文章：

T细胞配体可调节CD33/CD3双特异性T细胞衔接抗体构建体AMG 330的细胞溶解活性

T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330

原文发布日期：2015-08-21

DOI: 10.1038/bcj.2015.68

类型: Original Article

开放获取: 是

英文摘要：

Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpress individual T-cell ligands, we found that expression of the inhibitory ligands, PD-L1 and PD-L2, reduced the cytolytic activity of the BiTE antibody construct targeting CD33, AMG 330; conversely, expression of the activating ligands, CD80 and CD86, augmented the cytotoxic activity of AMG 330. Consistent with these findings, treatment with an activating antibody directed at the co-stimulatory T-cell receptor, CD28, significantly increased AMG 330-induced cytotoxicity in human AML cell lines. Using specimens from 12 patients with newly diagnosed or relapsed/refractory AML, we found that activation of CD28 also increased the activity of AMG 330 in primary human AML cells (P=0.023). Together, our findings indicate that T-cell ligands and co-receptors modulate the anti-tumor activity of the CD33/CD3 BiTE antibody construct, AMG 330. These findings suggest that such ligands/co-receptors could serve as biomarkers of response and that co-treatment strategies with pharmacological modulators of T-cell receptor signaling could be utilized to further enhance the activity of this targeted therapeutic.

摘要翻译： 

临床前及新兴临床研究表明，双特异性T细胞衔接（BiTE）抗体结构能有效裂解靶向肿瘤细胞，但其活性决定因素尚未完全明确。通过使用经工程改造过表达单个T细胞配体的人急性髓系白血病（AML）细胞系，我们发现抑制性配体PD-L1和PD-L2的表达会降低靶向CD33的BiTE抗体结构AMG 330的细胞溶解活性；相反，激活型配体CD80和CD86的表达则增强了AMG 330的细胞毒性作用。与这些发现一致的是，针对共刺激T细胞受体CD28的激活型抗体处理，显著提高了AMG 330在人AML细胞系中诱导的细胞毒性。通过对12例新诊断或复发/难治性AML患者标本的研究，我们发现CD28的激活同样能增强AMG 330在原发性人AML细胞中的活性（P=0.023）。综上，我们的研究结果表明T细胞配体及共受体可调节CD33/CD3 BiTE抗体结构AMG 330的抗肿瘤活性。这些发现提示此类配体/共受体可作为治疗反应的生物标志物，且与T细胞受体信号通路的药理调节剂联合治疗策略可被用于进一步增强该靶向治疗的活性。

原文链接：

T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330