eCIRP-Neutralizing mAb for Acute Lung Injury in Sepsis

项目描述：本项目的主要目标是证明 开发细胞外冷诱导RNA结合蛋白（eCIRP）中和单克隆抗体 #14（mAb 14）作为具有急性肺损伤（ALI）的脓毒症患者的新型治疗。阿里是一个关键的 脓毒症死亡率升高的一个组成部分，尚未批准任何特定的治疗方法来降低 这类患者的死亡率。我们已经发现eCIRP是由以下原因引起的ALI的关键诱导物： 败血症和其他炎性疾病。在我们最近的研究中，我们已经表明， eCIRP可加重盲肠结扎穿孔（CLP）脓毒症小鼠的ALI。注射 重组eCIRP足以在其他健康小鼠中诱导ALI。在初步研究中，我们 已经产生了大量的抗eCIRP单克隆抗体，以开发eCIRP靶向治疗 并筛选它们对eCIRP诱导的巨噬细胞释放TNF-α的抑制作用。我们 然后使用最有效的抗eCIRP单克隆抗体mAb 14治疗患有CLP诱导的ALI的小鼠。 与未免疫IgG（对照）相比，用mAb 14处理的CLP小鼠具有减毒的肺 炎症，如TNF-α、IL-1β、IL-6、CXCL 1和 CXCL 2，以及髓过氧化物酶指示的肺中性粒细胞浸润减少 活动基于这些新的发现，我们假设mAb 14可以被开发为一种新的， 是治疗脓毒症所致急性肺损伤的有效药物。在本项目中，我们将进一步确定mAb 14的eCIRP 体外和体内的中和能力。然后，我们将优化mAb 14的剂量以减弱脓毒症诱导的 ALI和治疗窗改善脓毒症小鼠的生存。我们还将评估mAb 14的 药代动力学（PK）和药物毒性性质。我们未来的步骤将包括开发一个 人源化形式的mAb 14，然后进行其ADME、PK、高级毒理学和免疫原性 问题研究然后，我们将向FDA提交研究性新药（IND）申请，以启动临床试验 治疗脓毒症患者的急性肺损伤我们的最终目标是获得mAb 14的商业利用， 和有效的药物来治疗脓毒症背景下的ALI患者。

PROJECT DESCRIPTION: The primary objective of this project is to demonstrate the feasibility of developing the extracellular cold-inducible RNA-binding protein (eCIRP)-neutralizing monoclonal antibody #14 (mAb14) as a novel treatment for septic patients with acute lung injury (ALI). ALI is a critical component of the elevated mortality rate in sepsis no specific treatment has yet been approved to reduce the mortality of such patients. We have discovered that eCIRP is a critical inducer of ALI caused by sepsis and other inflammatory diseases. In our recent studies, we have shown that increased levels of eCIRP aggravated ALI in mice with sepsis induced by cecal ligation and puncture (CLP). Injection of recombinant eCIRP was sufficient to induce ALI in otherwise healthy mice. In our preliminary studies, we have generated a large panel of anti-eCIRP monoclonal antibodies to develop an eCIRP-targeting treatment for ALI, and screened them for their inhibition of eCIRP-induced release of TNF-α by macrophages. We then used the most effective anti-eCIRP monoclonal antibody, mAb14, to treat mice with CLP-induced ALI. Compared with non-immunized IgG (control), CLP mice treated with mAb14 had attenuated lung inflammation as indicated by the decreased lung gene and protein levels of TNF-α, IL-1β, IL-6, CXCL1, and CXCL2, as well as the decreased neutrophil infiltration of the lungs as indicated by the myeloperoxidase activity. Based on these novel findings, we hypothesize that mAb14 can be developed as a new and effective drug to treat ALI caused by sepsis. In this project, we will further determine mAb14’s eCIRP neutralization ability in vitro and in vivo. We will then optimize mAb14’s dose to attenuate sepsis-induced ALI and therapeutic window to improve the survival of septic mice. We will also evaluate mAb14’s pharmacokinetics (PK) and pharmacotoxicity properties. Our future steps will include developing a humanized form of mAb14 and then conducting its ADME, PK, advanced toxicology, and immunogenicity studies. We will then file with the FDA an investigational new drug (IND) application to initiate clinical trials to treat ALI in patients with sepsis. Our ultimate goal is to obtain commercial utilization of mAb14 as a safe and effective drug to treat patients with ALI in the context of sepsis.