CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia.
CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia.
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DOI：
10.3324/haematol.2018.205252
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发表时间：
2019-04
期刊：
影响因子：
10.1
通讯作者：
Khoury JD
中科院分区：
文献类型：
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作者：
Angelova E;Audette C;Kovtun Y;Daver N;Wang SA;Pierce S;Konoplev SN;Khogeer H;Jorgensen JL;Konopleva M;Zweidler-McKay PA;Medeiros LJ;Kantarjian HM;Jabbour EJ;Khoury JD
cd123靶向治疗急性淋巴细胞白血病/淋巴瘤的潜力在很大程度上仍未被探索。我们检测了大量急性淋巴细胞白血病/淋巴瘤患者的CD123表达水平，并评估了IMGN632的体外影响，IMGN632是一种CD123结合抗体的结合物，具有一种新的dna烷基化负载。采用多色/多参数流式细胞术检测CD123在白血病细胞中的表达。研究了IMGN632对B急性淋巴细胞白血病/淋巴瘤细胞株和原代B急性淋巴细胞白血病/淋巴瘤母细胞的体外作用。研究队列（n=213）包括183例B型急性淋巴细胞白血病/淋巴瘤患者和30例T型急性淋巴细胞白血病/淋巴瘤患者。CD123在B型急性淋巴母细胞白血病/淋巴瘤中的表达高于T型急性淋巴母细胞白血病/淋巴瘤（164/183,89.6%比13/30,43.3%，P<0.0001），在B型急性淋巴母细胞白血病/淋巴瘤中，CD123在费城染色体阳性患者中的表达高于费城染色体阴性患者（96.6%比86.3%，P=0.033）。在T急性淋巴细胞白血病/淋巴瘤中，12/13 (92.3%)cd123阳性母细胞患者具有早期T前体（ETP）或早期非ETP免疫表型。IMGN632对B型急性淋巴母细胞白血病/淋巴瘤细胞系具有高度的细胞毒性，在0.6 ~ 20pm之间有一半的最大抑制浓度（IC50）。在8例患者样本中的5例中，低皮摩尔浓度的IMGN632消除了90%以上的B急性淋巴细胞白血病/淋巴瘤原细胞群，保留了正常淋巴细胞。总之，CD123在急性淋巴细胞白血病/淋巴瘤亚型中普遍表达，CD123靶向抗体-药物偶联物IMGN632在B急性淋巴细胞白血病/淋巴瘤临床前模型中显示出有希望的选择性活性。
The potential of CD123-targeted therapies in acute lymphoblastic leukemia/lymphoma remains largely unexplored. We examined CD123 expression levels in a large cohort of patients with acute lymphoblastic leukemia/lymphoma and assessed the in vitro impact of IMGN632, a conjugate of CD123-binding antibody with a novel DNA-alkylating payload. CD123 expression on leukemic blasts was surveyed using multicolor/multiparameter flow cytometry. The in vitro effect of IMGN632 was evaluated on B acute lymphoblastic leukemia/lymphoma cell lines and primary B acute lymphoblastic leukemia/lymphoma blasts. The study cohort (n=213) included 183 patients with B acute lymphoblastic leukemia/lymphoma and 30 with T acute lymphoblastic leukemia/lymphoma. CD123 expression was more prevalent in B acute lymphoblastic leukemia/lymphoma than in T acute lymphoblastic leukemia/lymphoma (164/183, 89.6% versus 13/30, 43.3%; P<0.0001), and within B acute lymphoblastic leukemia/lymphoma CD123 expression was more prevalent in Philadelphia chromosome-positive patients than in Philadelphia chromosome-negative patients (96.6% versus 86.3%; P=0.033). In T acute lymphoblastic leukemia/lymphoma, 12/13 (92.3%) patients with CD123-positive blasts had either early T precursor (ETP) or early non-ETP immunophenotype. IMGN632 was highly cytotoxic to B acute lymphoblastic leukemia/lymphoma cell lines, with half maximal inhibitory concentrations (IC50) between 0.6 and 20 pM. In five of eight patients’ samples, low picomolar concentrations of IMGN632 eliminated more than 90% of the B acute lymphoblastic leukemia/lymphoma blast population, sparing normal lymphocytes. In conclusion, CD123 expression is prevalent across acute lymphoblastic leukemia/lymphoma subtypes, and the CD123-targeted antibody-drug conjugate IMGN632 demonstrates promising selective activity in preclinical models of B acute lymphoblastic leukemia/lymphoma.