Araujo Gala, Valencia Leidy Marian, Martin-Ozimek Agata, Soto Yosdel, Proctor Spencer D
Metabolic and Cardiovascular Diseases Laboratory, Division of Human Nutrition, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
Department of Immunobiology, Centre for Molecular Immunology, Havana, Cuba.
Front Immunol. 2025 Jun 9;16:1485801. doi: 10.3389/fimmu.2025.1485801. eCollection 2025.
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, fibrous elements, and cellular debris in the blood vessels. The response-to-retention hypothesis, the leading theory on the pathogenesis of this cardiovascular disease, describes the initial event in atherosclerosis as when Apolipoprotein B-containing lipoproteins, including endogenous and dietary-derived lipoproteins, bind to the inner arterial wall, the tunica intima. The subsequent lipoprotein modifications trigger an immune response that promotes atherosclerotic plaque formation. Despite the prevalence of atherosclerosis globally, and its vascular nature, therapies directed to the artery wall are limited. Immunotherapies, most notably monoclonal antibodies (mAbs), are of special interest due to their high specificity, reliability and proven success in a variety of diseases. However, current mAbs for atherosclerosis tend to target disease risk factors, notably inflammation and circulating lipoprotein levels, rather than address the root cause of atherosclerosis. These treatments result in a phenomenon known as residual risk, defined by the occurrence of severe cardiovascular events, including myocardial infarction, during treatment. Per the "response to retention" hypothesis, a plausible strategy for atherosclerosis would be blocking cholesterol retention at the arterial extracellular matrix level to complement lipid-lowering therapies. One such immunotherapy is the chP3R99 mAb, which can bind to pro-atherogenic proteoglycan sugar branches, thus competitively inhibiting lipid retention at these sites. The aim of this review is twofold: 1) To provide a summary of mAbs and other therapies used for atherosclerosis treatment, focusing on anti-inflammatory and lipid-lowering therapies, and 2) To review data on the structural characteristics, theory, and therapeutic effect of the chP3R99 mAb.
动脉粥样硬化是一种慢性炎症性疾病，其特征是血管中脂质、纤维成分和细胞碎片的积累。“反应-滞留假说”是关于这种心血管疾病发病机制的主要理论，它将动脉粥样硬化的初始事件描述为含载脂蛋白B的脂蛋白（包括内源性和饮食来源的脂蛋白）与动脉内壁（内膜）结合。随后的脂蛋白修饰引发免疫反应，促进动脉粥样硬化斑块的形成。尽管动脉粥样硬化在全球范围内普遍存在，且具有血管性质，但针对动脉壁的治疗方法有限。免疫疗法，尤其是单克隆抗体（mAb），因其高特异性、可靠性以及在多种疾病中已被证实的成功而备受关注。然而，目前用于治疗动脉粥样硬化的单克隆抗体往往针对疾病风险因素，特别是炎症和循环脂蛋白水平，而不是解决动脉粥样硬化的根本原因。这些治疗会导致一种称为残余风险的现象，其定义为在治疗期间发生严重心血管事件（包括心肌梗死）。根据“反应-滞留”假说，一种合理的动脉粥样硬化治疗策略是在动脉细胞外基质水平阻断胆固醇滞留，以补充降脂疗法。一种这样的免疫疗法是chP3R99单克隆抗体，它可以与促动脉粥样硬化的蛋白聚糖糖支结合，从而竞争性抑制这些部位的脂质滞留。本综述的目的有两个：1）总结用于动脉粥样硬化治疗的单克隆抗体和其他疗法，重点是抗炎和降脂疗法；2）综述关于chP3R99单克隆抗体的结构特征、理论和治疗效果的数据。
