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Current Medicinal Chemistry

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ISSN (Online): 1875-533X

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Review Article

PCSK9 Inhibition-Based Therapeutic Approaches: An Immunotherapy Perspective

Author(s): Amir Abbas Momtazi-Borojeni, Matteo Pirro, Suowen Xu and Amirhossein Sahebkar*

Volume 29, Issue 6, 2022

Published on: 12 January, 2022

Page: [980 - 999] Pages: 20

DOI: 10.2174/0929867328666211027125245

Price: $65

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9-I) are novel therapeutic tools to decrease cardiovascular risk. These agents work by lowering the low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients who are statin resistant/intolerant. Current clinically approved and investigational PCSK9- I act generally by blocking PCSK9 activity in the plasma or suppressing its expression or secretion by hepatocytes. The most widely investigated method is the disruption of PCSK9/LDL receptor (LDLR) interaction by fully-humanized monoclonal antibodies (mAbs), evolocumab and alirocumab, which have been approved for the therapy of hypercholesterolemia and atherosclerotic cardiovascular disease (CVD). Besides, a small interfering RNA called inclisiran, which specifically suppresses PCSK9 expression in hepatocytes, is as effective as mAbs but with administration twice a year. Because of the high costs of such therapeutic approaches, several other PCSK9-I have been surveyed, including peptide-based anti-PCSK9 vaccines and small oral anti-PCSK9 molecules, which are under investigation in preclinical and phase I clinical studies. Interestingly, anti-PCSK9 vaccination has been found to serve as a more widely feasible and more cost-effective therapeutic tool over mAb PCSK9-I for managing hypercholesterolemia. The present review will discuss LDL-lowering and cardioprotective effects of PCSK9-I, mainly immunotherapy- based inhibitors including mAbs and vaccines, in preclinical and clinical studies.

Keywords: Alirocumab , evolocumab , immunotherapy , inclisiran , PCSK9 , vaccine .

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