Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab
Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab
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DOI：
10.3324/haematol.2010.030759
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Mutis, Tuna
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文献类型：
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作者：
van der Veer, Michael. S.;de Weers, Michel;Mutis, Tuna
背景在我们开发多发性骨髓瘤新的有效治疗方案的努力中，我们评估了联合免疫调节药物来那度胺和达雷妥尤单抗的潜在益处。达雷妥尤单抗（Daratumumab）是一种新型的人源性CD 38单克隆抗体，可通过抗体依赖性细胞介导的细胞毒性、补体依赖性细胞毒性和细胞凋亡等途径杀伤CD 38+多发性骨髓瘤细胞。我们首先进行了标准的抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性测定，其中CD 38+多发性骨髓瘤细胞系UM-1 9和从患者分离的原代多发性骨髓瘤细胞用作靶细胞。我们还直接在多发性骨髓瘤患者的骨髓单核细胞中检测了来那度胺对多发性骨髓瘤细胞的达雷妥单抗依赖性细胞介导的细胞毒性和补体依赖性细胞毒性的影响。最后，我们确定了达雷妥珠单抗依赖的细胞介导的细胞毒性使用外周血单核细胞的多发性骨髓瘤患者接受来那度胺treatment. ResultsDaratumumab依赖的细胞介导的细胞毒性纯化的原发性多发性骨髓瘤细胞，以及UM-9细胞系，显着增强来那度胺预处理的效应细胞来自健康个体的外周血单核细胞。更重要的是，我们在多发性骨髓瘤患者的骨髓单核细胞中直接证明了来那度胺和daratumumab诱导的抗体依赖性细胞介导的细胞毒性之间的明显协同作用，表明来那度胺还可以通过激活恶性细胞自然环境中的自体效应细胞来增强骨髓瘤细胞的daratumumab依赖性溶解。最后，达雷妥尤单抗依赖的细胞介导的细胞毒性显着上调来自3多发性骨髓瘤患者在来那度胺treatment.Conclusions外周血单个核细胞我们的研究结果表明，强大的和互补的效果可能会实现通过结合来那度胺和达雷妥尤单抗在多发性骨髓瘤的临床管理。
BackgroundIn our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis.Design and MethodsTo explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment.ResultsDaratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment.Conclusions Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.