Since their discovery in 1975, mAbs have been described as "magic bullets" with the potential to seek out and bind targets with high affinity and specificity (2). The potential of using mAbs to treat human disease was immediately apparent. Early treatment efforts using rodent systems to develop mAbs for use in humans proved ineffective because of the strong immune responses they elicited in humans, limiting their half-life in the body and potentially causing anaphylaxis (3–5). Strategies to overcome this obstacle have included humanization of rodent-derived mAbs and development of fully human mAbs (hu-mAbs).
Currently, there are 27 mAb therapeutics on the market, and mAbs account for more than 25% of the drugs in the FDA pipeline and approximately 50% of all new drug launches (6, 7). Despite significant promise as therapeutic agents, many challenges potentially block mAbs' successful clinical implementation, including low affinities of mAbs for their targets, allergic reactions to mAbs, and high clearance rates. To address these challenges, there is a need to develop new therapeutic mAbs that are fully human. Hu-mAbs advance through clinical trials quickly because of their high specificity and typically predictable toxicity (1). Murine antibodies previously used as therapeutics (e.g., Johnson and Johnson's Orthoclone OKT3) had to be withdrawn from the market because of immunogenicity issues, short half-life, and side effects. Humanized mAbs, such as Genetech/Roche's Herceptin, and hu-mAbs, such as Abbott's Humira, are clearly the more desirable antibody therapeutics.Methods for fully human antibody development
Several technologies exist for developing hu-mAbs, including:
Current technologies for hu-mAb development are suboptimal in that the therapeutics derived from these approaches are either not fully human, resulting in increased human antimouse immune response, or require several rounds of maturation to achieve high affinity. The high cost of developing fully hu-mAbs using these available technologies, prevents many therapeutics researchers from employing them in preclinical testing against novel targets.