Antibody-based therapies in multiple myeloma

Abstract

The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies have largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA) approval of therapeutic Abs for cancer and other diseases.

Figure 1

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.