Treatment of Inflammatory Complications of Viral Pneumonia

病毒性肺炎炎症并发症的治疗

• 批准号: 10383991
• 负责人: Andy Agrawal
• 金额: $ 30万
• 依托单位: RESPANA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-20 至 2023-08-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383991
• 关键词: 2019-nCoV; Acceleration; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Acute respiratory failure; Acute respiratory infection; Address; Adhesions; Advanced Development; Aftercare; Alveolar; Alveolar Macrophages; Animals; Antibodies; Antiviral Agents; Antiviral resistance; Attenuated; Bacterial Pneumonia; Biochemical; Biocompatible Materials; Biological Availability; Biological Models; Blood Chemical Analysis; Body Weight; COVID-19; Cells; Cellular Assay; Cessation of life; Critical Illness; Data; Development; Disease; Disease Outbreaks; Drug Kinetics; Effectiveness; Etiology; Fibrosis; Genetic study; Healthcare Systems; Hematology; Histopathology; Hospitalization; Host Defense; Human; Hypoxia; Immune; Immune response; Immunity; Immunocompromised Host; Immunologic Receptors; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Injectable; Intervention; Lead; Lung; Lung infections; Mediating; Medical; Methodology; Methods; Monoclonal Antibodies; Morbidity - disease rate; Mus; Organ; Pathogenicity; Patient-Focused Outcomes; Patients; Peripheral; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Phase; Play; Pre-Clinical Model; Predisposition; Prevention; Property; Protein Isoforms; Proteins; Public Health; Pulmonary Inflammation; Readiness; Reagent; Recovery; Reporting; Resolution; Respiratory Tract Infections; Risk; Role; SARS-CoV-2 infection; Safety; Shipping; Source; Surface; Symptoms; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; TimeLine; Toxic effect; Treatment Efficacy; United States; Vaccines; Viral; Viral Pneumonia; Virus; Virus Diseases; Work; airway obstruction; base; biophysical analysis; co-infection; combat; commercialization; cytokine; experience; extreme temperature; fighting; high risk; high risk population; humanized monoclonal antibodies; humanized mouse; improved outcome; influenza infection; innovation; lung health; lung injury; macrophage; monocyte; mortality; mouse model; murine monoclonal antibody; neonatal Fc receptor; novel; pandemic disease; pandemic influenza; pathogen; pre-clinical; prevent; product development; pulmonary function; research clinical testing; respiratory; response; restoration; seasonal influenza; superinfection; surfactant; surfactant protein A receptor; targeted treatment; trafficking; young adult

ABSTRACT Respana Therapeutics, Inc., is developing and commercializing a proprietary humanized monoclonal antibody (mAb) targeting morbidities and mortality associated with inflammatory complications of viral pneumonia. The initial anticipated product is an injectable mAb that calibrates the immune response to respiratory infection, attenuates injurious inflammation and expedites restoration of lung health after influenza A virus (IAV) infection, both seasonal and pandemic. Influenza is α major source of acute lung injury in critically ill patients worldwide. Emerging evidence that influenza coinfection exacerbates susceptibility to SARS-CoV-2 infection with increased mortality anticipates an even larger burden of respiratory critical illness in the post-pandemic era in the years to come. Respiratory infections like influenza create a widespread immune system response causing acute inflammation in the lung. This inflammatory response, while necessary to fight the virus, can persist in the lung long after the virus is cleared. This can lead to further morbidities, including secondary bacterial pneumonia, hospitalization due to serious lung injury, and even death. To address that, Respana intends to develop a safe, affordable, scalable and widely available product that can be used to improve outcomes for patients, beginning with high-risk influenza sufferers. We anticipate that Respana’s product will reduce duration of symptoms, and reduce post-influenza bacterial respiratory infections and mortality, thereby strengthening the health care system’s ability to combat seasonal and pandemic influenza. Respana’s innovative work on the surfactant protein (SP-A) receptor SP-R210 has shown that it increases phagocytosis of SP-A-bound pathogens and modulates cytokine secretion by immune cells. SP-A plays an important role in pulmonary immunity by enhancing opsonization and clearance of pathogens and by modulating macrophage inflammatory responses. The data Respana has generated supports a biological model in which SP-R210 isoforms differentially regulate trafficking, expression, and activation of innate immune receptors on macrophages. Completed proof of concept studies convincingly show that IAV-infected mice, when treated with SP-R210 targeted murine mAb P2H10, recover more quickly, have better post-infection lung function, and show better lung histopathology than untreated mice. Our specific objective is to advance the development of humanized-P2H10 mAb to fulfill federal requirements for an IND application by validating its safety, bioactivity, pharmacokinetics, and therapeutic efficacy in humanized FcRn and SP-A pre-clinical models of viral infection.

摘要 Respana治疗公司正在开发并商业化一种专有的人性化 针对与炎症性疾病相关的发病率和死亡率的单抗 病毒性肺炎的并发症。最初预期的产品是一种可注射的单抗 调整对呼吸道感染的免疫反应，减轻破坏性炎症和 加速甲型流感病毒(IAV)感染后肺部健康的恢复，包括季节性和 大流行。流感是世界各地危重患者急性肺损伤的主要来源。 新的证据表明，流感合并感染加剧了对SARS-CoV-2的易感性 死亡率增加的感染预计呼吸道危重疾病的负担会更大 在未来几年的大流行后时代。 像流感这样的呼吸道感染会引起广泛的免疫系统反应，导致 肺部的急性炎症。这种炎症反应虽然对抗击病毒是必要的， 可以在病毒清除后在肺内持续很长时间。这可能会导致更多的疾病， 包括继发性细菌性肺炎，因严重肺损伤住院，甚至 死亡。为了解决这个问题，Respana打算开发一种安全、负担得起、可扩展和广泛的 可用于改善患者预后的可用产品，从高风险开始 流感患者。我们预计，Respana的产品将缩短症状持续时间，并 减少流感后细菌性呼吸道感染和死亡率，从而加强 卫生保健系统抗击季节性和大流行性流感的能力。 Respana对表面活性蛋白(SP-A)受体SP-R210的创新研究表明，它 免疫增强SP-A结合病原体的吞噬功能和调节细胞因子的分泌 细胞。SP-A通过促进细胞调理和调节在肺免疫中发挥重要作用 通过调节巨噬细胞炎症反应清除病原体。数据 Respana已经产生了一个支持SP-R210异构体差异的生物学模型 调节巨噬细胞上天然免疫受体的运输、表达和激活。 完整的概念证明研究令人信服地表明，当用 SP-R210靶向鼠单抗P2H10，恢复较快，有较好的感染后肺 功能，并表现出比未经治疗的小鼠更好的肺组织病理学。 我们的具体目标是推动人源化P2H10单抗的开发，以满足联邦 通过验证IND的安全性、生物活性、药代动力学和 人源化FcRN和SP-A病毒感染临床前模型的疗效。