Engineered cytokines target atherosclerotic plaques and locally suppress inflammation

Lisa R. Volpatti, Joseph W. Reda, Gustavo Borjas, Zhengjie Zhou, Yun Fang, J. Hubbell
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Abstract

Chronic inflammatory diseases are often treated with corticosteroids or TNF blockers to suppress overactive immune responses. However, these immunosuppressants also dampen healthy immune responses to opportunistic pathogens (e.g., respiratory viruses) and are associated with adverse effects. Targeted immunotherapies are needed to provide local immunosuppression without systemic effects. In the context of atherosclerosis, the anti-inflammatory cytokine IL-10 has been shown to suppress vascular inflammation, but its poor pharmacokinetic profile and pleiotropic effects have limited its therapeutic potential. To overcome these challenges, we engineered IL-10 to specifically target atherosclerotic plaques. We accomplished this goal by constructing fusion proteins in which one side is IL-10 and the other side is an antibody fragment (Fab) that binds to protein epitopes of low-density lipoprotein (LDL). In murine models of atherosclerosis, we show that systemically administered Fab-IL-10 constructs bind circulating LDL and hitchhike a ride to atherosclerotic plaques. In a biodistribution study, we observe elevated levels of IL-10 in the aorta but not the lungs of hyperlipidemic mice, indicative of targeted delivery. The targeted Fab-IL-10 constructs significantly reduce aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that Fab-IL-10 constructs are preferentially taken up by macrophages to exert an anti-inflammatory effect. This platform technology can be applied to a variety of cytokines and shows promise as a potential targeted anti-inflammatory therapy. Supported by the Chicago Immunoengineering Innovation Center, the NIH National Heart, Lung, and Blood Institute, and the American Heart Association.
工程细胞因子靶向动脉粥样硬化斑块并局部抑制炎症
慢性炎症性疾病通常用皮质类固醇或TNF阻滞剂来抑制过度活跃的免疫反应。然而,这些免疫抑制剂也会抑制对机会性病原体(如呼吸道病毒)的健康免疫反应,并与不良反应有关。需要靶向免疫疗法来提供局部免疫抑制而不产生全身效应。在动脉粥样硬化的背景下,抗炎细胞因子IL-10已被证明可以抑制血管炎症,但其不良的药代动力学特征和多效性限制了其治疗潜力。为了克服这些挑战,我们设计了IL-10特异性靶向动脉粥样硬化斑块。我们通过构建融合蛋白来实现这一目标,其中一侧是IL-10,另一侧是与低密度脂蛋白(LDL)蛋白表位结合的抗体片段(Fab)。在小鼠动脉粥样硬化模型中,我们发现系统给药的Fab-IL-10构建物结合循环LDL并搭便车到达动脉粥样硬化斑块。在一项生物分布研究中,我们观察到高脂血症小鼠主动脉中IL-10水平升高,但肺部没有,这表明靶向给药。靶向Fab-IL-10构建可显著降低主动脉免疫细胞浸润至与健康小鼠相当的水平,而非靶向IL-10则没有治疗作用。在机制上,我们证明了Fab-IL-10结构优先被巨噬细胞吸收以发挥抗炎作用。该平台技术可应用于多种细胞因子,有望成为一种潜在的靶向抗炎疗法。由芝加哥免疫工程创新中心、美国国立卫生研究院国家心脏、肺和血液研究所和美国心脏协会支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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