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
- Radiation and Cancer Biology Team, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555 (Japan)
- Targetry and Target Chemistry Team, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555 (Japan)
Highlights: • MICA/B is expressed in several human cancer cells. • We generated an α-particle-emitting {sup 211}At-labelled antibody targeting MICA/B. • {sup 211}At-labelled antibody specifically killed human cancer cells expressing MICA/B. • {sup 211}At-labelled antibody targeting MICA/B showed anti-tumor activity in vivo. 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 ({sup 211}At)-labeled antibody targeting MICA/B ({sup 211}At-anti MICA/B Ab) efficiently ablates cancer cells in vitro and in vivo. We generated {sup 211}At-anti MICA/B Ab, an anti-MICA/B antibody conjugated with a highly cytotoxic α-particle emitting radionuclide {sup 211}At. {sup 211}At-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{sup −/−} positive for MICA/B expression, showed increased {sup 211}At in the xenografts for up to 22 h after injection as time proceeded. A single dose of {sup 211}At-anti MICA/B Ab (1 MBq) showed significant reduction in the tumor growth rate of HCT116 p53{sup −/−} xenografts compared to {sup 211}At-labeled mouse IgG (1 MBq) at 21 days after injection. No body weight loss and erythrocytopenia was evident in mice that received {sup 211}At-anti MICA/B. Leukocytopenia and thrombocytopenia were observed within a week after {sup 211}At-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 {sup 211}At-anti-MICA/B Ab emitting highly cytotoxic α-particles is a potential new therapeutic option for several types of cancer.
- OSTI ID:
- 23105667
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 506, Issue 4; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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