Targeted depletion of programmed death-1 positive cells, a method that not only stops autoimmune attack but also preserves adaptive immunity

定向清除程序性死亡-1阳性细胞，这种方法不仅可以阻止自身免疫攻击，还可以保留适应性免疫

• 批准号: 10321597
• 负责人: Mingnan Chen
• 金额: $ 15.09万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-25 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321597
• 关键词: Acute; Address; Affect; Albumins; American; Animals; Antibodies; Area; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Biological Markers; Cells; Chronic; Clinical; Data; Disease Progression; Disease model; Drug Kinetics; Effector Cell; Elements; Engineering; Exotoxins; Experimental Autoimmune Encephalomyelitis; Failure; Fc Receptor; Future; Goals; Hand; Human; Immune; Immune response; Immunity; Infection; Infiltration; Insulin-Dependent Diabetes Mellitus; Investigation; Kinetics; Leukocytes; Link; Lymphocyte; Lymphocyte Suppression; Maximum Tolerated Dose; Medical Care Costs; Methods; Modeling; Multiple Sclerosis; Mus; National Institute of Allergy and Infectious Disease; Opportunistic Infections; Organ; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Population; Predisposition; Prevention; Protein Binding Domain; Proteins; Pseudomonas; Pseudomonas aeruginosa toxA protein; Quality of life; Regimen; Relapse; Safety; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Vaccines; White Blood Cell Count procedure; adaptive immune response; adaptive immunity; anti-PD-1; autoimmune pathogenesis; autoreactivity; burden of illness; cell killing; clinically relevant; design; effector T cell; efficacious treatment; immunogenicity; improved; in vivo; insulin dependent diabetes mellitus onset; lymphoid organ; novel; novel therapeutic intervention; pharmacokinetics and pharmacodynamics; preservation; prevent; programmed cell death protein 1; public health relevance; receptor; systemic autoimmune disease; tool; treatment strategy

Project Summary Autoimmune diseases (ADs) affect 50 million Americans and 12.5% of people worldwide, and for the vast majority of AD patients, there is no cure or effective prevention methods. The root cause of ADs is immune attack on self-tissues by auto-reactive effector lymphocytes and antibodies secreted by the lymphocytes. Therefore, lymphocyte suppression has been utilized as a strategy to ameliorate ADs. This strategy has yielded drugs that slow the progression of some ADs but do not prevent or cure ADs. Further, these drugs cause long-term immune deficiency and render AD patients susceptible to lethal opportunistic infections. One core reason for these deficiencies is the failure of current lymphocyte suppression drugs to focus on autoreactive effector cells. The drugs suppress and deplete native lymphocytes that do not contribute to ADs, which cause unnecessary and broad immune deficiency. Meanwhile, the current drugs fail to suppress all autoreactive effector lymphocytes: only B effector cells or only T effector cells are suppressed. To address this issue, we propose a novel lymphocyte suppression approach that encompasses all autoreactive effector cells but not naive cells. The approach utilizes the programmed death-1 receptor (PD-1) as a biomarker to identify, target and eliminate autoreactive effector cells. PD-1 is expressed on both B and T effector lymphocytes. Thus, it is possible to target all autoreactive effector lymphocytes using the PD-1 marker. More importantly, PD-1-positive (PD-1+) cells have been found to infiltrated inflamed tissues in ADs, and the infiltration is intensified while the ADs progress. An enhancement of the activity and amplification of PD-1+ cells by blocking PD-1 on these cells induced and aggravated ADs in animals and humans. On the contrary, our preliminary data showed that depletion of PD-1+ cells is very promising to treat autoimmune type-1 diabetes and chronic experimental autoimmune encephalomyelitis (EAE). On the hand, naive lymphocytes do not express PD-1, so depletion of PD-1+ cells will keep them intact. Taken together, we hypothesize that targeted depletion of PD-1-positive cells not only ameliorates in ADs but also preserves healthy immunity. To test this hypothesis, we generated an elegant protein molecule for in vivo PD-1+ cell depletion, aPD-1-ABD-PE. aPD-1-ABD-PE was designed to have three functional elements, an anti-PD-1 antibody (aPD-1) to target PD-1+ cells, an albumin-binding domain (ABD) to increase plasma presence of aPD-1-ABD-PE, and a Pseudomonas exotoxin (PE) to kill the cells that aPD-1-ABD-PE enters. aPD-1-ABD-PE has selective toxicity to PD-1+ cells. In this project, we will test the hypothesis through three specific aims: Aim 1: Characterize and prepare aPD-1-ABD-PE as a tool for targeted PD-1+ cell depletion; Aim 2: Establish that PD-1+ cell depletion ameliorates T1D, EAE, and SLE, three representative ADs; Aim 3: Establish that long-term PD-1+ cell depletion does not cause long-term immune deficiency. This project responds directly to the prominent need to improve the treatment for ADs, a priority area of study of the National Institute of Allergy and Infectious Diseases.

项目概要 自身免疫性疾病 (AD) 影响着 5000 万美国人和全世界 12.5% 的人，并且影响着广大人群 对大多数AD患者来说，没有治愈或有效的预防方法。 AD的根本原因是免疫攻击 通过自身反应性效应淋巴细胞和淋巴细胞分泌的抗体作用于自身组织。所以， 淋巴细胞抑制已被用作改善 AD 的策略。这种策略已经产生了药物 减缓某些 AD 的进展，但不能预防或治愈 AD。此外，这些药物会导致长期免疫 缺乏，使 AD 患者容易受到致命的机会性感染。造成这些的一个核心原因 缺陷在于目前的淋巴细胞抑制药物未能集中作用于自身反应性效应细胞。这 药物会抑制和消耗不会导致 AD 的天然淋巴细胞，从而导致不必要的和 广泛的免疫缺陷。同时，目前的药物无法抑制所有自身反应性效应淋巴细胞： 仅 B 效应细胞或仅 T 效应细胞被抑制。为了解决这个问题，我们提出了一个小说 淋巴细胞抑制方法涵盖所有​​自身反应性效应细胞，但不包括初始细胞。这 该方法利用程序性死亡 1 受体 (PD-1) 作为生物标志物来识别、靶向和消除 自身反应性效应细胞。 PD-1 在 B 和 T 效应淋巴细胞上表达。因此，可以针对 所有自身反应性效应淋巴细胞均使用 PD-1 标记。更重要的是，PD-1阳性（PD-1+）细胞具有 研究发现，AD 会浸润炎症组织，并且随着 AD 的进展，浸润会加剧。一个 通过阻断 PD-1 在这些细胞上诱导和扩增，增强 PD-1+ 细胞的活性和扩增 动物和人类的 AD 加重。相反，我们的初步数据表明 PD-1+ 的耗竭 细胞非常有希望治疗自身免疫1型糖尿病和慢性实验性自身免疫性疾病 脑脊髓炎（EAE）。另一方面，初始淋巴细胞不表达 PD-1，因此 PD-1+ 细胞的耗竭将导致 保持它们完好无损。综上所述，我们假设 PD-1 阳性细胞的靶向清除不仅 改善 AD，同时还能保持健康的免疫力。为了检验这个假设，我们生成了一种优雅的蛋白质 用于体内 PD-1+ 细胞耗竭的分子，aPD-1-ABD-PE。 aPD-1-ABD-PE 被设计为具有三个功能 元素，一种针对 PD-1+ 细胞的抗 PD-1 抗体 (aPD-1)，一种白蛋白结合域 (ABD)，用于增加 血浆中存在 aPD-1-ABD-PE，以及一种假单胞菌外毒素 (PE)，可杀死 aPD-1-ABD-PE 的细胞 进入。 aPD-1-ABD-PE对PD-1+细胞具有选择性毒性。在这个项目中，我们将通过以下方式检验假设 三个具体目标： 目标 1：表征并制备 aPD-1-ABD-PE 作为靶向 PD-1+ 细胞耗竭的工具； 目标 2：确定 PD-1+ 细胞耗竭可改善 T1D、EAE 和 SLE（三种代表性 AD）；目标 3： 确定长期 PD-1+ 细胞耗竭不会导致长期免疫缺陷。本项目回应 直接满足改善 AD 治疗的突出需求，这是国家研究所的优先研究领域 过敏和传染病。