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：
10453601
负责人：
ROBERT TARRAN
金额：
$ 98.82万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453601
关键词：
Address Affect Animals Antibiotic Resistance Antibiotics Bacteremia 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 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 antagonist base clinical development effective therapy experimental study improved improved outcome lung health 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 public health relevance reconstitution resistant strain validation studies

项目摘要

Abstract 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.

抽象的医院获得的肺炎（HAP）是重症监护病房中最常见的死亡率原因，也是美国第二大最常见的医院感染。 P. Aeruginosa，S。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升高进一步使在该患者人群中提供有效治疗的挑战变得复杂。除传统抗生素以外的新方法迫切需要改善HAP患者的预后。先天性免疫蛋白短pa肺和鼻上皮克隆1（Splunc1）分泌到肺管腔中，可以在其中结合并调节离子通道。 Orai1是一种普遍表达的质膜Ca2+通道，其激活是炎症发作所必需的。我们已经确定了SPLUNC1的ORAI1抑制域，称为A6区域：Splunc1和A6负调节Orai1以中度Ca2+信号传导并减少注射。然而，Splunc1和A6肽都被嗜中性粒细胞弹性酶迅速降解，从而限制了它们在减少肺炎的Ca2+信号传导和炎症中的有效性，肺炎的特征是中性粒细胞。 Eldec Pharma开发了一种强大的，新型的肽组合，称为ELD607，它重构Splunc1/A6抑制Orai1的能力，但与A6相比，中性粒细胞弹性酶对降解的耐药性更大。在带有铜绿假单胞菌和金黄色葡萄球菌的鼠肺炎模型中，单个内部剂量的ELD607降低了肺嗜中性粒细胞增长90％，通过3-5 log10 cfus降低了肺细菌感染，减少败血症和增加生存率。这些确定的实验表明，在没有抗生素的情况下，通过ELD607通过ELD607重新平衡肺部炎症反应可以增强肺部清除病原体的自然能力。预计这种能力可以使同时施用的抗生素更有效，从而提供了一种重要的新治疗策略，以帮助解决抗生素耐药菌菌株的出现。 ELD607抑制Orai1和增加细菌清除的能力代表了改善HAP结局的革命性方法。在第一阶段对ELD607的强大验证将使ElDec Pharma要求与FDA进行预先会议，以便在II阶段进行辅助研究，并随后过渡到临床发展。第1阶段目标1。确认ELD607复制了用Splunc1/a6观察到的Orai1-热症。目标2。复制ELD607清除其他Eskape病原体的能力。第2阶段目标3生产GLP级ELD607以支持下游开发活动。目标4。确定在鼠模型中ELD607的最佳剂量方案。目标5。在HAP的恒河猕猴模型中验证ELD607的剂量方案。