A human immunoglobulin G1 (IgG1) monoclonal antibody directed against the natural-killer group 2, member D receptor protein (NKG2D or KLRK1) ligands MHC class I polypeptide-related sequence A (MICA) and B (MICB), with potential immunostimulating and antineoplastic activities. Upon administration, anti-MICA/MICB monoclonal antibody CLN-619 targets and binds to the alpha3 domain of MICA and MICB, and prevents the cleavage of MICA and MICB from the cell surface of tumor cells by proteases in the tumor microenvironment (TME). This enhances the binding of NKG2D-expressing immune cells, including natural killer (NK) cells and subset of T-cells, to MICA- and MICB-expressing tumor cells, which leads to the activation of NK cells and the lysis of tumor cells. CLN-619 also enhances antitumor response through antibody-dependent cell-mediated cytotoxicity (ADCC). MICA and MICB are stress-induced NKG2D ligands overexpressed on infected cells and many cancer cell types, but are not expressed on most normal, healthy cells. The shedding of MICA and MICB from tumor cell surface allows the tumor cells to evade NKG2D-expressing immune cells.