Enhanced SLAMF7 Homotypic Interactions by Elotuzumab Improves NK Cell Killing of Multiple Myeloma

Abstract

Elotuzumab (Elo) is an IgG 1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, and CD319), which is highly expressed on multiple myeloma (MM) cells, natural killer (NK) cells, and subsets of other leukocytes. By engaging with FcgRIIIA (CD16), Elo promotes potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) toward SLAMF7 þ MM tumor cells. Relapsed/refractory MM patients treated with the combination of Elo, lenalidomide, and dexamethasone have improved progression-free survival. We previously showed that Elo enhances NK cell activity via a costimulation mechanism, independent of CD16 binding. Here, we further studied the effect of Elo on cytotoxicity of CD16-negative NK-92 cells. Elo, but not other SLAMF7 antibodies, uniquely enhanced cytotoxicity mediated by CD16-negative NK-92 cells toward SLAMF7 þ target cells. Furthermore, this CD16-independent enhancement of cytotoxicity required expression of SLAMF7 containing the full cytoplasmic domain in the NK cells, implicating costimulatory signaling. The CD16-independent costimulation by Elo was associated with increased expression of NKG2D, ICAM-1, and activated LFA-1 on NK cells, and enhanced cytotoxicity was partially reduced by NKG2D blocking antibodies. In addition, an Fc mutant form of Elo that cannot bind CD16 promoted cytotoxicity of SLAMF7 þ target cells by NK cells from most healthy donors, especially if previously cultured in IL2. We conclude that in addition to promoting NK cell-mediated ADCC (CD16-dependent) responses, Elo promoted SLAMF7-SLAMF7 interactions in a CD16-independent manner to enhance NK cytotoxicity toward MM cells.

Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization

“…Elotuzumab is an IgG 1 mAb that targets signaling lymphocytic activation molecule F7 (SLAMF7), also known as CD319, which is highly expressed on MM, NK and other immune cells (132). Elotuzumab was found to activate NK cells and induce apoptosis of SLAMF7 + cells via both CD16dependent and CD16-independent mechanisms (132,133).…”

Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma

“…SLAMF7 engages with itself as a ligand and is highly expressed on both NK cells and MM cells [ 10 ]. We have previously shown that coordinate SLAMF7 expression on both NK cells and myeloma target cells significantly enhances natural cytotoxicity responses, since SLAMF7 is a co-stimulatory receptor in NK cells [ 51 ]. Here, we found substantially higher SLAMF7 levels on NK cells in BM, as compared to peripheral blood, in nearly all ND, RR, and pSCT patients, and the SLAMF7 expression levels on CD56 bright NK cells in the BM of most MM patients was higher than in the BM of three healthy controls ( Figure 2 F).…”

“…Since these patients received standard of care therapy, it is not known if SLAMF7 expression on NK cells would retain the same prognostic value for patients treated with the SLAMF7-targeting antibody elotuzumab. Therefore, it may be worthwhile to explore if ND patients with high SLAMF7 expression on NK cells are more responsive to treatment with elotuzumab, which stimulates the antibody-dependent killing of myeloma target cells by NK cells and monocytes and promotes the SLAMF7–SLAMF7-dependent co-stimulation of NK cells [ 10 , 51 , 52 ].…”

Elevated eosinophil level predicted long time to next treatment in relapsed or refractory myeloma patients treated with lenalidomide

“…Pazina et al demonstrated that elotuzumab increased NKG2D level in SKOV cells, which was a human ovarian cancer cell line, and expressed SLAM family member 7. Elotuzumab enhanced NK cytotoxicity to myeloma cells in an independent CD16 expression manner when the expression level of NKG2D was high on NK cells . On the contrary, daratumumab decreases the number of NK cells in patients with RRMM .…”