Therapeutic Monoclonal Antibodies to H5N1 Influenza

描述(由申请人提供)：大流行性流感病毒的自然出现或故意释放可能对全球公共卫生造成灾难性后果。1918年席卷全球、导致5000多万人死亡的西班牙流感大流行就是最好的例证。尽管随后的大流行的死亡率没有这么大，但其他高致病性甲型流感病毒在禽类水库中传播。一种这样的高致病性病毒H5N1目前在亚洲许多地区根深蒂固，并在地理范围和感染宿主数量上不断增长。在遏制这种病毒的失败尝试中，数百万只家禽被宰杀。在这次暴发中，已确认116人感染H5N1病毒，其中60人死亡。这种情况迫使国家和国际机构为潜在的大流行性流感暴发制定战略计划。这些计划中的大多数包括储存现有的抗流感药物以及开发新的药物。我们建议开发针对H5N1流感病毒的广泛交叉中和单抗(MAb)。该项目汇集了H5N1病毒学、人源单抗生产、人源化单抗生产和产品开发方面的专业知识。我们的方法将是生产人源化和人源化的单抗(来自正在进行的NIAID赞助的H5N1疫苗临床试验的受试者)，能够中和大多数(如果不是全部)亚洲H5N1毒株。对鼠类单抗的抗原性分析和我们对人类单抗的经验表明，可以针对H5N1的漂移变异体制造具有广泛反应的单抗。最近分离出了一株广泛中和的H5N1单抗，证明了这种可行性。将产生一大批H5N1单抗，在体外和体内筛选中和活性，然后亲和力成熟。从这些研究中，将选出一名主导产品候选人进行产品开发。该产品将包含两个单抗，以最大限度地减少逃逸突变和最大限度地中和效力。我们还将采用新的策略来生产具有独特性质的第二代抗体。铅抗体和第二代抗体将在H5N1感染的小鼠和雪貂模型中进行表征，以确定它们的治疗效果。这些研究的结果将是开发一种有效的、高度交叉反应的抗流感疗法，用于预防和潜在地治疗H5N1感染。

DESCRIPTION (provided by applicant): The natural emergence or intentional release of a pandemic influenza virus has the potential to have catastrophic consequences for global public health. This is no better illustrated than by the 1918 Spanish influenza pandemic that swept the globe killing upwards of 50 million people. Although the mortality from subsequent pandemics has not been of this magnitude, other highly pathogenic influenza A viruses circulate in avian reservoirs. One such highly pathogenic virus, H5N1, is now entrenched in many regions of Asia and is growing in geographic range and numbers of hosts infected. Millions of poultry have been slaughtered in unsuccessful attempts to contain this virus. H5N1 infections in this outbreak have been confirmed in 116 humans of which 60 have been fatal. This situation has forced national and international agencies to develop strategic plans for a potential pandemic influenza outbreak. Most of these plans include the stockpiling of currently available anti-influenza drugs as well as the development of new ones. We propose to develop broadly cross-neutralizing monoclonal antibodies (MAbs) specific for H5N1 influenza viruses. This project brings together expertise in H5N1 virology, human MAb production, humanized MAb production and product development. Our approach will be to produce humanized and human (derived from vaccinees in the ongoing NIAID sponsored H5N1 vaccine clinical trials) MAbs capable of neutralizing most if not all Asian H5N1 strains. Antigenic analysis of murine MAbs and our experience with human MAbs demonstrate that broadly reactive MAbs can be made against drift variants of H5N1. This feasibility is shown with the recent isolation of a broadly neutralizing H5N1 MAb. A large panel of H5N1 MAbs will be generated, screened in vitro and in vivo for neutralizing activity, and then affinity matured. From these studies a lead product candidate will be selected for product development. The product will contain two MAbs to minimize escape mutants and to maximize neutralizing potency. We will also employ novel strategies for the production of second generation antibodies with unique properties. The lead antibodies and the second generation antibodies will be characterized in murine and ferret models of H5N1 infection to determine their therapeutic efficacy. The results of these studies will be the development of an effective, highly cross-reactive anti-influenza therapeutic for prevention and potentially for treatment of H5N1 infections.