Bispecific NK-cell engager targeting BCMA elicits stronger antitumor effects and produces less proinflammatory cytokines than T-cell engager.
Bispecific NK-cell engager targeting BCMA elicits stronger antitumor effects and produces less proinflammatory cytokines than T-cell engager.
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DOI：
10.3389/fimmu.2023.1113303
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发表时间：
2023
影响因子：
7.3
通讯作者：
Sun, Haoyu
中科院分区：
文献类型：
--
作者：
Xiao, Xinghui;Cheng, Ying;Zheng, Xiaodong;Fang, Yuhang;Zhang, Yu;Sun, Rui;Tian, Zhigang;Sun, Haoyu
近年来，双特异性抗体在肿瘤治疗中受到了越来越多的关注，其中大部分针对CD3，CD3介导T细胞对肿瘤细胞的杀伤作用。然而，T细胞激活剂可能会引起严重的副作用，包括神经毒性和细胞因子释放综合征。仍然需要更安全的治疗来满足未得到满足的医疗需求，而基于NK细胞的免疫疗法是治疗肿瘤的一种更安全、更有效的方法。BT1(BCMA×CD3)可吸引T细胞和肿瘤细胞，而BK1(BCMA×CD16)可吸引NK细胞和肿瘤细胞。我们的研究表明，BK1介导了NK细胞的活化，上调了CD69、CD107a、干扰素-γ和肿瘤坏死因子的表达。此外，BK1在体外和体内均比BT1具有更强的抗肿瘤作用。体外实验和小鼠体内实验表明，联合用药(BK1+BT1)比单独用药有更强的抗肿瘤作用。更重要的是，在体外和体内，BK1比BT1诱导的促炎细胞因子更少。令人惊讶的是，BK1在联合治疗中减少了细胞因子的产生，表明NK细胞在控制T细胞分泌细胞因子方面发挥着不可或缺的作用。总而言之，我们的研究比较了以BCMA为靶点的NK细胞因子和T细胞因子。结果表明，NK细胞激活剂更有效，促炎细胞因子的产生更少。此外，NK细胞激活剂在联合治疗中的使用有助于减少T细胞分泌细胞因子，这表明NK细胞激活器在临床环境中有光明的前景。
Bispecific antibodies have attracted more attention in recent years for the treatment of tumors, in which most of them target CD3, which mediates the killing of tumor cells by T cells. However, T-cell engager may cause serious side effects, including neurotoxicity and cytokine release syndrome. More safe treatments are still needed to address unmet medical needs, and NK cell-based immunotherapy is a safer and more effective way to treat tumors. Our study developed two IgG-like bispecific antibodies with the same configuration: BT1 (BCMA×CD3) attracted T cells and tumor cells, while BK1 (BCMA×CD16) attracted NK cells and tumor cells. Our study showed that BK1 mediated NK cell activation and upregulated the expression of CD69, CD107a, IFN-γ and TNF. In addition, BK1 elicited a stronger antitumor effect than BT1 both in vitro and in vivo. Combinatorial treatment (BK1+BT1) showed a stronger antitumor effect than either treatment alone, as indicated by in vitro experiments and in vivo murine models. More importantly, BK1 induced fewer proinflammatory cytokines than BT1 both in vitro and in vivo. Surprisingly, BK1 reduced cytokine production in the combinatorial treatment, suggesting the indispensable role of NK cells in the control of cytokine secretion by T cells. In conclusion, our study compared NK-cell engagers and T-cell engagers targeting BCMA. The results indicated that NK-cell engagers were more effective with less proinflammatory cytokine production. Furthermore, the use of NK-cell engagers in combinatorial treatment helped to reduce cytokine secretion by T cells, suggesting a bright future for NK-cell engagers in clinical settings.
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影响因子：
8
作者：
Donlan AN;Sutherland TE;Marie C;Preissner S;Bradley BT;Carpenter RM;Sturek JM;Ma JZ;Moreau GB;Donowitz JR;Buck GA;Serrano MG;Burgess SL;Abhyankar MM;Mura C;Bourne PE;Preissner R;Young MK;Lyons GR;Loomba JJ;Ratcliffe SJ;Poulter MD;Mathers AJ;Day AJ;Mann BJ;Allen JE;Petri WA Jr
通讯作者：
Petri WA Jr
影响因子：
11.4
作者：
Hipp, S.;Tai, Y-T;Friedrich, M.
通讯作者：
Friedrich, M.
影响因子：
64.5
作者：
Gauthier, Laurent;Morel, Ariane;Vivier, Eric
通讯作者：
Vivier, Eric
影响因子：
20.3
作者：
Bartlett, Nancy L.;Herrera, Alex F.;Ansell, Stephen M.
通讯作者：
Ansell, Stephen M.
影响因子：
56.9
作者：
Bargou, Ralf;Leo, Eugen;Kufer, Peter
通讯作者：
Kufer, Peter