Anti-β₂M monoclonal antibodies kill myeloma cells via cell- and complement-mediated cytotoxicity

Our previous studies showed that anti-β₂M monoclonal antibodies (mAbs) at high doses have direct apoptotic effects on myeloma cells, suggesting that anti-β₂M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the ability of the mAbs at much lower concentrations to indirectly kill myeloma cells by utilizing immune effector cells or molecules. Our results showed that anti-β₂M mAbs effectively lysed MM cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which were correlated with and dependent on the surface expression of β₂M on MM cells. The presence of MM bone marrow stromal cells or addition of IL-6 did not attenuate anti-β₂M mAb-induced ADCC and CDC activities against MM cells. Furthermore, anti-β₂M mAbs only showed limited cytotoxicity toward normal B cells and nontumorous mesenchymal stem cells, indicating that the ADCC and CDC activities of the anti-β₂M mAbs were more prone to the tumor cells. Lenalidomide potentiated in vitro ADCC activity against MM cells and in vivo tumor inhibition capacity induced by the anti-β₂M mAbs by enhancing the activity of NK cells. These results support clinical development of anti-β₂M mAbs, both as a monotherapy and in combination with lenalidomide, to improve MM patient outcome. What's new? Multiple myeloma is currently not curable, and often recurs. New tactics to combat this disease are sorely needed. This study asked whether monoclonal antibodies could do the trick. The authors targeted a cell surface protein, β₂-Microglobulin, which is present in higher concentration in myeloma cells. They showed that mAbs against β₂-Microglobulin could direct the cell-destroying power of NK cells toward the cancer cells without harming normal cells. Addition of the drug lenalidomide, which is used to treat multiple myeloma, enhanced this attack, suggesting these antibodies could provide a useful treatment for MM patients.