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Selective killing of candidate AML stem cells by antibody targeting of IL1RAP

Maria Askmyr, Helena Ågerstam, Nils Hansen, Sandra Gordon, Alexandros Arvanitakis, Marianne Rissler, Gunnar Juliusson, Johan Richter, Marcus Järås and Thoas Fioretos

Key Points

  • IL1RAP is overexpressed on candidate AML stem cells and is a promising target for antibody-based therapy.

Abstract

IL1RAP, a co-receptor for interleukin (IL)-1 and IL-33 receptors, was previously found to be highly upregulated on candidate chronic myeloid leukemia stem cells, allowing for leukemia-selective killing using IL1RAP-targeting antibodies. We analyzed IL1RAP expression in a consecutive series of 29 patients with acute myeloid leukemia (AML) and, based on the level of expression in mononuclear cells (MNCs), we divided the samples into 3 groups: IL1RAP low (n = 6), IL1RAP intermediate (n = 11), and IL1RAP high (n = 12). Within the CD34+CD38− population, the intermediate and high groups expressed higher levels of IL1RAP than did corresponding normal cells. With the aim to target AML stem cells, an anti-IL1RAP monoclonal antibody was generated followed by isotype switching for improved antibody-dependent, cell-mediated cytotoxicity activity. Using this antibody, we achieved selective killing of AML MNC, CD34+CD38+, and CD34+CD38− cells. Our findings demonstrate that IL1RAP is a promising new therapeutic target in AML.

  • Submitted September 26, 2012.
  • Accepted March 4, 2013.
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