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 人偏肺病毒（MPV）是婴儿下呼吸道感染的第二大原因 和幼儿，以及免疫受损的成人和老年人呼吸道疾病的主要原因。 不幸的是，没有有效的治疗或疫苗的MPV，只有支持性的医疗服务 儿童和老年MPV患者。我们相信一种病原体特异性，安全，有效和局部 递送的抗病毒药物将提供一种强有力的选择， 干预措施。局部递送至粘膜表面的人单克隆抗体（mAb）提供了特殊的 承诺结合安全性，有效性和无与伦比的特异性。进一步增加mAb的承诺，我们 最近在粘液中发现了一种新的抗体功能--将单个病原体捕获在粘液中--并 开创了一项技术，基于精心调整的亲和力， IgG-Fc和粘蛋白之间的相互作用，其已被独家许可给Mucommune。在粘液中捕获病毒 防止它们感染靶细胞，促进从气道快速消除，并使有效的 体内保护。MPV感染的许多病理和临床表现， 呼吸道合胞病毒（RSV）。在MPV感染者的血液中没有检测到MPV病毒血症， 患者，暗示MPV是严格的局部呼吸道感染，类似于RSV， 从受感染细胞的顶端表面，在扩散到 相邻的细胞。我们已经能够稳定地雾化吸入“粘膜捕获”mAb以有效地治疗RSV 感染的棉鼠，更重要的是在新生羔羊，减少了近4个对数的病毒载量， 感染后第6天，在感染后第3天开始治疗。这促使我们利用我们的 该平台开发了一种针对MPV的“粘膜捕获”mAb，可通过以下方式直接递送至气道： 雾化，从而减少肺中MPV的传播并促进病毒的快速消除。在 目的1，我们将生产和表征抗MPV的mAb，包括其促进MPV固定化的能力， 新鲜未稀释人AM中的MPV。在目标2中，与位于华盛顿的泡菜实验室合作，该实验室记录了 将抗RSV抗体从顶部输送到RSV感染的气道培养物中可以限制感染的进一步传播，我们 将评估抗MPV mAb是否对生长在 空气-液体界面可以类似地限制或抑制预先建立的MPV感染的传播。成功 这些I期SBIR研究的完成将导致关注mAb优化的II期提案， 雾化制剂的开发，以及小型和大型动物的概念验证有效性研究 模型通过增强mAb在粘液分泌物中的功能，我们预计Mucommune将有助于铺平道路。 一种改进的分子靶向治疗和预防广谱病原体的方法， 所有主要粘膜表面的微生物。