Abstract
BackgroundLow Density Lipoprotein (LDL) hypercholesterolemia, and its associated cardiovascular diseases, are some of the leading causes of death worldwide. The ability of proprotein convertase subtilisin/kexin 9 (PCSK9) to modulate circulating LDL cholesterol (LDLc) concentrations made it a very attractive target for LDLc management. To date, the most advanced approaches for PCSK9 inhibition are monoclonal antibody (mAb) therapies. Although shown to lower LDLc significantly, mAbs face functional limitations because of their relatively short in vivo half-lives necessitating frequent administration. Here, we evaluated the long-term efficacy and safety of PCSK9-specific active vaccines in different preclinical models.Methods and FindingPCSK9 peptide-based vaccines were successfully selected by our proprietary technology. To test their efficacy, wild-type (wt) mice, Ldlr +/− mice, and rats were immunized with highly immunogenic vaccine candidates. Vaccines induced generation of high-affine PCSK9-specific antibodies in all species. Group mean total cholesterol (TC) concentration was reduced by up to 30%, and LDLc up to 50% in treated animals. Moreover, the PCSK9 vaccine-induced humoral immune response persisted for up to one year in mice, and reduced cholesterol levels significantly throughout the study. Finally, the vaccines were well tolerated in all species tested.ConclusionsPeptide-based anti-PCSK9 vaccines induce the generation of antibodies that are persistent, high-affine, and functional for up to one year. They are powerful and safe tools for long-term LDLc management, and thus may represent a novel therapeutic approach for the prevention and/or treatment of LDL hypercholesterolemia-related cardiovascular diseases in humans.
Highlights
Hypercholesterolemia, in particular that of low density lipoprotein cholesterol (LDLc) is a major risk factor for the development of atherosclerosis and associated ischemic cardiovascular diseases
Genetic evidence for the role of Proprotein convertase subtilisin/kexin 9 (PCSK9) as a major regulator of the cholesterol homeostasis [9] originates from studies showing that gain-of-function mutations are associated with decrease in the low density lipoprotein receptor (LDLR) expression and LDLc internalization, while loss-of-function mutations are associated with increase in the LDLR surface expression and increased levels of Low Density Lipoprotein (LDL) internalization [8]
We describe an alternative approach for PCSK9 inhibition that provides the opportunity for long-term, safe LDLc cholesterol management, by using a peptide-based anti-PCSK9 active vaccination approach
Summary
Hypercholesterolemia, in particular that of low density lipoprotein cholesterol (LDLc) is a major risk factor for the development of atherosclerosis and associated ischemic cardiovascular diseases. Several human mAbs were already evaluated in phase I and phase II clinical trials; these studies confirmed this approach as being beneficial and safe, as a monotherapy and in combination with statins [15, 16, 17]. Because of their relatively short in vivo half-lives, the use of mAbs faces functional limitations. We describe an alternative approach for PCSK9 inhibition that provides the opportunity for long-term, safe LDLc cholesterol management, by using a peptide-based anti-PCSK9 active vaccination approach
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
