eCIRP-Neutralizing mAb for Acute Lung Injury in Sepsis

eCIRP 中和单克隆抗体治疗脓毒症急性肺损伤

• 批准号: 10632117
• 负责人: Max Brenner
• 金额: $ 12.98万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10632117
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; Alveolar; Alveolar Macrophages; American; Animals; Antiinflammatory Effect; Area Under Curve; Attenuated; Bilirubin; Blood Cell Count; Blood specimen; Bone Marrow; CXCL1 gene; CXCL2 gene; Cells; Clinical Trials; Complication; Creatinine; Data; Development; Disease; Dose; Drug Kinetics; Dyes; Epithelial Cells; Evans blue stain; Future; Genes; Goals; Half-Life; Heart; Hemorrhage; Histologic; Histopathology; Hour; Immunoglobulin G; In Vitro; Inflammatory; Injections; Injury; Interleukin-1 beta; Interleukin-6; Intravenous; Investigational New Drug Application; Ischemia; Kidney; Laparotomy; Life; Liquid substance; Liver; Lung; Macrophage; Measures; Mesentery; Molecular; Monoclonal Antibodies; Mus; Neutrophil Infiltration; Normal saline; Patients; Pattern; Permeability; Peroxidases; Pharmaceutical Preparations; Pharmacology; Plasma; Pre-Clinical Model; Property; Proteins; Pulmonary Edema; Pulmonary Inflammation; RNA-Binding Proteins; Rattus; Recombinants; Safety; Sepsis; Serum; Small Intestines; Surface Plasmon Resonance; TNF gene; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Toxicology; Water; Western Blotting; alveolar epithelium; attenuation; cecal ligation puncture; cell type; chemokine; cytokine; effective therapy; extracellular; immunogenicity; improved; in vivo; interstitial; intravenous injection; lung injury; mortality; neutralizing monoclonal antibodies; neutrophil; novel; novel therapeutics; pharmacologic; pneumocyte; public health relevance; sepsis induced acute lung injury; septic; septic patients

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.

项目描述：该项目的主要目的是证明 开发细胞外冷诱导的RNA结合蛋白（ECIRP） - 中和单克隆抗体 ＃14（MAB14）是急性肺损伤患者（ALI）的新型治疗方法。阿里是关键 败血症死亡率升高的成分尚未批准尚未批准 此类患者的死亡率。我们发现ECIRP是由ALI的关键诱导者 败血症和其他炎症性疾病。在我们最近的研究中，我们表明水平有所增加 ECIRP在小鼠中与盲肠结扎和穿刺（CLP）诱导的败血症的小鼠汇总ALI。注射 重组ECIRP足以在其他健康小鼠中诱导ALI。在我们的初步研究中，我们 已经产生了大量的抗ECIRP单克隆抗体，以开发靶向ECIRP的治疗 对于Ali，并筛选了它们，以抑制ECIRP诱导的巨噬细胞释放TNF-α。我们 然后使用最有效的抗ECIRP单克隆抗体MAB14用CLP诱导的ALI治疗小鼠。 与非免疫IgG（对照）相比，用MAB14处理的CLP小鼠已减弱肺 炎症如TNF-α，IL-1β，IL-6，CXCL1和 CXCL2，以及肺过氧化物酶指示的肺中性粒细胞的改善 活动。根据这些新颖的发现，我们假设MAB14可以作为新的和 有效治疗由败血症引起的ALI的药物。在这个项目中，我们将进一步确定MAB14的ECIRP 体外和体内中和能力。然后，我们将优化MAB14的剂量以减弱败血症引起的 ALI和热窗，以改善化粪池小鼠的存活。我们还将评估MAB14的 药代动力学（PK）和药物毒性特性。我们未来的步骤将包括开发 MAB14的人性化形式，然后进行ADME，PK，晚期毒理学和免疫原性 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 治疗败血症患者的ALI。我们的最终目标是获得对MAB14的商业利用 在败血症的情况下治疗ALI患者的有效药物。