PET IMAGING CCR2 IN LUNG INFLAMMATION

 描述(由申请人提供)：肺部炎症可能是急性和慢性肺部疾病最恒定的特征，免疫细胞类型已被用于尝试对患者的表型进行分类。然而，可靠地检测和监测这种病理特征的能力一直是一个挑战。趋化因子引导携带同源受体的炎性细胞群体的迁移。细胞表面趋化因子(C-C基序)受体2(CCR2)及其配体CCL2是炎性单核细胞迁移的重要介质，并调节免疫细胞群的成熟。CCR2/CCL2轴在急性和慢性肺部疾病中都是活跃的，如急性肺损伤、肺移植后的原发移植物功能障碍、哮喘和慢性阻塞性肺疾病(COPD)。我们已经鉴定出一种7个氨基酸的多肽ECL1i，它能与CCR2受体特异性结合。64Cu-DOTA-ECL1i作为示踪剂组装后，在小鼠体内稳定，排泄迅速。当在多种急性和慢性肺损伤模型中进行评估时，静脉注射64CuDOTA-ECL1i在肺中提供了与单核细胞迁移相关的强大的正电子发射断层扫描(PET)信号。在利用CCR2充足和缺乏小鼠的临床前肺部疾病模型中进行的PET成像表明，64CuDOTA-ECL1i对于检测低水平的炎症是敏感的，并且对于识别与CCR2表达的免疫细胞相关的PET信号是特异的。此外，在表现出CCR2水平升高的晚期COPD患者的人肺组织中，ECL1i探针检测到CCR2表达增加并与免疫细胞结合，表明与人CCR2有亲和力。我们推测64Cu-DOTA-ECL1i可作为一种灵敏、特异和安全的放射示踪剂用于正电子发射计算机断层扫描(PET)检测肺部疾病中CCR2导向的炎症。我们的目标是(1)在小鼠肺损伤模型中测试特异性、敏感性和稳定性，(2)在细胞和人肺组织中表征针对人CCR2的BINDIG，(3)在0期临床安全性试验中将64Cu-DOTA-ECL1i翻译给人类。我们认为，肺中CCR2的无创PET成像可以特异性地表征个体的炎症状态和疾病活动。这将为急性和慢性肺部疾病的个性化治疗提供一个独特的机会来确定免疫学反应。(摘要结束)

 DESCRIPTION (provided by applicant):Summary Lung inflammation is perhaps the most constant feature of acute and chronic lung disease, and immune cell types have been used to attempt to classify patient phenotypes. However, the ability to reliably detect and monitor this pathologic feature has been a challenge. Chemokines guide the migration of populations of inflammatory cells that harbor their cognate receptor. Cell surface chemokine (C-C motif) receptor 2 (CCR2) and ligand CCL2 are essential mediators of inflammatory monocyte migration and modulate the maturation of immune cell populations. The CCR2/CCL2 axis is active in both acute and chronic lung diseases, such as acute lung injury, primary graft dysfunction following lung transplantation, asthma and chronic obstructive pulmonary disease (COPD). We have identified a 7 amino acid peptide, ECL1i, which specifically binds to the CCR2 receptor. When assembled as a radiotracer, 64Cu-DOTA-ECL1i, was stable in mice and rapidly excreted. When assessed in multiple models of acute and chronic lung injury, intravenous injection of 64Cu- DOTA-ECL1i provided a robust positron emission tomography (PET) signal in the lung associated with monocyte migration. PET imaging in preclinical mouse models of lung disease that utilized CCR2 sufficient and deficient mice demonstrated that 64Cu-DOTA-ECL1i is sensitive for the detection of low levels of inflammation and specific for identifying PET signals related to CCR2-expressing immune cells. Moreover, in human lung tissues from subjects with advanced COPD displaying increased CCR2 levels, ECL1i probes detected increased CCR2 expression and bound immune cells, suggesting an affinity for human CCR2. We hypothesize that 64Cu-DOTA-ECL1i performs as a sensitive, specific and safe radiotracer for PET detection of CCR2- directed inflammation in lung disease. Our aims will (1) test the specificity, sensitivity and stability in mouse lung injury models, (2) characterize bindig to human CCR2 in cells and human lung tissue and (3) translate 64Cu-DOTA-ECL1i to humans in a Phase 0 clinical safety trial. We propose that non-invasive PET imaging of CCR2 in the lung can specifically characterize an individual's inflammatory status and disease activity. This will provide a unique opportunity to define the immunologic response for personalized management in acute and chronic lung diseases. (End of Abstract)