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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要呼吸道合胞病毒（RSV）和偏肺病毒（MPV）是导致人类死亡的两种主要病毒原因婴儿和幼儿，是免疫功能低下的成人和儿童呼吸道疾病的主要原因不幸的是，目前还没有针对这两种感染的疫苗或有效疗法。每月肌肉注射单克隆抗体（mAb）帕利珠单抗，是 FDA 批准的唯一一种对一小部分高危婴儿进行干预作为免疫预防，但效果并不理想。目前尚无处于临床开发任何阶段的 MPV 治疗方法。对于数万名因 RSV 或 MPV 住院的患者，只能进行支持性治疗，发病率和死亡率都很高，这两种病毒都是通过脱落的女儿在肺部传播的。病毒仅进入气道腔；然后病毒必须穿过气道粘液（AM）感染邻近细胞，感染仍然主要局限于气道，几乎没有系统性感染我们相信，一种针对病毒的、安全的、有效的局部抗病毒药物将提供一种强大的治疗方法。 Mucommune 正在开发 MM004 来弥补目前药物干预方面的差距。基于我们的“粘液捕获”mAb 平台的 MM-004 是一种外用的毛细支气管炎治疗方案。 mAb 治疗基于 (i) 双特异性 mAb，其具有“粘膜捕获”Fc 和结合域，中和 RSV 和 MPV，以及 (ii) 使用振动网雾化器直接输送至肺部气道。将 MM004 集中在感染部位而不是全身输送，我们希望能够对 RSV 和 MPV 均有效且具有成本效益的治疗方法，且不良副作用的风险很小，因为肺部分娩后感染 RSV 的新生羔羊的有限全身吸收，这是一个高度相关的模型。对于儿科 RSV，我们针对 RSV 的粘膜捕获单克隆抗体大大降低了感染者的传染性 RSV 病毒载量新生羔羊肺组织中的含量降至不可检测的水平，并减少了细支气管炎、中性粒细胞浸润和与未感染的动物相比，炎症水平通常难以区分。令人鼓舞的结果，我们现在设计了一种双特异性单克隆抗体 (MM-004)，它可能同时捕获 RSV 和 MPV 在人类 AM 中并促进从小鼠肺部的快速清除。第一阶段 MM004 是否可以有效治疗仓鼠 MPV 感染，这是 MPV 的最佳可用模型。如果成功，我们将进入第二阶段，我们将开发主细胞库细胞系以实现高产量 MM-004 的生产（目标 1），并进行多项 IND 支持研究，包括 GLP 毒性研究大鼠、组织交叉反应性研究和 IND 申请前（目标 2）都是关键路径的一部分。快速推进MM-004进入临床开发，并使我们能够在12个月内提交IND 完成这个项目也将有助于为改进、分子靶向铺平道路。针对各种呼吸道感染的雾化疗法。