Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia.
Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia.
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DOI：
10.1158/1078-0432.ccr-16-1904
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发表时间：
2017-07-01
期刊：
影响因子：
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通讯作者：
Konopleva M
中科院分区：
文献类型：
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作者：
Han L;Jorgensen JL;Brooks C;Shi C;Zhang Q;Nogueras González GM;Cavazos A;Pan R;Mu H;Wang SA;Zhou J;Ai-Atrash G;Ciurea SO;Rettig M;DiPersio JF;Cortes J;Huang X;Kantarjian HM;Andreeff M;Ravandi F;Konopleva M
诱导治疗后含白血病干细胞（LSC）细胞的持续存在可能导致急性髓性白血病（AML）的微小残留病（MRD）和复发。我们研究了含CD34+CD123+ lsc细胞的临床相关性，以及一种新型抗体偶联物SL-101靶向CD123+ lsc的抗白血病效力。在一项对86名新诊断的AML患者的回顾性研究中，我们证明了更高比例的CD34+CD123+ lsc细胞缓解与持续MRD相关，并预测低风险细胞遗传学患者的无复发生存期更短。利用流式细胞术，我们探索了用SL-101靶向治疗CD34+CD38−CD123+细胞的潜在益处，SL-101是一种新型抗体偶联物，包括与假单胞菌外毒素a融合的抗CD123单链Fv。SL-101的抗白血病效力由AML细胞系中CD123抗原的表达水平确定。集落形成实验证实，SL-101强烈且有选择性地抑制白血病祖细胞的功能，同时保留正常祖细胞的功能。内化、蛋白合成抑制和流式细胞术分析揭示了SL-101细胞毒活性的机制包括快速有效的抗体内化、持续抑制蛋白合成、诱导细胞凋亡、阻断il -3诱导的p-STAT5和p-AKT信号通路。在NSG小鼠的患者源异种移植模型中，SL-101预处理的LSCs体外再生能力明显受损。我们的数据定义了SL-101靶向AML的机制，并为进一步研究SL-101和其他cd123靶向策略在AML中的临床应用提供了依据。
The persistence of leukemia stem cells (LSC)-containing cells after induction therapy may contribute to minimal residual disease (MRD) and relapse in acute myeloid leukemia (AML). We investigated the clinical relevance of CD34+CD123+ LSC-containing cells and anti-leukemia potency of a novel antibody-conjugate SL-101 in targeting CD123+ LSCs. In a retrospective study on 86 newly diagnosed AML patients, we demonstrated that a higher proportion of CD34+CD123+ LSC-containing cells in remission was associated with persistent MRD, and predicted shorter relapse-free survival in patients with poor-risk cytogenetics. Using flow cytometry, we explored the potential benefit of therapeutic targeting of CD34+CD38−CD123+ cells by SL-101, a novel antibody-conjugate comprising an anti-CD123 single-chain Fv fused to Pseudomonas exotoxin A. The anti-leukemia potency of SL-101 was determined by the expression levels of CD123 antigen in a panel of AML cell lines. Colony-forming assay established that SL-101 strongly and selectively suppressed the function of leukemic progenitors while sparing normal counterparts. The internalization, protein synthesis inhibition and flow cytometry assays revealed the mechanisms underlying the cytotoxic activities of SL-101 involved rapid and efficient internalization of antibody, sustained inhibition of protein synthesis, induction of apoptosis, and blockade of IL-3–induced p-STAT5 and p-AKT signaling pathways. In a patient-derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101 in vitro was significantly impaired. Our data define the mechanisms by which SL-101 targets AML and warrant further investigation of the clinical application of SL-101 and other CD123-targeting strategies in AML.