Development of novel immunotherapy for influenza virus infection

开发针对流感病毒感染的新型免疫疗法

• 批准号: 7933862
• 负责人: Kazue Takahashi
• 金额: $ 93.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933862
• 关键词: Acute; Adolescent Medicine; Alveolar Macrophages; Animal Model; Animals; Antiviral Agents; Applications Grants; Binding; Biotechnology; Boston; Carbohydrates; Cells; Chimera organism; Chimeric Proteins; Chronic Disease; Clinical; Clinical Research; Collectins; Complement; Complement 3; Data; Development; Drug Formulations; Drug Kinetics; Effectiveness; Elderly; Epithelial Cells; Foundations; General Hospitals; Generations; Goals; Half-Life; Hong Kong; Host Defense; Human; Immune; Immune system; Immunization; Immunoglobulins; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infant; Infection; Infection prevention; Influenza; Influenza A virus; Investigation; Israel; Knowledge; Lead; Lectin; Leukocytes; Life; Lung Inflammation; Mannose Binding Lectin; Mannose-Binding Lectins; Massachusetts; Medical center; Medicine; Microbiology; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Organism; Pathway interactions; Phagocytosis; Phase; Predisposition; Production; Property; Prophylactic treatment; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Recombinants; Relative (related person); Research Infrastructure; Research Personnel; Resources; Rights; Role; Route; Serum Proteins; Testing; Therapeutic; Universities; Viral; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; anti-influenza drug; antimicrobial; base; comparative efficacy; complement pathway; cost; cytokine; developmental immunology; experience; ficolin; ficolin-A; ficolin-beta; improved; in vivo; influenza virus strain; influenzavirus; intraperitoneal; medical schools; mortality; mouse model; neutrophil; novel; novel therapeutics; pathogen; pediatric department; prevent; product development; programs; prophylactic; protective efficacy; research study; response; uptake

The aim of this proposal is to develop a novel immunotherapeutic that will prevent and treat potentially life- threatening infection with influenza virus. The proposal is based on the fact that mannose-binding lectin (MBL) is a broad-spectrum molecule of innate immunity. This serum protein recognizes a wide range of pathogens including viruses. Preliminary data indicate that 1) recombinant human MBL (rhMBL) neutralizes influenza virus, and 2) There is increased susceptibility to virus infection in mice lacking MBL. These observations support MBL as a strong candidate as an immunotherapeutic agent to treat influenza virus infection. A key goal of this project is first to evaluate clinical grade rhMBL that has been used in Phase I clinical studies, and second generation derivatives incorporating a part of L-ficolin, another lectin-like serum protein, that may have increased activity and increased pharmacologic properties. Preliminary studies demonstrate that these novel chimeric lectins bind mannan, the same carbohydrate that is expressed on influenza viruses and activate the lectin complement pathway. This grant proposal will leverage the infrastructure of the Program of Developmental Immunology at Massachusetts General Hospital, the extensive scientific experience of the investigators in the field of innate immunity and lung inflammation, the specialized resources and extensive scientific knowledge of the investigators in the field of influenza virus infection at the Department of Medicine at Boston University School of Medicine and the Department of Paediatrics & Adolescent Medicine and Microbiology at The University of Hong Kong and The Department of Medicine at Beth Israel Deaconess Medical Center and the product development expertise of Enzon, a US biotechnology company that acquired rights to produce recombinant lectin chimeras. We will evaluate the efficacy of rhMBL and lectin chimeras to activate the lectin complement pathway and to modulate phagocytic functions in vitro. We will also investigate the therapeutic potential of these lectins in mice genetically deficient for the MBL, complement component 3, ficolin-A (equivalent to human L-ficolin) or combinations these materials to elucidate the relative roles of each innate immune molecule in influenza virus infection. The goal is to develop a formulation of rhMBL or a derivative that could be used as prophylactic and/or therapeutic agetns against influenza virus infection.

该提议的目的是开发一种新型的免疫治疗性，以预防和治疗潜在的生命 - 威胁流感病毒感染。该提议是基于以下事实 （MBL）是一种先天免疫的广谱分子。这种血清蛋白识别出广泛的 病原体包括病毒。初步数据表明1）重组人MBL（RHMBL）中和 流感病毒和2）缺乏MBL的小鼠对病毒感染的敏感性增加。这些 观察结果支持MBL作为强大的候选者作为治疗流感病毒的免疫治疗剂 感染。该项目的一个关键目标是首先评估已在I期使用的临床级RHMBL 临床研究和第二代衍生物融合了l-纤维蛋白的一部分，另一种凝集素样血清 蛋白质，可能增加活性并增加了药理特性。初步研究 证明这些新颖的嵌合凝集素结合曼南（Mannan），同一碳水化合物在 流感病毒并激活凝集素补体途径。该赠款提案将利用 马萨诸塞州综合医院的发展免疫学计划基础设施， 研究人员在先天免疫和肺部炎症领域的广泛科学经验， 流感病毒领域研究人员的专业资源和广泛的科学知识 波士顿大学医学院医学系感染和 香港大学的儿科与青少年医学和微生物学 贝丝以色列女执事医疗中心和美国恩宗产品开发专业知识的医学 生物技术公司获得了生产重组凝集素嵌合体的权利。我们将评估 RHMBL和凝集素嵌合体的功效激活凝集素补体途径并调节吞噬细胞 体外功能。我们还将研究这些凝集素在遗传上的治疗潜力 MBL，补体成分3，乳脂蛋白-A（相当于人L-纤维蛋白）或组合不足 这些材料阐明了每个先天免疫分子在流感病毒感染中的相对作用。 目的是开发一种可以用作预防性和/或的衍生物的配方 针对流感病毒感染的治疗性agetns。