Aerosol immunotherapy for treatment of human metapneumovirus infection

项目摘要 人类偏肺病毒(MPV)是婴儿下呼吸道感染的第二大原因。 和幼儿，以及免疫受损的成年人和老年人呼吸系统疾病的主要原因。 不幸的是，目前还没有针对MPV的有效疗法或疫苗，只有支持性的医疗服务可用。 适用于儿科和老年病MPV患者。我们相信一种针对病原体的、安全的、有效的和局部的 交付的抗病毒药物将提供一个强大的选择，以解决目前在药物方面的差距 干预措施。局部递送到粘膜表面的人类单抗(MAb)提供了特殊的 承诺结合安全性、有效性和无与伦比的专一性。进一步增加了单抗的前景，我们 最近发现了一种新的粘液抗体功能--捕获粘液中的个别病原体--并拥有 开创了一种技术，基于精心调节的亲和力，增强了单抗在粘膜分泌物中的使用 在免疫球蛋白-Fc和粘蛋白之间，粘蛋白已被独家授权给MuComme。将病毒困在粘液中 防止它们感染靶细胞，促进从呼吸道中快速消除，并使有效 体内保护。MPV感染的许多病理和临床表现与 呼吸道合胞病毒(RSV)。MPV感染者血液中未检测到MPV病毒血症 患者，暗示MPV严格地是一种局部的呼吸道感染，类似于唯一脱落的RSV 从受感染细胞的顶端表面传播，在传播到 相邻的细胞。我们已经能够稳定地雾化“粘液捕获”单抗来有效地治疗RSV。 在棉鼠和新生羔羊中都有感染，将病毒载量减少了近4个对数 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 开发一种针对MPV的“粘液捕捉型”单抗，可通过以下方式直接传递到呼吸道 雾化，从而减少MPV在肺部的传播，促进病毒的快速消除。在……里面 目的1，我们将生产和鉴定抗MPV的单抗，包括其促进固定化MPV的能力 新鲜、未稀释人AM中的MPV在Aim 2中，与北卡罗来纳大学的Pickles实验室合作，该实验室记录了 将抗RSV抗体注射到受RSV感染的呼吸道培养物中可以限制感染的进一步传播，我们 将评估是否将抗MPV单抗顶端注射到生长在 气-液界面同样可以限制或抑制预先建立的MPV感染的传播。成功 完成这些第一阶段SBIR研究将产生侧重于单抗优化的第二阶段提案， 雾化制剂的开发，以及在小动物和大动物上的概念验证疗效研究 模特们。通过在粘液分泌物中实现增强的mAb功能，我们预计MuComme将有助于铺平 改进的分子靶向治疗和预防广谱病原体和 微生物遍布所有主要的粘膜表面。

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.