German Cancer Research Centre (DKFZ) Unit F100, Heidelberg, Germany; Institut National de la Santé et de la Recherche Médicale Unit U1074, Heidelberg, Germany;
German Cancer Research Centre Unit F010, Heidelberg, Germany;
Blood. 2015 Mar 5;125(10):1601-10. doi: 10.1182/blood-2014-07-591412. Epub 2015 Jan 7.
The treatment of non-Hodgkin lymphomas has benefited enormously from the introduction of monoclonal antibody-based therapies. However, the efficacy of these treatments varies with lymphoma subtypes and typically decreases with subsequent relapses. Here, we report on antigen-armed antibodies (AgAbs) as a potential treatment of B-cell lymphoma. AgAbs include antigens from ubiquitous pathogens, such as Epstein-Barr virus (EBV), that persist in their host and elicit strong lifelong T-cell responses. They act as vectors by introducing antigen directly into tumor cells to induce an antigen-specific CD4(+) T-cell response against these cells. We have fused antibodies targeting human B-cell surface receptors (CD19-22) to immunodominant T-cell antigens from EBV proteins, including EBNA1, EBNA3B, and EBNA3C. Exposure of EBV-transformed B cells and of Burkitt lymphoma cells to AgAbs led to antigen presentation, T-cell recognition, and target cell killing. The efficiency of AgAb action paralleled the abundance of the targeted molecules on lymphoma cells as well as their HLA class II expression levels. AgAbs can also induce activation and proliferation of EBV-specific memory CD4(+) T cells ex vivo. These studies show the potential of AgAbs as an effective therapeutic strategy against B-cell lymphomas.
从引入基于单克隆抗体的疗法以来，非霍奇金淋巴瘤的治疗已经取得了巨大的收益。然而，这些治疗方法的疗效因淋巴瘤亚型而异，并且通常随着随后的复发而降低。在这里，我们报告了抗原武装抗体（AgAbs）作为治疗 B 细胞淋巴瘤的一种潜在方法。AgAbs 包括来自普遍存在的病原体的抗原，例如 Epstein-Barr 病毒（EBV），这些病原体在其宿主中持续存在，并引发强烈的终身 T 细胞反应。它们作为载体，通过将抗原直接引入肿瘤细胞中来诱导针对这些细胞的抗原特异性 CD4(+)T 细胞反应。我们已经将针对人类 B 细胞表面受体（CD19-22）的抗体与 EBV 蛋白中的免疫显性 T 细胞抗原融合，包括 EBNA1、EBNA3B 和 EBNA3C。AgAbs 暴露于 EBV 转化的 B 细胞和 Burkitt 淋巴瘤细胞中会导致抗原呈递、T 细胞识别和靶细胞杀伤。AgAb 作用的效率与淋巴瘤细胞上靶向分子的丰度以及它们的 HLA Ⅱ类表达水平平行。AgAbs 还可以诱导 EBV 特异性记忆 CD4(+)T 细胞在体外的激活和增殖。这些研究表明了 AgAbs 作为治疗 B 细胞淋巴瘤的有效治疗策略的潜力。
