Harnessing the immune system's arsenal: producing human monoclonal antibodies for therapeutics and investigating immune responses

Sullivan, Meghan; Kaur, Kaval; Pauli, Noel; Wilson, Patrick C.

Although mouse and rat hybridoma technology revolutionized modern biomedical science with many laboratory applications, ultimately the therapeutic potential of such monoclonal antibodies were limited by the risk of side effects. Treatments with nonhuman sera in particular and, to some extent, nonhuman monoclonal antibodies purified from sera could lead to a serious side effect known as serum sickness. Serum sickness, which can be fatal, is an immunological reaction against nonhuman proteins contained in the animal serum. More relevant to monoclonal antibody therapeutics, however, is the possibility for an anti-idiotypic host response; that is, when an antibody treats another antibody as an antigen. In these cases, the host mounts a response that targets the antigen-binding region of the therapeutic monoclonal antibody, effectively neutralizing its activity and rendering it ineffectual. However, these issues were alleviated in part by the advent of technologies to re-engineer nonhuman antibodies so that they were "humanized." Recombinant DNA technologies were developed to swap out the rodent structural domains for their human counterparts, leaving only the specificity-determining regions intact in a process known as complimentary determining region (CDR) grafting [7] . Most notably, the only antibody therapeutic that is licensed to prevent a viral infection (respiratory syncytial virus) was generated by humanization of a rodent monoclonal antibody [8] . Another approach used humanized mice that have either been transgenically engineered to express human antibody genes [9] or are immune deficient and have been transplanted with human lymphoid tissue [10] .