2572 Background: Elotuzumab (Elo), an anti-CS1 monoclonal antibody (mAb) in development for MM, exerts anti-MM effects via NK cell-mediated ADCC. CS1 is also expressed on NK cells. We provide data to suggest that Elo may enhance NK cell cytotoxicity via mechanisms beyond ADCC.
METHODS
Primary cells were procured under IRB-approved protocols. Interferon-gamma (IFN-g) and granzyme B (GrB) production were measured by ELISPOT, NK92 cytotoxicity was determined by chromium release. Flow cytometry characterized NK cell subsets and effects of Elo on NK cell activation. Elo, Elo-G2M3 (non-CD16 binding), and isotype mAbs were from Abbott Biotherapeutics Results: Pts with advanced MM have proportionally fewer cytotoxic CD56dim NK cells in peripheral blood (22%+/-2) vs. pts with early MM (69%+/-10, n=8, p=0.005). While Elo increased CD69 expression on healthy donor NK cells (22.8%+/-7) vs. isotype (4.8% +/- 3, n=5, p = 0.01), no increase in NK cell cytotoxicity against autologous NK cells was observed. Across a range of effector:target (E:T) ratios, Elo (and G2M3 at higher E:Ts) enhanced NK cell IFN-g production (e.g., E:T 25:1, control = 86+/-6, G2M3= 109+/-4, Elo = 275+/-12, p = 0.0001, all pair-wise comparisons significant) and GrB production (e.g., E:T 50:1, control = 113+/-11, G2M3 = 179+/-6, Elo = 331+/-25, p=0.0001, all pair-wise comparisons significant). Elo increased CD107a expression (9.3%+/-2.2) on NK cells in MM bone marrow aspirates vs. isotype control (5.8%+/-0.5, n=3, p = 0.04). Elo also enhanced the killing of CS1+ targets by CD16- NK92 cells.
CONCLUSIONS
Elo activates NK cells and promotes cytotoxicity via IFN-g and GrB degranulation specifically directed against MM targets, observations confirmed by increased CD107a expression on NK cells in bone marrow of pts with MM. Elo facilitates NK cell function against MM by mechanisms in addition to ADCC based on 1) G2M3 enhancement of IFN-g and GrB production against MM cells, 2) Elo induced CD69 expression independent of presence of MM targets and 3) Elo-enhanced killing of CS1 expressing target cells by a CD16 negative NK cell line. Elo does not induce cytotoxicity against NK cells.