Painted erythrocyte carriers for therapy of acute myeloid leukemia

 描述(申请人提供)：急性髓系白血病(AML)约占成人急性白血病的90%，5年存活率仅为25%。死亡的主要原因是髓系造血祖细胞的增殖不受控制。尽管有许多实验策略，但这种癌症的护理标准在过去30年中并没有显著改变或改善。AML是一种遗传异质性疾病，这使得定制治疗的设计具有挑战性。阿糖胞苷和蒽环类药物的积极化疗是减少原始细胞计数、诱导稳定缓解和延长生存期的最有效的治疗方法。不幸的是，对于免疫功能低下的老年患者，激进的化疗会导致严重的发病率和死亡率，甚至可能是致命的。有一个广泛的未得到满足的治疗方法的需求，可以减少化疗的全身毒性。这项建议的目标是开发以红细胞为基础的AML治疗方法。我们之前描述了一种用抗体和小分子对红细胞(RBC)膜进行快速而有效的修饰(涂抹)的方法，并在动物淋巴瘤模型中证明了这些细胞可以特异性地耗尽循环细胞。药代动力学模拟表明，绘制的红细胞在小鼠体内的半衰期为3天，在人类体内的半衰期可达30天，这表明红细胞给药具有巨大的潜力，可以发展成高度实用的方法。在强大的初步数据的支持下，这项建议的目标是开发彩绘红细胞，用于在AML的临床前模型中有效地消融原始细胞。消融的机制包括捕获循环中的原始细胞，然后通过肝脏巨噬细胞消除它们。由于绘制的红细胞有效地聚集在脾和骨髓(原始细胞居留的主要部位)，我们将用伊达比星的脂类前体药物涂覆红细胞，以消除这些器官中的原始细胞，同时降低全身剂量和毒性。我们的研究目标如下：1)展示髓系标志物CD33和CD123的抗体标记的红细胞在体外有效靶向AML细胞；2)研究影响抗体标记的红细胞体内消融效率的因素；3)合成伊达比星 红细胞膜涂布前药及体外细胞毒性试验；4)检测抗体及药物涂布红细胞对急性髓系白血病临床前期小鼠模型的体内治疗作用。如果成功，我们认为后续的临床研究将是可行的。涂抹红细胞(自体或供者来源)是一种非常实用和有效的程序，可以在临床环境中进行。RBC介导的白血病原始细胞消融是一种新的方法，它可以减少达到稳定缓解所需的化疗量，同时降低患者与治疗相关的发病率和死亡率。

 DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) represents ~90% of all acute leukemias in adults with only 25% survival at 5 years. The main cause of death is the uncontrolled proliferation of hematopoietic progenitor blast cells of myeloid lineage. Despite numerous experimental strategies, the standard of care for this cancer has not significantly changed or improved over 30 years. AML is a genetically heterogeneous disease, which renders the design of tailored therapy challenging. Aggressive chemotherapy with cytarabine and an anthracycline is the most efficient treatment that reduces blast counts, induces stable remission and prolongs survival. Unfortunately, for elderly, immunocompromised patients, aggressive chemotherapy causes severe morbidity and mortality, and could be fatal. There is a broad unmet need for therapeutic approaches that can decrease the systemic toxicity of chemotherapy. The objective of this proposal is to develop red blood cell-based therapy for AML. We previously described a rapid and efficient modification ("painting") of the membrane of red blood cells (RBCs) with antibodies and small molecules and demonstrated that these cells specifically can deplete circulating cells in animal lymphoma models. Pharmacokinetic simulations suggest that a 3-day half-life of painted RBCs in mice scales up to 30 days of lifespan in humans, suggesting that RBC administration has great potential to be developed into a highly practical approach. Supported by strong preliminary data, the objective of this proposal is to develop painted RBCs for efficient ablation of blasts in a preclinical model of AML. The mechanism of ablation involves capturing blasts in the circulation and subsequently eliminating them by liver macrophages. Since painted RBCs efficiently accumulate in the spleen and bone marrow (the main sites of blast residence), we will paint RBCs with a lipid prodrug of idarubicin in order to ablate blasts in these organs, while lowering systemic dose and toxicity. We developed the following Specific Aims: 1) Demonstrate efficient in vitro targeting of AML blasts by RBCs painted with antibodies specific for myeloid markers CD33 and CD123; 2) Investigate factors that control in vivo ablation efficiency of antibody-painted RBCs; 3) Synthesize idarubicin prodrugs for painting the RBC membrane and test in vitro cytotoxicity; 4) Determine the in vivo therapeutic effect of antibody- and drug-painted RBCs in vivo in preclinical mouse models of AML. If successful, we presume that subsequent clinical studies will be feasible. Painting of RBCs (autologous or donor-sourced) is a highly practical and effective procedure that can be carried out in a clinical setting. RBC-mediated ablation of leukemic blasts is a novel approach that can decrease the amount of chemotherapy required to achieve stable remission while decreasing treatment-associated morbidity and mortality in patients.