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

项目概述/摘要本项目旨在开发一种有效的免疫pet治疗特发性肺纤维化（IPF）的药物。特发性肺纤维化（IPF）是一种进行性纤维化肺病，自诊断起平均生存期仅为2-3年。高分辨率CT扫描通常可以无创诊断IPF，特异性高，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性。IPF在疾病进展和发病机制上都具有明显的异质性。不同的促纤维化途径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针对IPF药理学治疗的临床试验失败的原因。单克隆抗体（mab）是最有希望用于IPF治疗的候选药物之一，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，针对？v？6整合素和？v？在动物模型中，抑制已被证明可以预防肺纤维化。个性化医疗可以极大地促进针对IPF的药物开发，并最终改善疾病的预后。通过影像学评估单个患者的靶标丰度、可及性和药物摄取，为快速、无创地识别治疗的潜在反应提供了宝贵的工具。免疫PET，其中抗体被标记为长寿命的正电子发射器，如长寿命的PET同位素Zr-89 (t1/2 = 78 h)，代表了一种临床可翻译的方法，可以更好地表征疾病和治疗反应。在这个项目中，我们将开发新的双功能螯合剂，用于放射性标记和与Zr-89的免疫偶联，并将这种新技术与最先进的技术进行比较。我们将利用鉴定出的最好的螯合剂开发一种针对？v？6整合素。v ?6靶向免疫pet探针将用于解决关于单抗治疗IPF和肺部病理生物学的4个关键问题：1)能否？靶向免疫pet可用于无创检测肺纤维化，探针摄取与疾病进展相关吗？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)对于像IPF这样的异质性疾病，静脉单抗治疗能否达到所有的生物学靶点？4) ？当肺纤维化病灶不同时，不同肺纤维化模型的表达也不同。这项工作的成果将是一种新型的电子产品的开发。可转化为临床试验的6靶向免疫pet探针，以及针对一般免疫pet应用优化的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 ?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.