Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia
Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia
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DOI：
10.1073/pnas.1422749112
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发表时间：
2015-08-25
影响因子：
11.1
通讯作者：
Fioretos, Thoas
中科院分区：
文献类型：
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作者：
Agerstam, Helena;Karlsson, Christine;Fioretos, Thoas
急性髓性白血病（AML）的生存率较低，迫切需要新的、更有效的治疗方法，理想的治疗目标是维持疾病所必需的AML干细胞。白细胞介素1受体辅助蛋白（IL1RAP; IL1R3）在大多数AML患者的候选白血病干细胞上表达，但在正常造血干细胞上不表达。我们在这里表明，靶向IL1RAP的单克隆抗体在人类AML的异种移植模型中具有很强的抗白血病作用。我们证明了效应细胞介导的杀伤对于观察到的治疗效果是必不可少的，自然杀伤细胞构成了关键的人类效应细胞类型。由于IL-1信号传导对AML细胞的生长很重要，我们产生了一种能够阻断IL-1信号传导的靶向il1rapp抗体，并表明该抗体抑制了原代人AML细胞的增殖。因此，IL1RAP可以有效地靶向抗IL1RAP抗体，既能实现抗体依赖的细胞毒性，又能阻断IL-1信号传导。总的来说，这些结果为支持IL1RAP作为基于抗体治疗AML的靶点提供了重要证据。
Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.