A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies.
A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies.
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DOI：
10.1186/1756-8722-7-33
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发表时间：
2014-04-14
影响因子：
28.5
通讯作者：
Back J
中科院分区：
文献类型：
--
作者：
Breton CS;Nahimana A;Aubry D;Macoin J;Moretti P;Bertschinger M;Hou S;Duchosal MA;Back J
CD 19是一种B细胞谱系特异性表面受体，其广泛表达，从前B细胞到早期浆细胞，使其成为B细胞恶性肿瘤免疫治疗的有吸引力的靶标。在这项研究中，我们提出了一种新的人源化抗CD 19单克隆抗体（mAb），GBR 401的产生，并研究其对人类B细胞恶性肿瘤的治疗潜力。GBR 401被部分去岩藻糖基化以增强其细胞毒性功能。我们分析了在存在或不存在从健康供体分离的纯化NK细胞的情况下，GBR 401对来自患者的B细胞系和原发性恶性B细胞的体外耗竭作用。在体内，在B细胞耗竭模型和恶性B细胞耗竭模型中评估GBR 401的抗体依赖性细胞毒性（ADCC）功效，所述B细胞耗竭模型由注射健康人供体PBMC的SCID小鼠组成，所述恶性B细胞耗竭模型中SCID小鼠异种移植有原代人B-CLL肿瘤和异源人NK细胞。此外，还使用静脉内异种移植Raji细胞的小鼠在人伯基特淋巴瘤的异种嵌合小鼠模型中评价了GBR 401的抗肿瘤活性。药理学抑制试验用于表征GBR 401诱导的细胞死亡的机制。GBR 401对来自代表各种B细胞恶性肿瘤的患者的原代样品发挥有效的体外和体内细胞毒性活性。当与岩藻糖基化类似mAb和利妥昔单抗（目前用于B细胞恶性肿瘤的抗CD 20 mAb标准免疫治疗）相比时，GBR 401在原发性恶性B细胞上引起显著更高水平的ADCC，显示在低500倍的浓度下的杀伤。令人感兴趣的是，GBR 401还在不同的恶性B细胞系中表现出有效的直接杀伤作用，该细胞系涉及由肌动蛋白重定位介导的同型聚集。这些结果有助于巩固开发GBR 401用于治疗造血B细胞恶性肿瘤的临床兴趣，特别是对于抗CD 20 mAb治疗难治的患者。
CD19 is a B cell lineage specific surface receptor whose broad expression, from pro-B cells to early plasma cells, makes it an attractive target for the immunotherapy of B cell malignancies. In this study we present the generation of a novel humanized anti-CD19 monoclonal antibody (mAb), GBR 401, and investigate its therapeutic potential on human B cell malignancies. GBR 401 was partially defucosylated in order to enhance its cytotoxic function. We analyzed the in vitro depleting effects of GBR 401 against B cell lines and primary malignant B cells from patients in the presence or in absence of purified NK cells isolated from healthy donors. In vivo, the antibody dependent cellular cytotoxicity (ADCC) efficacy of GBR 401 was assessed in a B cell depletion model consisting of SCID mice injected with healthy human donor PBMC, and a malignant B cell depletion model where SCID mice are xenografted with both primary human B-CLL tumors and heterologous human NK cells. Furthermore, the anti-tumor activity of GBR 401 was also evaluated in a xenochimeric mouse model of human Burkitt lymphoma using mice xenografted intravenously with Raji cells. Pharmacological inhibition tests were used to characterize the mechanism of the cell death induced by GBR 401. GBR 401 exerts a potent in vitro and in vivo cytotoxic activity against primary samples from patients representing various B-cell malignancies. GBR 401 elicits a markedly higher level of ADCC on primary malignant B cells when compared to fucosylated similar mAb and to Rituximab, the current anti-CD20 mAb standard immunotherapeutic treatment for B cell malignancies, showing killing at 500 times lower concentrations. Of interest, GBR 401 also exhibits a potent direct killing effect in different malignant B cell lines that involves homotypic aggregation mediated by actin relocalization. These results contribute to consolidate clinical interest in developing GBR 401 for treatment of hematopoietic B cell malignancies, particularly for patients refractory to anti-CD20 mAb therapies.
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影响因子：
3.8
作者：
Iida S;Kuni-Kamochi R;Mori K;Misaka H;Inoue M;Okazaki A;Shitara K;Satoh M
通讯作者：
Satoh M
DOI：
10.3324/haematol.2011.047159
发表时间：
2011-12-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Boross, Peter;Jansen, J. H. Marco;Leusen, Jeanette H. W.
通讯作者：
Leusen, Jeanette H. W.
DOI：
10.1182/asheducation-2011.1.243
发表时间：
2011-12-01
影响因子：
3
作者：
Hoelzer, Dieter
通讯作者：
Hoelzer, Dieter
影响因子：
20.3
作者：
Beers, Stephen A.;French, Ruth R.;Cragg, Mark S.
通讯作者：
Cragg, Mark S.
影响因子：
5.8
作者：
Cardarelli, Pina M.;Rao-Naik, Chetana;King, David J.
通讯作者：
King, David J.