A novel monoclonal antibody-based anti-NK cell anti-inflammatory strategy for treating autoimmune and checkpoint inhibitor induced myocarditis

一种基于单克隆抗体的新型抗 NK 细胞抗炎策略，用于治疗自身免疫和检查点抑制剂诱导的心肌炎

• 批准号: 10258059
• 负责人: Dror Luger
• 金额: $ 30.87万
• 依托单位: INFLAMMA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2022-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258059
• 关键词: Acute; Acute Myocarditis; Acute myocardial infarction; Address; Anti-Inflammatory Agents; Autoimmune; Autoimmune Diseases; Autoimmune Process; Binding; COVID-19; COVID-19 mortality; Cancer Patient; Cardiogenic Shock; Cells; Cessation of life; Chimera organism; Chronic; Clinical Trials; Complex; Complication; Congestive Heart Failure; Data; Disease; Dose; Echocardiography; Etiology; Flow Cytometry; Heart; Histology; Human; IgG1; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunization; Immunoglobulin Variable Region; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Intravenous; Knowledge; Legal patent; Measures; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocarditis; Natural Killer Cells; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Prevention; Prognosis; Rheumatoid Arthritis; Severities; Steroids; TNF gene; Therapeutic; Therapeutic Agents; Therapeutic immunosuppression; Tissues; Treatment Efficacy; Virus; Virus Diseases; autoimmunity checkpoint; base; cancer cell; checkpoint therapy; chronic myocarditis; cytokine release syndrome; effective therapy; human disease; immunoreaction; improved; improved outcome; in vivo; inhibiting antibody; innovation; mortality; novel; pre-clinical; preclinical study; response; side effect; single molecule; success; therapeutic target; validation studies

Summary The Problem: Despite current therapies, the prognosis of various forms of acute and chronic inflammation of the heart (myocarditis) remains poor. Immune reactions that attack a patient’s own tissues (autoimmune disease) is one major cause of myocarditis. Additionally, one of the complications of immune checkpoint inhibitors (ICI), which attack cancer cells though activation of inflammation, is myocarditis. Innovation: Inflammation involves multiple molecules and multiple redundant pathways. The anti-inflammatory monoclonal antibodies (mAbs) forming the basis of treatment of inflammation-related diseases target a single molecule and a single inflammatory pathway. Therapeutic efficacy is thereby limited. NK cells are major orchestrators of multiple inflammatory pathways. Inflamma Therapeutics (IFT) therefore developed a novel mAb—IFT100—that depletes NK cells. By inhibiting NK cells IFT100 inhibits multiple inflammatory pathways. As proof-of-concept of the efficacy of an NK cell depleting strategy, we demonstrated that an anti-NK cell mAb that depletes mouse NK cells improves myocardial function in mice with acute heart attacks or with chronic heart failure. IFT therefore decided to develop an anti-human NK cell mAb—IFT100—to serve as an immunosuppressive therapeutic agent to treat inflammation-exacerbated human disease. IFT found that IFT 101 binds to and depletes human NK cells. IFT100 was sequenced and patents submitted. The AIMS of the current proposal, using IFT100: Aim 1: Determine the dose response for in-vivo NK cell depletion in mice. Aim 2: Determine the impact of NK cell depletion on the prevention of Experimental Autoimmune Myocarditis. Aim 3: Determine the impact of NK cell depletion on the prevention of Experimental Autoimmune Myocarditis with or without the burden of ICI treatment. Aim 4: Humanize our mAb. In this project we will be validating the ability of our specific mAb (IFT100) to improve autoimmune-induced and ICI-induced myocarditis. Importantly, however, we believe IFT100 will also be effective for improving outcomes in many other diseases that are worsened by excessive inflammation. These include myocardial dysfunction in patients with chronic heart failure, with cardiogenic shock, and with acute MI. Another important additional therapeutic target for IFT100 is the massive inflammatory response responsible for most of the deaths seen in Covid-19. Each of these conditions has no current effective therapy and, as such, constitute conditions for which there are major unmet therapeutic needs.

摘要 问题：尽管目前有各种治疗方法，但各种形式的急性和慢性炎症的预后 心脏(心肌炎)的情况仍然很差。攻击患者自身组织的免疫反应(自身免疫 疾病)是心肌炎的主要原因之一。此外，免疫检查点的一个并发症 抑制物(ICI)通过激活炎症来攻击癌细胞，是心肌炎。 创新： 炎症涉及多个分子和多个多余的途径。抗炎单抗 形成治疗炎症相关疾病的基础的抗体(MAbs)针对单个分子和 一条单一的炎症途径。因此，治疗效果是有限的。NK细胞是人类免疫系统的主要协调者。 多种炎症途径。因此，炎症治疗(IFT)开发了一种新的单抗-IFT100- 消耗NK细胞。通过抑制NK细胞，IFT100抑制多种炎症途径。 作为NK细胞去除策略有效性的概念验证，我们证明了一种抗NK细胞单抗 耗尽小鼠NK细胞可改善急性心脏病发作或慢性心脏病小鼠的心肌功能 心力衰竭。IFT因此决定开发一种抗人NK细胞单抗-IFT100-作为一种 免疫抑制治疗剂，用于治疗炎症加重的人类疾病。IFT发现IFT 101结合并耗尽人类NK细胞。对IFT100进行了测序，并提交了专利。 使用IFT100的当前提案的目标是： 目的1：测定小鼠体内自然杀伤细胞耗竭的剂量效应。 目的2：探讨NK细胞耗竭对实验性自身免疫性心肌炎的预防作用。 目的3：确定NK细胞耗竭对预防实验性自身免疫性心肌炎的影响 无论有没有ICI治疗的负担。 目标4：人源化我们的单抗。 在这个项目中，我们将验证我们的特异性单抗(IFT100)在改善自身免疫诱导和 ICI所致心肌炎。然而，重要的是，我们相信IFT100也将有效地改善 因过度炎症而恶化的许多其他疾病的结果。这些措施包括 慢性心力衰竭、心源性休克和急性心肌梗死患者的心肌功能障碍。 IFT100的另一个重要的额外治疗靶点是负责的大规模炎症反应 新冠肺炎上看到的大多数死亡事件。这些疾病中的每一种目前都没有有效的治疗方法， 这些构成了存在重大未得到满足的治疗需求的条件。