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

描述（由申请人提供）：项目摘要/摘要本提案旨在开发一种有效的免疫PET药物治疗特发性肺纤维化（IPF）。特发性肺纤维化（IPF）是一种进行性纤维化肺部疾病，从诊断时起平均生存期仅为2-3年。高分辨率CT扫描通常可以以高特异性非侵入性方式诊断IPF，但CT无法准确预测预后或目前正在评估的治疗方法的反应性。IPF是一种在疾病进展和发病机制方面均具有显著异质性的疾病。不同的促纤维化途径可能在个体患者中或多或少被激活。这种生物学异质性可能是大量旨在进行IPF药物治疗的临床试验失败的原因。单克隆抗体（mAb）是IPF治疗最有希望的候选药物之一，目前有5种mAb处于临床开发阶段。这些mAb之一，STX-100，靶向α v β 6整联蛋白，并且α v β 6抑制已被证明在动物模型中预防肺纤维化。个体化用药可以大大改善IPF的药物开发，并最终改善疾病结局。通过成像评估个体患者的靶丰度、可及性和药物摄取，为快速和非侵入性地识别对治疗的潜在反应提供了宝贵的工具。免疫PET，其中抗体标记有长寿命正电子发射体，如长寿命PET同位素Zr-89（t1/2 = 78 h），代表了一种临床上可转化的方法，以更好地表征疾病和治疗反应。在本项目中，我们将开发新的双功能螯合剂，用于放射性标记和与Zr-89的免疫缀合，并将这种新技术与最先进的技术进行比较。我们将应用已鉴定的最佳螯合剂开发靶向α v β 6整合素的免疫PET探针。α v β 6靶向免疫PET探针将用于解决关于基于mAb的IPF治疗和肺病理学的4个关键问题：1）α v β 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，PET检测到的变化是否先于纤维化负荷的变化？3)在IPF这样的异质性疾病中，静脉单克隆抗体治疗能否达到其所有生物学靶点？4)当潜在病灶不同时，α v β 6的表达在不同的肺纤维化模型中是否不同？这项工作的成果将是开发一种可用于临床试验的α v β 6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。

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.