Targeted cancer cell ablation in mice by an α-particle-emitting astatine-211-labeled antibody against major histocompatibility complex class I chain-related protein A and B

Abstract

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 α-particle emitting astatine-211 (²¹¹At)-labeled antibody targeting MICA/B (²¹¹At-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 α-particle emitting radionuclide ²¹¹At. ²¹¹At-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. Biodistribution analysis using xenograft mouse models of HCT116 p53^-/- positive for MICA/B expression, showed increased ²¹¹At in the xenografts for up to 22 h after injection as time proceeded. A single dose of ²¹¹At-anti MICA/B Ab (1 MBq) showed significant reduction in the tumor growth rate of HCT116 p53^-/- xenografts compared to ²¹¹At-labeled mouse IgG (1 MBq) at 21 days after injection. No body weight loss and erythrocytopenia was evident in mice that received ²¹¹At-anti MICA/B. Leukocytopenia and thrombocytopenia were observed within a week after ²¹¹At-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 α-particle therapy using ²¹¹At-anti-MICA/B Ab emitting highly cytotoxic α-particles is a potential new therapeutic option for several types of cancer.

Keywords: Alpha-particle therapy; Astatine-211; Cancer; Major histocompatibility complex class I chain-related protein A and B; Radioimmunotherapy; Targeted radionuclide therapy.