Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.
Blood. 2013 May 2;121(18):3709-13. doi: 10.1182/blood-2012-09-458935. Epub 2013 Mar 11.
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.
白细胞介素 1 受体相关蛋白 (IL1RAP) 是白细胞介素 (IL)-1 和 IL-33 受体的共受体，先前发现在候选慢性髓系白血病干细胞上高度上调，允许使用针对 IL1RAP 的抗体进行白血病选择性杀伤。我们分析了 29 例急性髓系白血病 (AML) 患者的连续系列中的 IL1RAP 表达，并根据单核细胞 (MNC) 中的表达水平将样本分为 3 组：IL1RAP 低 (n = 6)、IL1RAP 中 (n = 11) 和 IL1RAP 高 (n = 12)。在 CD34+CD38- 群体中，中间组和高组表达的 IL1RAP 水平高于相应的正常细胞。为了靶向 AML 干细胞，我们生成了一种抗 IL1RAP 单克隆抗体，然后进行同种型转换以提高抗体依赖性细胞介导的细胞毒性活性。使用该抗体，我们实现了对 AML MNC、CD34+CD38+和 CD34+CD38- 细胞的选择性杀伤。我们的研究结果表明，IL1RAP 是 AML 中一种有前途的新治疗靶标。
