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Human monoclonal antibodies in the clinic: novel insights into the choice of specific targets.

The clinical use of therapeutic antibodies made a great stride forward in 1975 when Köhler and Milstein introduced the hybridoma method [1]. This procedure enabled the production of unlimited amounts of antibodies with predetermined specificity, but it was not applicable to human B cells. Although monoclonal antibodies derived from deliberate immunization of mice, rats and rabbits were not appropriate for the clinic, humanization of these antibodies rendered them pertinent. Thus, a variety of methods was developed to produce monoclonal antibodies for the clinic, even if they were originally fashioned as mouse and rat monoclonal antibodies. Indeed, chimeric and humanized antibodies against cytokines, pathogens and assumed tumor antigens have been approved for therapy. The alternative means for creating human monoclonal antibodies is the Epstein-Barr virus (EBV) method [2]. This technique, which was the first to generate human monoclonal antibodies, signified a new approach. Its objective was to produce monoclonal antibodies mirroring the human antibody repertoire, presumably reflecting those immune and natural (innate) antibodies that in vivo successfully cope with targets such as pathogens, toxins, tumor cells. Later, this very same concept was extended to the production of human monoclonal antibodies by applying molecular methods in conjunction with single B cell methodologies. Accordingly, antibodies against a variety of antigens (such as bacteria, viruses, toxins, auto-antigens, human blood group antigens and amyloid-beta) were developed from healthy immune individuals. Obviously, human monoclonal antibodies that neutralize viruses can be used for passive immunization of infected patients. In addition, they can serve to define the exact relevant immunogenic molecular moieties, molecules which resemble those which provide protection. Exact definition of such molecules, as shown for the Dengue virus, provides essential information for the preparation of protective anti-virus vaccines. Numerous studies in animal models and in humans showed that the cellular immune response was responsible for the rejection of cancer cells. Still, many attempts have been made to develop anti-cancer therapies in the form of monoclonal antibodies to eliminate tumor cells. Antibodies that target receptors expressed on the surface of target cells can be classified on the basis of their primary mechanism: antagonist antibodies, which block the interaction between receptors and ligands and thus inhibit cell activation, and agonist antibodies which induce receptor-mediated signaling. Recently, a dramatic change took place in the field of immunotherapy, particularly in the field of tumor immunotherapy, related to the type of target chosen for therapeutic monoclonal antibodies. This strategy is based on the cytotoxic potential of lymphoid cells, combined with the use of monoclonal antibodies. Accordingly, antibodies that target lymphocyte surface-specific receptors able to potentiate and unmask the arrested cell’s cytotoxic capacity, defined as agonist antibodies, are being developed. Indeed, today pharmaceutical companies are placing much effort on the creation of such antibodies against co-inhibitory cell surface receptors to enhance T and NK cell activities. There is a continuous increase in the number of identified receptors expressed on lymphoid cells which mediate the interaction of lymphoid cells with their target cells. At present, several cell-surface molecules