Major histocompatibility complex class I chain-related protein A and B (MICA/B) are ligands of the immune receptor, natural-killer group 2 member D. MICA/B expression is often found in several types of cancer but is restricted in normal tissues. Here, we show that an e-particle emitting astatine-211(At-211)-labeled antibody targeting MICA/B (At-211-anti MICA/B Ab) efficiently ablates cancer cells in vitro and in vivo. We generated 211At-anti MICA/B Ab, an anti-MICA/B antibody conjugated with a highly cytotoxic alpha-particle emitting radionuclide At-211. At-211-anti MICA/B Ab binds to human osteosarcoma SaOS2 and U2OS cells that exhibit high levels of MICA/B expression and efficiently kills those cells in vitro. Bio-distribution analysis using xenograft mouse models of HCT116 p53(-/-) positive for MICA/B expression, showed increased At-211 in the xenografts for up to 22 h after injection as time proceeded. A single dose of At-211-anti MICA/B Ab (1 MBq) showed significant reduction in the tumor growth rate of HCT116 p53(-/-) xenografts compared to At-211-labeled mouse IgG (1 MBq) at 21 days after injection. No body weight loss and erythrocytopenia was evident in mice that received At-211-anti MICA/B. Leukocytopenia and thrombocytopenia were observed within a week after At-211-anti MICA/B injection, but counts of red blood cells and platelets were recovered to control levels at about 3-4 weeks after injection. Taken together, these data strongly demonstrate that targeted alpha-particle therapy using At-211-anti-MICA/B Ab emitting highly cytotoxic alpha-particles is a potential new therapeutic option for several types of cancer. (C) 2018 Elsevier Inc. All rights reserved.