Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates expression of low-density lipoprotein (LDL) receptors via receptor internalization and subsequent lysosomal degradation. Thus, an anti-PCSK9 antibody is well known as an anti-hyperlipidemia drug. Here, we aimed to develop vaccine for a long-term treatment of dyslipidemia targeted to PCSK9. In This study, we designed a peptide vaccine for mouse PCSK-9, which consisted of short peptides conjugated to keyhole limpet hemocyanin (KLH) as a carrier protein. Vaccines were administered to male apolipoprotein E (ApoE) deficient mice with adjuvants and significantly elicited an antibody response against PCSK9. The PCSK9 vaccines were administered to mice three times in 2-week intervals, and antibody titers and lipoprotein levels were evaluated up to 24 weeks after the first immunization to determine the therapeutic effect. Anti-PCSK9 antibody titers reached peak levels 6 weeks after the first immunization, and theses titers were maintained for up to 24 weeks. Decreased plasma levels of total cholesterol, very low-density lipoprotein (VLDL), and chylomicron (CM) were maintained for up to 24 weeks. Immunized mice exhibited a significant increase in cell-surface LDL receptor expression. Stimulation with KLH, but not PCSK9, induced the production of INF-gamma and interleukin-4 (IL-4), as determined with ELISPOT assays, thus indicating that PCSK9 vaccine did not elicit T-cell activation in our vaccine system. The present anti-PCSK9 vaccine induced long-lasting anti-PCSK9 antibody production and improved lipoprotein profiles. Thus, anti-PCSK9 vaccine could become a new option for the treatment of dyslipidemia as a long-acting therapy in future.

Vaccines Targeting PSCK9 for the Treatment of Hyperlipidemia

“…Another preclinical study of [47] testing anti-PCSK9 on apolipoprotein E deficient mouse used a similar approach as described by Galabova et al [37]. The vaccine itself consisted of short peptides consisting of 9-10 amino acids (C-terminal sequence of PCSK9 580-589 amino acids) conjugated with KLH as a carrier protein.…”

Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies

“…This could be achieved by using PCSK9-peptide-based vaccines (Figure 2). 95,96 So far preclinical studies in mice have shown that immunization induces a strong and long-lasting immune response resulting in reduced plasma levels of PCSK9, total cholesterol and non-HDL-C (VLDL-C and LDL-C), as well as systemic inflammation. 97 Moreover, immunization resulted in reduced atherosclerotic lesion area and aortic inflammation compared with control mice.…”

Proprotein convertase subtilisin/kexin type 9 inhibition in cardiovascular disease: current status and future perspectives

“…Therefore, active immunization could provide an efficient and durable therapeutic approach for hypercholesterolemia. Recently, several preclinical studies have revealed promising results in producing long-term anti-PCSK9 antibodies by vaccination [13,[82][83][84]. Most recently, Momtazi-Borojeni et al [84] evaluated the effect of a nanoliposomal PCSK9-specific active vaccine in producing long-lasting anti-PCSK9 antibodies in a BALB/c mice model.…”