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Long-term generation of antiPCSK9 antibody using a nanoliposome-based vaccine delivery system

Published on Apr 1, 2019in Atherosclerosis 4.25
· DOI :10.1016/j.atherosclerosis.2019.02.001
Amir Abbas Momtazi-Borojeni9
Estimated H-index: 9
(MUMS: Mashhad University of Medical Sciences),
Mahmoud Reza Jaafari31
Estimated H-index: 31
(MUMS: Mashhad University of Medical Sciences)
+ 1 AuthorsAmirhossein Sahebkar53
Estimated H-index: 53
(MUMS: Mashhad University of Medical Sciences)
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Abstract
Abstract Background and aims Proprotein convertase subtilisin kexin type 9 (PCSK9) is a liver secretory enzyme that controls plasma low-density lipoprotein cholesterol (LDL-C) levels through modulation of LDL receptor (LDLR). Inhibition of PCSK9 using monoclonal antibodies (mAbs) can efficiently lower plasma LDL-C. However, the relatively short half-life of mAbs necessitates frequent passive immunization, which is costly. These limitations can be circumvented by active immunization. Here, we evaluated the long-term antiPCSK9 antibody generation in BALB/c mice vaccinated with a nanoliposomal PCSK9-specific active vaccine. Methods Negatively charged nanoliposomes were used as a vaccine delivery system and prepared via lipid-film hydration method. We constructed a peptide vaccine termed Immunogenic Fused PCSK9-Tetanus (IFPT) by linking a short PCSK9 peptide (as B cell epitope) to a tetanus peptide (as T cell epitope). The IFPT peptide was conjugated to the surface of nanoliposome carriers using a DSPE-PEG- Maleimide (1,2-distearoyl- sn -glycero-3-phosphoethanolamine- N -[maleimide(PEG)-2000]) linker. Nanoliposomal IFPT (L-IFPT) construct was formulated with alum vaccine adjuvant (L-IFPTA + ). To evaluate induction of antiPCSK9 antibody in vivo, BALB/c mice were subcutaneously inoculated four times in bi-weekly intervals with prepared vaccine formulations, including L-IFPT, L-IFPTA + , IFPTA + , IFPT, and empty liposomes as negative control. The long-term efficacy of antiPCSK9 antibodies was evaluated over 48 weeks after prime inoculation. Specificity of generated antiPCSK9 antibodies was assessed using ELISA method. To evaluate immunogenic safety, production of IL-4 and IFN-γ, and population of CD8 + and CD4 + T cells in splenic cells isolated from the vaccinated mice were analyzed. Results The L-IFPTA + vaccine was found to elicit the highest IgG antibody response against PCSK9 peptide in the vaccinated mice, when compared with the other vaccine formulations. Antibody titer analyses over 48 weeks post-prime vaccination revealed that the L-IFPTA + vaccine was able to stimulate a long-lasting humoral immune response against PCSK9 peptide, and thereby decrease plasma PCSK9. Generated antibodies could specifically target PCSK9 and thereby inhibit PCSK9-LDLR interaction. Analysis of splenic cells showed that the population of anti-inflammatory CD4 + Th2 cells and production and secretion of IL-4 cytokine were increased in mice vaccinated with the L-IFPTA + vaccine, while population of inflammatory CD4 + Th1 cell and cytotoxic CD8 + T cells as well as production and secretion of IFN-γ were not altered. Conclusions The results indicate efficient activity of the tested nanoliposomal construct (L-IFPTA + ) to induce humoral immune response against PCSK9 in BALB/c mice. L-IFPTA + vaccine can induce immunogenic-safe and long-term generation of antiPCSK9 antibodies in BALB/c mice.
  • References (37)
  • Citations (3)
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References37
Newest
Published on Dec 1, 2018
Mayuresh M. Abhyankar10
Estimated H-index: 10
(University of Virginia Health System),
Mark T. Orr21
Estimated H-index: 21
(UW: University of Washington)
+ 10 AuthorsJames Elvecrog3
Estimated H-index: 3
Amebiasis caused by Entamoeba histolytica is the third leading cause of parasitic mortality globally, with some 100,000 deaths annually, primarily among young children. Protective immunity to amebiasis is associated with fecal IgA and IFN-γ in humans; however, no vaccine exists. We have previously identified recombinant LecA as a potential protective vaccine antigen. Here we describe the development of a stable, manufacturable PEGylated liposomal adjuvant formulation containing two synthetic Tol...
Published on Sep 1, 2018in PharmacoEconomics 3.71
Max Korman1
Estimated H-index: 1
,
Kjetil Retterstøl20
Estimated H-index: 20
(University of Oslo)
+ 1 AuthorsTorbjørn Wisløff14
Estimated H-index: 14
(University of Oslo)
The objective of this study was to review available health economic evaluations of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. These drugs reduce low-density lipid cholesterol levels and cardiovascular risk, but their cost effectiveness has been questioned. We searched Medline and Embase for economic evaluations in any language at any time. Studies were included if they analysed any PCSK9 inhibitor compared with either statin alone or in combination with ezetimibe or any ot...
Published on Jul 1, 2018in Journal of Cellular Physiology 4.52
Parvin Zamani4
Estimated H-index: 4
(MUMS: Mashhad University of Medical Sciences),
Amir Abbas Momtazi-Borojeni9
Estimated H-index: 9
(MUMS: Mashhad University of Medical Sciences)
+ 2 AuthorsAmirhossein Sahebkar53
Estimated H-index: 53
(MUMS: Mashhad University of Medical Sciences)
Published on Feb 1, 2018in Immunologic Research 2.61
Atefeh Arab6
Estimated H-index: 6
(MUMS: Mashhad University of Medical Sciences),
Jessica Nicastro4
Estimated H-index: 4
(UW: University of Waterloo)
+ 8 AuthorsMahmoud Reza Jaafari31
Estimated H-index: 31
(MUMS: Mashhad University of Medical Sciences)
We have investigated the in vitro immunogenicity and in vivo prophylactic and therapeutic potential of lambda (λ) phage particles displaying the E75 peptide (derived from HER2 protein) in an implantable TUBO breast tumor model of BALB/c mice. The mice were immunized with the E75-displaying phage (λF7-gpD::E75) every 2-week intervals over a 6-week period, and the generated immune responses were studied. Results showed in vitro induction of immune responses by the λF7 (gpD::E75) construct compared...
Published on Dec 1, 2017in Scientific Reports 4.01
Yajie Pan2
Estimated H-index: 2
(HUST: Huazhong University of Science and Technology),
Yanzhao Zhou5
Estimated H-index: 5
(HUST: Huazhong University of Science and Technology)
+ 6 AuthorsYuhua Liao33
Estimated H-index: 33
(HUST: Huazhong University of Science and Technology)
Vaccination provides a promising approach for treatment of hypercholesterolemia and improvement in compliance. In this study, the appropriate virus-like particle (VLP)-peptide vaccines targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) were screened. The screening criteria of target peptides were as follows: (1) located in catalytic domain of PCSK9, or regulating the binding of PCSK9 and LDL receptors (LDLR); (2) having low/no-similarity when matched with the host proteome; (3) poss...
Published on Dec 13, 2016in JAMA 51.27
Stephen J. Nicholls53
Estimated H-index: 53
(University of Adelaide),
R. Puri Mbbs32
Estimated H-index: 32
(Cleveland Clinic)
+ 16 AuthorsJingyuan Yang5
Estimated H-index: 5
(Amgen)
Importance Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. Objective To determine the effects of PCSK9 inhibition with evolocumab on progression of co...
Published on Aug 16, 2016in JAMA 51.27
Dhruv S. Kazi25
Estimated H-index: 25
,
Andrew E. Moran43
Estimated H-index: 43
(Columbia University)
+ 6 AuthorsKirsten Bibbins-Domingo51
Estimated H-index: 51
Importance Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain. Objective To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spe...
Published on Aug 1, 2016in Current Opinion in Lipidology 4.84
Bryce Chackerian27
Estimated H-index: 27
,
Alan T. Remaley65
Estimated H-index: 65
mAbs targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have the potential to become groundbreaking therapies for the treatment of hypercholesterolemia. However, one major drawback of mAb-based therapy for a chronic condition like dyslipidemia is its relatively high cost. This review summarizes two recent studies describing novel vaccine approaches for lowering LDL-cholesterol by active immunization against PCSK9.PCSK9 is a plasma protein secreted by the liver that controls choleste...
Published on Oct 1, 2015in Vaccine 3.27
Erin Crossey3
Estimated H-index: 3
(UNM: University of New Mexico),
Marcelo Amar33
Estimated H-index: 33
(NIH: National Institutes of Health)
+ 4 AuthorsAlan T. Remaley65
Estimated H-index: 65
(NIH: National Institutes of Health)
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 decr...
Cited By3
Newest
Published on Jul 4, 2019in Iubmb Life 3.05
Eskandar Taghizadeh2
Estimated H-index: 2
(MUMS: Mashhad University of Medical Sciences),
Reza Jafarzadeh Esfehani3
Estimated H-index: 3
(MUMS: Mashhad University of Medical Sciences)
+ 6 AuthorsAlireza Pasdar11
Estimated H-index: 11
(MUMS: Mashhad University of Medical Sciences)
Amir Abbas Momtazi-Borojeni9
Estimated H-index: 9
(MUMS: Mashhad University of Medical Sciences),
Sarvenaz Sabouri-Rad2
Estimated H-index: 2
(MUMS: Mashhad University of Medical Sciences)
+ 5 AuthorsAmirhossein Sahebkar53
Estimated H-index: 53
(MUMS: Mashhad University of Medical Sciences)
Published on Jun 1, 2019in Annual Review of Physiology 17.90
Rita Del Pinto3
Estimated H-index: 3
(University of L'Aquila),
Davide Grassi22
Estimated H-index: 22
(University of L'Aquila)
+ 2 AuthorsClaudio Ferri43
Estimated H-index: 43
(University of L'Aquila)
Proprotein convertase subtilisin/kexin type 9 (PCSK9)-related discoveries of the turn of the century have translated into substantial novelty in dyslipidemia treatment in the last 5 years. With chronic preventable atherosclerotic cardiovascular diseases (ASCVD) representing an epidemic of morbidity and mortality worldwide, low-density lipoprotein cholesterol (LDL-c) reduction represents a public health priority. By overcoming two major statin-related issues, namely intolerance and ineffectivenes...