Improving the disposition of antileukemic asparaginase after drug-induced immunotoxicity

改善药物引起的免疫毒性后抗白血病天冬酰胺酶的处置

• 批准号: 9927599
• 负责人: Christian Antonio Fernandez
• 金额: $ 32.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-07 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927599
• 关键词: Acute Lymphocytic Leukemia; Adverse reactions; Antibodies; Antigen-Antibody Complex; Antigens; Attenuated; Autoimmune Diseases; B-Cell Acute Lymphoblastic Leukemia; Binding; Biological Markers; Blood Cells; Calcineurin; Cause of Death; Cells; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Clinical; Corticosteroid Receptors; Data; Development; Dipyridamole; Dose; Drug Exposure; Drug Kinetics; Drug toxicity; Drug usage; Ensure; Enzymes; Escherichia coli; Flow Cytometry; Genetic; Goals; Half-Life; Histamine Antagonists; Hypersensitivity; IgE; Immune response; Immunoglobulin G; Immunologic Monitoring; Incidence; Label; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Monitor; Mus; NFAT Pathway; PDGFRB gene; Patients; Pegaspargase; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Platelet Activating Factor; Property; Proteins; Reaction; Relapse; Rheumatoid Arthritis; Risk; Sampling; Testing; Therapeutic; Therapeutic Effect; Treatment outcome; Variant; Work; asparaginase; base; bcr-abl Fusion Proteins; design; drug efficacy; high risk; immunogenicity; immunoregulation; immunotoxicity; improved; inhibitor/antagonist; leukemia; leukemia treatment; mouse model; nuclear factors of activated T-cells; prevent; receptor; transcription factor; transplant model

Project Summary Asparaginase (ASNase) is one of the main drugs used for the treatment of pediatric acute lymphoblastic leukemia (ALL). The most common adverse reaction of ASNase is the development of an immune response that can compromise drug exposure and lead to worse treatment outcome. Therefore, therapeutic strategies that prevent or overcome the immune response to ASNase and retain sufficient drug exposure are urgently needed. PEGylated ASNase (PEG-ASNase) is the first-line agent used for ALL therapy, and it remains prone to immunotoxicity during treatment. Our preliminary results showed that: 1) ASNase-induced immune responses can decrease drug exposure through direct drug neutralization and by accelerating the pharmacokinetic clearance of ASNase; 2) therapeutic drug levels can be attained after sensitization to PEG-ASNase but may require drug doses higher than in naïve patients to achieve similar therapeutic effects; 3) there is a higher risk of ASNase hypersensitivity among carriers of the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) rs6021191 variant, which leads to higher expression of this transcription factor involved in the regulation of immune responses; 4) both IgG and IgE antigen-specific antibodies are involved in the mechanism of ASNase hypersensitivity, which will be used to facilitate the development of a cell-based approach to monitor PEG-ASNase immunogenicity; and 5) we have established two mouse models of transplantable B cell ALL that can be used to study drug efficacy and toxicity. Based on these observations, we hypothesize that (1) pretreatment strategies that can overcome immune responses to PEG-ASNase by blocking the mediators of hypersensitivity and restoring drug concentrations can maintain the antileukemic properties of PEG-ASNase. (2) Genetic and pharmacological inhibition of NFATC2 can prevent or attenuate sensitization to PEG-ASNase. (3) IgG and/or IgE-mediated binding of peripheral blood cells (PBCs) to PEG-ASNase can be used as a biomarker of immunotoxicity. We propose three specific aims to test our hypotheses: 1) to determine whether combining pretreatment drugs that block the mediators of hypersensitivity and PEG-ASNase dose adjustments can overcome immune responses and retain antileukemic efficacy using two murine models of PEG-ASNase hypersensitivity and B cell ALL; 2) to determine whether inhibition of the NFAT pathway can prevent sensitization to PEG-ASNase and maintain antileukemic efficacy; and 3) to determine if sensitized PBCs can be identified through their binding to fluorescently labeled PEG-ASNase ex vivo using flow cytometry. The proposed work will identify strategies to overcome, prevent, and monitor the immune response to PEG- ASNase. The three aims are not interdependent but are logically related with a singular focus on improving PEG- ASNase therapy. The long-term goal of this project is to improve pediatric ALL survival by overcoming or preventing the drug-induced immune response and ensuring that patients receive adequate PEG-ASNase exposure during ALL treatment.

项目概要 天冬酰胺酶（ASNase）是治疗小儿急性淋巴细胞白血病的主要药物之一。 白血病（全部）。 ASNase 最常见的不良反应是产生免疫反应， 可能会影响药物暴露并导致更差的治疗结果。因此，治疗策略 迫切需要预防或克服对 ASNase 的免疫反应并保持足够的药物暴露。 聚乙二醇化 ASNase (PEG-ASNase) 是用于 ALL 治疗的一线药物，但仍然容易发生 治疗期间的免疫毒性。 我们的初步结果表明：1）ASNase 诱导的免疫反应可以减少药物暴露 通过直接药物中和并加速 ASNase 的药代动力学清除； 2）治疗性 对 PEG-ASNase 致敏后可以达到药物水平，但可能需要比初始剂量更高的药物剂量 患者达到类似的治疗效果； 3）携带者发生ASNase过敏的风险较高 活化 T 细胞核因子、细胞质、钙调神经磷酸酶依赖性 2 (NFATC2) rs6021191 变体， 这导致参与免疫反应调节的转录因子的更高表达； 4） IgG 和 IgE 抗原特异性抗体都参与 ASNase 超敏反应的机制， 将用于促进基于细胞的方法的开发，以监测 PEG-ASNase 免疫原性；和 5）我们建立了两种可移植B细胞ALL小鼠模型，可用于研究药物疗效 和毒性。 基于这些观察，我们假设（1）可以克服免疫的预处理策略 通过阻断超敏反应介质和恢复药物来对 PEG-ASNase 做出反应 浓度可以维持 PEG-ASNase 的抗白血病特性。 (2) 遗传和 NFATC2 的药理学抑制可以预防或减弱对 PEG-ASNase 的敏感性。 (3) 免疫球蛋白G 和/或 IgE 介导的外周血细胞 (PBC) 与 PEG-ASNase 的结合可用作生物标志物 的免疫毒性。我们提出三个具体目标来检验我们的假设：1）确定是否结合 阻断过敏介质的预处理药物和 PEG-ASNase 剂量调整可以 使用 PEG-ASNase 的两种小鼠模型克服免疫反应并保留抗白血病功效 超敏反应和 B 细胞 ALL； 2) 确定抑制NFAT通路是否可以预防致敏 PEG-ASNase 并维持抗白血病功效； 3) 确定是否可以识别致敏 PBC 通过流式细胞术将它们与荧光标记的 PEG-ASNase 离体结合。 拟议的工作将确定克服、预防和监测对 PEG- 的免疫反应的策略 氨基酸酶。这三个目标并不相互依赖，但在逻辑上是相关的，都集中于改善 PEG- ASNase 疗法。该项目的长期目标是通过克服或改善儿童 ALL 的生存率 预防药物引起的免疫反应并确保患者接受足够的 PEG-ASNase ALL 治疗期间的暴露。