Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system
Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system
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DOI：
10.1038/leu.2013.243
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发表时间：
2014-01-01
期刊：
影响因子：
11.4
通讯作者：
Bachmann, M.
中科院分区：
文献类型：
--
作者：
Arndt, C.;Feldmann, A.;Bachmann, M.
由于它们的临床成功，人们对用于将T细胞重靶向肿瘤细胞的新型双特异性抗体（bsAb）（包括用于治疗急性髓性白血病（AML））的兴趣日益增长。将T细胞重靶向AML母细胞的一个潜在靶标是表面分子CD33。在这里，我们描述了一种新的模块化靶向平台，由通用效应模块（EM）和单个靶向模块（TM）组成。两个模块都可以通过肽表位形成免疫复合物。所得的靶向复合物可以在功能上替代常规的bsAb。通过共刺激结构域（例如，细胞外CD137配体结构域）与TM的融合，靶向复合物甚至可以在重定向的T细胞与肿瘤细胞相互作用的一侧向重定向的T细胞提供共刺激信号。此外，我们观察到，有效杀死表达低水平肿瘤靶CD33的肿瘤细胞在低效应细胞与靶细胞比率下变得至关重要，但可以通过使用我们的新型靶向系统经由CD137的共刺激来改善。
Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.