使用T细胞介导的双亲和重靶向平台靶向CD123在淋巴细胞白血病中的研究

icartab

Targeting CD123 in acute myeloid leukemia using a T-cell–directed dual-affinity retargeting platform


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 CD3×CD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the VH of 1 antibody in tandem with the VL 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 CD3×CD123 DART binds to both human CD3 and CD123 to mediate target-effector cell association, T-cell activation, proliferation, and receptor diversification. The CD3×CD123 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 CD3×CD123 DART in the treatment of patients with CD123+ AML.

使用T细胞介导的双亲和重靶向平台靶向CD123在淋巴细胞白血病中的研究
T细胞介导的使用双特异性抗体杀伤肿瘤是一个很有前途的治疗淋巴细胞白血病的方式。这篇文章中，我们描述了一个临床前研究，利用靶向CD3和CD123的抗体，构建一个双亲和性重靶向（DART）分子，介导T 细胞对抗急性淋巴细胞白血病的爆发。CD3×CD123 DART分子，由两个独立的多肽构成，每一个由某一个抗体的VH 部分串联另一个抗体的VL 部分。靶向抗原CD123在急性淋巴细胞白血病中，与正常造血干细胞、祖细胞相比，高度和差异化表达。这篇文章阐述了CD3×CD123 DART结合到人类CD3和CD123抗原上，从而介导靶效应细胞相关的，T细胞活性，增殖和受体多样化。CD3×CD123 DART在体内和体外实验中，均能够诱导剂量相关的杀伤AML细胞和原始AML细胞爆发的能力。这些结果提供了可以通过CD3×CD123 DART治疗CD123阳性的AML病人。

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