Polyclonal human antibody in cloned HAC-transgenic cows

描述（由申请人提供）：由于肠毒素的致命性和持久性，它被认为是一种可能的生物恐怖主义威胁。葡萄球菌和链球菌肠道毒素包括一组被称为热原毒素超级抗原的毒素。暴露于高剂量的这些超级抗原可能是致命的，而暴露于低剂量并不致命，但可能相当虚弱。有人认为肉毒杆菌毒素是战场上最重要的两种毒素威胁。暴露于SEB被认为是主要的风险，因为潜在的致命性以及SEB对暴露个体的丧失能力的影响。过去有几个国家的生物武器项目产生了大量的肠毒素细菌。没有针对这些毒素的大规模疫苗接种计划。在没有疫苗的情况下，有人建议对接触细菌性肠毒素的人进行静脉注射免疫球蛋白（IVIG）的被动免疫，但由于缺乏大量可识别的此类个体，因此这种方法不切实际。

DESCRIPTION (provided by applicant): Enterotoxins are considered a possible bioterrorism threat because of its lethality and its durability. Staphylococcal and streptococcal enterotoxins include a group of toxins known as pyrogenic toxin superantigens. Exposure to a high dose of these superantigens can be fatal while exposure to lower doses is not fatal but can be quite debilitating. It has been suggested that botulinum toxin SEB are the two most important toxin threats on the battlefield. Exposure to SEB is thought to be major risk because of potential lethality as well the incapacitating effects SEB has on exposed individuals. Several nations have had bioweapons programs in the past that produced large quantities of enterotoxin bacteria. No mass vaccination program is envisioned for these toxins. In the absence of a vaccine, passive immunization with intravenous immunoglobulin (IVIG) of people exposed to bacterial enterotoxins has been suggested however the lack of a large and identifiable pool of such individuals makes this approach impractical. This proposal is to develop a large animal system for producing human polyclonal antibody against an enterotoxin peptide. It has been shown that transgenic mice carrying a 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 will 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 enterotoxin in normal and in cloned transgenic calves. This novel and practical solution to the limited supply of human IVIG has several advantages. First, it would enable the production of large quantities 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.