Development of RespiraClear for targeted mucosal treatment of RSV infections

摘要 项目概述呼吸道合胞病毒(RSV)是婴幼儿病毒性死亡的主要原因，也是免疫功能低下的成年人和老年人呼吸道疾病的主要原因。不幸的是，目前还没有针对RSV的疫苗或有效疗法。Synagis是每月肌肉注射单抗palivizumab，是FDA批准的唯一对极少数高危婴儿进行免疫预防的干预措施。然而，它在治疗RSV方面并不有效。因此，对于因呼吸道合胞病毒而住院的数万名婴儿来说，只有支持性治疗可用，发病率和死亡率很高。有趣的是，呼吸道合胞病毒通过病毒排入呼吸道而在肺内传播；因此，在感染邻近细胞之前，呼吸道合胞病毒必须穿过呼吸道粘液(AM)，而呼吸道合胞病毒主要局限于呼吸道，几乎没有全身性病毒血症。我们相信，一种针对RSV的、安全、有效和局部递送的抗病毒药物将提供一个强有力的选择，解决目前药物干预方面的空白。MuComme正在开发RespiraClear以实现这一目标，该平台基于一种专有的“粘液捕捉”单抗技术平台，其核心主张得到了美国专利商标局的许可，并从北卡罗来纳大学获得了独家许可。RespiraClear是一种局部单抗治疗，其基础是：(I)重新设计RSV结合单抗，提高完全人类Fc糖基化的表达，增强其在AM中捕获RSV的能力，并通过自然的粘液纤毛清除机制将病毒从呼吸道清除，以及(Ii)使用振动网状雾化器将其稳定地输送到肺部。通过在感染部位集中优化的mAb而不是系统地传递它，我们期望能够有效和经济地治疗RSV，并且几乎没有由于肺部吸收有限而产生不良副作用的风险。我们的初步研究表明，RespiraClear可以有效地捕获人类AM中的RSV，促进病毒颗粒从小鼠肺部的快速消除，并在使用振动网状雾化器进行雾化时保持稳定。在这些有希望的结果的基础上，我们试图在FastTrack提案的第一阶段验证RespiraClear在治疗棉花鼠的RSV感染方面确实优于肌肉注射的Palivizumab，迄今为止，Palivizumab是最常用的RSV感染动物模型。如果成功，该项目的第二阶段将专注于加速RespiraClear的临床前开发。这包括建立一个稳定的CHO细胞系，用于高产生产RespiraClear(Aim 1)，与Pari(领先的雾化器制造商)合作，为RespiraClear开发定制的振动网状喷雾器(Aim 2A)，在儿科肺模型(Aim 2B)中验证其输送性能，最后，在新生羔羊模型中评估RespiraClear的疗效(Aim 3)。如果成功，拟议的工作将极大地加快RespiraClear的临床评估。这项工作还将有助于为针对所有主要粘膜表面的广泛病原体进行改进的分子靶向治疗铺平道路。

Abstract Project Summary Respiratory Syncytial Virus (RSV) is the leading cause of viral death in infants and young children, and a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is currently no vaccine or effective therapy available for RSV. Synagis, a monthly intramuscular injection of the monoclonal antibody (mAb) palivizumab, is the only FDA-approved intervention given to a very small subset of high-risk infants as immunoprophylaxis. However, it is not effective at treating RSV. Thus, for the tens of thousands of infants hospitalized for RSV, only supportive therapy is available, and morbidity and mortality are substantial. Interestingly, RSV spreads in the lung via shedding of virus exclusively into the airway; thus, RSV must traverse airway mucus (AM) before infecting neighboring cells, and RSV remains primarily restricted to the airways with little to no systemic viremia. We believe an RSV-specific, safe, effective and topically- delivered antiviral would provide a powerful option addressing the current gap in pharmacological interventions. Mucommune is developing RespiraClear to meet this goal, based on a proprietary “muco- trapping” mAb technology platform with core claims allowed by the USPTO and exclusively licensed from UNC. RespiraClear is a topical mAb treatment based on (i) re-engineering RSV-binding mAb with elevated expression of a fully human Fc glycosylation that enhances its ability to trap RSV in AM and purges the virus from the airways via natural mucociliary clearance mechanisms, and (ii) stably delivering it to the lung airways using a vibrating mesh nebulizer. By concentrating an optimized mAb at the site of infection rather than delivering it systemically, we expect to enable efficacious and cost-effective treatment of RSV, with little risk of adverse side effects due to limited systemic adsorption from pulmonary delivery. Our pilot studies demonstrate that RespiraClear can potently trap RSV in human AM, facilitate rapid elimination of viral particles from the mouse lung airways, and remain stable when nebulized using a vibrating mesh nebulizer. Building off these promising results, we seek to verify in Phase I of this FastTrack proposal that RespiraClear is indeed superior to palivizumab injected intramuscularly in treating RSV infections in cotton rats, to date the most commonly used animal model for RSV infections. If successful, Phase II of the project will focus on accelerating the preclinical development of RespiraClear. This includes generating a stable CHO cell line for high yield production of RespiraClear (Aim 1), partnering with PARI (a leading nebulizer manufacturer) to develop a customized vibrating mesh nebulizer for RespiraClear (Aim 2A), validating its delivery performance in a pediatric lung model (Aim 2B), and finally, evaluating RespiraClear's efficacy in a neonatal lamb model (Aim 3). If successful, the proposed work will greatly accelerate the clinical evaluation of RespiraClear. The work will also help pave the way for improved, molecularly-targeted therapies against a broad spectrum of pathogens across all major mucosal surfaces.