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.

项目摘要人类影响力病毒（IFFV）的季节性感染代表了伯宁的主要公共卫生。流感疫苗仅避免约15％的医疗就诊和约12％的住院治疗，而当前抗病人只有在症状出现后不久就适度有效，这仅在一半受感染的患者由于实际限制了如何诊断IFV感染的速度。人类单克隆抗体（MAB）局部递送至粘膜表面提供了异常的抗病人，作为抗病毒药，结合安全性，有效性和无与伦比的特异性。进一步增加了mab的承诺，我们有最近在粘液中发现了一种新型的AB功能 - 诱捕个体病原体 - 并开创了A 基于IgG-FC之间精心调整的亲和力，可以增强MAB在粘膜分泌中的使用和粘蛋白，已专门授予粘膜。粘液中的捕获病原体预防它们来自感染的靶细胞并在本地扩散，促进了从气道快速发展，在体内实现有效的保护。我们认为，该技术非常适合治疗IFV感染， IFV的独特病理生理学。研究表明，IFV专门从芽上皮细胞。 IFV还与呼吸道合胞症共享许多病理和临床表现病毒（RSV），它也仅从受感染细胞的顶部表面脱落，必须穿越气道粘液（AM）在扩散到相邻细胞之前。这意味着将粘液捕获mab传递到航空公司可以通过将AM中的后代病毒捕获并支持，从而提供直接的治疗益处它们的快速清除率与口服抗病毒药不同，这些抗病毒药在分布到肺部的延迟。我们有严格的雾化的“粘液捕获” mAb治疗新生儿羔羊的RSV感染，从而减少了病毒载量在感染后第3天开始治疗后，感染后第6天将近4 log。这激发了我们要利用我们的平台开发针对IFV的“粘液捕获” mAb。在AIM 1中，我们将生产并表征粘液捕获MAB对IFV的MAB，包括它们结合和中和INFV的能力。在AIM 2中，使用IBT生物科学（专门研究传染病动物模型的CRO），我们将评估粘液捕获的mAb是否针对鼻内服用的INFV是否可以提高生存率，临床评分并降低肺病毒滴度相对于用奥斯塔米维尔（Oseltamivir）治疗，即当前的金标准护理标准感染后的治疗。成功完成这些I阶段SBIR研究将导致II期建议专注于mab优化，可干纤维公式的开发以及效率/传播研究较大的动物模型。通过在粘液分泌中启用增强的mAb功能，我们期望粘液将有助于为改进，分子靶向疗法和预防范围铺平道路所有主要粘膜表面的病原体和微生物。