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首页> 外文期刊>Cell stem cell >Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells.
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Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells.

机译：单克隆抗体介导的针对CD123，IL-3受体α链的靶向，消除了人类急性髓样白血病干细胞。

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摘要

Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor alpha chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 inhibited IL-3-mediated intracellular signaling of isolated AML CD34(+)CD38(-) cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.
机译：白血病干细胞（LSC）启动并维持急性髓细胞白血病（AML）克隆等级，并具有使其对常规化学疗法具有抗性的生物学特性。 AML患者的不良生存率引发了人们对以LSC为目标的疗法可能获得持久缓解的期望。我们报告说，抗白介素3（IL-3）受体α链（CD123）中和抗体（7G3）靶向AML-LSC，损害归巢到骨髓（BM）并激活非肥胖糖尿病/严重合并的先天免疫力。免疫缺陷（NOD / SCID）小鼠。 7G3处理可大大减少AML-LSC植入并改善小鼠存活率。患有预先确​​诊疾病的小鼠在治疗后显示出BM和外周的AML负担减轻，并且二次移植受损，这证明AML-LSC是直接靶向的。 7G3抑制离体的AML CD34（+）CD38（-）细胞的IL-3介导的细胞内信号传导，并降低其存活率。这些结果为靶向治疗AML-LSC的单克隆抗体（mAb）以及将体内临床前研究结果转化为临床应用提供了明确的验证。

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