文章：

人源化抗CD123抗体通过ARF6/PLD-1促进NK细胞对霍奇金淋巴瘤靶点的抗体依赖性细胞介导的细胞毒性（ADCC）

Humanized anti-CD123 antibody facilitates NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of Hodgkin lymphoma targets via ARF6/PLD-1

原文发布日期：2019-01-15

DOI: 10.1038/s41408-018-0168-2

类型: Article

开放获取: 是

英文摘要：

CD123 (IL-3Rα) is frequently expressed by malignant Hodgkin lymphoma (HL) cells. Naked monoclonal antibodies (mAb) against HL lack clinical benefit, partially due to absence of natural killer (NK) cells in the tumor microenvironment. Here we show that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro. First, we confirmed high expression of CD123 in 2 of the 3 HL cell lines (KM-H2 and L-428), and its absence in NK cells. Cytotoxicity of haNK cells against CD123-positive HL cells was significantly higher in the presence of CSL362. This was also shown with IL-15-activated primary NK cells, although haNK cells showed a 10.87-fold lower estimated half-maximal stimulatory effective concentration (EC50). CSL362 facilitated a significant increase in the expression of CD107a, intracellular IFN-γ and TNF-α and enhanced expression of c-JUN, PLD-1, and ARF6 by NK cells. Inhibition of the ARF6–PLD-1 axis (NAV2729), but not of the MAPK pathway (U0126), completely abrogated CSL362-facilitated antibody-dependent cell-mediated cytotoxicity (ADCC) in haNK and activated primary NK cells. Our results support CD123 as an immunotherapeutic target for HL and the combination of NK cells and CSL362 as a treatment strategy for HL.

摘要翻译： 

CD123（IL-3Rα）在恶性霍奇金淋巴瘤（HL）细胞中频繁表达。针对HL的裸单克隆抗体（mAb）缺乏临床疗效，部分原因是肿瘤微环境中自然杀伤（NK）细胞的缺失。本研究显示，全人源化抗CD123单克隆抗体（CSL362）与高亲和力Fcγ受体NK-92细胞（haNK）联用，可在体外有效靶向并杀伤HL细胞。首先，我们证实3个HL细胞系中有2个（KM-H2和L-428）高表达CD123，而NK细胞不表达。在CSL362存在的情况下，haNK细胞对CD123阳性HL细胞的细胞毒性显著增强。IL-15激活的原代NK细胞也呈现类似效果，但haNK细胞的半数最大刺激有效浓度（EC50）估计值降低了10.87倍。CSL362能显著提升NK细胞CD107a表达量、细胞内IFN-γ和TNF-α水平，并增强c-JUN、PLD-1和ARF6的表达。抑制ARF6-PLD-1轴（使用NAV2729）可完全阻断haNK细胞和激活的原代NK细胞中CSL362介导的抗体依赖性细胞介导的细胞毒性作用（ADCC），而抑制MAPK通路（使用U0126）则无此效果。我们的研究结果支持CD123作为HL的免疫治疗靶点，以及NK细胞与CSL362联用作为HL的治疗策略。

原文链接：

Humanized anti-CD123 antibody facilitates NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of Hodgkin lymphoma targets via ARF6/PLD-1