Development of novel immunotherapy for influenza virus infection

描述(申请人提供)：这项建议的目的是开发一种新的免疫疗法，将预防和治疗潜在威胁生命的流感病毒感染。该建议是基于这样一个事实，即甘露糖结合凝集素(MBL)是一种广谱的天然免疫分子。这种血清蛋白可识别包括病毒在内的多种病原体。初步数据表明，1)重组人MBL(RhMBL)中和流感病毒，2)缺乏MBL的小鼠对病毒感染的易感性增加。这些观察结果支持MBL作为治疗流感病毒感染的免疫治疗剂的有力候选者。该项目的一个关键目标是首先评估已用于I期临床研究的临床级别的重组人MBL，以及含有另一种凝集素样血清蛋白L-菲科林的第二代衍生物，后者可能具有更高的活性和更好的药理特性。初步研究表明，这些新型嵌合凝集素与甘露聚糖结合，甘露聚糖与流感病毒上表达的碳水化合物相同，并激活凝集素补体途径。这项赠款计划将利用马萨诸塞州总医院发育免疫学计划的基础设施、先天免疫和肺部炎症领域研究人员的丰富科学经验、波士顿大学医学院医学系、香港大学儿科和青少年医学与微生物学系和贝斯以色列女执事医学中心流感病毒感染领域研究人员的专业资源和广博的科学知识，以及美国生物技术公司Enzon的产品开发专业知识。我们将评估重组人MBL和凝集素嵌合体在体外激活凝集素补体途径和调节吞噬功能的效果。我们还将研究这些凝集素在MBL、补体成分3、FICLOIN-A(相当于人的L-FICNOLIN)基因缺陷小鼠身上的治疗潜力，或将这些材料结合起来，以阐明每个先天免疫分子在流感病毒感染中的相对作用。其目标是开发一种可用于预防和/或治疗流感病毒感染的重组人MBL或其衍生物的配方。

DESCRIPTION (provided by applicant): 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 agents against influenza virus infection.