Aerosol immunotherapy for treatment of human metapneumovirus infection

气溶胶免疫疗法治疗人类偏肺病毒感染

• 批准号: 10081759
• 负责人: RICHARD CONE
• 金额: $ 26.17万
• 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: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081759
• 关键词: Address; Adult; Aerosols; Affinity; Age; Air; Animal Model; Antibodies; Antiviral Agents; Apical; Back; Blood; Bronchiolitis; Caring; Cell Culture Techniques; Cell Line; Cells; Child; Childhood; Chinese Hamster Ovary Cell; Clinical; Cotton Rats; Cyclic GMP; Development; Diffuse; Documentation; Dose; Ebola; Effectiveness; Elderly; Engineering; Enhancement Technology; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelium; Formulation; Functional disorder; Gel; Herpesvirus 1; Human; Human Metapneumovirus; Immobilization; Immune; Immunoglobulin G; Immunotherapy; In Vitro; Individual; Infant; Infection; Influenza; Intervention; Lead; Life Cycle Stages; Liquid substance; Literature; Lower Respiratory Tract Infection; Lung; Medical; Metapneumovirus; Methods; Microbe; Modeling; Monoclonal Antibodies; Mucins; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Mus; Nebulizer; Neonatal; Parainfluenza; Paramyxovirus; Particulate; Pathologic; Patients; Penetration; Pharmacology; Phase; Phase II Clinical Trials; Pilot Projects; Pneumonia; Polysaccharides; Proliferating; Prophylactic treatment; Recombinants; Reporting; Research Personnel; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Safety; Small Business Innovation Research Grant; Specificity; Structure; Surface; Symptoms; System; Technology; Testing; Topical application; Vaccines; Variant; Viral; Viral Load result; Viral load measurement; Viremia; Virion; Virus; Virus Diseases; Virus Shedding; Western Blotting; airway epithelium; antigen binding; asthma exacerbation; base; bronchial epithelium; crosslink; effective therapy; efficacy study; glycosylation; human monoclonal antibodies; improved; in vivo; molecular targeted therapies; novel; pathogen; prevent; purge; respiratory; vaginal transmission

Project Summary Human Metapneumovirus (MPV) is the second leading cause of lower respiratory tract infections in infants and young children, and a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is no effective therapy or vaccine for MPV, and only supportive medical care is available for both pediatric and geriatric MPV patients. We believe a pathogen-specific, safe, effective and topically delivered antiviral would provide a powerful option addressing the current gap in pharmacological interventions. Human monoclonal antibodies (mAb) delivered locally to mucosal surfaces offer exceptional promise 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 in mucus – 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 viruses in mucus prevents them from infecting target cells, facilitates rapid elimination from the airways, and enables effective protection in vivo. Infection by MPV shares many of the pathological and clinical manifestations of Respiratory Syncytial Virus (RSV). There is no detectable MPV viremia in the blood of MPV-infected patients, implicating MPV to be strictly a localized respiratory infection, similar to RSV that sheds exclusively from the apical surface of infected cells and must traverse airway mucus (AM) before spreading to neighboring cells. We have been able to stably nebulize “muco-trapping” mAb to effectively treat RSV infections in both cotton rats and more importantly in neonatal lambs, reducing the viral load by nearly 4-log by Day 6 post-infection with treatment that is initiated on Day 3 post infection. This motivated us to harness our platform to develop a “muco-trapping” mAb against MPV that can be delivered directly to the airways by nebulization, thereby reducing the spread of MPV in the lung and facilitating rapid elimination of the virus. In Aim 1, we will produce and characterize mAb against MPV, including its ability to facilitate immobilization of MPV in fresh, undiluted human AM. In Aim 2, working with the Pickles Lab at UNC, which documented that anti-RSV Ab delivered apically to airway cultures infected by RSV could restrict further spread of infection, we will assess whether anti-MPV mAb dosed apically to well-differentiated human airway epithelium grown at the air-liquid interface can similarly restrict or inhibit the spread of pre-established MPV infections. Successful completion of these Phase I SBIR studies will lead to a Phase II proposal focused on mAb optimization, development of nebulizable formulation, and proof-of-concept efficacy studies in small and large animal models. By enabling enhanced mAb function 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.

项目总结