Development of novel immunotherapy for influenza virus infection

这项提案的目的是开发一种新的免疫系统，将预防和治疗潜在的生命- 可能感染流感病毒。该提议基于甘露糖结合凝集素 (MBL)是一种广谱的天然免疫分子这种血清蛋白识别广泛的 病原体包括病毒。初步数据表明：1）重组人MBL（rhMBL） 流感病毒，和2）在缺乏MBL的小鼠中对病毒感染的易感性增加。这些 观察结果支持MBL作为治疗流感病毒的免疫抑制剂的强有力候选物 感染该项目的一个关键目标是首先评估已用于I期的临床级rhMBL 临床研究，以及第二代衍生物，其中包含另一种凝集素样血清L-纤维胶凝蛋白的一部分 蛋白质，可能具有增加的活性和增加的药理学特性。初步研究 证明这些新的嵌合凝集素结合甘露聚糖，甘露聚糖是在 流感病毒和激活凝集素补体途径。这项赠款提案将利用 马萨诸塞州总医院发育免疫学项目的基础设施， 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和 香港大学儿科及青少年医学及微生物学系 贝斯以色列女执事医疗中心的医学和美国 获得生产重组凝集素嵌合体的权利。我们将评估 rhMBL和凝集素嵌合体激活凝集素补体途径和调节吞噬细胞的功效 在体外发挥作用。我们还将研究这些凝集素在小鼠遗传学上的治疗潜力 缺乏MBL、补体成分3、纤维胶凝蛋白-A（相当于人L-纤维胶凝蛋白）或其组合 这些材料来阐明每个先天免疫分子在流感病毒感染中的相对作用。 目标是开发rhMBL或衍生物的制剂，其可用作预防和/或治疗。 抗流感病毒感染的治疗药物。

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.