Human Monoclonal Antibodies to Replace VIG for Therapy

描述（由申请人提供）：在爱德华·詹纳（Edward Jenner）于1796年证明牛痘免疫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，一场利用牛痘免疫预防天花感染的全球运动消灭了天花。随后，世卫组织建议所有国家停止疫苗接种，销毁实验室库存或转移到美国疾病预防控制中心或俄罗斯莫斯科病毒准备研究所的两个储存库之一。常规疫苗接种在美国已经有30多年的历史了。因此，绝大多数人口都有感染天花的危险。正如天花在疫苗开发之前被用作生物武器一样，它目前代表着一种潜在的生物武器，使世界上大多数人口处于危险之中。在接触后最初几天内接种疫苗可有效预防感染，并显著降低死亡率。然而，在一些接种疫苗的个体中有罕见和严重的并发症。这种疫苗在一些人群中是禁忌的。牛痘免疫球蛋白（VIG）已被用作治疗存在天花疫苗反指征的个体和治疗接种疫苗并发症的预防措施。鉴于天花可能被用作生物恐怖主义的一种手段，开发VIG用于预防和治疗的替代品是谨慎的。鉴于30多年来个人没有系统地接种疫苗，免疫球蛋白的供应十分短缺。此外，VIG的有效性和安全性仍然是一个问题。因此，我们建议产生人单克隆抗体作为VIG的替代品。单克隆抗体可以产生具有精致的特异性，并可以修改以增强功能活性。全人单克隆抗体的使用消除了与异种、嵌合或人源化抗体相关的问题，包括免疫原性、生物半衰期和低效的效应功能。开发一种人类单克隆抗体鸡尾酒，可中和病毒和/或介导抗体依赖性细胞毒性，可作为VIG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.