The development of hybridomas and the treatment of a non-Hodgkin lymphoma patient with antibody AB89 are commonly heralded as the landmarks of the monoclonal antibody therapy field (1,2). After three decades, over 600 of these agents have entered clinical development (3); however, only a few are currently approved for the treatment of cancer patients. Novel technologies, including phage display, recombinant-antibody engineering, and transgenic-animal generation, allow for the production of highly potent, fully human antibodies or antibody constructs that may facilitate the development of more effective and less toxic monoclonal antibody therapies.

On a structural basis, monoclonal antibodies can be classified into “naked” antibodies that relay direct effects on target antigens and immunoconjugates. Naked antibodies can be employed for serum clearance of growth factors, and the activation or blockade of cell-surface receptors. These effects are mediated by the antibody Fab (fragment antibody binding) portion, which contains the hypervariable complementarity-determining regions of the light and heavy chains that constitute the antigen binding site (Figure 80.1), while the Fc portion mediates immunological effects. Fc (fragment crystallizable) binding and activation of FcγRs on effector cells transduce activating or inhibitory signals. Fc-dependent stimulatory signals are mainly transduced by FcγRI, FcγRIIa, and FcγRIIIa, whereas FcγRIIb is inhibitory. Natural killer cells express almost exclusively FcγRIIIa that is responsible for mediating ADCC by these cells, whereas macrophages express FcγRI, FcγRIIa, and FcγRIIIa, with FcγRIIa being the key receptor responsible for the induction of phagocytosis (4). Variations in antibody isotype backbone determine their ability to bind FcγRs and to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP). Naturally occurring human IgG2 antibodies weakly bind FcγRIIa and constitute ideal molecules when specific target inhibition or activation, without immunologically mediated effects, is the desired attribute (5). In contrast, murine IgG2a, and human IgG1 and IgG3 antibodies bind all activatory FcγRs and are effective inducers of ADCC and ADCP. IgG3 and IgM molecules are also strong inducers of complement fixation through the classical C1q pathway, driving complement-dependent cytotoxicity (CDC). The IgG3 backbone, however, is not commonly used in therapeutic antibody development due to the short half-life (>7 days) of these molecules. Also, the large size of IgM pentamers, the functional IgM unit, limits its ability to reach the interstitial compartment, and IgM monoclonals are rarely employed in therapeutic antibody development.