Mechanisms of actions associated with therapeutic monoclonal antibodies. (a) Therapeutic antibodies could directly induce apoptosis or growth arrest upon binding to cell surface antigen on tumor cells. Rituximab and Mapatumumab (anti-TRAIL-R1) could induce growth inhibition or apoptosis signaling to directly block tumor cell growth and survival. Such mechanism of action was employed by mAbs conjugated with toxins, that is, maytansinoids (DM1, DM4) for BB-10901 (anti-CD56) and BT062 (anti-CD138), thus directly target and eliminate tumor cells. Most of the approved therapeutic mAbs belong to IgG1 subclass, which has a long half-life and trigger potent immune-effector functions. (b) Following the binding of mAbs to a specific target on a tumor cells, antibody-dependent cellular cytotoxicity (ADCC) is triggered by interactions between the Fc region of an antibody bound to a tumor cell and Fc receptors, particularly FcRI and FcRIII, on immune effector cells such as neutrophils, macrophages, and natural killer cells. MAb-coated tumor cells are phagocytosed by macrophages or undergo cytolysis by NK cells. (c) In the case of complement-dependent cytotoxicity (CDC), recruitment of C1q by IgG bound to the tumor cell surface is an obligatory first step. This triggers a proteolytic cascade that leads to generation of the effector molecule, C3b, and then to formation of a membrane attack complex that kills the target cell by disrupting its cell membrane.
