Human Monoclonal Antibodies to Replace VIG for Therapy

描述（由申请人提供）：在1796年Edward詹纳证明接种牛痘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，一场使用牛痘免疫保护免受天花感染的全球运动导致了天花的根除。随后，世卫组织建议所有国家停止接种疫苗，并将实验室库存销毁或转移到美国疾病控制和预防中心或俄罗斯莫斯科病毒制剂研究所的两个储存库之一。在美国，常规疫苗接种已经有30多年没有进行了。因此，绝大多数人都有感染天花的危险。正如天花在疫苗接种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可以有效地预防感染，并显著降低死亡率。 然而，在一些接种疫苗的个体中存在罕见和严重的并发症。疫苗接种禁忌在一些人群中。 牛痘免疫球蛋白（VIG）已被用作预防治疗存在天花疫苗禁忌症的个体和治疗接种并发症的个体。随着天花被用作生物恐怖主义的威胁，谨慎的做法是开发VIG用于预防和治疗的替代品。由于人们30多年来没有系统地接种疫苗，VIG的供应非常稀缺。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精确的特异性，并且可以被修饰以增强功能活性。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、生物半衰期和无效的效应子功能。中和病毒和/或介导抗体依赖性细胞毒性的人单克隆抗体的混合物的开发可以作为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.