Human Monoclonal Antibodies to Replace VIG for Therapy

描述(申请人提供)：在1796年Edward Jenner证明接种牛痘疫苗可以预防天花感染之前，几乎每个人都感染了天花，死亡率高达或高于30%。1977年，一项利用牛痘免疫预防天花感染的全球运动根除了天花。随后，世卫组织建议所有国家停止接种疫苗，并销毁实验室库存，或将其转移到美国疾控中心或俄罗斯莫斯科病毒准备研究所的两个储存库之一。美国的常规疫苗接种已经有30多年没有出现过了。因此，绝大多数人口面临感染天花的风险。正如天花在疫苗接种发展之前被用作生物武器一样，它目前是一种潜在的生物武器，使世界上大多数人口处于危险之中。在接触后的头几天内接种疫苗在一些地方有效地预防感染，并显著降低死亡率。然而，在一些接种疫苗的人中，出现了罕见而严重的并发症。疫苗接种在一些人群中是禁忌的。痘苗免疫球蛋白(VIG)已被用作预防天花疫苗禁忌症的个体和治疗接种疫苗并发症的个体。由于天花有可能被用作生物恐怖主义的媒介，因此开发VIG用于预防和治疗的替代品是谨慎的。鉴于个人30多年来没有系统地接种疫苗，VIG的供应很少。此外，VIG的有效性和安全性仍然是一个问题。因此，我们建议制备人源单抗作为VIG的替代物。可以产生具有极高特异性的单抗，并可以对其进行修饰以增强功能活性。全人单抗的使用消除了与异种抗体、嵌合抗体或人源化抗体相关的问题，包括免疫原性、生物半衰期和低效效应器功能。开发一种能中和病毒和/或介导抗体依赖的细胞毒作用的人单抗鸡尾酒可以作为VIG的安全、有效的替代品。

DESCRIPTION (provided by applicant): Prior to Edward Jenner's demonstration in 1796 that immunization with cowpox protected against smallpox infection, virtually everyone contracted smallpox with mortality as high or higher than 30%. A global campaign using vaccinia immunization for protection from smallpox infection resulted in the eradication of smallpox in 1977. Subsequently the WHO recommended that all countries cease vaccination and laboratory stocks be destroyed or transferred to one of two repositories at the CDC in the United States or the Institute of Virus Preparations in Moscow, Russia. Routine vaccination in the United States has not occurred for more than thirty years. Therefore, the vast majority of the population is at risk of smallpox infection. Just as smallpox was used as a bioweapon prior to the development of vaccination, it currently represents a potential biological weapon with the majority of the world population at risk. Vaccination within the first few days after exposure is effective at preventing infection in some with a significant decrease in mortality. However, there are rare and serious complications in some vaccinated individuals. The vaccination is contraindicated in a number of groups of people. Vaccinia immune globulin (VIG) has been used as prophylaxis for treating individuals for which contra indications exist for smallpox vaccine and for treatment of those with complications of vaccinations. With the threat of smallpox being used as an agent of bioterrorism, it is prudent to develop alternatives for the use of VIG for prophylaxis and treatment. Supplies of VIG are scarce given that individuals have not been systematically vaccinated for more than 30 years. Furthermore, the validation and safety of VIG remains an issue. Therefore, we propose to generate human monoclonal antibodies as a replacement for VIG. Monoclonal antibodies can be produced with exquisite specificity and can be modified to enhance functional activity. The use of fully human monoclonal antibodies eliminates problems associated with xenogeneic, chimeric or humanized antibodies which include immunogenicity, biological half-life, and inefficient effector function. The development of a cocktail of human monoclonal antibodies that neutralize virus and/or mediate antibody-dependent cellular cytotoxicity can serve as a safe, effective replacement for VIG.