SBIR: In vivo validation and IND-enabling development of MM004, a bispecific inhaled immunotherapy for RSV and MPV

项目摘要 呼吸道合胞病毒(RSV)和偏肺病毒(MPV)是导致人类死亡的两大病毒原因 婴儿和幼儿，是免疫功能低下的成年人和 老年人。不幸的是，目前还没有针对这两种感染的疫苗或有效疗法。Synagis，a 每月肌肉注射的单抗(MAb)palivizumab，是唯一获得FDA批准的 对极少数高危婴儿进行干预，作为免疫预防。然而，这并不是有效的 在治疗呼吸道合胞病毒感染方面。目前还没有MPV疗法处于临床开发的任何阶段。因此， 对于因RSV或MPV而住院的数万名患者来说，只有支持性治疗可用， 发病率和死亡率都很高。有趣的是，这两种病毒都通过脱落的女儿在肺部传播。 病毒只进入气道腔；然后排出的病毒必须在进入呼吸道粘液(AM)之前 感染邻近细胞，感染主要局限于呼吸道，很少或没有系统性感染 病毒血症。我们相信，一种针对病毒的、安全、有效和局部递送的抗病毒药物将提供强大的 解决目前在药理学干预方面的差距的选择。MuComme正在开发MM004以满足 迫切需要一种毛细支气管炎的治疗方法，基于我们的粘液捕捉型单抗平台。MM-004是一个热门话题 基于(I)具有“粘液捕获”Fc和结合结构域的双特异性单抗的单抗治疗 中和RSV和MPV，以及(Ii)使用振动网状雾化器直接输送到肺部。通过 将MM004集中在感染部位，而不是系统地传递它，我们希望能够 对于RSV和MPV都是有效和经济的治疗，几乎没有副作用的风险，由于 肺部分娩后全身吸收受限。在感染RSV的新生羔羊中，一个高度相关的模型 对于儿童呼吸道合胞病毒，我们的抗RSV粘液捕捉型单抗大大降低了感染的RSV病毒载量。 新生羔羊肺组织中的含量降至无法检测到的水平，并减少了毛细支气管炎、中性粒细胞的浸润和 与未感染的动物相比，炎症的程度往往难以区分。在此基础上构建 很有希望的结果是，我们现在已经设计出一种双特异性mAb(MM-004)，它可以有效地捕获RSV和MPV 在人AM中，并有助于快速从小鼠肺中清除。在本提案中，我们寻求验证 阶段1 MM004能否有效治疗仓鼠MPV感染，是目前治疗MPV的最佳模型。如果 成功后，我们将进入第二阶段，在那里我们将开发出高产的主细胞库细胞系 生产MM-004(目标1)，并进行一些支持IND的研究，包括#年的GLP TOX研究 大鼠、组织交叉反应性研究和IND前归档(目标2)。两个阶段2的目标都是关键路径的一部分 迅速推动MM-004进入临床开发，并将使我们能够在12个月内提交IND 完成这个项目。我们的工作也将有助于为改进分子靶向铺平道路 针对各种呼吸道感染的雾化治疗。

Project Summary Respiratory syncytial virus (RSV) and metapneumovirus (MPV) are the two leading viral causes of death in infants and young children, and are major causes of respiratory illness in immunocompromised adults and the elderly. Unfortunately, there is currently no vaccine or effective therapy available for either infection. 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 infections. There are no MPV treatments currently in any stage of clinical development. Thus, for the tens of thousands of patients hospitalized for either RSV or MPV, only supportive therapy is available, and morbidity and mortality are substantial. Interestingly, both viruses spread in the lung by shedding daughter viruses exclusively into the airway lumen; shed viruses must then traverse airway mucus (AM) before infecting neighboring cells, and infections remain primarily restricted to the airways with little to no systemic viremia. We believe a virus-specific, safe, effective and topically-delivered antiviral would provide a powerful option to address the current gap in pharmacological interventions. Mucommune is developing MM004 to meet the urgent need for a bronchiolitis treatment, based on our “muco-trapping” mAb platform. MM-004 is a topical mAb treatment based on (i) bispecific mAb possessing “muco-trapping” Fc and binding domains that neutralizes both RSV and MPV, and (ii) direct delivery to the lung airways using a vibrating mesh nebulizer. By concentrating MM004 at the site of infection rather than delivering it systemically, we expect to enable efficacious and cost-effective treatment for both RSV and MPV, with little risk of adverse side effects, due to limited systemic adsorption after pulmonary delivery. In RSV-infected neonatal lambs, a highly relevant model for pediatric RSV, our muco-trapping mAb against RSV greatly reduced infectious RSV viral load in infected neonatal lambs in lung tissues to non-detectible levels, and reduced bronchiolitis, neutrophil infiltration and inflammation to levels that were often indistinguishable compared to uninfected animals. Building off this promising result, we have now engineered a bispecific mAb (MM-004) that potently traps both RSV and MPV in human AM and facilitates rapid clearance from the mouse lung. In this proposal, we seek to validate in Phase 1 whether MM004 can effectively treat MPV infections in hamsters, the best available model for MPV. If successful, we will advance to Phase 2, where we will develop a Master Cell Bank cell line for high yield production of MM-004 (Aim 1), and conduct a number of IND-enabling studies including, GLP tox studies in rats, tissue cross reactivity studies, and pre-IND filing (Aim 2). Both Phase 2 Aims are part of the critical path to quickly advance MM-004 into clinical development, and will put us in a position to 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.