文章：

γ-分泌酶抑制剂增强BCMA靶向双特异性抗体对多发性骨髓瘤细胞的疗效，且不影响T细胞活化与分化

γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation

原文发布日期：2022-08-16

DOI: 10.1038/s41408-022-00716-3

类型: Article

开放获取: 是

英文摘要：

We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138+ but not CD3+ patient cells, concomitantly with minimum soluble/shed BCMA (sBCMA) in 1 day-culture supernatants. In ex vivo MM-T-cell co-cultures, GSIs overcame sBCMA-inhibited MM cell lysis and further enhanced autologous patient MM cell lysis induced by BCMAxCD3 BisAbs, accompanied by significantly enhanced cytolytic markers (CD107a, IFNγ, IL2, and TNFα) in patient T cells. In longer 7 day-co-cultures, LY-411575 minimally affected BCMAxCD3 BisAb (PL33)-induced transient expression of checkpoint (PD1, TIGIT, TIM3, LAG3) and co-stimulatory (41BB, CD28) proteins, as well as time-dependent increases in % effector memory/central memory subsets and CD8/CD4 ratios in patient T cells. Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome.
 

摘要翻译： 

本研究明确了γ-分泌酶抑制剂（GSIs）对T细胞依赖性BCMA特异性多发性骨髓瘤（MM）细胞裂解的影响及其对双特异性抗体（BisAbs）诱导的免疫调节效应。在MM细胞系及患者MM细胞中，GSIs诱导的膜结合型BCMA（mBCMA）积累在4小时内接近峰值，并在42小时研究期间持续维持。GSIs（即2 nM LY-411575或1 μM DAPT）能显著提升CD138+患者细胞（而非CD3+细胞）的mBCMA密度，同时在1天培养上清液中检测到最低水平的可溶性/脱落型BCMA（sBCMA）。在原代MM-T细胞共培养体系中，GSIs可逆转sBCMA对MM细胞裂解的抑制，并进一步增强BCMAxCD3双抗诱导的自体患者MM细胞裂解，同时患者T细胞中的溶细胞标志物（CD107a、IFNγ、IL2及TNFα）显著增加。在为期7天的长时程共培养中，LY-411575对BCMAxCD3双抗（PL33）诱导的检查点蛋白（PD1、TIGIT、TIM3、LAG3）与共刺激蛋白（41BB、CD28）的瞬时表达影响微弱，对患者T细胞中效应记忆/中央记忆亚群百分比及CD8/CD4比值的时序性升高亦无显著干预。值得注意的是，在重建人源化T细胞的MM荷瘤NSG小鼠模型中，LY411575能快速清除循环系统中的sBCMA，显著增强PL33的抗MM疗效并延长宿主存活期。综上，本研究结果为进一步推进GSI与靶向BCMA免疫疗法的联合临床研究提供了理论支撑，有望改善患者预后。

原文链接：

γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation