Aerosol immunotherapy for treatment of human metapneumovirus infection

气溶胶免疫疗法治疗人类偏肺病毒感染

• 批准号: 10081759
• 负责人: RICHARD CONE
• 金额: $ 26.17万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081759
• 关键词: Address; Adult; Aerosols; Affinity; Age; Air; Animal Model; Antibodies; Antiviral Agents; Apical; Back; Blood; Bronchiolitis; Caring; Cell Culture Techniques; Cell Line; Cells; Child; Childhood; Chinese Hamster Ovary Cell; Clinical; Cotton Rats; Cyclic GMP; Development; Diffuse; Documentation; Dose; Ebola; Effectiveness; Elderly; Engineering; Enhancement Technology; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelium; Formulation; Functional disorder; Gel; Herpesvirus 1; Human; Human Metapneumovirus; Immobilization; Immune; Immunoglobulin G; Immunotherapy; In Vitro; Individual; Infant; Infection; Influenza; Intervention; Lead; Life Cycle Stages; Liquid substance; Literature; Lower Respiratory Tract Infection; Lung; Medical; Metapneumovirus; Methods; Microbe; Modeling; Monoclonal Antibodies; Mucins; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Mus; Nebulizer; Neonatal; Parainfluenza; Paramyxovirus; Particulate; Pathologic; Patients; Penetration; Pharmacology; Phase; Phase II Clinical Trials; Pilot Projects; Pneumonia; Polysaccharides; Proliferating; Prophylactic treatment; Recombinants; Reporting; Research Personnel; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Safety; Small Business Innovation Research Grant; Specificity; Structure; Surface; Symptoms; System; Technology; Testing; Topical application; Vaccines; Variant; Viral; Viral Load result; Viral load measurement; Viremia; Virion; Virus; Virus Diseases; Virus Shedding; Western Blotting; airway epithelium; antigen binding; asthma exacerbation; base; bronchial epithelium; crosslink; effective therapy; efficacy study; glycosylation; human monoclonal antibodies; improved; in vivo; molecular targeted therapies; novel; pathogen; prevent; purge; respiratory; vaginal transmission

Project Summary Human Metapneumovirus (MPV) is the second leading cause of lower respiratory tract infections in infants and young children, and a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is no effective therapy or vaccine for MPV, and only supportive medical care is available for both pediatric and geriatric MPV patients. We believe a pathogen-specific, safe, effective and topically delivered antiviral would provide a powerful option addressing the current gap in pharmacological interventions. Human monoclonal antibodies (mAb) delivered locally to mucosal surfaces offer exceptional promise 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 in mucus – 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 viruses in mucus prevents them from infecting target cells, facilitates rapid elimination from the airways, and enables effective protection in vivo. Infection by MPV shares many of the pathological and clinical manifestations of Respiratory Syncytial Virus (RSV). There is no detectable MPV viremia in the blood of MPV-infected patients, implicating MPV to be strictly a localized respiratory infection, similar to RSV that sheds exclusively from the apical surface of infected cells and must traverse airway mucus (AM) before spreading to neighboring cells. We have been able to stably nebulize “muco-trapping” mAb to effectively treat RSV infections in both cotton rats and more importantly in neonatal lambs, reducing the viral load by nearly 4-log by Day 6 post-infection with treatment that is initiated on Day 3 post infection. This motivated us to harness our platform to develop a “muco-trapping” mAb against MPV that can be delivered directly to the airways by nebulization, thereby reducing the spread of MPV in the lung and facilitating rapid elimination of the virus. In Aim 1, we will produce and characterize mAb against MPV, including its ability to facilitate immobilization of MPV in fresh, undiluted human AM. In Aim 2, working with the Pickles Lab at UNC, which documented that anti-RSV Ab delivered apically to airway cultures infected by RSV could restrict further spread of infection, we will assess whether anti-MPV mAb dosed apically to well-differentiated human airway epithelium grown at the air-liquid interface can similarly restrict or inhibit the spread of pre-established MPV infections. Successful completion of these Phase I SBIR studies will lead to a Phase II proposal focused on mAb optimization, development of nebulizable formulation, and proof-of-concept efficacy studies in small and large animal models. By enabling enhanced mAb function 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 人元病毒（MPV）是婴儿下呼吸道感染的第二主要原因 和幼儿，这是免疫疾病折衷的成年人和老年人中呼吸道疾病的主要原因。 不幸的是，MPV没有有效的疗法或疫苗，仅提供支持的医疗服务 针对小儿和老年MPV患者。我们相信病原体特异性，安全，有效且局部 交付的抗病毒将提供一个强大的选择，以解决药理当前差距 干预措施。人类单克隆抗体（MAB）在本地传递到粘膜表面提供了例外 承诺结合安全性，有效性和无与伦比的特异性。进一步增加了mab的承诺，我们 最近在粘液中发现了一种新颖的AB功能 - 诱捕粘液中的个体病原体 - 并具有 开创了一项技术，可以增强基于精心调整亲和力的MAB在粘膜分泌中的使用 在IgG-FC和粘蛋白之间，该粘液已仅获得粘膜的许可。将病毒捕获在粘液中 防止他们免受感染的靶细胞，促进从气道快速发展，并有效 在体内保护。 MPV感染分享了许多病理和临床表现 呼吸综合病毒（RSV）。 MPV感染的血液中没有可检测的MPV病毒血症 患者，隐式MPV是严格的局部呼吸道感染，类似于仅脱落的RSV 从感染细胞的顶端表面，必须遍历气道粘液（AM），然后扩散到 相邻的细胞。我们已经能够稳定地雾化“粘液捕获” mAb以有效治疗RSV 棉大鼠的感染和新生儿羔羊的感染，从近4-log中降低病毒载量 感染后第6天，在感染后第3天开始进行治疗。这促使我们利用我们的 针对MPV开发“粘液捕获” mAb的平台，可以通过 雾化，从而减少了MPV在肺部的扩散并支持快速消除病毒。 AIM 1，我们将产生并表征MAB针对MPV的MAB，包括其促进固定的能力 MPV在新鲜的，未稀释的人类中。在AIM 2中，与UNC的Pickles Lab合作，该实验室记录了 抗RSV AB将顶端传递到被RSV感染的气道培养物中可能限制感染的进一步传播，我们 将评估抗MPV MAB是否对剂量分化的人类气道上皮在 空气界面可以类似地限制或抑制预先建立的MPV感染的扩散。成功的 这些I阶段SBIR研究的完成将导致II期提案的重点是MAB优化， 大小动物的概念公式的开发以及概念概念的有效性研究 型号。通过在粘液分泌中启用增强的mAb功能，我们预计粘膜将有助于铺路 改善，分子靶向的疗法和预防剂的方法，以针对广泛的病原体和 所有主要粘膜表面的微生物。