Development of Next-Generation Precision Medicine RNAi Therapeutics to Treat AML

开发治疗 AML 的下一代精准医学 RNAi 疗法

• 批准号: 10044943
• 负责人: STEVEN F DOWDY
• 金额: $ 40.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044943
• 关键词: Acute Myelocytic Leukemia; Adult; Antibodies; Antibody-drug conjugates; Cell surface; Cells; Charge; Chromosomal translocation; Cleaved cell; Clinical; Cytoplasm; Development; Disease remission; Disease-Free Survival; Endosomes; Engineering; Gemtuzumab Ozogamicin; Genes; Genetic; Genome; Goals; Growth; Hematologic Neoplasms; Liver; MLL gene; MLL-AF9; MLLT3 gene; Malignant Neoplasms; Masks; Modeling; Monoclonal Antibodies; Normal Cell; Oncogenes; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Prodrugs; Property; RNA Interference; RNA Interference Therapy; Radioisotopes; Relapse; Small Interfering RNA; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Tissues; Vertebral column; absorption; acute myeloid leukemia cell; anti-PD-1; antibody conjugate; base; care outcomes; chemical group; chemotherapy; falls; fusion gene; high risk; in vivo; inhibitor/antagonist; inorganic phosphate; leukemia; leukemia/lymphoma; mouse model; mutant; neoplastic cell; next generation; novel; pre-clinical; precision medicine; response; siRNA delivery; side effect; small molecule inhibitor; standard of care; success; targeted delivery; technology development; therapeutic target; young adult

ABSTRACT Acute myeloid leukemia (AML) is one of the most prevalent hematological malignancies. Unfortunately, due to a high relapse rate from chemotherapy, disease-free survival (DFS) remains at 40%. Greater than 80% of AMLs express high levels of the CD33 marker on their cell surface. Alternative therapeutic approaches, including Antibody-Drug Conjugate (ADC), anti-CD33 Mylotarg (gemtuzumab ozogamicin), and Radionuclide Antibody-Conjugates (RACs), have shown some promising results. However, both of these antibody therapeutic agents have significant side effects and suffer from indiscriminant killing of normal cells expressing CD33 as well as from killing normal cells due to non-specific tissue absorption and drug shedding. Unfortunately, AML also does not respond to anti-PD1 and PD-1L check-point inhibitors. Due to chromosomal translocations, the MLL gene fuses to many other genes, including the AF9 gene, resulting in MLL-fusion oncogenes that drive AML growth and survival. Expression of MLL- AF9 driver oncogene in AML has a particularly poor clinical outcome. Consequently, there is a great need to develop novel precision medicine therapeutics that selectively targets and kills only AML tumor cells based on their oncogenic genetic translocations, while sparing normal CD33 positive cells. RNA Interference (RNAi) responses have great potential to target MLL-AF9 and other MLL translocation fusion genes. Unfortunately, despite its promising therapeutic features, due to their requisite negatively charged phosphate backbone, siRNAs have no ability to enter cells and require a delivery agent. To tackle the RNAi delivery problem, we pioneered development of a next-generation RNAi trigger, called RiboNucleic Neutral (siRNN) prodrugs. siRNNs represent a “Prodrug” approach where the negative charge is directly neutralized by a bioreversible phosphotriester chemical group that is selectively cleaved off in the cytoplasm, but not outside of cells. The rate-limiting RNAi delivery step is escape from the endosome into the cytoplasm. To enhance endosomal escape, we will synthesize a next-generation endosomal escape domain (EED). We will target delivery of MLL-AF9 siRNN RNAi triggers to AML cells by conjugation to anti-CD33 antibodies, called Antibody-RNAi Conjugates (ARCs). The goal of this high risk/high gain technology development proposal is treat AML by generating precision medicine anti-CD33 Antibody-RNAi Conjugates (ARCs) that selectively target the MLL-AF9 fusion oncogene and kill AML cells based on their mutant genetics, but unlike ADCs and RACs, have no effect on CD33-positive normal cells.

抽象的 急性髓样白血病（AML）是最普遍的血液恶性肿瘤之一。很遗憾， 由于化学疗法的高继电器率高，无病生存率（DFS）仍为40％。更大 超过80％的AML在其细胞表面表达高水平的CD33标记。替代疗法 方法，包括抗体 - 药物缀合物（ADC），抗CD33 mylotarg（gemtuzumab ozogamicin）， 放射性抗体偶联物（RAC）显示出一些希望的结果。但是，两个 这些抗体治疗剂具有显着的副作用，并遭受了不加区分的杀害 表达CD33的正常细胞以及由于非特异性组织滥用而杀死正常细胞 和毒品脱落。不幸的是，AML也对抗PD1和PD-1L检查点没有响应 抑制剂。由于染色体易位，MLL基因融合了许多其他基因，包括 AF9基因，导致促进AML生长和存活的MLL融合癌基因。 MLL的表达 AML中的AF9驱动器癌基因的临床结果特别差。因此，有一个很棒的 需要开发新颖的精确医学理论，该理论有选择地靶向和杀死AML肿瘤 细胞基于它们的致癌遗传易位，同时保留正常的CD33阳性细胞。 RNA 干扰（RNAi）响应具有靶向MLL-AF9和其他MLL易位的巨大潜力 融合基因。不幸的是，由于其必要的否定，其承诺的治疗特征 带电的磷酸骨架，siRNA没有能力进入细胞并需要递送剂。到 解决了RNAi交付问题，我们开发了下一代RNAi触发器，称为 核糖核中性（SIRNN）前药。 Sirnns代表了一种“前药”方法，其中负面 电荷由生物可逆的磷光化学基团直接中和 在细胞质中裂开，但不在细胞外。限制速率的RNAi交付步骤是逃脱 内体进入细胞质。为了增强内体逃生，我们将合成下一代 内体逃生域（EED）。我们将针对MLL-AF9 SIRNN RNAi触发到AML细胞的递送 通过与抗CD33抗体的结合，称为抗体-RNAI结合物（ARCS）。这个高昂的目标 风险/高收益技术开发建议是通过生成Precision Medicine抗CD33来治疗AML 抗体-RNAI偶联物（ARC）有选择地靶向MLL-AF9融合癌基因并杀死AML 基于其突变遗传学的细胞，但与ADC和RAC不同，对CD33阳性没有影响 正常细胞。