Targeting the P Selectin Pathway to Improve ARDS Survival

摘要 急性呼吸窘迫综合征（ARDS）是一种危重病，死亡率为30 - 40%，目前尚无 FDA批准的疗法。Quell Pharma和Aqualung Therapeutics已经开发了一种重组可溶性， 重组人P-选择素糖蛋白配体-1（PSGL-1）的无细胞形式，称为串联P-选择素 糖蛋白配体-1免疫球蛋白（TSGL-Ig）是一种潜在的泛选择素拮抗剂 作为一种新型的ARDS治疗方法。TSGL-Ig通过抑制多形核白细胞（PMN）粘附于 活化的内皮细胞（EC）是ARDS和系统性呼吸窘迫综合征（ARDS）发展和进展的关键驱动因素， 其他器官的血管炎症。中性粒细胞通过激活的内皮细胞的"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贩运过程 与从相对细胞表面向外粘附的配体结合，这一过程被描述为"分子结合"。 免疫系统的“魔术贴”。PSGL-1，最重要的选择素配体，具有结合所有三种的能力 选择素类型，P-选择素、L-选择素和E-选择素。我们的研究小组是第一个发现选择素P 配体基因（SELPLG），与非洲裔美国人对ARDS的易感性增加有关。 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， 细胞模型和ARDS的临床前模型。我们的初步数据表明，TSGL-Ig是一个有前途的 然而，对于ARDS的治疗选择，最佳剂量和治疗窗尚未确定， ARDS的临床前模型。本STTR的具体目标（SA）将确定最佳剂量和治疗 C57 B16小鼠（SA #1）和Sprague道利大鼠（SA #2）中TSGL-Ig的窗口， LPS/VILI诱导的肺损伤模型。将给予三个剂量的TSGL-Ig（0.1 mg/kg、0.5 mg/kg和1 mg/kg，IV）， 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， 和LPS注射后6小时但在VILI暴露之前，以确定治疗窗。读数包括 支气管肺泡灌洗（BAL）液细胞计数、BAL蛋白、血浆细胞因子和组织学定量的肺 受伤分数最后，SA #3研究将在临床相关的猪ARDS模型中验证这些结果。 第二阶段规划。成功完成第一阶段SA后，我们将进入第二阶段， 评估TSGL-Ig的药代动力学（PK）、药效学（PD）和安全性（毒理学）特征以及 开发化学、生产和控制（CMC）合同基础设施，以支持临床 发展成功完成II期SA将使我们能够申请并获得IND批准， 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）。

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).