Polyclonal human antibody in cloned HAC-transgenic cows

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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.