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.

项目摘要 自身免疫性疾病（AD）影响了5000万美国人和全球12.5％的人，对于广大 大多数AD患者，没有治愈或有效的预防方法。广告的根本原因是免疫攻击 在自身反应效应子淋巴细胞和由淋巴细胞分泌的抗体上的自我激烈。所以， 淋巴细胞抑制已被用作改善广告的策略。该策略产生了药物 减慢某些广告的进展，但不能预防或治愈广告。此外，这些药物会导致长期免疫 缺乏和使AD患者容易受到致命的机会感染。这些核心原因之一 缺陷是当前淋巴细胞抑制药物无法专注于自动反应性效应细胞的失败。这 药物抑制和耗尽不影响广告的天然淋巴细胞，这会导致不必要的 广泛的免疫缺陷。同时，目前的药物无法抑制所有自动反应性效应子淋巴细胞： 仅抑制B效应细胞或仅抑制T效应细胞。为了解决这个问题，我们提出了一本小说 淋巴细胞抑制方法涵盖了所有自动反应性效应细胞，而不是天真的细胞。这 方法利用编程的死亡-1受体（PD-1）作为生物标志物来识别，靶向和消除 自动反应性效应细胞。 PD-1在B和T效应淋巴细胞上均表达。因此，有可能针对 使用PD-1标记物的所有自动反应效应子淋巴细胞。更重要的是，PD-1阳性（PD-1+）细胞具有 发现在AD中渗透了发炎的组织，并且在ADS进行时，浸润会加强。一个 通过在这些细胞上阻止PD-1的PD-1+细胞的活性和扩增的增强和扩增 动物和人类中的广告加重。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性1型糖尿病和慢性实验自身免疫性 脑脊髓炎（EAE）。在手上，天真的淋巴细胞不表达PD-1，因此PD-1+细胞的耗竭将 保持它们完整。综上所述，我们假设PD-1阳性细胞的靶向耗竭不仅 改善广告，但也可以保留健康的免疫力。为了检验这一假设，我们产生了一个优雅的蛋白质 体内PD-1+细胞耗竭的分子，APD-1-ABD-PE。 APD-1-ABD-PE设计为具有三个功能 元素，一种抗PD-1抗体（APD-1），靶向PD-1+细胞，一种白蛋白结合结构域（ABD）以增加 APD-1-ABD-PE的血浆存在和假单胞菌Exotoxin（PE）杀死APD-1-1-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 三个特定目的：目标1：表征并准备APD-1-ABD-PE作为靶向PD-1+细胞耗竭的工具； 目标2：确定PD-1+细胞耗竭可以改善T1D，EAE和SLE，这是三个代表广告。目标3： 确定长期的PD-1+细胞耗竭不会导致长期免疫缺陷。这个项目做出回应 直接满足了改善广告疗法的突出需求，这是国家研究所的优先研究领域 过敏和传染病。