Division of Epidemiology and Clinical Research, Department of Pediatrics.
Blood. 2014 May 8;123(19):3016-26. doi: 10.1182/blood-2013-10-533398. Epub 2014 Mar 20.
Myelodysplastic syndromes (MDS) are stem cell disorders that can progress to acute myeloid leukemia. Although hematopoietic cell transplantation can be curative, additional therapies are needed for a disease that disproportionally afflicts the elderly. We tested the ability of a CD16xCD33 BiKE to induce natural killer (NK) cell function in 67 MDS patients. Compared with age-matched normal controls, CD7(+) lymphocytes, NK cells, and CD16 expression were markedly decreased in MDS patients. Despite this, reverse antibody-dependent cell-mediated cytotoxicity assays showed potent degranulation and cytokine production when resting MDS-NK cells were triggered with an agonistic CD16 monoclonal antibody. Blood and marrow MDS-NK cells treated with bispecific killer cell engager (BiKE) significantly enhanced degranulation and tumor necrosis factor-α and interferon-γ production against HL-60 and endogenous CD33(+) MDS targets. MDS patients had a significantly increased proportion of immunosuppressive CD33(+) myeloid-derived suppressor cells (MDSCs) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells. Treatment with the CD16xCD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis. Lastly, the BiKE induced optimal MDS-NK cell function irrespective of disease stage. Our data suggest that the CD16xCD33 BiKE functions against both CD33(+) MDS and MDSC targets and may be therapeutically beneficial for MDS patients.
骨髓增生异常综合征（MDS）是一种干细胞疾病，可进展为急性髓系白血病。尽管造血细胞移植可以治愈，但对于 disproportionately 影响老年人的疾病，还需要额外的治疗方法。我们测试了 CD16xCD33 BiKE 诱导 67 例 MDS 患者自然杀伤（NK）细胞功能的能力。与年龄匹配的正常对照相比，MDS 患者的 CD7(+) 淋巴细胞、NK 细胞和 CD16 表达明显降低。尽管如此，当用激动性 CD16 单克隆抗体触发静止的 MDS-NK 细胞时，逆转抗体依赖性细胞介导的细胞毒性测定显示出强大的脱颗粒和细胞因子产生。用双特异性杀伤细胞衔接子（BiKE）处理的血液和骨髓 MDS-NK 细胞显著增强了针对 HL-60 和内源性 CD33(+) MDS 靶标的脱颗粒以及肿瘤坏死因子-α和干扰素-γ的产生。MDS 患者具有明显增加的抑制性 CD33(+)髓系来源抑制细胞（MDSC）比例，与 MDS 淋巴细胞群和 NK 细胞上 CD16 的缺失呈负相关。用 CD16xCD33 BiKE 治疗成功地逆转了 MDSC 对 NK 细胞的免疫抑制作用，并诱导了 MDSC 靶细胞裂解。最后，BiKE 诱导了最佳的 MDS-NK 细胞功能，而与疾病阶段无关。我们的数据表明，CD16xCD33 BiKE 对 CD33(+) MDS 和 MDSC 靶标均起作用，并且可能对 MDS 患者具有治疗益处。
