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治疗特发性肺纤维化(IPF)的有效免疫PET试剂。特发性肺纤维化(IPF)是一种进行性纤维化的肺部疾病，从确诊之日起平均存活期仅为2-3年。高分辨率CT扫描可以无创、特异性高地诊断IPF，但CT不能准确预测预后或对目前正在评估的治疗方法的反应。IPF在疾病进展和发病机制上都是一种明显的异质性疾病。不同的促纤维化途径在个别患者中可能或多或少被激活。这种生物异质性可能是大量针对药理学IPF治疗的临床试验失败的原因。单抗是IPF治疗最有前景的候选抗体之一，目前有5种单抗正在临床开发中。其中一种单抗，STX-100，靶向αv？6整合素和α？v？6抑制，已被证明可以在动物模型中预防肺纤维化。个体化药物可以极大地改善IPF的药物开发，并最终改善疾病结局。通过成像的方式评估靶点丰度、可及性和个体患者的药物摄取，为快速和非侵入性地确定治疗的潜在反应提供了宝贵的工具。免疫正电子发射体用长寿命正电子发射体标记抗体，如长寿命正电子发射体如长寿命正电子发射体铀-89(t1/2=78h)，代表了一种临床上可翻译的方法，以更好地表征疾病和治疗反应。在这个项目中，我们将开发新的用于放射性标记和免疫标记的双功能螯合剂，并将这一新技术与最先进的技术进行比较。我们将把确定的最好的螯合剂应用于针对αv？6整合素的免疫正电子发射计算机断层扫描探针的开发。αv？6-靶向免疫PET探针将用于解决基于单抗治疗肺间质纤维化和肺部病理生物学的4个关键问题：1)αv？6-靶向免疫PET能否用于非侵入性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能否用于监测特发性肺纤维化小鼠模型的治疗反应，以及在纤维化负担改变之前正电子发射计算机断层扫描检测到的变化？3)在像特发性肺纤维化这样的异质性疾病中，静脉注射单抗治疗能达到其所有的生物靶点吗？4)当潜在的病灶不同时，不同的肺纤维化模型中αv？6的表达是否不同？这项工作的成果将是开发一种可转化为临床试验的αvü6靶向免疫正电子发射计算机断层扫描探针，以及优化的用于普通免疫正电子发射计算机断层扫描的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.