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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：急性髓细胞性白血病（AML）占成年人所有急性白血病的90％，在5年时仅生存25％。死亡的主要原因是髓样谱系的造血祖细胞细胞的不受控制。尽管有许多实验策略，但该癌症的护理标准在30年中没有显着改变或改善。 AML是一种遗传性异质疾病，它构成了量身定制的治疗挑战的设计。侵略性化疗与蒽环类药物疗法是最有效的治疗方法，可降低爆炸数，诱导稳定的缓解并延长生存率。不幸的是，对于年龄较大的免疫功能低下的患者，侵略性化疗会导致严重的发病率和死亡率，可能是致命的。对治疗方法的需求很大，可以降低化学疗法的全身毒性。该提案的目的是开发基于红细胞的AML治疗。我们先前用抗体和小分子描述了红细胞（RBC）的膜（RBC）的快速有效的修饰（“绘画”），并证明这些细胞可以在动物淋巴瘤模型中专门耗尽循环细胞。药代动力学模拟表明，在人类中，在人类的30天寿命中，为期3天的半衰期涂有漆的RBC，这表明RBC给药具有很大的潜力，可以发展为一种非常实用的方法。在强大的初步数据的支持下，该提案的目的是开发涂漆的RBC，以在AML的临床前模型中有效消融爆炸。消融的机制涉及在循环中捕获爆炸，然后通过肝巨噬细胞消除它们。由于涂有RBC的RBC有效地积聚在脾脏和骨髓中（爆炸式住宅的主要部位），因此我们将用脂质的iDarubicin前药将RBC涂在这些器官中，同时降低全身剂量和毒性。我们开发了以下具体目的：1）通过RBC涂有针对髓样标记CD33和CD123的抗体的RBC对AML爆炸的有效靶向； 2）研究控制抗体涂成RBC的体内消融效率的因素； 3）合成伊达比辛用于绘画RBC膜和测试体外细胞毒性的前药； 4）确定AML临床前小鼠模型中抗体和药物涂成rbcs抗体和药物涂成的RBC的体内治疗作用。如果成功，我们认为随后的临床研究将是可行的。 RBC（自体或供体）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介导的白血病爆炸的消融是一种新型方法，可以减少实现稳定缓解所需的化学疗法量，同时降低患者的治疗相关的发病率和死亡率。