抗CD44纳米抗体/砷偶联物靶向治疗AML的作用及机制研究

Acute myeloid leukemia (AML) is a common and dangerous leukemia type. In recent years, biological targeted therapy has become an important trend in the treatment of AML. CD44 is a specific target for AML treatment, which located on the membrane surface of AML cells. Anti-CD44 monoclonal antibodies are potential AML targeted drugs. However, these Anti-CD44 antibodies have shown several disadvantages, such as complicate structure, high cost, lack of lethality, which limit its application in AML treatment. The development of high efficiency and miniaturization of CD44 antibody drugs, may help to overcome these defects. This project will design a new type of CD44 antibody drug: CD44 nanobody / arsenic drug conjugate, which may exert synergistic and complementary effect of these two reagents. The targeting and anti-leukemia effect of this new drug will be investigated in this project. We will also study on the mechanism of action of this drug from four aspects: the cellular uptake pathway of the drug, the influence on target protein signal pathway, the change of cell cycle, and the signal pathway of apoptosis induced by the drug. These original studies could promote the development of miniaturization and high efficiency of anti-CD44 antibody drugs, as well as improve the targeting effect of arsenic drugs.

急性髓性白血病（AML）是一种常见而危险的白血病类型，生物靶向治疗是当前AML治疗的重要发展趋势。CD44是AML白血病细胞表面的特异性靶点，针对CD44的单克隆抗体是潜在的AML靶向药物。然而，现有的CD44抗体存在结构复杂、成本高昂、杀伤力不足等诸多缺点，限制了其在AML治疗上的应用。研究高效化、小型化的CD44抗体药物，有助于克服这些缺陷。本项目将从抗体药物的小型化和高效化出发，设计一种新型CD44纳米抗体/药物偶联物，以发挥两种药物的协同性和互补作用。项目将研究抗CD44纳米抗体/砷偶联物在AML靶向治疗中的作用，并从药物的细胞摄取、对靶蛋白通路、对细胞周期、对细胞凋亡通路的影响四个方面，研究其作用机理。这些原创性的研究将具有促进以CD44为靶点的抗体药物的小型化和高效化，以及实现砷药物的靶向化的双重意义。

急性髓性白血病（AML）是一种常见而危险的白血病类型，生物靶向治疗是当前AML治疗的重要发展趋势。CD44是AML白血病细胞表面的特异性靶点，针对CD44的抗体药物是潜在的AML靶向药物。在此项目中，我们筛选了三株序列特异性的CD44纳米抗体，并完成了大量制备工作。但进一步的研究表明，这些抗体在对天然CD44的靶向性及对AML细胞的抑制作用都远远低于预期，导致项目后期工作无法开展。经过调整之后，我们将研究方向转移到HER2纳米抗体在乳腺癌诊疗一体化的应用上面。我们成功制备了一种HER2纳米抗体，研究结果显示此抗体能够作用于HER2靶点蛋白，通过抑制AKT和ERK的磷酸化发挥作用，此抗体对两种乳腺癌细胞BT474以及SKBR3均有非常好的抑制作用，进一步工作正在进行当中。