Inhaled 'muco-trapping' antibody as universal immunotherapy for influenza virus infections

吸入“粘膜捕获”抗体作为流感病毒感染的通用免疫疗法

基本信息

批准号：
10081777
负责人：
RICHARD CONE
金额：
$ 27.54万
依托单位：
MUCOMMUNE, LLC
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：
2020-06-23 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081777
关键词：
Affinity Aftercare Animal Model Animals Antibodies Antiviral Agents Apical Attenuated Binding Biological Assay Biological Sciences Bronchiolitis Cell Line Cells Chinese Hamster Ovary Cell Clinical Cyclic GMP Development Diagnosis Diffuse Documentation Dose Ebola Effectiveness Enhancement Technology Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Epithelium Exhibits Formulation Functional disorder Gold Herpesvirus 1 Hospitalization Human Immobilization Immunoglobulin G Immunotherapy In Vitro Inbred BALB C Mice Individual Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Inhalation Intercept Lead Life Cycle Stages Literature Lung Medical Microbe Modeling Monitor Monoclonal Antibodies Mucins Mucociliary Clearance Mucous Membrane Mucous body substance Mus Nebulizer Neonatal Neutrophil Infiltration Oseltamivir Parents Particulate Pathologic Patients Penetration Performance Phase Phase II Clinical Trials Polysaccharides Proliferating Prophylactic treatment Public Health Reporting Respiratory Syncytial Virus Infections Respiratory Tract Infections Respiratory syncytial virus Safety Saline Signs and Symptoms Small Business Innovation Research Grant Specificity Structure Surface Symptoms System Technology Temperature Testing Texas Therapeutic Therapeutic Effect Topical application Variant Viral Viral Load result Viremia Virion Virus Virus Diseases Virus Shedding Visit Weight Western Blotting airway remodeling anti-influenza antigen binding apical membrane base clinical development crosslink human monoclonal antibodies improved in vivo infectious disease model influenza virus vaccine influenzavirus molecular targeted therapies mouse model novel pathogen pre-clinical prevent purge standard of care transmission process vaginal transmission

项目摘要

Project Summary Seasonal infections from human influenza virus (INFV) represents a major public health burden. The flu vaccine only averts ~15% of medical visits and ~12% of hospitalizations due to INFV, whereas current antivirals are only modestly effective if given soon after symptoms emerge, which is achievable in only half of infected patients due to practical limitations in how quickly INFV infections can be diagnosed. Human monoclonal antibodies (mAb) delivered topically to mucosal surfaces offer exceptional promise as antivirals, combining safety, effectiveness and unparalleled specificity. Adding further to the promise of mAb, we have recently discovered a novel Ab function in mucus – trapping individual pathogens– and have pioneered a technology enhancing the use of mAb in mucosal secretions based on carefully-tuned affinity between IgG-Fc and mucins, which has been exclusively licensed to Mucommune. Trapping pathogens in mucus prevents them from infecting target cells and spreading locally, facilitates rapid elimination from the airways, and enables effective protection in vivo. We believe the technology is uniquely suited to treat INFV infections, due to the unique pathophysiology of INFV. Studies have shown INFV to bud exclusively from the apical surface of epithelial cells. INFV also shares many pathological and clinical manifestations with Respiratory Syncytial Virus (RSV), which also sheds exclusively from the apical surface of infected cells and must traverse airway mucus (AM) before spreading to neighboring cells. This implies delivery of muco-trapping mAb into the airways can provide an immediate therapeutic benefit by trapping shed progeny virus in AM and facilitating their rapid clearance, unlike oral antivirals that have substantial delay in distribution to the lung. We have stably nebulized “muco-trapping” mAb to treat RSV infections in neonatal lambs, reducing the viral load by nearly 4-log by Day 6 post-infection after starting treatment as late as Day 3 post-infection. This motivated us to harness our platform to develop a “muco-trapping” mAb against INFV. In Aim 1, we will produce and characterize muco-trapping mAb against INFV, including their ability to bind and neutralize INFV. In Aim 2, working with IBT Biosciences (a CRO that specializes in animal models of infectious disease), we will assess whether muco-trapping mAb against INFV dosed intranasally can improve survival, clinical scores, and reduce lung viral titers relative to treatment with oseltamivir, the current gold standard of care, even after delayed treatment post-infection. Successful completion of these Phase I SBIR studies will lead to a Phase II proposal focused on mAb optimization, development of a nebulizable formulation, and efficacy/transmission studies in larger animal models. By enabling enhanced mAb functionality in mucus secretions, we expect Mucommune will help pave the way for improved, molecularly targeted therapies and prophylaxis against a broad spectrum of pathogens and microbes across all major mucosal surfaces.

项目概要人类流感病毒（INFV）的季节性感染是一项重大的公共卫生负担。疫苗只能避免约 15% 的就诊和约 12% 的 INFV 住院治疗，而目前的疫苗如果在症状出现后立即服用抗病毒药物，效果有限，只有一半的人可以达到这种效果由于诊断人类感染 INFV 的速度存在实际限制。局部递送至粘膜表面的单克隆抗体 (mAb) 作为抗病毒药物具有非凡的前景，我们将安全性、有效性和无与伦比的特异性结合在一起，进一步增强了单克隆抗体的前景。最近在粘液中发现了一种新的抗体功能——捕获单个病原体——并开创了一种基于 IgG-Fc 之间精心调整的亲和力，增强 mAb 在粘膜分泌物中的使用的技术和粘蛋白，已独家授权给 Mucommune，以捕获粘液中的病原体来预防。防止它们感染靶细胞并在局部传播，有助于快速从气道中消除，并且我们相信该技术特别适合治疗 INFV 感染，因为研究表明，INFV 只从根尖表面萌芽。 INFV 也与呼吸道合胞体细胞有许多共同的病理和临床表现。病毒 (RSV)，也仅从受感染细胞的顶端表面脱落，并且必须穿过气道粘液（AM）在扩散到邻近细胞之前这意味着粘液捕获单克隆抗体被递送到细胞中。气道可以通过将脱落的后代病毒捕获在 AM 中并促进它们的清除速度快，与口服抗病毒药物不同，口服抗病毒药物在肺部的分布有明显的延迟。稳定雾化的“粘液捕获”单克隆抗体可治疗新生羔羊的 RSV 感染，从而减少病毒载量直到感染后第 3 天开始治疗后，到感染后第 6 天，该结果已接近 4 个对数，这激励了我们。利用我们的平台开发针对 INFV 的“粘膜捕获”单克隆抗体在目标 1 中，我们将生产和生产。表征针对 INFV 的粘液捕获单克隆抗体，包括其结合和中和 INFV 的能力。与 IBT Biosciences（一家专门研究传染病动物模型的 CRO）合作，我们将评估鼻内给药的针对 INFV 的粘液捕获单克隆抗体是否可以提高生存率、临床评分并减少相对于奥司他韦治疗（当前治疗的金标准）的肺部病毒滴度，即使在延迟后成功完成这些 I 期 SBIR 研究将导致 II 期提案。专注于 mAb 优化、雾化制剂的开发以及功效/传播研究通过增强单克隆抗体在粘液分泌物中的功能，我们期望 Mucommune 能够应用于更大的动物模型。将有助于为改进的分子靶向治疗和广谱预防铺平道路所有主要粘膜表面的病原体和微生物。