In vivo dose finding for IN-002 in neonatal lambs for inhaled immunotherapy of RSV

项目摘要 呼吸道合胞病毒（RSV）是婴幼儿病毒性死亡的主要原因， 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 目前没有疫苗或有效的治疗可用于RSV。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亚群的干预措施 作为免疫预防。然而，它对治疗RSV无效。十年之后， 成千上万的婴儿因RSV住院，只有支持性治疗可用，发病率和死亡率是 相当可观有趣的是，RSV在肺中通过将病毒排到气道中而传播;因此，RSV在肺中传播的可能性很小。 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 呼吸道几乎没有系统性病毒血症我们相信一种特异性的，安全的，有效的局部- 递送的抗病毒药物将提供一种强有力的选择， 干预措施。Mucommune正在开发MM-002以实现这一目标，基于专有的“粘膜捕获” mAb技术平台，其核心权利要求由已发布的美国专利涵盖，并由美国专利局独家授权。 MM-002是一种局部mAb治疗，其基于（i）重新配制RSV结合mAb， 完全人Fc糖基化，增强了其在AM中捕获RSV的能力，这迅速清除了病毒， 通过天然的粘膜纤毛清除机制将其稳定地递送到气道，以及（ii）使用 一种振动网孔喷雾器。通过将优化的mAb集中在感染部位，而不是将其递送 在全身性方面，我们期望能够实现RSV的有效和成本有效的治疗，而不良反应的风险很小。 由于肺部给药的全身吸收有限而引起的副作用。在试点研究中，我们发现， 重组的RSV结合mAb可以有效地抑制新鲜人AM中的RSV， 的粘膜捕获mAb促进RSV从小鼠肺的快速消除。我们刚刚完成了呼吸道合胞病毒- 感染的新生羔羊研究，儿科RSV的高度相关模型，显示雾化MM-002 在肺匀浆和BALF中，感染的新生羔羊中的感染性RSV病毒载量降低至几乎 不可检测的水平。基于这一有希望的结果，我们寻求开发主细胞库的艾德，稳定CHO 用于MM-002高产率生产的细胞系（目的1），优化雾化制剂并表征 体外儿科肺模型中的递送性能（目的2），并进行严格的剂量探索研究， 确定RSV感染的新生羔羊模型中的最佳MM-002剂量，这将影响 随后的GLP毒理学和I/II期临床试验设计（目标3）。所有这三个目标都是关键路径的一部分， 快速推进MM-002进入临床开发，并使我们能够完成IND使能研究 并在完成本项目后12个月内提交IND。我们的工作还将有助于为改进、 针对各种呼吸道感染的分子靶向雾化疗法。

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 MM-002 to meet this goal, based on a proprietary “muco-trapping” mAb technology platform with core claims covered by an issued US patent and exclusively licensed from UNC. MM-002 is a topical mAb treatment based on (i) reformulating RSV-binding mAb with elevated expression of a fully human Fc glycosylation that enhances its ability to trap RSV in AM, which quickly 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. In pilot studies, we showed that reformulated RSV-binding mAb can potently immobilize RSV in fresh human AM, and that intranasal delivery of muco-trapping mAb facilitated rapid elimination of RSV from the mouse lung. We just completed a RSV- infected neonatal lamb study, a highly relevant model for pediatric RSV, showing that nebulized MM-002 reduced infectious RSV viral load in infected neonatal lambs in lung homogenates and BALF down to almost non-detectible levels. Building off this promising result, we seek to develop a Master Cell Bank'ed, stable CHO cell line for high yield production of MM-002 (Aim 1), optimize the nebulization formulation and characterize delivery performance in an in vitro pediatric lung model (Aim 2), and perform rigorous dose finding studies to determine the optimal MM-002 dosing in the RSV-infected neonatal lamb model, which would impact design of subsequent GLP tox and Phase I/II clinical trial design (Aim 3). All three aims are all part of the critical path to quickly advance MM-002 into clinical development, and puts us in a position to complete IND-enabling studies and file IND within 12 months from completing this project. Our work will also help pave the way for improved, molecularly-targeted aerosolized therapies against various respiratory infections.