Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform
Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform
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DOI：
10.1182/blood-2014-05-575704
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发表时间：
2016-01-07
期刊：
影响因子：
20.3
通讯作者：
DiPersio, John F.
中科院分区：
文献类型：
--
作者：
Al-Hussaini, Muneera;Rettig, Michael P.;DiPersio, John F.
使用双特异性抗体的T细胞定向杀伤肿瘤细胞是治疗血液恶性肿瘤的有前景的方法。在这里，我们描述了我们的临床前工作与双亲和重靶向（DART）分子产生的抗体CD 3和CD 123，旨在重定向T细胞对急性髓性白血病母细胞。CD 3xCD 123 DART（也称为MGD 006/S80880）由2个独立的多肽组成，每个多肽由1个抗体的V-H与另一个抗体的V-L串联组成。与正常造血干细胞和祖细胞相比，靶抗原CD 123（白细胞介素3RA）在急性髓性白血病（AML）原始细胞中高度表达且差异表达。在这项研究中，我们证明了CD 3xCD 123 DART与人CD 3和CD 123结合，以介导靶效应细胞缔合、T细胞活化、增殖和受体多样化。CD 3xCD 123 DART还在体外和体内诱导AML细胞系和原代AML母细胞的剂量依赖性杀伤。这些结果为检测CD 3xCD 123 DART治疗CD 123（+）AML患者提供了基础。
T-cell-directed killing of tumor cells using bispecific antibodies is a promising approach for the treatment of hematologic malignancies. Here we describe our preclinical work with a dual-affinity retargeting (DART) molecule generated from antibodies to CD3 and CD123, designed to redirect T cells against acute myeloid leukemia blasts. The CD3xCD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the V-H of 1 antibody in tandem with the V-L of the other antibody. The target antigen CD123 (interleukin 3RA) is highly and differentially expressed in acute myeloid leukemia (AML) blasts compared with normal hematopoietic stem and progenitor cells. In this study we demonstrate that the CD3xCD123 DART binds to both human CD3 and CD123 to mediate target-effector cell association, T-cell activation, proliferation, and receptor diversification. The CD3xCD123 DART also induces a dose-dependent killing of AML cell lines and primary AML blasts in vitro and in vivo. These results provide the basis for testing the CD3xCD123 DART in the treatment of patients with CD123(+) AML.