Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of low-density lipoprotein cholesterol (LDL-C). LDL-C lowering drugs such as statins or monoclonal antibodies (mAbs) against proprotein convertase subtilisin/kexin type 9 (PCSK9) are known to reduce the risk of cardiovascular diseases, however statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30 to 40% reduction in blood LDL-C. In this paper, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C lowering effects in non-human primates (NHP). Additionally, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in NHP under good laboratory practices (GLP toxicity) indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.

中文翻译：

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VXX-401 是一种新型抗 PCSK9 疫苗，可降低食蟹猴的 LDL-C。

动脉粥样硬化性心血管疾病（ASCVD）仍然是世界上疾病负担的主要原因，并且与低密度脂蛋白胆固醇（LDL-C）的慢性升高高度相关。众所周知，他汀类药物或抗前蛋白转化酶枯草杆菌蛋白酶/kexin 9 (PCSK9) 的单克隆抗体 (mAb) 等降低 LDL-C 的药物可降低心血管疾病的风险，但他汀类药物的疗效有限且治疗依从性较差，而 PCSK9抑制剂仅适用于“高风险”患者群体或其他治疗失败的患者。基于现有单克隆抗体经过验证的功效和安全性，我们开发了一种针对 PCSK9 的肽疫苗 VXX-401，作为治疗高胆固醇血症和预防 ASCVD 的替代选择。VXX-401 旨在触发针对 PCSK9 的安全体液免疫反应，从而产生内源性抗体，随后使血液 LDL-C 降低 30% 至 40%。在本文中，VXX-401 在非人灵长类动物 (NHP) 中表现出强大的免疫原性和持续的血清 LDL-C 降低作用。此外，VXX-401 诱导的抗体以高亲和力与人 PCSK9 结合，并阻断 PCSK9 对肝细胞模型中 LDL-C 摄取的抑制作用。在 NHP 中按照良好实验室规范（GLP 毒性）进行的重复剂量毒性研究表明了适当的安全性和耐受性特征，其中注射部位反应是主要发现。作为一种有前景的安全有效的 LDL-C 降低疗法，VXX-401 可能代表了一种广泛可及且方便的治疗高胆固醇血症和预防 ASCVD 的选择。