Painted erythrocyte carriers for therapy of acute myeloid leukemia

治疗急性髓系白血病的彩绘红细胞载体

• 批准号: 9195709
• 负责人: Dmitri Simberg
• 金额: $ 35.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195709
• 关键词: Ablation; Acute Myelocytic Leukemia; Acute leukemia; Adult; Animals; Anthracyclines; Antibodies; Ara-C; Autologous; Binding; Blast Cell; Blood Circulation; Bone Marrow; Cause of Death; Cell Death; Cell Therapy; Cell membrane; Cells; Cholesterol; Clinical; Clinical Research; Complement; Complex; Cytarabine; Data; Development; Disease; Disease Progression; Disease remission; Dose; Drug Kinetics; Elderly; Engraftment; Enzymes; Erythrocytes; Formulation; HL60; Half-Life; Hematopoietic; Hematopoietic stem cells; Human; Human Cell Line; IL3RA gene; Idarubicin; Immunocompromised Host; In Vitro; Kidney; Kupffer Cells; Leukocytes; Lipids; Longevity; Lung; Lymphoma; MS4A1 gene; Mediating; Membrane; Membrane Lipids; Modeling; Modification; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Organ; Pain; Paint; Patients; Pharmaceutical Preparations; Phospholipids; Pre-Clinical Model; Procedures; Prodrugs; Regimen; Resistance; Role; Site; Source; Specificity; Spleen; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Toxicity due to chemotherapy; antibody conjugate; base; biomaterial compatibility; cancer care; chemotherapy; cytotoxicity; design; improved; in vivo; leukemia treatment; macrophage; mortality; mouse model; novel; novel strategies; older patient; pre-clinical; progenitor; public health relevance; residence; scale up; simulation; small molecule; standard of care; systemic toxicity

 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.

 描述（由申请人提供）：急性髓性白血病（AML）占成人所有急性白血病的约90%，5年生存率仅为25%。死亡的主要原因是骨髓系造血祖细胞母细胞的不受控制的增殖。尽管有许多实验策略，这种癌症的护理标准在30年内没有显着改变或改善。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强化化疗是最有效的治疗方法，可减少原始细胞计数，诱导稳定缓解和延长生存期。不幸的是，对于老年人，免疫功能低下的患者，积极的化疗会导致严重的发病率和死亡率，并可能是致命的。对于可以降低化疗的全身毒性的治疗方法存在广泛的未满足的需求。该提案的目标是开发基于红细胞的急性粒细胞白血病疗法。我们先前描述了用抗体和小分子对红细胞（RBC）的膜进行快速有效的修饰（“涂染”），并证明这些细胞可以特异性地耗尽动物淋巴瘤模型中的循环细胞。药代动力学模拟表明，小鼠中涂红细胞的3天半衰期可扩展至人类中的30天寿命，这表明红细胞给药具有开发成为高度实用方法的巨大潜力。在强有力的初步数据的支持下，该提案的目的是开发着色RBC，用于AML临床前模型中的原始细胞的有效消融。消融的机制涉及捕获循环中的原始细胞，随后通过肝脏巨噬细胞消除它们。由于涂染的RBC有效地在脾脏和骨髓（原始细胞驻留的主要部位）中积累，我们将用依达鲁肽的脂质前药涂染RBC以消融这些器官中的原始细胞，同时降低全身剂量和毒性。我们开发了以下具体目的：1）证明用骨髓标志物CD 33和CD 123特异性抗体涂覆的RBC对AML原始细胞的有效体外靶向; 2）研究控制抗体涂覆的RBC的体内消融效率的因素; 3）合成艾达罗肽， 用于涂染RBC膜的前药并测试体外细胞毒性; 4）在AML的临床前小鼠模型中体内确定抗体涂染和药物涂染的RBC的体内治疗效果。如果成功，我们认为后续的临床研究将是可行的。红细胞（自体或供体来源）的绘画是一种高度实用和有效的程序，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方法，可以减少实现稳定缓解所需的化疗量，同时降低患者治疗相关的发病率和死亡率。