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: 10166793
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166793
• 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; 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 relapse; 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.

项目摘要 门冬酰胺酶是治疗小儿急性淋巴细胞白血病的主要药物之一 白血病（ALL）。ASNase最常见的不良反应是免疫反应的发展， 会影响药物暴露并导致更差的治疗结果。因此， 预防或克服对ASNase的免疫应答并保持足够的药物暴露是迫切需要的。 聚乙二醇化ASNase（PEG-ASNase）是用于ALL治疗的一线药物， 治疗期间的免疫毒性。 我们的初步研究结果表明：1）ASNase诱导的免疫应答可以减少药物暴露 通过直接药物中和和通过加速ASNase的药代动力学清除; 2）治疗性 PEG-ASNase致敏后可达到药物水平，但可能需要比未致敏患者更高的药物剂量 患者达到相似的治疗效果; 3）携带者中ASNase超敏反应的风险较高 活化T细胞的核因子，细胞质，钙调神经磷酸酶依赖性2（NFATC 2）rs6021191变体， 这导致参与免疫应答调节的该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;以及 5)我们建立了两种可移植性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对PEG-ASNase的反应 浓度可以维持PEG-ASNase的抗白血病特性。(2)遗传和 NFATC 2的药理学抑制可以防止或减弱对PEG-ASNase的致敏。(3)IgG 和/或IgE介导的外周血细胞（PBMC）与PEG-ASNase的结合可用作生物标志物 免疫毒性。我们提出了三个具体的目标来检验我们的假设：1）确定是否结合 阻断超敏反应介质的预处理药物和PEG-ASNase剂量调整可 使用PEG-ASNase的两种小鼠模型克服免疫应答并保持抗白血病功效 超敏反应和B细胞ALL; 2）确定抑制NFAT通路是否可以防止致敏 PEG-ASNase和维持抗白血病功效;和3）确定是否可以鉴定致敏的PBMC 通过使用流式细胞术离体结合荧光标记的PEG-ASNase。 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- ASNase。这三个目标并不相互依赖，但在逻辑上是相关的，其唯一重点是改善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。 预防药物诱导的免疫反应，并确保患者获得足够的PEG-ASNase ALL治疗期间的暴露。

项目成果

Adalimumab Immunogenicity Is Negatively Correlated with Anti-Hinge Antibody Levels in Patients with Rheumatoid Arthritis.

阿达木单抗免疫原性与类风湿关节炎患者的抗铰链抗体水平呈负相关。

• DOI: 10.1124/jpet.120.000179
• 发表时间: 2020
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Hoshitsuki,Keito;Rathod,Sanjay;Ramsey,MandaJ;Zhu,Lei;Moreland,LarryW;Fernandez,ChristianA
• 通讯作者: Fernandez,ChristianA

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice.

• DOI: 10.1016/j.apsb.2021.11.022
• 发表时间: 2021-12
• 期刊: Acta pharmaceutica Sinica. B
• 作者: Kumar GVN;Hoshitsuki K;Rathod S;Ramsey MJ;Kokai L;Kershaw EE;Xie W;Fernandez CA
• 通讯作者: Fernandez CA

Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias.

• DOI: 10.3389/fonc.2021.694526
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Bhingarkar A;Vangapandu HV;Rathod S;Hoshitsuki K;Fernandez CA
• 通讯作者: Fernandez CA

Pharmacogenomics for Drug Dosing in Children: Current Use, Knowledge, and Gaps.

儿童药物剂量的药物基因组学：当前使用，知识和差距。

• DOI: 10.1002/jcph.1891
• 发表时间: 2021-06
• 期刊: Journal of clinical pharmacology
• 影响因子: 2.9
• 作者: Hoshitsuki K;Fernandez CA;Yang JJ
• 通讯作者: Yang JJ

Asparaginase immune complexes induce Fc-γRIII-dependent hypersensitivity in naive mice.

天冬酰胺酶免疫复合物在幼鼠中诱导 Fc-γRIII 依赖性超敏反应。

• DOI: 10.1096/fj.201900857
• 发表时间: 2019
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Rathod,Sanjay;Ramsey,Manda;DiGiorgio,Danielle;Berrios,Roberto;Finkelman,FredD;Fernandez,ChristianA
• 通讯作者: Fernandez,ChristianA