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）是导致儿童死亡的两种主要病毒。 婴儿和幼儿，是免疫功能低下的成年人呼吸道疾病的主要原因， 老人不幸的是，目前没有疫苗或有效的治疗方法可用于任何感染。Synagis，a 每月肌肉注射单克隆抗体（mAb）帕利珠单抗，是唯一FDA批准的 对极少数高危婴儿进行免疫预防干预。然而，它并不有效 治疗呼吸道合胞病毒感染目前没有处于任何临床开发阶段的MPV治疗。因此，在本发明中， 对于因RSV或MPV而住院的数万名患者，仅可获得支持性治疗， 发病率和死亡率都很高。有趣的是，这两种病毒都是通过排出子体在肺部传播的。 病毒只能进入气道腔;然后，脱落的病毒必须穿过气道粘液（AM）， 感染邻近细胞，并且感染主要限于气道，几乎没有全身性 病毒血症。我们相信，一种病毒特异性的、安全的、有效的、局部给药的抗病毒药物将提供一种强大的、 这是解决目前药理学干预方面差距的一种选择。Mucommune正在开发MM 004，以满足 迫切需要基于我们的“粘膜捕获”mAb平台的毛细支气管炎治疗。MM-004是一种局部 基于（i）具有“粘膜捕获”Fc和结合结构域的双特异性mAb治疗， 中和RSV和MPV，和（ii）使用振动网孔喷雾器直接递送至肺气道。通过 将MM 004集中在感染部位，而不是全身性地输送，我们希望能够 RSV和MPV的有效且具有成本效益的治疗，不良副作用风险很小， 肺部给药后全身吸收有限。在RSV感染的新生羔羊中， 对于儿科RSV，我们的抗RSV粘膜捕获mAb大大降低了感染者中的感染性RSV病毒载量， 新生羔羊的肺组织中的浓度降低至不可检测水平，毛细支气管炎、中性粒细胞浸润和 炎症水平与未感染的动物相比通常难以区分。以此为基础 我们现在已经设计了一种双特异性单克隆抗体（MM-004），可以有效地捕获RSV和MPV 在人AM中，并促进从小鼠肺中快速清除。在这份提案中，我们试图验证 第1阶段：MM 004是否可以有效治疗仓鼠中的MPV感染，这是MPV的最佳可用模型。如果 如果成功，我们将进入第二阶段，在那里我们将开发一个高产量的主细胞库细胞系 生产MM-004（目标1），并进行了许多IND使能研究，包括GLP毒性研究， 大鼠、组织交叉反应性研究和IND前备案（Aim 2）。两个阶段2目标都是关键路径的一部分 快速推进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。我们的工作还将有助于为改进分子靶向 雾化治疗各种呼吸道感染。

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.