Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL
Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL
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DOI：
10.1182/bloodadvances.2018029371
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发表时间：
2019-03-26
期刊：
影响因子：
7.5
通讯作者：
Bachanova, Veronika
中科院分区：
文献类型：
--
作者：
Felices, Martin;Kodal, Behiye;Bachanova, Veronika
慢性淋巴细胞白血病（CLL）的特点是成熟表达cd19的B淋巴细胞的慢性克隆扩增和免疫效应器（包括自然杀伤（NK）细胞）的整体功能障碍。CLL仍然无法治愈，需要新的方法来治疗难治性CLL。我们的小组以前已经描述了三特异性杀手接合（TriKE）分子，重定向NK细胞对肿瘤细胞的功能。TriKE试剂同时结合NK细胞、CD16和肿瘤抗原上的激活受体，同时通过白细胞介素-15片段提供NK细胞扩增信号。在这里，我们开发了新的靶向cd19的161519 TriKE。我们证明了161519 TriKE诱导了表达cd19的伯基特淋巴瘤细胞系的杀伤，并使用健康供体和患者NK细胞检测了对原发性CLL靶点的影响。161519 TriKE诱导健康供体NK细胞激活、增殖和定向杀伤。此外，161519 TriKE恢复了从CLL患者外周血中获得的NK细胞的炎症功能。最后，我们发现与利妥昔单抗相比，161519 TriKE能更好地诱导体外靶向杀伤CLL。综上所述，161519 TriKE在NK细胞上驱动一个有效的激活和增殖信号，导致NK细胞扩增和CLL靶标杀伤增强。我们的研究结果表明161519 TriKE在CLL中的潜在免疫治疗价值。
Chronic lymphocytic leukemia (CLL) is characterized by chronic clonal expansion of mature CD19-expressing B lymphocytes and global dysfunction of immune effectors, including natural killer (NK) cells. CLL remains incurable, and novel approaches to refractory CLL are needed. Our group has previously described trispecific killer engager (TriKE) molecules that redirect NK cell function against tumor cells. TriKE reagents simultaneously bind an activating receptor on NK cells, CD16, and a tumor antigen while also providing an NK cell expansion signal via an interleukin-15 moiety. Here we developed the novel CD19-targeting 161519 TriKE. We demonstrate that 161519 TriKE induced killing of a CD19-expressing Burkitt's lymphoma cell line and examined the impact on primary CLL targets using healthy donor and patient NK cells. 161519 TriKE induced potent healthy donor NK cell activation, proliferation, and directed killing. Furthermore, 161519 TriKE rescued the inflammatory function of NK cells obtained from CLL patient peripheral blood samples. Finally, we show that 161519 TriKE induced better directed killing of CLL in vitro when compared with rituximab. In conclusion, 161519 TriKE drives a potent activating and proliferative signal on NK cells, resulting in enhanced NK cell expansion and CLL target killing. Our findings indicate the potential immunotherapeutic value of 161519 TriKE in CLL.