Development of RespiraClear for targeted mucosal treatment of RSV infections

摘要 呼吸道合胞病毒（RSV）是婴幼儿病毒性死亡的主要原因，也是免疫受损成人和老年人呼吸道疾病的主要原因。不幸的是，目前没有针对RSV的疫苗或有效疗法。Synagis，每月肌肉注射单克隆抗体（mAb）帕利珠单抗，是FDA批准的唯一一种用于极少数高危婴儿的免疫预防干预措施。然而，它对治疗RSV无效。因此，对于因RSV住院的数万名婴儿，仅可获得支持性治疗，并且发病率和死亡率很高。有趣的是，RSV在肺中通过将病毒排到气道中而传播;因此，RSV在感染邻近细胞之前必须穿过气道粘液（AM），并且RSV仍然主要限于气道，几乎没有或没有全身性病毒血症。我们相信，RSV特异性的、安全的、有效的和局部递送的抗病毒药物将提供解决目前药理学干预的差距的强有力的选择。Mucommune正在开发RespiraClear以实现这一目标，该平台基于专有的“粘膜捕获”mAb技术平台，其核心声明得到了美国专利商标局的允许，并获得了美国专利局的独家许可。RespiraClear是一种局部mAb治疗，基于（i）重新设计RSV结合mAb，提高全人Fc糖基化的表达，增强其在AM中捕获RSV的能力，并通过天然粘膜纤毛清除机制将病毒从气道中清除，以及（ii）使用振动网孔雾化器将其稳定递送至肺气道。通过将优化的mAb浓缩在感染部位而不是全身递送，我们期望能够有效且具有成本效益地治疗RSV，并且由于肺部递送的全身吸收有限而几乎没有不良副作用的风险。我们的初步研究表明，RespiraClear可以有效地捕获人AM中的RSV，促进病毒颗粒从小鼠肺气道中的快速消除，并在使用振动网孔雾化器雾化时保持稳定。在这些有希望的结果的基础上，我们试图在本FastTrack提案的I期中验证RespiraClear在治疗棉鼠RSV感染方面确实上级肌内注射帕利珠单抗，棉鼠是迄今为止最常用的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。这包括生成用于高产量生产RespiraClear的稳定CHO细胞系（Aim 1），与PARI（领先的雾化器制造商）合作开发用于RespiraClear的定制振动网孔雾化器（Aim 2A），验证其在儿科肺模型中的递送性能（Aim 2B），最后，评估RespiraClear在新生儿羔羊模型中的疗效（Aim 3）。如果成功，拟议的工作将大大加快RespiraClear的临床评价。这项工作还将有助于为针对所有主要粘膜表面的广谱病原体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.