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.

Unfortunately, eliminating immunogenic domains on monoclonal antibodies is not sufficient to prevent all potential side effects. For instance, antibodies raised in animals may cross-react unpredictably to human tissues. Such autoreactive antibodies (also called autoantibodies) target our own tissues and cause much of the pathology in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. B cells expressing autoantibodies are normally culled from the human immune system. However, antibodies that are deemed nonautoreactive by a rodent's immune system, but have the potential to react against human proteins, survive because they never encounter these human proteins in the rodent system. Therefore, they may retain some latent antihuman reactivity and may cross-react catastrophically to uniquely human proteins. One approach developed to alleviate some of these issues, while maintaining the flexibility of using laboratory B cells are immune cells that circulate in the blood, each producing antibodies with unique amino acid sequences and binding specificities. Monoclonal antibody (mAb) technology first relied on technologies that immortalized B cells of interest. As these protocols primarily used rodent cells, technologies designed to humanize antibodies were needed to make them safe for human use. Later, the idea emerged that monoclonal antibodies were truly the product of the genes that code for the variable region of their structure (their V genes). This gave way to technologies that relied on the cloning of antibody genes and their production in vitro, which allowed researchers to paint a detailed portrait of the in vivo immune response. One of the most important advances in monoclonal antibody technology was the adaptation and specialization of these protocols for human samples, allowing researchers to study directly relevant and translatable human responses. CDR, complimentary determining region; CPG, -C-phosphate-G-; EBV, Epstein-Barr virus.