ELD607 Orai1 Antagonist Increases Bacterial Clearance from the Lung

ELD607 Orai1 拮抗剂可增加肺部细菌清除率

• 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
• 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

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.

摘要