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

• 批准号: 10319687
• 负责人: RICHARD CONE
• 金额: $ 65.84万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-19 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319687
• 关键词: Address; Adsorption; Adult; Affinity; Age; Animal Model; Antibody Therapy; Antigens; Antiviral Agents; Back; Binding; Biological; Biological Assay; 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

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 项目摘要呼吸道合胞病毒（RSV）是婴儿和幼儿病毒死亡的主要原因，也是免疫损害的成年人和年龄较大的呼吸道疾病的主要原因。不幸的是，目前尚无RSV的疫苗或有效疗法。犹太半子是单克隆抗体（MAB）PALIVIZUMAB的每月肌内注射，是唯一对FDA批准的干预措施，以一小部分高风险婴儿作为免疫预防症。但是，它在治疗RSV方面无效。对于数以万计的RSV住院的婴儿，仅提供支持的治疗，发病率和死亡率很大。有趣的是，RSV通过仅将病毒脱落到气道中，在肺中传播。因此，在感染邻近细胞之前，RSV必须穿越气道粘液（AM），并且RSV主要仅限于几乎没有全身性病毒性的气道。我们认为，RSV特异性，安全，有效且局部交付的抗病毒将为当前的药理学干预措施提供有力的选择。 Mucommune正在基于专有的“ Muco-Trapping” MAB技术平台，正在开发呼吸道实现这一目标，该平台具有USPTO允许的核心要求，并仅获得UNC的许可。 RESSIRECLEAR是一种基于（i）重新设计的RSV结合MAB的局部MAB处理，具有完全人类FC糖基化的表达升高，增强了其在AM中TRAP RSV的能力，并通过自然的粘膜循环清除机制从气道中清除病毒，并使用IT（II）稳定地将其运送到vibrize vibrize vibrize。通过将优化的mAb集中在感染部位，而不是系统地递送，我们希望能够对RSV进行有效且具有成本效益的治疗，而由于肺部递送的全身吸附有限，副作用的风险很小。我们的试点研究表明，呼吸道验证可能会在人类AM中捕获RSV，从而有助于从小鼠肺气道中快速进化病毒颗粒，并在使用振动网状雾化器雾化时保持稳定。建立这些承诺结果，我们试图在第一阶段的FastTrack提案中验证呼吸道扫描确实优于在棉花大鼠中治疗RSV感染时，呼吸道确实优于palivizumab，这是RSV感染最常用的动物模型。如果成功的话，该项目的第二阶段将集中于加速呼吸道临床前的发展。这包括生成一条稳定的CHO细胞系，用于高产量的呼吸道清除（AIM 1），与Pari（领先的雾化器制造商）合作开发了用于呼吸道呼吸呼吸器的定制振动网状雾化器（AIM 2A）（AIM 2A），验证其在小儿肺模型（AIM 2B）中的交付性能（AIM 2B），并评估了3个型号的效应（AIM 2B）。如果成功，提议的工作将大大加速呼吸道临床评估。这项工作还将有助于为改进，分子靶向的疗法铺平道路，以针对所有主要粘膜表面的各种病原体。