目的 构建粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor，GM-CSF）Fc与小分子药物DXd偶联物（GM-DXd），并探究其靶向杀伤急性髓系白血病（acute myeloid leukemia，AML）细胞的治疗效果。 方法 制备靶向GM-CSF受体（GM-CSF receptor，GMR）的GM-DXd，并通过还原性SDS-PAGE鉴定GM-DXd。采用蛋白质印迹检测GM-DXd的生物活性，流式细胞术检测AML细胞MV4-11、THP-1对GM-DXd的内化情况，细胞增殖-毒性检测和流式细胞术分别评价GM-DXd对GMR阳性AML细胞的活性抑制和凋亡诱导能力，蛋白质印迹检测诱导凋亡蛋白的表达。 结果 制备的GM-DXd生物活性稳定，能成功被AML细胞内吞；与未给药组相比，GM-DXd抑制了AML细胞活性（对MV4-11和THP-1细胞的抑制中浓度分别为15.91和37.64 nmol/L）并促进AML细胞凋亡（20 nmol/L GM-DXd分别诱导~90%、~60%的MV4-11、THP-1细胞凋亡），细胞杀伤能力比DXd更强。 结论 小分子偶联药物GM-DXd通过靶向GMR能够有效杀伤AML细胞，可以作为治疗AML的潜在药物。

Objective To construct a granulocyte-macrophage colony-stimulating factor (GM-CSF) Fc and DXd conjugate (GM-DXd), and explore its therapeutic effect on targeted killing of acute myeloid leukemia (AML) cells. Methods The GM-CSF receptor (GMR) targeting GM-DXd was prepared, and identified by reducing SDS-PAGE. The biological activity of GM-DXd was detected by Western blot, and the internalization of GM-DXd by AML cell lines MV4-11 and THP-1 was detected by flow cytometry. The viability inhibition and apoptosis induction in GMR-positive AML cells by GM-DXd were assessed by cell proliferation-cytotoxicity detection and flow cytometry, respectively, and the expression of apoptotic proteins in GMR-positive AML cells was detected by Western blot. Results The GM-DXd prepared had stable biological activity and was successfully endocytosed by AML cells. Compared to control group, GM-DXd inhibited AML cell viability and the median inhibitory concentrations to MV4-11 and THP-1 cells were 15.91 and 37.64 nmol/L, respectively. GM-DXd (20 nmol/L) greatly promoted apoptosis in AML cells with ~90% and ~60% apoptotic cells in MV4-11 and THP-1 cells, respectively, and the AML cell killing ability was stronger than DXd only. Conclusion The small molecule conjugate drug GM-DXd can effectively kill AML cells by targeting GMR and can be a potential drug for the treatment of AML.