Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

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.

Revealing the Impact of Structural Variants in Multiple Myeloma

“…Previous studies of SVs in multiple myeloma have focused on translocations without consideration of complex events (11,15,55,56), and our previous WGS study of 30 patients lacked both the expression correlate and the power to perform comprehensive driver discovery (21). Here, applying a robust statistical approach 40 (43,45) and MCL1 (48); the latter of which has also been implicated in resistance to the BCL2-inhibitor venetoclax (46). With all of these targets either currently or imminently in clinical use, it will be of great clinical importance to determine the impact of these genomic alterations as predictive biomarkers for treatment response.…”

Revealing the impact of recurrent and rare structural variants in multiple myeloma

“…Here, applying a robust statistical approach 37 , we identified 100 SV hotspots, 85 of which have not previously been reported. Integrated analysis of copy number changes, gene expression and the distribution of SV breakpoints revealed 31 new potential driver genes, including the emerging drug targets TNFRSF17 (BCMA) and SLAMF7 41,56 . Overall, our comprehensive catalogue of SV hotspots expands the current understanding of driver gene deregulation by recurrent CNAs and SVs and identified promising new driver candidates.…”

Targeting Multiple Myeloma through the Biology of Long-Lived Plasma Cells

“…Other potential targets for CAR-T cell therapy include CD138 [102], CD38 [103], and SLAMF7 [104], which are all cell surface proteins expressed on MM cells. Other strategies include monoclonal antibodies directed to cell surface receptors with current drugs approved for targeting SLAMF7 [105] and BCMA [106]. It is also possible that treatments, which target MM could be used in autoimmune disorders driven by plasma cell production of auto-antibodies.…”