T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct
T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct
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DOI：
10.1038/leu.2012.341
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发表时间：
2013-05-01
期刊：
影响因子：
11.4
通讯作者：
Krause, S. W.
中科院分区：
文献类型：
--
作者：
Aigner, M.;Feulner, J.;Krause, S. W.
急性髓性白血病（AML）患者迫切需要新型靶向治疗。在这里，我们探索了AMG 330的离体活性，AMG 330是一种新型的T细胞接合BiTE（双特异性T细胞增殖剂）抗体（Ab）构建体，其对骨髓分化抗原CD 33和CD 3具有双特异性，在来自AML患者（N = 23）和AML细胞系的原代样品中。KG-1和U937细胞在与健康供体T细胞共培养时裂解，AMG 330浓度低至0.1 ng/ml（1.8 pM）。发现来源于AML患者样品的T细胞在AMG 330的重定向裂解中与来自健康供体的T细胞一样具有活性。在自体环境中，AMG 330可以激活和扩增原发性AML患者样本中的T细胞，并有效介导AML原始细胞和正常骨髓细胞的重定向裂解。靶细胞溶解的缺陷仅在具有非常低的初始效应物-靶（E：T）比的样品中观察到。然而，如果先前刺激的自体T细胞以更高的E：T比率在患者样品中进行测试，则可以克服这一点。免疫缺陷小鼠的体内实验证明，AMG 330可显著抑制肿瘤生长，并可诱导人T细胞浸润至皮下HL 60肿瘤中。CD 33/CD 3双特异性BiTE Ab构建体AMG 330的活性保证了进一步开发用于治疗AML。
Patients with acute myelogenous leukemia (AML) are in high need of novel targeted therapies. Here we explored the ex vivo activity of AMG330, a novel T-cell-engaging BiTE (bi-specific T-cell engagers) antibody (Ab) construct, that is bispecific for the myeloid differentiation antigen, CD33 and CD3, in primary samples from AML patients (N = 23) and AML cell lines. KG-1 and U937 cells were lysed in co-culture with healthy donor T-cells at AMG330 concentrations as low as 0.1 ng/ml (1.8 pM). T-cells derived from AML patient samples were found to be as active in redirected lysis by AMG330 as T-cells from healthy donors. In an autologous setting, AMG330 could activate and expand T-cells in primary AML patient samples, and effectively mediated the redirected lysis of AML blasts and normal myeloid cells. A deficiency in target-cell lysis was only observed in samples with very low initial effector-to-target (E: T) ratio. However, this could be overcome if previously stimulated autologous T-cells were tested in patient samples at a higher E: T ratio. In vivo experiments in immunodeficient mice demonstrated significant inhibition of tumor growth by AMG330 and an inducible infiltration of human T-cells into subcutaneous HL60 tumors. The activities of the CD33/CD3-bispecific BiTE Ab construct AMG330 warrant further development for the treatment of AML.