Dataset Information

Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

ABSTRACT:

Background

Proprotein convertase subtilisin/kexin 9 (PCSK9) is an important regulator of low-density lipoprotein receptor (LDLR) and plasma levels of LDL cholesterol (LDL-C). PCSK9 inhibition is an efficient therapeutic approach for the treatment of dyslipidemia. We tested the therapeutic effect of a PCSK9 vaccine on dyslipidemia and atherosclerosis.

Methods

Lipid film hydration method was used to prepare negatively charged nanoliposomes as a vaccine delivery system. An immunogenic peptide called immunogenic fused PCSK9-tetanus (IFPT) was incorporated on the surface of nanoliposomes using DSPE-PEG-maleimide lipid (L-IFPT) and adsorbed to Alhydrogel® (L-IFPTA⁺). The prepared vaccine formulation (L-IFPTA⁺) and empty liposomes (negative control) were inoculated four times with bi-weekly intervals in C57BL/6 mice on the background of a severe atherogenic diet and poloxamer 407 (thrice weekly) injection. Antibody titers were evaluated 2 weeks after each vaccination and at the end of the study in vaccinated mice. Effects of anti-PCSK9 vaccination on plasma concentrations of PCSK9 and its interaction with LDLR were determined using ELISA. To evaluate the inflammatory response, interferon-gamma (IFN-γ)- and interleukin (IL)-10-producing splenic cells were assayed using ELISpot analysis.

Results

L-IFPTA⁺ vaccine induced a high IgG antibody response against PCSK9 peptide in the vaccinated hypercholesterolemic mice. L-IFPTA⁺-induced antibodies specifically targeted PCSK9 and decreased its plasma consecration by up to 58.5% (- 164.7 ± 9.6 ng/mL, p = 0.0001) compared with the control. PCSK9-LDLR binding assay showed that generated antibodies could inhibit PCSK9-LDLR interaction. The L-IFPTA⁺ vaccine reduced total cholesterol, LDL-C, and VLDL-C by up to 44.7%, 51.7%, and 19.2%, respectively, after the fourth vaccination booster, compared with the control group at week 8. Long-term studies of vaccinated hypercholesterolemic mice revealed that the L-IFPTA⁺ vaccine was able to induce a long-lasting humoral immune response against PCSK9 peptide, which was paralleled by a significant decrease of LDL-C by up to 42% over 16 weeks post-prime immunization compared to control. Splenocytes isolated from the vaccinated group showed increased IL-10-producing cells and decreased IFN-γ-producing cells when compared with control and naive mice, suggesting the immune safety of the vaccine.

Conclusions

L-IFPTA⁺ vaccine could generate long-lasting, functional, and safe PCSK9-specific antibodies in C57BL/6 mice with severe atherosclerosis, which was accompanied by long-term therapeutic effect against hypercholesterolemia and atherosclerosis.

SUBMITTER: Momtazi-Borojeni AA

PROVIDER: S-EPMC6902459 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

Momtazi-Borojeni Amir Abbas AA Jaafari Mahmoud Reza MR Badiee Ali A Banach Maciej M Sahebkar Amirhossein A

BMC medicine 20191210 1

<h4>Background</h4>Proprotein convertase subtilisin/kexin 9 (PCSK9) is an important regulator of low-density lipoprotein receptor (LDLR) and plasma levels of LDL cholesterol (LDL-C). PCSK9 inhibition is an efficient therapeutic approach for the treatment of dyslipidemia. We tested the therapeutic effect of a PCSK9 vaccine on dyslipidemia and atherosclerosis.<h4>Methods</h4>Lipid film hydration method was used to prepare negatively charged nanoliposomes as a vaccine delivery system. An immunogeni ...[more]

PMID: 31818299

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Project description:Background The vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in melanoma development and progression. Peptide vaccines have shown great potential in cancer immunotherapy by targeting VEGFR-2 as a tumor-associated antigen and boosting the immune response against both tumor cells and tumor endothelial cells. Despite this, the low efficiency of peptide vaccines has resulted in moderate therapeutic results in the majority of studies. Enhancing the delivery of peptide vaccines using nanoliposomes is an important strategy for improving the efficacy of peptide vaccines. In this regard, we designed VEGFR-2-derived peptides restricted to both mouse MHC I and human HLA-A*02:01 using immunoinformatic tools and selected three peptides representing the highest binding affinities. The peptides were encapsulated in nanoliposomal formulations using the film method plus bath sonication and characterized for their colloidal properties. Results The mean diameter of peptide-encapsulated liposomes was around 135 nm, zeta potential of − 17 mV, and encapsulation efficiency of approximately 70%. Then, vaccine formulations were injected subcutaneously in mice bearing B16F10-established melanoma tumors and their efficiency in triggering immunological, and anti-tumor responses was evaluated. Our results represented that one of our designed VEGFR-2 peptide nanoliposomal formulations (Lip-V1) substantially activated CD4+ (p < 0.0001) and CD8+ (P < 0.001) T cell responses and significantly boosted the production of IFN-γ (P < 0.0001) and IL-4 (P < 0.0001). Furthermore, this formulation led to a significant decrease in tumor volume (P < 0.0001) and enhanced survival (P < 0.05) in mice. Conclusion Our findings suggest that the nanoliposomal formulation containing VEGFR-2 peptides could be a promising therapeutic vaccination approach capable of eliciting strong antigen-specific immunologic and anti-tumor responses. Supplementary Information The online version contains supplementary material available at 10.1186/s12645-023-00213-7.

Project description:BackgroundHER2-targeted therapies have revolutionized the treatment of HER2-positive breast cancer patients, leading to significant improvements in tumor response rates and survival. However, resistance and incomplete response remain considerable challenges. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel therapeutic strategy for the management of dyslipidemia by enhancing the clearance of low-density lipoprotein cholesterol receptors, however recent evidence also shows links between PCSK9 and cancer cells. We present an innovative immunization approach combining capsid virus-like particle (cVLP)-based vaccines against HER2 and PCSK9.MethodsThe therapeutic activity of the combined vaccine was evaluated in female mice challenged with HER2-positive mammary carcinoma cells. Controls included untreated mice and mice treated with cVLP-PCSK9 and cVLP-HER2 as standalone therapies. Antibodies elicited by vaccinations were detected through ELISA immunoassay. The functional activity of the antibodies was tested in 3D-soft agar assay on human HER2 + + + trastuzumab sensitive and resistant cells.ResultsMice vaccinated with cVLP-HER2 + cVLP-PCSK9 displayed tumor regression from the 40th day after cell challenge in 100% of mice remaining tumor-free even 4 months later. In contrast, 83% of mice treated with cVLP-HER2 vaccine alone experienced an initial tumor regression, followed by tumor relapse in 60% of subjects. Untreated mice and mice treated with the cVLP-PCSK9 vaccine alone developed progressive tumors within 1-2 months after cell injection. The combined vaccine approach elicited strong anti-human HER2 antibody responses (reaching 1-2 mg/ml range) comprising multiple immunoglobulins isotypes. cVLP-PCSK9 vaccine elicited anti-PCSK9 antibody responses, resulting in a marked reduction in PCSK9 serum levels. Although the anti-PCSK9 response was reduced when co-administered with cVLP-HER2, it remained significant. Moreover, both cVLP-HER2 + cVLP-PCSK9 and cVLP-HER2 alone induced anti-HER2 antibodies able to inhibit the 3D growth of human HER2 + + + BT-474 and trastuzumab-resistant BT-474 C5 cells. Strikingly, antibodies elicited by the combined vaccination were more effective than those elicited by the cVLP-HER2 vaccine alone in the inhibition of trastuzumab-resistant C5 cells.ConclusionsThe results indicate that cVLP-PCSK9 vaccination shows adjuvant activity when combined with cVLP-HER2 vaccine, enhancing its therapeutic efficacy against HER2-positive breast cancer and holding promise in overcoming the challenges posed by resistance and incomplete responses to HER2-targeted therapy.

Dataset Information

Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

Background

Methods

Results

Conclusions

Publications

Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

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