phase pinocytosis or receptor mediated endocytosis, followed by intracellular degradation of the IgG in the lysosome. A significant fraction of IgG is not targeted toward lysosomal degradation, but is redirected to the cell surface and released into the plasma through a process mediated by FcRn. (D) PCSK9-mAbs complex elimination. The elimination is presumably mediated by PCSK9 through a mechanism similar to PCSK9-mediated degradation of LDLR (degradation through endosomal/lysosomal route). However, a clear mechanism has not been described.Abbreviations: LDL, low-density lipoprotein; LDLR, LDL receptor; mAbs, monoclonal antibodies; IgG, immunoglobulin G; PCSK9, pro-protein convertase subtilisin/kexin type 9; FcRn, neonatal Fc receptor.

Mentions: The mechanism of internalization of LDL by LDLR was first described in 1976 in human fibroblasts (Figure 1A).34 LDL binds to LDLR on coated pits, which then invaginate and get internalized as coated vesicles that expand to become endosomes, from where LDL is delivered to the lysosome while LDLR returns to the cell surface.35,36 The LDLR makes one round trip every 10–15 minutes for a total of over 100 trips in its 20-hour lifespan.37


New developments in atherosclerosis: clinical potential of PCSK9 inhibition.

Giunzioni I, Tavori H - Vasc Health Risk Manag (2015)

Mechanism of action and clearance for PCSK9 and anti-PCSK9 antibodies.Notes: (A) Mechanism of LDL internalization by LDLR. Once LDL binds to LDLR it invaginates and is internalized into coated endocytic vesicles that form endosomes. LDL dissociates from LDLR, and LDLR is recycled on the cell surface. The entire cycle takes 10–15 minutes. (B) PCSK9 (unbound PCSK9 or LDL-bound PCSK9) directly binds the EGF-A domain of LDLR and targets LDLR toward intracellular degradation through an endosomal/lysosomal route. PCSK9 half-life in plasma is approximately 5 minutes. It is unknown whether the kinetics of unbound PCSK9 or LDL-bound PCSK9 differ. (C) IgG elimination. IgG internalization is mediated by fluid phase pinocytosis or receptor mediated endocytosis, followed by intracellular degradation of the IgG in the lysosome. A significant fraction of IgG is not targeted toward lysosomal degradation, but is redirected to the cell surface and released into the plasma through a process mediated by FcRn. (D) PCSK9-mAbs complex elimination. The elimination is presumably mediated by PCSK9 through a mechanism similar to PCSK9-mediated degradation of LDLR (degradation through endosomal/lysosomal route). However, a clear mechanism has not been described.Abbreviations: LDL, low-density lipoprotein; LDLR, LDL receptor; mAbs, monoclonal antibodies; IgG, immunoglobulin G; PCSK9, pro-protein convertase subtilisin/kexin type 9; FcRn, neonatal Fc receptor.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4554462&req=5

f1-vhrm-11-493: Mechanism of action and clearance for PCSK9 and anti-PCSK9 antibodies.Notes: (A) Mechanism of LDL internalization by LDLR. Once LDL binds to LDLR it invaginates and is internalized into coated endocytic vesicles that form endosomes. LDL dissociates from LDLR, and LDLR is recycled on the cell surface. The entire cycle takes 10–15 minutes. (B) PCSK9 (unbound PCSK9 or LDL-bound PCSK9) directly binds the EGF-A domain of LDLR and targets LDLR toward intracellular degradation through an endosomal/lysosomal route. PCSK9 half-life in plasma is approximately 5 minutes. It is unknown whether the kinetics of unbound PCSK9 or LDL-bound PCSK9 differ. (C) IgG elimination. IgG internalization is mediated by fluid phase pinocytosis or receptor mediated endocytosis, followed by intracellular degradation of the IgG in the lysosome. A significant fraction of IgG is not targeted toward lysosomal degradation, but is redirected to the cell surface and released into the plasma through a process mediated by FcRn. (D) PCSK9-mAbs complex elimination. The elimination is presumably mediated by PCSK9 through a mechanism similar to PCSK9-mediated degradation of LDLR (degradation through endosomal/lysosomal route). However, a clear mechanism has not been described.Abbreviations: LDL, low-density lipoprotein; LDLR, LDL receptor; mAbs, monoclonal antibodies; IgG, immunoglobulin G; PCSK9, pro-protein convertase subtilisin/kexin type 9; FcRn, neonatal Fc receptor.
Mentions: The mechanism of internalization of LDL by LDLR was first described in 1976 in human fibroblasts (Figure 1A).34 LDL binds to LDLR on coated pits, which then invaginate and get internalized as coated vesicles that expand to become endosomes, from where LDL is delivered to the lysosome while LDLR returns to the cell surface.35,36 The LDLR makes one round trip every 10–15 minutes for a total of over 100 trips in its 20-hour lifespan.37

Bottom Line: In contrast, loss-of-function mutations of PCSK9 result in increased surface LDLR and improved LDL-C clearance.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, with alirocumab (commercial name--PRALUENT(®)) and, Amgen with evolocumab (commercial name--Repatha™).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.

View Article: PubMed Central - PubMed

Affiliation: Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.

ABSTRACT
Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted 692-amino acid protein that binds surface low-density lipoprotein (LDL) receptor (LDLR) and targets it toward lysosomal degradation. As a consequence, the number of LDLRs at the cell surface is decreased, and LDL-cholesterol (LDL-C) clearance is reduced, a phenomenon that is magnified by gain-of-function mutations of PCSK9. In contrast, loss-of-function mutations of PCSK9 result in increased surface LDLR and improved LDL-C clearance. This provides the rationale for targeting PCSK9 in hypercholesterolemic subjects as a means to lower LDL-C levels. Monoclonal antibodies (mAbs) against PCSK9 that block its interaction with the LDLR have been developed 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, 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.

No MeSH data available.


Related in: MedlinePlus