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Targeting the P Selectin Pathway to Improve ARDS Survival

靶向 P 选择通路以提高 ARDS 生存率

基本信息

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
项目类别：
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

项目摘要

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).

抽象的急性呼吸窘迫综合征（ARDS）是一种危重疾病，死亡率为 30-40%，目前尚无治疗方法。 FDA 批准的疗法。 Quell Pharma 和 Aqualung Therapeutics 开发了一种重组可溶性、无细胞形式的重组人 P-选择素糖蛋白配体-1 (PSGL-1)，称为串联 P-选择素糖蛋白配体-1免疫球蛋白（TSGL-Ig），是一种具有巨大潜力的有效的泛选择素拮抗剂作为一种新型 ARDS 疗法。 TSGL-Ig 通过抑制多形核 (PMN) 白细胞在激活的内皮细胞 (EC) 是 ARDS 和全身性疾病发生和进展的关键驱动因素其他器官的血管炎症。 PMN 白细胞跨激活 EC 的“运输”与细胞粘附分子如 P-选择素的上调。选择素通过以下方式启动 PMN 运输过程与从相对细胞表面向外伸出的配体结合，这一过程被描述为“分子免疫系统的 Velcro”。PSGL-1 是最重要的选择素配体，具有结合所有这三种配体的能力选择素类型：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蛋白 P 中变异的人配体基因（SELPLG），与非裔美国人 ARDS 易感性增加有关。选择素拮抗剂在肝移植、镰状细胞病等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 是一种有前途的 ARDS 的治疗选择，然而，最佳剂量和治疗窗尚未确定 ARDS 的临床前模型。该 STTR 的具体目标 (SA) 将确定最佳剂量和治疗 C57Bl6 小鼠 (SA #1) 和 Sprague Dawley 大鼠 (SA #2) 中 TSGL-Ig 的窗口 LPS/VILI诱导的肺损伤模型。三种剂量的 TSGL-Ig（0.1 mg/kg、0.5 mg/kg 和 1mg/kg，IV）将与LPS同时注射以确定最佳有效剂量。接下来，TSGL-Ig 将在 0、1、3、以及 LPS 注射后 6 小时但 VILI 暴露前确定治疗窗。读数包括支气管肺泡灌洗液 (BAL) 液体细胞计数、BAL 蛋白、血浆细胞因子和组织学定量肺伤害评分。最后，SA #3 研究将在临床相关的 ARDS 猪模型中验证这些结果。二期规划。成功完成第一阶段 SA 将使我们能够进入第二阶段，我们将评估 TSGL-Ig 的药代动力学 (PK)、药效学 (PD) 和安全性（毒理学）概况以及开发化学、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 SA 将使我们能够申请并获得 IND 批准 FDA，并验证 TSGL-Ig 作为健康志愿者（第一阶段试验）和受试者的治疗方法与ARDS（第二阶段试验）。