文章：

双特异性抗体释放-间充质干细胞装置用于将T细胞重定向至急性髓系白血病原始细胞

Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts

原文发布日期：2015-09-18

DOI: 10.1038/bcj.2015.73

类型: Original Article

开放获取: 是

英文摘要：

Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.

摘要翻译： 

双特异性T细胞衔接抗体（bsAbs）作为一种新兴的免疫治疗工具，在血液系统恶性肿瘤治疗中展现出广阔前景。由于分子量较低，bsAbs半衰期较短，为达到临床疗效需对患者进行长期持续输注。作为有效替代方案，我们研究了间充质基质细胞（MSCs）作为自主细胞工厂持续生产新型全人源化抗CD33/CD3双特异性抗体的可行性，该抗体能引导T细胞靶向CD33阳性白血病细胞。通过基因改造永生化人MSC系SCP-1，使其表达足量双特异性抗体，在体外和免疫缺陷小鼠模型中均能有效引导T细胞攻击CD33阳性靶细胞。此外，在分泌双特异性抗体的MSCs存在下，急性髓系白血病急变期患者的T细胞可随时间推移有效清除自体白血病细胞。通过MSCs表达CD137配体经CD137-CD137配体轴为T细胞提供额外共刺激信号，可进一步增强对AML细胞的免疫应答。本研究证实MSCs未来有望成为基于双特异性抗体的肿瘤免疫治疗的细胞生产平台。

原文链接：

Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts