Effect of Anti-ADAM17 Monoclonal Antibody MEDI3622 on Natural-Killer-Cells-Mediated Killing of Multiple Myeloma
Multiple Myeloma (MM) is a relatively uncommon, though increasing, hematological cancer that affects the spectrum of plasma cell dyscrasias. Natural Killer (NK) cells have a cytotoxic effect on MM. However, MM cells evolved ways to escape NK cell recognition and mitigate their anti-tumor activity. A Tri-specific Killer Engager (TriKE) has been synthesized to maximize the NK-cell-mediated antibody dependent cellular cytotoxicity (ADCC) to MM. While preliminary 2D cultures have proven the efficacy of TriKE at boosting ADCC, in this study we aimed to construct 3D spheroids that can better simulate the tumor-microenvironment (TME). TriKE enhances NK cell activation in a CD16-dependent manner. ADAM17 proteolytically cleaves CD16 receptors from NK cells surfaces. MEDI3622 inhibits the shedding function of ADAM17, thereby increasing ADCC. In this study, we used MEDI3622 to restore the NK function of exhausted patient NK cells. MEDI3622 enhanced NK cell proliferation as well as ADCC in response to TriKE against U266 but not MM1S MM cell lines. Our last objective was to assess the cytotoxic effect of the co-administration of MEDI3622 with different classes of engineered NK cells: anti B7-H3 or anti MICA/B chimeric antigen receptor NK cells. In general, the administration of MEDI3622 was associated with greater cytotoxicity than the control, yet the difference was barely noticeable and insignificant.