Changing the management of hypercholesterolemia: Focus on PCSK9 peptide vaccines

Summary

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a therapeutic target for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). Two recent studies published by Fang et al. and Zhang et al. in Cell Reports Medicine and Cell Reports, respectively, show the effectiveness of peptide vaccines in creating an antibody response against PCSK9 and reducing plasma cholesterol levels.

In detail

Proprotein convertase subtilisin / kexin type 9 (PCSK9) peptide vaccines appear as a promising method in the treatment of dyslipidemia and atherosclerosis, showing particular success in animal models. These vaccines have shown efficacy in generating a strong immune response and reducing plasma levels of PCSK9. The vaccines reduce LDL cholesterol (LDL-C) levels and atherosclerotic plaque, improve cholesterol transport, and reduce inflammation and apoptosis by producing high-level immunoglobulin G (IgG) antibodies against PCSK9.

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Recent studies have explored new ways to deliver PCSK9 vaccines. Vaccines based on virus-like particles (VLP) have shown increased ability to increase PCSK9 clearance in plasma. In addition to producing long-lasting immune responses and anti-inflammatory effects, nanoliposomal anti-PCSK9 vaccines have shown efficacy in reducing LDL-C levels in hypercholesterolemic mice. A recent approach has been reported by Fang et al. in Cell Reports addressed the fabrication of a PCSK9 nanoparticle (NP) vaccine through conjugation of the PCSK9 catalytic domain with self-assembled 24-mer ferritin NPs, which is another innovative strategy. This NP vaccine reduced plaque lesion areas and macrophage infiltration in atherosclerotic animals, effectively produced interfering antibodies against PCSK9, and reduced plasma lipid levels in high-fat-induced hypercholesterolemic mouse models. hPCSK174Y diet. The study found that follicular helper T cells and LDL receptors are necessary for the vaccine to be effective.

Despite these advances, problems remain in creating PCSK9 peptide vaccines. A recent report by Zhang et al. published in Cell Reports first suggested that plasma levels of PCSK9 would be increased due to the formation of an immune complex, which could change the half-life of PCSK9 and worsen the effect of the vaccine. In the aforementioned study, the researchers showed that a vaccine with an imaginary human PCSK9 known as HIT01 could elicit a strong antibody response in mice and cynomolgus monkeys, at the same time as a reduction in serum LDL cholesterol. However, a 5- to 10-fold increase in PCSK9 serum concentrations was observed after vaccination, which may be attributed to FcRn-mediated reactivation of PCSK9 by the generated antibodies, which prolongs the half-life. PCSK9 and modify the therapeutic effects of the vaccine. Whether this phenomenon is expected for other PCSK9 peptide vaccines deserves further investigation. However, there is great potential for therapeutic application for PCSK9 peptide vaccines. They can be used as a long-term dyslipidemia treatment, providing sustained reductions in plasma LDL-C and PCSK9 levels while increasing LDL receptor expression offering a potential therapeutic approach against atherosclerosis through additional mechanisms such as regulating reverse cholesterol transport and inhibition of apoptosis and inflammation. Furthermore, in non-human primates, VXX-401, a peptide-based vaccine against PCSK9, showed strong immunogenicity and lasting effects on serum LDL-C levels. This vaccine produced high-affinity antibodies that blocked the inhibitory action of PCSK9 on LDL-C uptake in liver cells and showed an acceptable safety and tolerability profile in toxicity studies.

Although experimental studies in animal models have shown that PCSK9 peptide vaccines can induce the production of long-lasting anti-PCSK9 antibodies and improve lipoprotein profiles, supporting evidence from clinical trials is still lacking. In a phase I, single-blind, randomized, placebo-controlled study involving 72 healthy subjects, 2 AFFITOPE peptide vaccines, AT04A and AT06A, were evaluated for safety, tolerability, antibody development, and lowering LDL-C. Subjects received 4 subcutaneous vaccines over 60 weeks. The study found that both vaccines were safe and induced strong and long-lasting antibody responses that crossed the physiological target of the naïve PCSK9 protein. However, only AT04A showed significant LDL-C lowering activity, with a maximum mean reduction of 11.2% and 13.3% from baseline compared to placebo at weeks 20 and 70, respectively. The mean LDL-C reduction for AT04A over the study period was -7.2%. This reduction was associated with PCSK9 epitope targeting targets greater than 50, resulting in clinically relevant LDL-C reductions with a maximum individual reduction of 39%. Both vaccines were safe and well tolerated, with injection site reactions being the most common adverse events (63% of adverse events occurring). These reactions were mild to moderate, and adverse reactions were rare and transient. This further confirms that stimulating a humoral response against PCSK9 may be a safe approach, which is consistent with the findings of preclinical studies in rodents and non-human primates. However, since different types of peptide vaccines are included, safety aspects such as lack of induction of autoimmune responses against autoantigens and chronic inflammation must be clinically verified for each individual platform. In addition, the efficacy of such vaccines must be determined in high-risk patients and those with atherosclerotic cardiovascular disease (ASCVD) who are receiving statin therapy at the maximum tolerated dose. The high efficacy and expected safety of anti-PCSK9 vaccines, assuming excellent adherence to treatment, make them the best tool for patients with familial hypercholesterolemia (requiring effective lifelong treatments ), as well as those who do not comply with the treatment. with statins or intolerance to statins.

Overall, as a safe and effective LDL cholesterol-lowering therapy, PCSK9 peptide vaccines may represent an affordable long-term option for the treatment of hypercholesterolemia and prevention of ASCVD, which remains a leading cause of death worldwide.

Ronald Palacios Castrillo