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

• 批准号: 8804773
• 负责人: Eszter Boros
• 金额: $ 13.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/8804773
• 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; Mus; Output; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Positron; Positron-Emission Tomography; Property; Pulmonary Fibrosis; Radioimmunoconjugate; Radiolabeled; Specificity; Staging; Techniques; Technology; Therapeutic; Time; Translating; Work; X-Ray Computed Tomography; abstracting; base; design; drug development; imaging modality; immunoreactivity; improved; in vivo; indexing; lung injury; molecular imaging; mouse model; new technology; novel; outcome forecast; personalized medicine; prevent; radiochemical; radiotracer; response; therapeutic target; tool; treatment response; uptake

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 ?v?6 integrin and ?v?6 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 ?v?6 integrin. The ?v?6-targeted immunoPET probe will be used to address 4 key questions regarding mAb-based therapy for IPF and pulmonary pathobiology: 1) Can ?v?6-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 ?v?6 expression vary among different models of pulmonary fibrosis when the underlying nidus is different? The output of this work will be development of an ?v?6-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，自诊断后平均生存期仅为 2-3 年。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 IPF 治疗最有前途的候选药物之一，目前有 5 种 mAb 正在临床开发中。其中一种单克隆抗体 STX-100 以 αvβ6 整合素为靶点，αvβ6 抑制已被证明可以在动物模型中预防肺纤维化。个性化医疗可以极大地改善 IPF 的药物开发并最终改善疾病结果。通过成像评估个体患者的靶点丰度、可及性和药物摄取，为快速、非侵入性地识别治疗的潜在反应提供了宝贵的工具。在免疫PET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小时），代表了一种可临床转化的方法，可以更好地表征疾病和治疗反应。在这个项目中，我们将开发用于放射性标记和 Zr-89 免疫缀合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。我们将应用已确定的最佳螯合剂来开发针对 αvβ6 整合素的免疫PET探针。 ?v?6 靶向免疫 PET 探针将用于解决有关基于 mAb 的 IPF 治疗和肺部病理学的 4 个关键问题：1) ?v?6 靶向免疫 PET 能否用于无创检测肺纤维化以及探针摄取是否相关随着疾病进展？ 2) 免疫PET可以用于监测IPF小鼠模型的治疗反应吗？PET检测到的变化是否在纤维化负荷变化之前观察到？ 3) 对于像IPF这样的异质性疾病，静脉注射mAb疗法能否达到其所有生物学目标？ 4）当潜在病灶不同时，不同肺纤维化模型之间的?v?6 表达是否有所不同？这项工作的成果将是开发一种可转化为临床试验的 αvβ6 靶向免疫 PET 探针，以及用于一般免疫 PET 应用的优化 Zr-89 标记技术。