Human Abs to B. Anthracis in Cloned Transgenic Cattle

描述（由申请人提供）：炭疽被认为是一种可能的生物恐怖主义威胁，因为它的致命性和持久性。一些国家过去曾有生产大量炭疽菌的生物武器项目。大量的炭疽恐慌和最近因接触通过邮件发送的炭疽孢子而死亡的事件加剧了人们对保护民众免受炭疽感染的关注。由于现有的炭疽疫苗供应不足，没有大规模疫苗接种计划的设想。在没有疫苗的情况下，对接触炭疽孢子的人进行静脉注射免疫球蛋白（IVIG）的被动免疫是一种合理的策略。本研究旨在建立大型动物系统，制备人炭疽多克隆抗体。已有研究表明，携带人工人染色体（HAC）的转基因小鼠在受到抗原刺激时，可产生所有类别的人抗体，且抗体库广泛。在目前的工作中，类似的策略将应用于牛，那里的抗体产量将远远高于小鼠。我们已经证明，我们可以创造出含有人类IG基因的HAC的牛克隆，并且染色体是稳定的，并在胎儿发育到新生儿的整个过程中表达。在正常犊牛和克隆犊牛中对炭疽疫苗和纯化炭疽蛋白的免疫反应进行表征。这种新颖实用的解决人类IVIG有限供应的方法有几个优点。首先，它将能够以合理的成本生产大量的人类抗体。其次，它将为设计免疫策略提供更大的灵活性，以生产高滴度、高特异性的抗体，这是人类志愿者无法做到的。第三，它将为生产针对其他细菌和病毒病原体的临床重要的人抗体试剂提供一种新的使能技术。

DESCRIPTION (provided by the applicant): Anthrax is considered a possible bioterrorist threat because of its lethality and its durability. Several nations have had bioweapons programs in the past that produced large quantities of anthrax. Numerous anthrax scares and the recent deaths from exposure to anthrax spores sent through the mail have heightened concerns about protecting the population against anthrax. No mass vaccination program is envisioned because the existing anthrax vaccine is in short supply. In the absence of a vaccine, passive immunization with intravenous immunoglobulin (IVIG) of people exposed to anthrax spores is a reasonable strategy. This proposal is to develop a large animal system for producing human polyclonal antibody against anthrax. It has been shown that transgenic mice carrying an artificial human chromosome (HAC) produce human antibody of all classes and with a broad repertoire when challenged with antigen. In the current work, a similar strategy would be applied to cattle, where the yield of antibody would be far greater than with mice. We have already shown that we can create cattle clones that have a HAC containing the human IG genes, and that the chromosome is stable and is expressed throughout fetal development into neonatal life. Work is proposed to characterize the immune response to anthrax vaccine and purified anthrax proteins in normal and in cloned calves. This novel and practical solution to the limited supply of human IVIG has several advantages. First, it would enable the production of large quanitites of human antibody at a reasonable cost. Second, it would provide greater flexibility in designing immunization strategies for producing high, titer, high specificity antibody beyond what is possible with human volunteers. Third, it would provide a new enabling technology for producing clinically important human antibody reagents against other bacterial and viral pathogens.