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）是一种重症疾病，死亡率为30-40％，目前没有 FDA批准的疗法。 Quell Pharma和Aqualung Therapeutics已发展出重组固体重组人P-选择蛋白糖蛋白配体1（PSGL-1）的无细胞形式指定串联P-选择蛋白糖蛋白配体1免疫球蛋白（TSGL-Ig），它是一种潜在的泛蛋白拮抗剂作为一种新颖的ARDS疗法。 TSGL-Ig通过抑制多形核（PMN）白细胞在上的粘附作用激活的内皮细胞（ECS），ARDS和全身发展的主要驱动力其他器官的血管炎症。 PMN白细胞在激活的EC中“贩运”与细胞粘附分子（如P-选择素）的上调。 Selectins通过结合与相对细胞表面向外伸出的配体的结合，该过程被描述为“分子免疫系统的Velcro”。最重要的选择配体PSGL-1具有结合所有三个的能力选择素类型，P-选择素，L-选择素和E-选择素。我们的小组是第一个识别Selectin P中的变体的人配体基因（SELPLG），与非裔美国人对ARDS的敏感性增加有关。 Selectin拮抗剂在肝移植，镰刀的缺血再灌注模型中表现出了很大的希望 ARDS的细胞模型和临床前模型。我们的初步数据表明TSGL-Ig是一个有前途的但是，ARDS的治疗选择，最佳剂量和热窗口尚未确定 ARDS的临床前模型。该STTR的具体目的（SAS）将确定最佳剂量和治疗 C57BL6鼠小鼠（SA＃1）和Sprague Dawley Rats（SA＃2）的TSGL-Ig的窗口 LPS/VILI诱导的肺损伤模型。三剂TSGL-Ig（0.1 mg/kg，0.5 mg/kg和1 mg/kg，IV）为与LPS同时注射以确定最佳有效剂量。接下来，将TSGL-Ig注入0、1、3， LPS注射后6小时，但在Vili暴露之前确定治疗窗口。读数包括支气管肺泡灌洗（BAL）流体细胞计数，BAL蛋白，血浆细胞因子和组织学定量的肺伤病得分。最后，SA＃3研究将在临床上与ARDS的猪猪模型中验证这些结果。第二阶段计划。成功完成I期SAS将使我们能够继续进行第二阶段，我们将在其中评估TSGL-Ig的药代动力学（PK），药效学（PD）和安全性（毒理学）曲线以及化学，制造和控制（CMC）签约基础设施以支持临床发展。成功完成第二阶段SAS将使我们申请并获得IND的批准 FDA并验证TSGL-Ig作为健康志愿者的治疗方法（I期试验）和受试者与ARDS（第二阶段试验）。