Inhaled 'muco-trapping' antibody as universal immunotherapy for influenza virus infections

吸入“粘膜捕获”抗体作为流感病毒感染的通用免疫疗法

• 批准号: 10081777
• 负责人: RICHARD CONE
• 金额: $ 27.54万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-23 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081777
• 关键词: Affinity; Aftercare; Animal Model; Animals; Antibodies; Antiviral Agents; Apical; Attenuated; Binding; Biological Assay; Biological Sciences; Bronchiolitis; Cell Line; Cells; Chinese Hamster Ovary Cell; Clinical; Cyclic GMP; Development; Diagnosis; Diffuse; Documentation; Dose; Ebola; Effectiveness; Enhancement Technology; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Epithelium; Exhibits; Formulation; Functional disorder; Gold; Herpesvirus 1; Hospitalization; Human; Immobilization; Immunoglobulin G; Immunotherapy; In Vitro; Inbred BALB C Mice; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Inhalation; Intercept; Lead; Life Cycle Stages; Literature; Lung; Medical; Microbe; Modeling; Monitor; Monoclonal Antibodies; Mucins; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Mus; Nebulizer; Neonatal; Neutrophil Infiltration; Oseltamivir; Parents; Particulate; Pathologic; Patients; Penetration; Performance; Phase; Phase II Clinical Trials; Polysaccharides; Proliferating; Prophylactic treatment; Public Health; Reporting; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Safety; Saline; Signs and Symptoms; Small Business Innovation Research Grant; Specificity; Structure; Surface; Symptoms; System; Technology; Temperature; Testing; Texas; Therapeutic; Therapeutic Effect; Topical application; Variant; Viral; Viral Load result; Viremia; Virion; Virus; Virus Diseases; Virus Shedding; Visit; Weight; Western Blotting; airway remodeling; anti-influenza; antigen binding; apical membrane; base; clinical development; crosslink; human monoclonal antibodies; improved; in vivo; infectious disease model; influenza virus vaccine; influenzavirus; molecular targeted therapies; mouse model; novel; pathogen; pre-clinical; prevent; purge; standard of care; transmission process; vaginal transmission

Project Summary Seasonal infections from human influenza virus (INFV) represents a major public health burden. The flu vaccine only averts ~15% of medical visits and ~12% of hospitalizations due to INFV, whereas current antivirals are only modestly effective if given soon after symptoms emerge, which is achievable in only half of infected patients due to practical limitations in how quickly INFV infections can be diagnosed. Human monoclonal antibodies (mAb) delivered topically to mucosal surfaces offer exceptional promise as antivirals, combining safety, effectiveness and unparalleled specificity. Adding further to the promise of mAb, we have recently discovered a novel Ab function in mucus – trapping individual pathogens– and have pioneered a technology enhancing the use of mAb in mucosal secretions based on carefully-tuned affinity between IgG-Fc and mucins, which has been exclusively licensed to Mucommune. Trapping pathogens in mucus prevents them from infecting target cells and spreading locally, facilitates rapid elimination from the airways, and enables effective protection in vivo. We believe the technology is uniquely suited to treat INFV infections, due to the unique pathophysiology of INFV. Studies have shown INFV to bud exclusively from the apical surface of epithelial cells. INFV also shares many pathological and clinical manifestations with Respiratory Syncytial Virus (RSV), which also sheds exclusively from the apical surface of infected cells and must traverse airway mucus (AM) before spreading to neighboring cells. This implies delivery of muco-trapping mAb into the airways can provide an immediate therapeutic benefit by trapping shed progeny virus in AM and facilitating their rapid clearance, unlike oral antivirals that have substantial delay in distribution to the lung. We have stably nebulized “muco-trapping” mAb to treat RSV infections in neonatal lambs, reducing the viral load by nearly 4-log by Day 6 post-infection after starting treatment as late as Day 3 post-infection. This motivated us to harness our platform to develop a “muco-trapping” mAb against INFV. In Aim 1, we will produce and characterize muco-trapping mAb against INFV, including their ability to bind and neutralize INFV. In Aim 2, working with IBT Biosciences (a CRO that specializes in animal models of infectious disease), we will assess whether muco-trapping mAb against INFV dosed intranasally can improve survival, clinical scores, and reduce lung viral titers relative to treatment with oseltamivir, the current gold standard of care, even after delayed treatment post-infection. Successful completion of these Phase I SBIR studies will lead to a Phase II proposal focused on mAb optimization, development of a nebulizable formulation, and efficacy/transmission studies in larger animal models. By enabling enhanced mAb functionality in mucus secretions, we expect Mucommune will help pave the way for improved, molecularly targeted therapies and prophylaxis against a broad spectrum of pathogens and microbes across all major mucosal surfaces.

项目摘要 人类流感病毒（INFV）的季节性感染是一个重大的公共卫生负担。流感 疫苗只能避免约15%的就诊和约12%的因INFV住院，而目前的 如果在症状出现后立即给予抗病毒药物，则效果有限，这在只有一半的人中是可以实现的。 由于INFV感染的诊断速度的实际限制，感染的患者。人类 局部递送至粘膜表面的单克隆抗体（mAb）提供了作为抗病毒药物的特别前景， 结合了安全性、有效性和无与伦比的特异性。进一步增加mAb的承诺，我们有 最近在粘液中发现了一种新的抗体功能--捕获单个病原体--并开创了一种新的抗体治疗方法。 基于IgG-Fc之间的精心调节的亲和力， 和粘蛋白，它已被独家授权给Mucommune。将病原体捕获在粘液中， 它们感染靶细胞和局部扩散，促进从气道快速消除， 能够在体内进行有效的保护。我们相信这项技术是唯一适合治疗INFV感染， INFV独特的病理生理学。研究表明，INFV仅从植物的顶端表面出芽， 上皮细胞INFV还与呼吸道合胞病毒有许多共同的病理和临床表现， 病毒（RSV），也仅从受感染细胞的顶端表面脱落，必须穿过气道 粘液（AM）扩散到邻近细胞之前。这意味着将粘膜捕获mAb递送到粘膜中。 气道可以通过捕获AM中的脱落子代病毒并促进 它们的快速清除，不像口服抗病毒药物在分布到肺部方面有很大的延迟。我们有 稳定雾化的“粘膜捕获”mAb治疗新生羔羊的RSV感染，通过 在感染后第6天开始治疗后至感染后第3天接近4 log。这激励了我们 利用我们的平台开发针对INFV的“粘膜捕获”mAb。在目标1中，我们将生产和 表征针对INFV的粘膜捕获mAb，包括其结合和中和INFV的能力。在目标2中， 与IBT Biosciences（一家专门研究传染病动物模型的CRO）合作，我们将评估 鼻内给予抗INFV的粘膜捕获mAb是否可以改善生存率、临床评分， 肺病毒滴度相对于奥司他韦治疗，目前的金标准治疗，即使在延迟 感染后的治疗。成功完成这些第一阶段SBIR研究将导致第二阶段的建议 专注于mAb优化、可雾化制剂的开发以及在 大动物模型通过增强粘液分泌物中mAb的功能，我们预期Mucommune 将有助于为改进分子靶向治疗和预防广谱 病原体和微生物遍布所有主要粘膜表面。