Monoclonal antibodies in multiple myeloma therapy
Multiple myeloma (MM) results from the proliferation of a malignant plasma cell and frequently leads to complications such as lytic bone disease, hypercalcemia, renal failure, and impaired immunity. Over the past 2 decades, progression-free survival (PFS) and overall survival for MM have more than doubled, largely due to improvements in therapy with the addition of novel agents such as immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs). The understanding of MM pathobiology has undergone a similar period of growth, leading to the discovery of novel targets and pathways that impact proliferation and survival of the malignant clone. Despite these significant improvements, MM remains largely incurable, making new therapies with novel targets essential for continued improvements in clinical end points for patients with this disorder.
Targets for monoclonal antibody (mAb) therapy
The high expression of a number of surface antigens on malignant plasma cells makes these appealing targets for immune therapy with mAbs. The mechanisms of mAbs are diverse, including directly targeting a receptor and its downstream activity, recruiting effector cells such as natural killer (NK) cells and macrophages to promote antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), fixing complement for complement-dependent cytotoxicity (CDC), or inducing cell death by delivery of a drug, toxin, or radioisotope to the malignant cell Although the ideal target for mAb therapy would be one that is solely expressed on malignant plasma cells and not on normal cells (including plasma cells), most suitable targets are expressed to some degree on either normal plasma cells, other hematopoietic cells, and/or other cells/tissues. Plasma cell surface targets of mAbs that have already demonstrated significant clinical activity either alone or in combination with other approved myeloma drugs include signaling lymphocytic activation molecule F7 (SLAMF7) (elotuzumab [ELO]) and CD38 (daratumumab [DARA], isatuximab [ISA] [SAR659084], and MOR-202). Other mAbs directed against MM cellular antigens that have demonstrated at least stable disease include those directed against CD138 (BT062), CD54/ICAM-1 (BI-505), and CD74 (milatuzumab).
The development of therapeutic mAbs for the treatment of MM has also been directed against growth factors and their receptors (eg, interleukin-6, interleukin-6 receptor, insulin-like growth factor-1 or -2, vascular endothelial growth factor, and B-cell activating factor). Antibodies that augment the host immune response through immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and PD ligand 1 (PD-L1) are also in development. The role of mAbs continues to expand in MM as the number of targets and subsequent successful clinical applications continue to grow.
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Journal of Chromatography & Separation Techniques