Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo.
Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo.
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DOI：
10.7150/thno.20919
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发表时间：
2017
期刊：
影响因子：
12.4
通讯作者：
Thornton CR
中科院分区：
文献类型：
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作者：
Davies G;Rolle AM;Maurer A;Spycher PR;Schillinger C;Solouk-Saran D;Hasenberg M;Weski J;Fonslet J;Dubois A;Boschetti F;Denat F;Gunzer M;Eichner M;Ryder LS;Jensen M;Schibli R;Pichler BJ;Wiehr S;Thornton CR
侵袭性肺曲霉病是由环境真菌烟曲霉引起的恶性血液病或骨髓移植患者的一种危及生命的肺部疾病。目前对该疾病的诊断测试缺乏敏感性和特异性，并且从侵入性肺活检中培养真菌，被认为是IPA检测的金标准，是缓慢的，并且在危重患者中通常是不可能的。在以前的研究中，我们报告了一种新的非侵入性程序IPA诊断的基础上，抗体引导的正电子发射断层扫描和磁共振成像（免疫PET/MRI）使用[64 Cu] DOTA标记的小鼠单克隆抗体（mAb），mJF 5，特异性曲霉。为了使示踪剂能够翻译到临床环境中，我们在这里报告了抗体（hJF 5）的人源化版本的开发，以及使用[64 Cu] NODAGA-hJF 5示踪剂的肺部感染的临床前成像。人源化抗体示踪剂显示A.与其放射性标记的鼠对应物[64 Cu] NODAGA-mJF 5相比，烟曲霉感染的肺。使用病原体的反向遗传学，我们表明抗体结合抗原决定簇β 1，5-呋喃半乳糖（Galf），该抗原决定簇存在于病原体在肺中侵袭性生长期间释放的诊断甘露糖蛋白抗原中。在哺乳动物碳水化合物中不存在表位Galf，加上hJF 5抗体增强的成像能力，意味着这里开发的[64 Cu] NODAGA-hJF 5示踪剂代表了IPA诊断和翻译到临床环境的理想候选物。
Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus. To enable translation of the tracer to the clinical setting, we report here the development of a humanised version of the antibody (hJF5), and pre-clinical imaging of lung infection using a [64Cu]NODAGA-hJF5 tracer. The humanised antibody tracer shows a significant increase in in vivo biodistribution in A. fumigatus infected lungs compared to its radiolabeled murine counterpart [64Cu]NODAGA-mJF5. Using reverse genetics of the pathogen, we show that the antibody binds to the antigenic determinant β1,5-galactofuranose (Galf) present in a diagnostic mannoprotein antigen released by the pathogen during invasive growth in the lung. The absence of the epitope Galf in mammalian carbohydrates, coupled with the enhanced imaging capabilities of the hJF5 antibody, means that the [64Cu]NODAGA-hJF5 tracer developed here represents an ideal candidate for the diagnosis of IPA and translation to the clinical setting.