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特发性肺纤维化（IPF）的有效免疫特药物。特发性肺纤维化（IPF）是一种逐渐纤维化的肺部疾病，自诊断时的平均存活率仅为2 - 3年。高分辨率CT扫描通常可以以高特异性诊断IPF，但CT无法准确预测当前正在评估的治疗方法的预后或反应性。 IPF在疾病进展和发病机理中都是一种明显的异质疾病。在个别患者中，不同的纤维化途径可能或多或少被激活。这种生物学异质性可能是旨在用于药理学IPF疗法的大量临床试验失败的原因。单克隆抗体（mAb）是目前正在临床发育中使用5个单克重的IPF治疗的最有希望的候选者之一。这些mAb之一的STX-100靶向？V？6整合素和？V？6抑制作用已被证明以防止动物模型中的肺纤维化。个性化医学可以极大地改善IPF的药物开发，并最终改善疾病预后。通过成像的方式评估个别患者的目标丰度，可及性和药物吸收，为快速和非侵入性鉴定潜在的治疗反应提供了宝贵的工具。免疫集用长寿命的发射极标记，例如长寿命的PET同位素ZR-89（T1/2 = 78 h），代表了一种可以更好地表征疾病和治疗反应的临床翻译方法。在这个项目中，我们将开发新的双功能螯合剂，用于使用ZR-89进行放射标记和免疫缀合，并将这项新技术与最先进的状态进行比较。我们将应用最佳的螯合剂，以开发针对？6整联蛋白的免疫集探测器。 “ V” 6靶向免疫集探针将用于解决有关基于MAB的IPF和肺病理生物学治疗的4个关键问题：1）可以使用？V？v？v？v？6靶向的免疫集可非侵袭性检测肺纤维化，并且探测摄取是否与疾病的进展相关？ 2）可以使用免疫集在IPF小鼠模型中监测治疗反应，并且在纤维化负担变化之前观察到的PET检测到的变化是否？ 3）在像IPF这样的异质疾病中，静脉内MAB疗法可以达到其所有生物学靶标吗？ 4）当底层nidus不同时，不同模型的肺纤维化模型中的表达会有所不同吗？这项工作的输出将是可以将可以转化为临床试验的“ V” 6靶向免疫集探针的开发，以及针对一般免疫物应用的优化ZR-89标记技术。