Design, synthesis and evaluation of anti-CD123 antibody drug conjugates.
Design, synthesis and evaluation of anti-CD123 antibody drug conjugates.
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DOI：
10.1016/j.bmc.2016.09.043
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发表时间：
2016-11-15
影响因子：
3.5
通讯作者：
Dong Y
中科院分区：
文献类型：
--
作者：
Li B;Zhao W;Zhang X;Wang J;Luo X;Baker SD;Jordan CT;Dong Y
白血病干细胞（LSC）是急性髓细胞白血病（AML）患者产生耐药性和复发率增加的原因。白血病干细胞的靶向药物递送仍然是AML化疗的主要挑战。据报道，白血病干细胞表面上过表达的白细胞介素-3受体α链（CD 123）是AML治疗的潜在靶点。在这里，我们设计并开发了一种抗体药物偶联物（CD 123-CPT），通过将抗CD 123抗体与化疗药物喜树碱（CPT）通过二硫键连接体整合。该连接体在谷胱甘肽（GSH，细胞中的内源性组分）存在下可生物降解，导致CPT释放。抗CD 123抗体偶联物在CD 123过表达的肿瘤细胞中显示出显著更高的细胞摄取。更重要的是，CD 123-CPT对CD 123过表达的肿瘤细胞表现出有效的抑制作用。因此，这些结果为AML治疗提供了有希望的靶向化疗策略。
Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker. The linker is biodegradable in the presence of Glutathione (GSH, an endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment.