Title:PCSK9 Inhibition-Based Therapeutic Approaches: An Immunotherapy
Perspective
Volume: 29
Issue: 6
关键词:
Alirocumab、evolocumab、免疫疗法、inclisiran、PCSK9、疫苗
摘要: 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.
