Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma
Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma
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DOI：
10.1182/bloodadvances.2017006866
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发表时间：
2017-10-24
期刊：
影响因子：
7.5
通讯作者：
Sasser, A. Kate
中科院分区：
文献类型：
--
作者：
Casneuf, Tineke;Xu, Xu Steven;Sasser, A. Kate
Daratumumab 是一种人 CD38 免疫球蛋白 G 1k 单克隆抗体，在复发和/或难治性多发性骨髓瘤的单一疗法和联合疗法临床试验中已显示出临床活性和可控的安全性。 CD38 在骨髓瘤细胞上高水平表达，在免疫效应细胞上表达水平较低，包括自然杀伤 (NK) 细胞，这对于达雷妥尤单抗介导的抗体依赖性细胞毒性 (ADCC) 很重要。在此，评估了 daratumumab 单一疗法对 NK 细胞的药效学影响，以及 NK 细胞动力学对 daratumumab 疗效和安全性的影响。与其他 CD38 抗体一样，Daratumumab 可以在体外减少健康捐献者外周血单核细胞 (PBMC) 中的 NK 细胞计数。 NK 细胞计数、临床疗效和不良事件的数据来自两项单药 daratumumab 研究（GEN501 和 SIRIUS）。在接受 daratumumab 治疗的骨髓瘤患者中，首次给药后外周血中的 NK 细胞总数和活化 NK 细胞计数迅速减少，在治疗过程中保持较低水平，并在治疗结束后恢复。达雷妥尤单抗剂量与 NK 细胞最大减少量之间存在明显的最大效应关系。在骨髓中也观察到类似的减少。来自接受达雷妥尤单抗治疗的患者的 PBMC 在体外通过 ADCC 诱导 CD381 肿瘤细胞裂解，表明剩余的 NK 细胞保留了细胞毒性功能。 NK 细胞计数减少与达雷妥尤单抗的疗效或安全性之间没有关系。此外，尽管达雷妥尤单抗治疗后 NK 细胞数量减少，但它们并未完全耗尽，仍可能有助于 ADCC、临床疗效和感染控制。
Daratumumab, a human CD38 imunoglobulin G 1k monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed. Daratumumab, like other CD38 antibodies, reduced NK-cell counts in peripheral blood mononuclear cells (PBMCs) of healthy donors in vitro. Data on NK-cell counts, clinical efficacy, and adverse events were pooled from two single-agent daratumumab studies, GEN501 and SIRIUS. In daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low over the course of treatment, and recovered after treatment ended. There was a clear maximum effect relationship between daratumumab dose andmaximum reduction in NK cells. Similar reductions were observed in bone marrow. PBMCs from daratumumab-treated patients induced lysis by ADCC of CD381 tumor cells in vitro, suggesting that the remaining NK cells retained cytotoxic functionality. There was no relationship between NK-cell count reduction and the efficacy or safety profile of daratumumab. Furthermore, although NK cell numbers are reduced after daratumumab treatment, they are not completely depleted and may still contribute to ADCC, clinical efficacy, and infection control.