Xie L H, Biondo M, Busfield S J, Arruda A, Yang X, Vairo G, Minden M D
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.
Blood Cancer J. 2017 Jun 2;7(6):e567. doi: 10.1038/bcj.2017.52.
Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML. In vitro studies demonstrated that CSL362 potently induced antibody-dependent cell cytotoxicity (ADCC) of AML blasts including CD34CD38CD123 LSCs by natural killer cells (NKs). Importantly, compared with healthy donor (HD) NKs, NKs drawn from AML patients in remission had a comparable ADCC activity against leukemic cells; of note, during remission, immature NKs were five times higher in AML patients than that in HDs. Significantly, we report a case where leukemic cells were resistant to autologous ADCC; however, the blasts were effectively lysed by CSL362 together with donor-derived NKs after allogeneic hematopoietic stem cell transplantation. These studies highlight CSL362 as a promising therapeutic option following chemotherapy and transplant so as to improve the outcome of AML patients.
尽管急性髓系白血病（AML）具有异质性，但在分化程度较高的白血病母细胞和白血病干细胞（LSCs）上白细胞介素-3受体α（CD123）的过表达为抗体治疗提供了一个治疗靶点。在此，我们展示了关于单克隆抗体CSL362潜在临床活性的数据，该抗体与CD123具有高亲和力。我们首先验证了100%（52/52）的患者样本中CD123的表达，以及NPM1和FLT3-ITD突变与AML中CD123高频率的相关性。体外研究表明，CSL362能有效诱导自然杀伤细胞（NKs）对包括CD34CD38CD123 LSCs在内的AML母细胞的抗体依赖性细胞毒性（ADCC）。重要的是，与健康供体（HD）NKs相比，从缓解期AML患者中提取的NKs对白血病细胞具有相当的ADCC活性；值得注意的是，在缓解期，AML患者中未成熟NKs比HDs中的高五倍。值得注意的是，我们报告了一例白血病细胞对自体ADCC耐药的病例；然而，在异基因造血干细胞移植后，CSL362与供体来源的NKs一起有效地裂解了母细胞。这些研究突出了CSL362作为化疗和移植后一种有前景的治疗选择，以改善AML患者的预后。
