Development of Zr-89 based ImmunoPET agents for Idiopathic Pulmonary Fibrosis

开发基于 Zr-89 的特发性肺纤维化免疫PET药物

基本信息

批准号：
9146368
负责人：
Eszter Boros
金额：
$ 17.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2015-09-18 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9146368
关键词：
Address Animal Model Antibodies Automobile Driving Biochemical Biological Bleomycin Blood Vessels Chelating Agents Chemistry Clinical Clinical Trials Computer Simulation Deferoxamine Development Diagnosis Disease Disease Outcome Disease Progression Drug Delivery Systems Drug Kinetics Drug Targeting Epithelial Evaluation Failure Fibrosis Fluorescence Half-Life Hamman-Rich syndrome Heterogeneity High Resolution Computed Tomography IgG1 Image In Vitro Individual Injury Integrins Intravenous Isotopes Label Libraries Life Lung Lung diseases Metabolic Methods Modeling Molecular Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Mus Output Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Positron Positron-Emission Tomography Property Pulmonary Fibrosis Radioimmunoconjugate Radiolabeled Specificity Staging Techniques Technology Therapeutic Time Transforming Growth Factor beta Translating Work X-Ray Computed Tomography abstracting base biological heterogeneity design drug development imaging modality immunoreactivity improved in vivo indexing individual patient lung injury molecular imaging mouse model new technology novel outcome forecast personalized approach personalized medicine prevent radiochemical radiotracer response therapeutic target tool treatment response uptake

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract This proposal aims to develop an effective immunoPET agent for idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic lung disease with an average survival of only 2-3 years from the time of diagnosis. High resolution CT scanning can frequently diagnose IPF non-invasively with high specificity, but CT cannot accurately predict prognosis or responsiveness to therapeutic approaches currently under evaluation. IPF is a markedly heterogeneous disease both in disease progression and pathogenesis. Different pro-fibrotic pathways may be more or less activated in individual patients. This biological heterogeneity is the likely cause of failure of a large number of clinical trials aimed at pharmacological IPF therapy. Monoclonal antibodies (mAbs) are among the most promising candidates for IPF therapy with 5 mAbs currently in clinical development. One of these mAbs, STX-100, targets the αvß6 integrin and αvß6 inhibition has been demonstrated to prevent pulmonary fibrosis in animal models. Personalized medicine can greatly improve drug development for IPF and ultimately improve disease outcomes. Evaluation of target abundance, accessibility and drug uptake in individual patients by way of imaging provides an invaluable tool for the rapid and non-invasive identification of the potential response to therapy. ImmunoPET, where the antibody is labeled with a long-lived positron emitter such as the long-lived PET isotope Zr-89 (t1/2 = 78 h), represents a clinically translatable approach to better characterizing disease and treatment response. In this project we will develop new bifunctional chelators for radiolabeling and immunoconjugation with Zr-89 and compare this new technology with the state of the art. We will apply the best chelators identified to the development of an immunoPET probe targeting the αvß6 integrin. The αvß6-targeted immunoPET probe will be used to address 4 key questions regarding mAb-based therapy for IPF and pulmonary pathobiology: 1) Can αvß6-targeted immunoPET be used to noninvasively detect pulmonary fibrosis and does probe uptake correlate with disease progression? 2) Can immunoPET be used to monitor treatment response in an IPF mouse model, and are the changes detected by PET observed prior to changes in fibrotic burden? 3) In a heterogeneous disease like IPF, can the intravenous mAb therapy reach all of its biological target? 4) Does αvß6 expression vary among different models of pulmonary fibrosis when the underlying nidus is different? The output of this work will be development of an αvß6-targeted immunoPET probe that can be translated to clinical trials, as well as optimized Zr-89 labeling technology for general immunoPET applications.

描述（由申请人提供）：项目摘要/摘要该提案旨在开发一种有效治疗特发性肺纤维化（IPF）的免疫PET药物。特发性肺纤维化（IPF）是一种进行性纤维化肺部疾病，平均生存期仅为2-3年。从诊断时起，高分辨率 CT 扫描通常可以以高特异性非侵入性地诊断 IPF，但 CT 无法准确预测预后或对目前正在评估的治疗方法的反应。 IPF 是一种在疾病进展和发病机制上都具有明显异质性的疾病，不同的促纤维化途径可能在个体患者中或多或少地被激活，这种生物异质性可能是大量针对 IPF 药物治疗的临床试验失败的原因。单克隆抗体 (mAb) 是最有前途的 IPF 治疗候选药物之一，目前有 5 种单克隆抗体正在临床开发中，其中一种单克隆抗体 STX-100 靶向 αvß6 整合素和 αvß6 整合素。 αvß6 抑制已被证明可以在动物模型中抑制肺纤维化，从而极大地改善 IPF 的药物开发，并最终改善通过影像学方式预防个体患者的靶点丰度、可及性和药物摄取，为治疗 IPF 提供了宝贵的工具。快速、非侵入性地识别对治疗的潜在反应，其中抗体用长寿命正电子发射体标记，例如长寿命 PET 同位素 Zr-89 (t1/2 = 78 h），代表了一种可更好地表征疾病和治疗反应的临床可转化方法，在该项目中，我们将开发用于放射性标记和 Zr-89 免疫偶联的新型双功能螯合剂，并将这项新技术与现有技术进行比较。确定用于开发针对 αvß6 整合素的免疫PET探针的最佳螯合剂靶向αvß6的免疫PET探针将用于解决有关基于mAb的4个关键问题。 IPF 治疗和肺部病理学：1) αvß6 靶向免疫 PET 能否用于无创检测肺纤维化，探针摄取是否与疾病进展相关？ 2) 免疫 PET 能否用于监测 IPF 小鼠模型的治疗反应，变化是什么？在纤维化负荷变化之前通过 PET 检测到？ 3) 在 IPF 这样的异质性疾病中，静脉注射 mAb 疗法能否达到其所有生物学目标？当潜在的病灶不同时，αvß6 表达在不同的肺纤维化模型中会有所不同？这项工作的成果将是开发可转化为临床试验的 αvß6 靶向免疫 PET 探针，以及针对一般情况的优化 Zr-89 标记技术。免疫PET应用。