Abstract
Multiple myeloma (MM) is a bone marrow plasma cell neoplasm and is the second most-common hematologic malignancy. Despite advances in therapy, MM remains largely incurable. Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7, which is highly expressed on myeloma cells, and the antibody is approved for the treatment of relapsed and/or refractory (RR) MM in combination with lenalidomide and dexamethasone. Elotuzumab can stimulate robust antibody-dependent cellular cytotoxicity (ADCC) through engaging with FcγRIIIA (CD16) on NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Interestingly, SLAMF7 is also expressed on cytolytic NK cells, which also express the requisite adaptor protein, EAT-2, to mediate activation signaling. Accumulating evidence indicates that antibody crosslinking of SLAMF7 on human and mouse NK cells can stimulate EAT-2-dependent activation of PLCγ, ERK, and intracellular calcium mobilization. The binding of SLAMF7 by elotuzumab can directly induce signal transduction in human NK cells, including co-stimulation of the calcium signaling triggered through other surface receptors, such as NKp46 and NKG2D. In RRMM patients, elotuzumab monotherapy did not produce objective responses, but did enhance the activity of approved standard of care therapies, including lenalidomide or bortezomib, which are known to enhance anti-tumor responses by NK cells. Taken together, these preclinical results and accumulating experience in the clinic provide compelling evidence that the mechanism of action of elotuzumab in MM patients involves the activation of NK cells through both CD16-mediated ADCC and direct co-stimulation via engagement with SLAMF7, as well as promoting ADCP by macrophages. We review the current understanding of how elotuzumab utilizes multiple mechanisms to facilitate immune-mediated attack of myeloma cells, as well as outline goals for future research.
Highlights
Multiple myeloma (MM) is a deadly hematopoietic cancer characterized by the expansion of monotypic plasma cells in the bone marrow, accumulation of monoclonal immunoglobulin in the serum, and end-organ damage such as anemia, lytic bone lesions, and renal dysfunction [1]
Patients treated with daratumumab exhibit significant loss of NK cells in peripheral blood, due to ADCCmediated fratricide [42], daratumumab-treated patients alternatively benefit from depletion of immunosuppressive regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells to boost anti-myeloma immune responses [9]
There is no evidence that EAT-2 and SH2 domain-containing 5′-inositol phosphatase (SHIP)-1 compete for binding to Signaling Lymphocyte Activation Marker Family member 7 (SLAMF7). These results indicate that the inhibitory function of mouse SLAMF7 in the absence of EAT-2 is mediated by SHIP1 and requires Y261 on SLAMF7
Summary
Multiple myeloma (MM) is a deadly hematopoietic cancer characterized by the expansion of monotypic plasma cells in the bone marrow, accumulation of monoclonal immunoglobulin in the serum, and end-organ damage such as anemia, lytic bone lesions, and renal dysfunction [1]. A variety of recently-developed therapies have contributed to the extended survival of MM patients, including proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory imide drugs (IMiDs; namely thalidomide, lenalidomide and pomalidomide), and monoclonal antibodies (daratumumab and elotuzumab). Clinical results with these therapies have been previously summarized in a variety of quality reviews [3,4,5,6] and will not be further discussed here. SLAMF7 AS A PROMINENT BIOMARKER AND POTENTIAL THERAPEUTIC TARGET ON MYELOMA CELLS
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