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.

Importantly, phage display allows the production of a large variety of potentially high-affinity monoclonal antibodies that may be rare or nonexistent in the human body. For example, phage display has been used to generate what are, in essence, autoantibodies targeting human proteins for the treatment of cancer or autoimmune diseases; these antibodies would not survive the human body's normal mechanisms for culling autoreactive antibodies. In fact, the anti-TNFa (tumor necrosis factor alpha) inhibitory antibody HUMIRA ("Human Monoclonal Antibody in Rheumatoid Arthritis"), the world's first structurally human monoclonal antibody therapeutic, was identified using phage display. Furthermore, the ability to iteratively screen for reactive molecules in the lab also allows for the isolation of exceedingly rare antibodies by phage display. For example, in 2009, two papers described the crystal structure of phage-display antibodies that bound to a region of the hemagglutinin protein on the surface of influenza. This region is highly conserved on many divergent influenza strains and is critical for viral function, and thus can be targeted by antibodies to neutralize the virus [20, 21] . This finding demonstrated that at least some critical influenza epitopes are evolutionarily conserved and can be targets for therapeutics, including monoclonal antibody drugs, as well as targets to improve influenza vaccines with broader protection across many influenza strains. Demonstrating a convergence of approaches in the antibody community, Lanzavecchia and colleagues later found that, although rare, screening large numbers of EBV-transformed human memory B cell clones could detect natural antibodies targeting similar regions of hemagglutinin [22] .