文章：

CD123靶点验证以及抗CD123抗体CSL362与缓解期AML患者NK细胞联合的ADCC活性的临床前评估

CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission

原文发布日期：2017-06-02

DOI: 10.1038/bcj.2017.52

类型: Original Article

开放获取: 是

英文摘要：

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 CD34+CD38−CD123+ 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.

摘要翻译： 

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）上过度表达的白细胞介素-3受体α（CD123）为抗体治疗提供了靶点。本文展示了单克隆抗体CSL362的潜在临床活性数据，该抗体能以高亲和力结合CD123。我们首先验证了100%（52/52）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AML母细胞（包括CD34+CD38−CD123+ LSCs）的抗体依赖性细胞毒性（ADCC）。重要的是，与健康供体（HD）NKs相比，缓解期AML患者来源的NKs对白血病细胞具有相当的ADCC活性；值得注意的是，缓解期间AML患者的未成熟NKs数量是HDs的五倍。显著的是，我们报告了一例白血病细胞对自体ADCC抵抗的病例；然而，在同种异体造血干细胞移植后，供体来源的NKs与CSL362联合能有效裂解这些母细胞。这些研究强调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。

原文链接：

CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission