Canadian Journal of Cardiology
Review| Volume 32, ISSUE 12, P1552-1560, December 2016

Monoclonal Antibodies for the Treatment of Hypercholesterolemia: Targeting PCSK9


      More than a century after German physician Paul Ehrlich put forth the idea of a “magic bullet” that could seek out and neutralize disease-causing agents in the body, the first monoclonal antibodies (mAbs) to lower low-density lipoprotein cholesterol (LDL-C) have been introduced into clinical use. This novel class of lipid-lowering agents targets proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that chaperones hepatic LDL receptors (LDLRs) toward intracellular degradation, reducing LDLR-mediated endocytosis and the clearance of LDL-C from the circulation. These new drugs represent the first mAb therapy intended for long-term cardiovascular use. We review the development of mAbs, the selection of PCSK9 as a target, and the current safety and efficacy data and regulatory status of these new therapeutic agents. We also provide guidance to clinicians regarding the potential role for these new agents in clinical practice.


      Plus d’un siècle après que le médecin allemand Paul Ehrlich a avancé l’idée d’un « projectile magique » capable de trouver et de neutraliser les agents pathogènes présents dans l’organisme, les premiers anticorps monoclonaux visant à réduire le taux de cholestérol des lipoprotéines de basse densité (C-LDL) ont fait leur apparition dans l’usage clinique. Cette nouvelle classe d’agents hypolipidémiants cible la proprotéine convertase subtilisine/kexine de type 9 (PCSK9), une enzyme qui se fixe aux récepteurs des LDL (LDLR) hépatiques et induit la dégradation intracellulaire, réduisant ainsi l’endocytose provoquée par les LDLR et l’élimination du C-LDL de la circulation. Ces nouveaux médicaments sont les premiers anticorps monoclonaux destinés au traitement cardiovasculaire à long terme. Dans cet article, nous passons en revue l’historique de la mise au point des anticorps monoclonaux et du choix de la PCSK9 comme cible, ainsi que les données actuelles relatives à l’innocuité et à l’efficacité et le statut réglementaire de ces nouveaux agents thérapeutiques. Nous adressons aussi quelques conseils aux cliniciens sur le rôle que ces nouveaux médicaments pourraient jouer dans la pratique clinique.
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