Peptide-Based Anti-PCSK9 Vaccines - An Approach for Long-Term LDLc Management

Galabova, Gergana; Brunner, Sylvia; Winsauer, Gabriele; Juno, Claudia; Wanko, Bettina; Mairhofer, Andreas; Lührs, Petra; Schneeberger, Achim; Bonin, Arne von; Mattner, Frank; Schmidt, W.; Staffler, Günther

doi:10.1371/journal.pone.0114469

Cited by 120 publications

(103 citation statements)

References 27 publications

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“…Previous studies have shown that the presence of anti-PCSK9 antibodies actually raises total soluble PCSK9 levels in the plasma [25, 26], suggesting that anti-PCSK9 antibodies may engage PCSK9 in vivo and form an immune complex. To assess this phenomenon, we measured PCSK9 levels in plasma from mice prior to vaccination and after three immunizations with Qβ-PCSK9 207-223 VLPs or wild-type Qβ VLPs.…”

Section: Resultsmentioning

confidence: 99%

A cholesterol-lowering VLP vaccine that targets PCSK9

Crossey

Amar

Sampson

et al. 2015

Vaccine

131

120

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the low-density lipoprotein receptor (LDL-R). Mutations that cause increased activity of PCSK9 are associated with hypercholesterolemia, atherosclerosis and early cardiovascular disease (CVD), whereas individuals with loss-of-function mutations in PCSK9 are apparently healthy but are hypocholesterolemic and have a dramatically decreased risk of CVD. In this study, we generated Virus-like Particle (VLP)-based vaccines targeting PCSK9. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides. A vaccine targeting PCSK9 may, therefore, be an attractive alternative to monoclonal antibody-based therapies.

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Section: Resultsmentioning

confidence: 99%

A cholesterol-lowering VLP vaccine that targets PCSK9

Crossey

Amar

Sampson

et al. 2015

Vaccine

131

120

View full text Add to dashboard Cite

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“…The scoring of liver steatosis was performed in a blinded manner. The area under the curve (AUC) was calculated using the linear trapezoidal method based on a linear interpolation between data points 49 . The AUC was calculated as follows: AUC = 1/2 (C1+C2), where C indicates the concentration of lipids in two incremental FPLC fractions.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Wagschal

Najafi‐Shoushtari

Wang

et al. 2015

Nat Med

233

257

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Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

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“…Specifically, lipidoid nanoparticles achieving liver-specific RNAi silencing of PCSK9 (60) are currently in phase II and have a potential for bi-annual dosing (Alnylam Pharmaceuticals). PCSK9 vaccines, peptide-or virus-like particle-based, were also developed and achieved ϳ50% lower total and/or LDLc levels for up to 1 year in rodents and/or primates (61,62).…”

Section: Figure 8 In Vivo Efficacy Of the Sdab P140 After Two Injecmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Single Domain Antibodies Are Potent Inhibitors of Low Density Lipoprotein Receptor Degradation

Weider

Susan‐Resiga

Essalmani

et al. 2016

Journal of Biological Chemistry

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Single domain antibodies (sdAbs) correspond to the antigenbinding domains of camelid antibodies. They have the same antigen-binding properties and specificity as monoclonal antibodies (mAbs) but are easier and cheaper to produce. We report here the development of sdAbs targeting human PCSK9 (proprotein convertase subtilisin/kexin type 9) as an alternative to anti-PCSK9 mAbs. After immunizing a llama with human PCSK9, we selected four sdAbs that bind PCSK9 with a high affinity and produced them as fusion proteins with a mouse Fc. All four sdAb-Fcs recognize the C-terminal Cys-His-rich domain of PCSK9. We performed multiple cellular assays and demonstrated that the selected sdAbs efficiently blocked PCSK9-mediated low density lipoprotein receptor (LDLR) degradation in cell lines, in human hepatocytes, and in mouse primary hepatocytes. We further showed that the sdAb-Fcs do not affect binding of PCSK9 to the LDLR but rather block its induced cellular LDLR degradation. Pcsk9 knock-out mice expressing a human bacterial artificial chromosome (BAC) transgene were generated, resulting in plasma levels of ϳ300 ng/ml human PCSK9. Mice were singly or doubly injected with the best sdAb-Fc and analyzed at day 4 or 11, respectively. After 4 days, mice exhibited a 32 and 44% decrease in the levels of total cholesterol and apolipoprotein B and ϳ1.8-fold higher liver LDLR protein levels. At 11 days, the equivalent values were 24 and 46% and ϳ2.3-fold higher LDLR proteins. These data constitute a proof-of-principle for the future usage of sdAbs as PCSK9-targeting drugs that can efficiently reduce LDL-cholesterol, and as tools to study the Cys-His-rich domain-dependent sorting the PCSK9-LDLR complex to lysosomes.For over 30 years, a large number of clinical trials have firmly consolidated the importance of lowering LDL-cholesterol (LDLc) 3 in the prevention of cardiovascular diseases (CVD) and its associated devastating sequelae (1). Healthy diets and exercise are highly recommended to lower LDLc in patients with high baseline levels. However, many individuals, including those suffering from familial hypercholesterolemia (FH), cannot reach the recommended LDLc levels to prevent cardiovascular complications. With an overall incidence of ϳ1:200, FH is a common inherited disease that affects at least 30 million people, of whom Յ1% have been diagnosed. It is characterized by plasma LDLc levels greater that the 95th percentile, which result in tendon xanthomas, xanthelasmas, corneal arcus, and premature atherosclerosis, leading to premature ischemic vascular disease and mortality if left untreated. In most cases, FH subjects exhibit mutations in the LDL receptor (LDLR; 67%) and its ligand apolipoprotein B (apoB; 14%), hampering LDL clearance from the circulation (2). In 2003, merging biological studies with human genetics led to the discovery of PCSK9, the 9th and last member of the family of proprotein convertases related to subtilisin and kexin (3), and the demonstration that the PCSK9 gene represents the 3rd locus of autosomal domin...

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Peptide-Based Anti-PCSK9 Vaccines - An Approach for Long-Term LDLc Management

Cited by 120 publications

References 27 publications

A cholesterol-lowering VLP vaccine that targets PCSK9

A cholesterol-lowering VLP vaccine that targets PCSK9

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Single Domain Antibodies Are Potent Inhibitors of Low Density Lipoprotein Receptor Degradation

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