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， 免疫功能低下的成年人和老年人患呼吸道疾病的主要原因。不幸的是，有 目前还没有针对RSV的疫苗或有效疗法。Synagis，每月肌肉注射一次 单抗(MAb)palivizumab是FDA批准的唯一针对极小亚群的干预措施 作为免疫预防的高危婴儿。然而，它在治疗RSV方面并不有效。因此，对于几十个人来说 数以千计的婴儿因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，呼吸道合胞病毒通过将病毒排入呼吸道而在肺内传播；因此， 在感染邻近细胞之前必须穿过呼吸道粘液(AM)，RSV仍然主要限于 呼吸道很少或根本没有全身性病毒血症。我们相信一种针对呼吸道合胞病毒的，安全，有效和局部的- 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。MuComme正在开发MM-002，以实现这一目标，其基础是一种专有的“粘液捕捉器” MAB技术平台，核心主张由一项已颁发的美国专利涵盖，并由北卡罗来纳大学独家授权。 MM-002是一种局部单抗治疗方法，其基础是：(I)重新配制RSV结合单抗，并上调a基因的表达 全人Fc糖基化，增强其在AM中捕获RSV的能力，从而快速将病毒从AM中清除 通过自然的粘液纤毛清除机制，以及(Ii)稳定地将其输送到肺通道 一种振动网状喷雾器。通过在感染部位浓缩优化的单抗而不是递送它 从系统上讲，我们希望能够有效和经济地治疗呼吸道合胞病毒，几乎没有不良反应的风险。 肺部给药的全身吸收有限所致的副作用。在试点研究中，我们表明 重组RSV结合单抗能有效地固定新鲜人AM中的RSV，且鼻腔给药 粘液捕捉型单抗可促进呼吸道合胞病毒从小鼠肺内快速清除。我们刚刚完成了RSV- 感染新生儿羔羊研究，一个与儿童RSV高度相关的模型，显示雾化MM-002 肺匀浆和BALF中受感染的新生羔羊的传染性RSV病毒载量降低到几乎 检测不到的水平。在这个有希望的结果的基础上，我们寻求开发一个主细胞库，稳定的CHO MM-002高产细胞系(目标1)，雾化配方优化及表征 在体外儿童肺模型(AIM 2)中的给药性能，并执行严格的剂量发现研究 在RSV感染的新生羔羊模型中确定MM-002的最佳剂量，这将影响设计 随后的GLP毒性和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，使我们能够完成使IND成为可能的研究 并在完成这个项目后12个月内提交IND。我们的工作也将有助于为改善， 针对各种呼吸道感染的分子靶向雾化治疗。

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.