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) 是婴儿和幼儿病毒性死亡的主要原因，也是免疫受损的成人和老年人呼吸道疾病的主要原因。不幸的是，目前没有针对 RSV 的疫苗或有效疗法。 Synagis 是每月肌肉注射单克隆抗体 (mAb) 帕利珠单抗的药物，是 FDA 批准的唯一一种针对一小部分高危婴儿作为免疫预防的干预措施。然而，它对治疗 RSV 无效。因此，对于数以万计因 RSV 住院的婴儿来说，只能进行支持性治疗，并且发病率和死亡率很高。有趣的是，RSV 通过将病毒完全排入气道而在肺部传播。因此，RSV 在感染邻近细胞之前必须穿过气道粘液 (AM)，并且 RSV 仍然主要局限于气道，几乎没有或没有全身性病毒血症。我们相信，RSV 特异性、安全、有效和局部给药的抗病毒药物将提供一个强有力的选择，弥补目前药物干预方面的差距。 Mucommune 正在开发 RespiraClear 来实现这一目标，该平台基于专有的“粘液捕获”mAb 技术平台，其核心主张得到了美国专利商标局 (USPTO) 的允许，并获得了北卡罗来纳大学 (UNC) 的独家许可。 RespiraClear 是一种局部单克隆抗体治疗方法，基于 (i) 重新设计 RSV 结合单克隆抗体，提高全人源 Fc 糖基化的表达，增强其在 AM 中捕获 RSV 的能力，并通过自然粘膜纤毛清除机制清除气道中的病毒，以及 (ii) 使用振动网状雾化器将其稳定地输送至肺部气道。通过将优化的单克隆抗体浓缩在感染部位而不是全身输送，我们期望能够有效且经济高效地治疗 RSV，并且由于肺部输送的全身吸收有限而产生不良副作用的风险很小。我们的初步研究表明，RespiraClear 可以有效捕获人类 AM 中的 RSV，促进快速消除小鼠肺气道中的病毒颗粒，并在使用振动网雾化器雾化时保持稳定。基于这些有希望的结果，我们试图在 FastTrack 提案的第一阶段中验证 RespiraClear 在治疗棉鼠 RSV 感染方面确实优于肌肉注射帕利珠单抗，棉鼠是迄今为止最常用的 RSV 感染动物模型。如果成功，该项目的第二阶段将重点加速 RespiraClear 的临床前开发。这包括生成用于高产量生产 RespiraClear 的稳定 CHO 细胞系（目标 1），与 PARI（领先的雾化器制造商）合作开发用于 RespiraClear 的定制振动网状雾化器（目标 2A），验证其在儿科肺模型中的输送性能（目标 2B），最后评估 RespiraClear 在新生儿羔羊模型中的功效（目标 3）。如果成功，拟议的工作将大大加速 RespiraClear 的临床评估。这项工作还将有助于为针对所有主要粘膜表面的广泛病原体的改进的分子靶向疗法铺平道路。