Development of RespiraClear for targeted mucosal treatment of RSV infections

开发 RespiraClear 用于 RSV 感染的粘膜靶向治疗

基本信息

批准号：
10402916
负责人：
RICHARD CONE
金额：
$ 89.16万
依托单位：
MUCOMMUNE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-19 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402916
关键词：
Address Adsorption Adult Affinity Age Animal Model Antibody Therapy Antigens Back Binding Biological Assay Biological Products Bronchiolitis Cell Line Cells Cessation of life Child Childhood Chinese Hamster Chinese Hamster Ovary Cell Clinical Clinical Trials Cotton Rats Coughing Custom DHFR gene Data Deglutition Development Dose Effectiveness Elderly Engineering Enzyme-Linked Immunosorbent Assay FDA approved Functional disorder Future Gastric Acid Gel Goals Heating Hospitalization Human Immune Immunoglobulin G In Vitro Infant Infection Influenza Intervention Intramuscular Intramuscular Injections Investments Lead Lung Manufacturer Name Methotrexate Modeling Monoclonal Antibodies Morbidity - disease rate Mucins Mucociliary Clearance Mucous Membrane Mucous body substance Mus Nebulizer Neonatal Ovary Palivizumab Performance Pharmacology Phase Pilot Projects Plaque Assay Pneumonia Polysaccharides Pregnancy Production Proteins Recombinants Recording of previous events Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Risk Site Small Business Innovation Research Grant Structure Structure of mucous membrane of nose Supportive care Surface System Technology Therapeutic Topical application Vaccine Therapy Vaccines Viral Viral Load result Viral load measurement Viremia Virion Virus Virus Diseases Virus Shedding Work base comparative efficacy cost effective treatment crosslink design effective therapy gel electrophoresis glycosylation high risk high risk infant immunoprophylaxis improved lamb model molecular targeted therapies mortality mucus clearance off-patent particle pathogen preclinical development prophylactic public health relevance purge research clinical testing respiratory side effect transmission process vector

项目摘要

Abstract 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 RespiraClear to meet this goal, based on a proprietary “muco- trapping” mAb technology platform with core claims allowed by the USPTO and exclusively licensed from UNC. RespiraClear is a topical mAb treatment based on (i) re-engineering RSV-binding mAb with elevated expression of a fully human Fc glycosylation that enhances its ability to trap RSV in AM and 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. Our pilot studies demonstrate that RespiraClear can potently trap RSV in human AM, facilitate rapid elimination of viral particles from the mouse lung airways, and remain stable when nebulized using a vibrating mesh nebulizer. Building off these promising results, we seek to verify in Phase I of this FastTrack proposal that RespiraClear is indeed superior to palivizumab injected intramuscularly in treating RSV infections in cotton rats, to date the most commonly used animal model for RSV infections. If successful, Phase II of the project will focus on accelerating the preclinical development of RespiraClear. This includes generating a stable CHO cell line for high yield production of RespiraClear (Aim 1), partnering with PARI (a leading nebulizer manufacturer) to develop a customized vibrating mesh nebulizer for RespiraClear (Aim 2A), validating its delivery performance in a pediatric lung model (Aim 2B), and finally, evaluating RespiraClear's efficacy in a neonatal lamb model (Aim 3). If successful, the proposed work will greatly accelerate the clinical evaluation of RespiraClear. The work will also help pave the way for improved, molecularly-targeted therapies against a broad spectrum of pathogens across all major mucosal surfaces.

抽象的摘要呼吸道同步病毒（RSV）是婴儿和老年人的婴儿疾病的主要原因。单克隆抗体（MAB）palivizumab是FDA批准的intprovention to sumall bset的高风险婴儿，作为免疫预防症，但是，它在rsv上不可能有效。可用的SV通过将病毒排除在肺中，因此在感染相邻细胞之前，RSV必须穿越气道粘液（AM），并主要限于无系统性病毒性。目前的呼吸是基于专有的“粘液捕获” MAB技术平台，以实现USPTO允许的索赔，并专门从UNC进行了呼吸道，是基于UNC的局部MAB治疗， - 用自然的粘液性锻炼机制从AM中提高FC Gllycosylation的表达，从而增强了AM中的陷阱RSV，并通过浓缩优化的MESH雾化器将其从气道中清除。在感染部位，而不是系统地交付，我们希望能够有效且具有成本效益的RSV治疗，而由于肺部递送的全身吸附有限，副作用很小。在人类的AM中，促进了小鼠肺气道的快速小电子实际上，在棉花大鼠的RSV中，肌肉发达的肌肉是最常见的RSV动物模型。领先的雾化器制造商）为呼吸道验证（AIM 2A）开发了定制的振动网状ZER，在A中验证了其在新生儿羔羊模型中的疗效（AIM 3）。呼吸系统疗法将为整个病原体的病原体范围内改善，分子靶向的疗法铺平了道路。