Targeting the P Selectin Pathway to Improve ARDS Survival

靶向 P 选择通路以提高 ARDS 生存率

• 批准号: 10481283
• 负责人: Stanley Miele
• 金额: $ 25.96万
• 依托单位: AQUALUNG THERAPEUTICS CORP.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2023-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481283
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Adhesions; African; African American population; Alteplase; Alveolar; Animals; Attenuated; Avidity; Binding; Blood Vessels; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cadaver; Cell Adhesion Molecules; Cell Count; Cell model; Cells; Chemistry; Clinical; Clinical Trials; Coagulation Process; Contracts; Critical Illness; Data; Development; Dose; Drug Kinetics; E-Selectin; Endothelial Cells; Evaluation; Exhibits; Exposure to; Extravasation; FDA approved; Functional disorder; Gene Expression; Genes; Grant; Histologic; Hour; Human; Immune; Immune system; Immunoglobulins; Inflammatory; Inflammatory Response; Infrastructure; Injections; Intravenous Immunoglobulins; Ischemia; Kidney Transplantation; L-Selectin; Lead; Leukocyte Trafficking; Ligands; Lipopolysaccharides; Lung; Modeling; Molecular; Monoclonal Antibodies; Mus; Myocardial Infarction; Organ; P-Selectin; P-selectin ligand protein; Pain; Pathway interactions; Patients; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Positioning Attribute; Pre-Clinical Model; Predisposition; Process; Proteins; Pulmonary Inflammation; RNA Interference; Rattus; Recombinants; Reperfusion Injury; Reperfusion Therapy; Reporting; Safety; Selectins; Sickle Cell; Small Business Technology Transfer Research; Sprague-Dawley Rats; Surface; Testing; Therapeutic; Thrombolytic Therapy; Toxicology; Transplantation; Up-Regulation; Variant; Ventilator-induced lung injury; Viral Respiratory Tract Infection; Work; antagonist; clinical development; clinically relevant; cytokine; healthy volunteer; humanized monoclonal antibodies; improved; knock-down; liver transplantation; lung injury; mortality; mouse model; neutrophil; novel; phase I trial; phase II trial; porcine model; pre-clinical; prevent; safety study; systemic inflammatory response; trafficking; vascular inflammation

ABSTRACT Acute respiratory distress syndrome (ARDS) is a critical illness with 30- 40% mortality and currently there are no FDA-approved therapies. Quell Pharma and Aqualung Therapeutics have developed a recombinant soluble, cell-free form of recombinant human P-selectin glycoprotein ligand-1 (PSGL-1) designated Tandem P-Selectin glycoprotein ligand-1 immunoglobulin (TSGL-Ig), which is a potent pan-selectin antagonist with great potential as a novel ARDS therapy. TSGL-Ig works by inhibiting the adhesion of polymorphonuclear (PMN) leukocytes on activated endothelial cells (ECs), a key driver in the development and progression of ARDS and systemic vascular inflammation in other organs. PMN leukocyte “trafficking” across activated ECs is associated with the upregulation of cell adhesion molecules such as P-selectin. Selectins initiate the PMN trafficking process by binding to ligands that stick outwards from surface of opposing cells, a process described as the “molecular Velcro” of the immune system. PSGL-1, the most important selectin ligand, has the capacity to bind all three selectin types, P-selectin, L-selectin, and E-selectin. Our group was the first to identify variants in the selectin P ligand gene (SELPLG), to be associated with increased susceptibility to ARDS among African-Americans. Selectin antagonists have shown great promise in ischemia reperfusion models of liver transplantation, sickle cell models and preclinical models of ARDS. Our preliminary data indicates that TSGL-Ig is a promising therapeutic option for ARDS, however, the optimal dose and therapeutic window has not been determined in preclinical models of ARDS. The Specific Aims (SAs) of this STTR will determine optimal dose and therapeutic window for TSGL-Ig in C57Bl6 murine mice (SA #1) and Sprague Dawley rats (SA #2) subjected to a combined LPS/VILI-induced lung injury model. Three doses of TSGL-Ig (0.1 mg/kg, 0.5 mg/kg, and 1mg/kg, IV) will be injected concurrently with LPS to determine optimal efficacious dose. Next, TSGL-Ig will be injected at 0, 1, 3, and 6 hours post LPS injection but prior to VILI exposure to determine the therapeutic window. Readouts include bronchoalveolar lavage (BAL) fluid cell counts, BAL protein, plasma cytokines, and histologically quantified lung injury score. Finally, SA #3 studies will validate these results in a clinically-relevant porcine model of ARDS. Phase II planning. Successful completion of Phase I SAs will allow us to proceed to Phase II, where we will assess pharmacokinetic (PK), pharmacodynamic (PD), and safety (toxicology) profiles of TSGL-Ig as well as the development of a chemistry, manufacturing, and control (CMC) contracted infrastructure to support clinical development. Successful completion of the Phase II SAs will position us to apply and receive IND approval from the FDA, and to validate TSGL-Ig as a therapeutic approach in healthy volunteers (Phase I trial) and in subjects with ARDS (Phase II trial).

摘要 急性呼吸窘迫综合征(ARDS)是一种死亡率为30%-40%的危重疾病，目前还没有 FDA批准的疗法。Quell Pharma和Aquung Treateutics已经开发出一种重组可溶性， 重组人P-选择素糖蛋白配体-1(PSGL-1)的无细胞形式串联P-选择素 糖蛋白配体-1免疫球蛋白(TSGL-Ig)是一种很有潜力的泛选项素拮抗剂 作为一种新的ARDS疗法。TSGL-Ig通过抑制中性粒细胞(PMN)与 激活的内皮细胞(ECs)是ARDS和系统性红斑狼疮发生发展的关键驱动因素 其他器官的血管炎症。中性粒细胞在激活的内皮细胞间的“转运”与 上调细胞黏附分子，如P-选择素。选择素通过以下方式启动PMN贩运进程 与从对立细胞表面向外粘着的配体结合，这一过程被描述为“分子 免疫系统的魔术贴。PSGL-1是最重要的选择素配体，具有与这三种配体结合的能力 选择素类型：P-选择素、L-选择素和E-选择素。我们的小组是第一个发现选择素P的变异体的 配体基因(SELPLG)，与非裔美国人对ARDS易感性增加有关。 选择素拮抗剂在肝移植缺血再灌注模型中显示出巨大的前景 ARDS的细胞模型和临床前模型。我们的初步数据表明，TSGL-Ig是一种很有前途的 ARDS的治疗选择，然而，最佳剂量和治疗窗口尚未确定 ARDS的临床前模型。本研究的特定目标(SA)将决定最佳剂量和治疗方法 C57BL6小鼠(SA#1)和SD大鼠(SA#2)联合应用TSGL-Ig的窗口 脂多糖/VILI诱导的肺损伤模型。三种剂量的TSGL-Ig(0.1 mg/kg，0.5 mg/kg，1 mg/kg，静脉注射) 同时注射脂多糖，确定最佳有效剂量。接下来，TSGL-Ig将在0，1，3， 注射内毒素后6h、VILI暴露前6h确定治疗窗。读数包括 支气管肺泡灌洗(BAL)液细胞计数、BAL蛋白、血浆细胞因子和肺组织学定量 伤病记分。最后，SA#3研究将在临床相关的ARDS猪模型中验证这些结果。 第二阶段规划。成功完成第一阶段SAS将使我们能够进入第二阶段，在此阶段，我们将 评价TSGL-Ig的药代动力学(PK)、药效学(PD)和安全性(毒理学)谱，以及 开发化学、制造和控制(CMC)合同基础设施以支持临床 发展。成功完成第二阶段SAS将使我们能够申请并获得IND的批准 FDA，并验证TSGL-Ig作为健康志愿者(I期试验)和受试者的治疗方法 ARDS(II期试验)。