ELD607 Orai1 Antagonist Increases Bacterial Clearance from the Lung

ELD607 Orai1 拮抗剂可增加肺部细菌清除率

基本信息

批准号：
10080273
负责人：
ROBERT TARRAN
金额：
$ 30万
依托单位：
ELDEC PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-22 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080273
关键词：
Address Affect Animals Antibiotic Resistance Antibiotics Bacteria Bacterial Antibiotic Resistance Bacterial Infections Binding Biological Assay Biotechnology Bronchoalveolar Lavage Cell Line Cell membrane Cells Clinical Data Contracts Critical Illness Data Development Diagnosis Dose Drug Kinetics ESKAPE pathogens Early treatment Effectiveness Frequencies Glosso-Sterandryl Health Immune Immune system Immunofluorescence Immunologic Infection Inflammation Inflammatory Response Inhalation Intensive Care Units Ion Channel Klebsiella pneumoniae Lead Leukocyte Elastase Lung Macaca mulatta Modeling Mus Nasal Epithelium Neutrophilia Nosocomial Infections Nosocomial pneumonia Organism Outcome Palate Patients Peptides Pharmacologic Substance Pharmacology and Toxicology Phase Play Pneumonia Population Production Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Public Health Regimen Resistance Role Sepsis Signal Transduction Specificity Staphylococcus aureus Testing Therapeutic Toxicology Tropism Validation Western Blotting base clinical development effective therapy experimental study improved improved outcome lung injury meetings methicillin resistant Staphylococcus aureus mortality mouse model neutrophil novel novel strategies novel therapeutic intervention pathogen patient population peptidomimetics pneumonia model polypeptide pre-clinical programs reconstitution resistant strain validation studies

项目摘要

Hospital acquired pneumonia (HAP) is most common cause of mortality in intensive care units and the 2nd most common nosocomial infection in the US. P. aeruginosa, S. aureus (including MRSA) and other ESKAPE pathogens are common causes of HAP. The rise in antibiotic-resistant bacteria, including MRSA, further complicates the challenges of delivering effective treatments in this patient population. New approaches beyond traditional antibiotics are urgently need to improve outcomes in HAP patients. The innate immune protein Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is secreted into the lung lumen, where it can bind to and regulate ion channels. Orai1 is a ubiquitously-expressed plasma membrane Ca2+ channel, whose activation is required for the onset of inflammation. We have identified SPLUNC1’s Orai1-inhibitory domain, termed the a6 region: SPLUNC1 and a6 negatively regulate Orai1 to moderate Ca2+ signaling and reduce inflammation. However, both SPLUNC1 and the a6 peptide are rapidly degraded by neutrophil elastase, limiting their effectiveness in reducing Ca2+ signaling and inflammation in pneumonia, which is characterized by neutrophilia. Eldec Pharma has developed a robust, novel peptidomimetic called ELD607, which reconstitutes SPLUNC1/a6’s ability to inhibit Orai1, yet is significantly more resistant to degradation by neutrophil elastase than a6. In murine pneumonia models with P. aeruginosa and S. aureus, a single, inhaled dose of ELD607 reduced lung neutrophilia by 90%, decreased lung bacterial infection by 3-5 log10 CFUs, reduced sepsis, and increased survival. These definitive experiments demonstrate that rebalancing the lung’s inflammatory response via ELD607 enhances the lungs’ natural ability to clear pathogens, in the absence of antibiotics. This capacity is predicted to make concurrently-administered antibiotics more effective, providing an important new therapeutic strategy to help address the emergence of antibiotic-resistant strains of bacteria. The ability of ELD607 to inhibit Orai1 and increase bacterial clearance represents a revolutionary approach to improving HAP outcomes. Robust validation of ELD607 in Phase I will enable Eldec Pharma to request a pre-IND meeting with the FDA, in order to perform IND-enabling studies in Phase II and to make the subsequent transition to clinical development. Phase 1 Aim 1. To confirm that ELD607 replicates the Orai1-tropism observed with SPLUNC1/a6. Aim 2. To replicate ELD607’s ability to clear other ESKAPE pathogens. Phase 2 Aim 3 To produce GLP grade ELD607 to support downstream development activities. Aim 4. To determine the optimal dosing regimen of ELD607 in a murine model. Aim 5. To validate the ELD607 dosing regimen in a Rhesus macaque model of HAP.

医院获得性肺炎 (HAP) 是重症监护病房最常见的死亡原因，也是第二大死亡原因美国常见的院内感染包括铜绿假单胞菌、金黄色葡萄球菌（包括 MRSA）和其他 ESKAPE。病原体是 HAP 的常见原因，包括 MRSA 在内的抗生素耐药细菌的增加。为这一患者群体提供有效治疗的挑战变得更加复杂。迫切需要传统抗生素来改善 HAP 患者的预后。腭肺和鼻上皮克隆 1 (SPLUNC1) 分泌到肺腔中，在那里它可以结合并 Orai1 是一种普遍表达的质膜 Ca2+ 通道，其激活是我们已经确定了 SPLUNC1 的 Orai1 抑制结构域，称为 a6。区域：SPLUNC1 和 a6 负向调节 Orai1 以调节 Ca2+ 信号传导并减少炎症。然而，SPLUNC1 和 a6 肽都会被中性粒细胞弹性蛋白酶快速降解，限制了它们的作用。有效减少以中性粒细胞增多为特征的肺炎中的 Ca2+ 信号传导和炎症。 Eldec Pharma 开发了一种强大的新型肽模拟物，称为 ELD607，它可以重构 SPLUNC1/a6 能够抑制 Orai1，但对中性粒细胞弹性蛋白酶降解的抵抗力显着增强在铜绿假单胞菌和金黄色葡萄球菌的小鼠肺炎模型中，单次吸入剂量的 ELD607。肺部中性粒细胞减少 90%，肺部细菌感染减少 3-5 log10 CFU，减少败血症，这些明确的实验表明，重新平衡肺部的炎症反应。在没有抗生素的情况下，ELD607 增强了肺部清除病原体的自然能力。预计将使同时使用的抗生素更加有效，从而提供一种重要的新疗法 ELD607 的能力有助于解决抗生素耐药菌株的出现。抑制 Orai1 并增加细菌清除率是改善 HAP 的革命性方法 ELD607 在第一阶段的稳健验证将使 Eldec Pharma 能够请求与 IND 召开预会议。 FDA，以便在 II 期中进行 IND 支持研究并随后过渡到临床发展。第一阶段目标 1. 确认 ELD607 复制了 SPLUNC1/a6 观察到的 Orai1 向性。目标 2. 复制 ELD607 清除其他 ESKAPE 病原体的能力。第二阶段目标 3 生产 GLP 级 ELD607 以支持下游开发活动。目标 4. 确定 ELD607 在小鼠模型中的最佳给药方案。目标 5. 在 HAP 恒河猴模型中验证 ELD607 给药方案。