CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody
CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody
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DOI：
10.1182/blood-2009-06-229039
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发表时间：
2010-02-11
期刊：
影响因子：
20.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Awan, Farrukh T.;Lapalombella, Rosa;Byrd, John C.
CD19是一种在慢性淋巴细胞白血病（CLL）细胞上表达的B细胞特异性抗原，但迄今为止尚未被治疗性单克隆抗体有效靶向。XmAb5574是一种新型工程抗cd19单克隆抗体，具有修饰的恒定片段（Fc）结构域，旨在增强Fc γ RIIIa的结合。在这里，我们证明了XmAb5574介导有效的抗体依赖性细胞毒性（ADCC），适度的直接细胞毒性和抗体依赖性细胞吞噬，但不介导补体介导的CLL细胞毒性。有趣的是，与它衍生的人源抗cd19非工程抗体和利妥昔单抗（一种广泛用于治疗CLL的治疗性抗体）相比，XmAb5574介导的ADCC显著更高。依赖xmab5574的ADCC是由自然杀伤细胞通过颗粒酶b依赖机制介导的。与非工程抗体相比，使用XmAb5574的NK细胞介导的细胞溶解和分泌功能与增强NK细胞活化、干扰素产生、细胞外信号调节的Fc γ受体下游激酶磷酸化有关，并且未增加NK细胞凋亡。值得注意的是，来那度胺进一步增强了XmAb5574介导的NK细胞介导的ADCC。这些发现为进一步临床开发XmAb5574作为CLL和相关CD19(+) b细胞恶性肿瘤的单药治疗和与来那度胺联合治疗提供了强有力的支持。(血。2010;115:1204 - 1213)
CD19 is a B cell-specific antigen expressed on chronic lymphocytic leukemia (CLL) cells but to date has not been effectively targeted with therapeutic monoclonal antibodies. XmAb5574 is a novel engineered anti-CD19 monoclonal antibody with a modified constant fragment (Fc)-domain designed to enhance binding of Fc gamma RIIIa. Herein, we demonstrate that XmAb5574 mediates potent antibody-dependent cellular cytotoxicity (ADCC), modest direct cytotoxicity, and antibody-dependent cellular phagocytosis but not complement-mediated cytotoxicity against CLL cells. Interestingly, XmAb5574 mediates significantly higher ADCC compared with both the humanized anti-CD19 nonengineered antibody it is derived from and also rituximab, a therapeutic antibody widely used in the treatment of CLL. The XmAb5574-dependent ADCC is mediated by natural killer (NK) cells through a granzyme B-dependent mechanism. The NK cell mediated cytolytic and secretory function with XmAb5574 compared with the nonengineered antibody is associated with enhanced NK-cell activation, interferon production, extracellular signal-regulated kinase phosphorylation downstream of Fc gamma receptor, and no increased NK-cell apoptosis. Notably, enhanced NK cell-mediated ADCC with XmAb5574 was enhanced further by lenalidomide. These findings provide strong support for further clinical development of XmAb5574 as both a monotherapy and in combination with lenalidomide for the therapy of CLL and related CD19(+) B-cell malignancies. (Blood. 2010;115:1204-1213)