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

SBIR：MM004 的体内验证和 IND 开发，MM004 是一种针对 RSV 和 MPV 的双特异性吸入免疫疗法

• 批准号: 10157638
• 负责人: RICHARD CONE
• 金额: $ 30.65万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-04 至 2022-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157638
• 关键词: Address; Adsorption; Adult; Affinity; Aftercare; Animals; Antibody Therapy; Antigens; Antiviral Agents; Attention; Back; Binding; Biological Assay; Bispecific Monoclonal Antibodies; Bronchiolitis; Cause of Death; Cell Line; Cells; Cessation of life; Characteristics; Child; Childhood; Clinic; Clinical; Critical Pathways; Cyclic GMP; Data; Daughter; Development; Dose; Elderly; Engineering; Ensure; FDA approved; Hamsters; Hospitalization; Human; Immunocompromised Host; Immunotherapy; In Vitro; Infant; Infection; Infection prevention; Inflammation; Inhalation; Intercept; Intervention; Intramuscular Injections; Lung; Metapneumovirus; Modality; Modeling; Molecular Target; Monoclonal Antibodies; Morbidity - disease rate; Mucins; Mucous body substance; Mus; Nebulizer; Neonatal; Neutrophil Infiltration; Palivizumab; Pathologic; Patients; Pharmacology; Phase; Pneumonia; Positioning Attribute; Production; Rattus; Research; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Safety; Site; Small Business Innovation Research Grant; Structure of parenchyma of lung; Supportive care; Therapeutic; Tissues; Topical application; Vaccine Therapy; Vaccines; Validation; Viral; Viral Load result; Viremia; Virus; Virus Shedding; Work; aerosolized; base; cell bank; clinical development; cost; cost effective treatment; cross reactivity; effective therapy; high risk infant; immunoprophylaxis; improved; in vivo; meetings; mortality; mucus clearance; necrotic tissue; pre-clinical; programs; purge; research and development; respiratory; side effect; single molecule; success

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.

项目摘要 呼吸综合病毒（RSV）和元瘤病毒（MPV）是两个主要的死亡原因死亡原因 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， 老年。目前尚无疫苗或有效治疗可用于任何一种感染。下议院，a 每月肌内注射单克隆抗体（MAB）Palivizumab是唯一批准的FDA 干预涉及一小部分的高危婴儿作为免疫预防。但是，这无效 治疗RSV感染。目前在临床发育的任何阶段都没有MPV治疗。那， 对于成千上万用于RSV或MPV住院的患者，仅提供支持治疗， 发病率和死亡率很大。有趣的是，这两种病毒都被脱落的女儿在肺部传播 病毒专门进入气道管腔；然后，棚病毒必须然后穿越气道粘液（AM） 感染邻近细胞，并且感染主要仅限于气道，几乎没有全身性 病毒血症。我们认为病毒特异性，安全，有效且额外交付的抗病毒将提供强大的功能 解决当前药理干预措施差距的选项。 Mucommune正在开发MM004以满足 迫切需要基于我们的“粘液捕获” mAb平台进行支气管炎治疗。 MM-004是局部 基于（i）双特异性mAb具有“粘液捕获” FC和结合域的mAb处理 使用振动的网状雾化器中和（ii）直接向肺气道传递到肺气道。经过 将MM004集中在感染部位，而不是系统地交付，我们希望启用 RSV和MPV的有效且具有成本效益的治疗 肺输送后有限的全身吸附。在RSV感染的新生儿羔羊中，高度相关的模型 对于小儿RSV，我们针对RSV的粘液捕获MAB大大降低了感染的感染性RSV病毒负荷 肺组织中的新生儿羔羊至不可检测的水平，细支气管炎，中性粒细胞浸润和 与未感染的动物相比，炎症到通常无法区分的水平。建立这个 有希望的结果，我们现在已经设计了一个双特异性mAB（MM-004），该单元素可能会捕获RSV和MPV 在人类中，并促进了小鼠肺的快速清除。在此提案中，我们试图验证 MM004是否可以有效地治疗仓鼠中的MPV感染，这是MPV最佳可用模型。如果 成功，我们将晋升为第2阶段，在那里我们将开发出高产的大型细胞库细胞系 MM-004的生产（AIM 1），并进行了许多辅助研究，包括GLP TOX研究 大鼠，组织交叉反应性研究和预先提交（AIM 2）。这两个阶段的目标都是关键路径的一部分 快速将MM-004推进到临床开发中，并将使我们在12个月内提交IND 从完成这个项目。我们的工作还将有助于改善，分子靶向的道路 针对各种呼吸道感染的气溶剂化疗法。