Granzyme B PET imaging as a marker of inflammatory bowel disease activity

颗粒酶 B PET 成像作为炎症性肠病活动的标志物

• 批准号: 10254339
• 负责人: Umar Mahmood
• 金额: $ 57.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254339
• 关键词: Activated Lymphocyte; Affinity; Anti-Inflammatory Agents; Area; Biodistribution; Biological Assay; Biological Markers; Biopsy Specimen; Caring; Cell Death; Clinic; Clinical; Colitis; Crohn' s disease; Cytotoxic T-Lymphocytes; Data; Detection; Diagnostic; Diagnostic Procedure; Disease; Disease Management; Early Diagnosis; Early treatment; Endoscopy; Evaluation; Extracellular Matrix; Functional disorder; Future; Granzyme; Heart failure; Hematologic Neoplasms; Histopathology; Human; Image; Immune response; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestinal Mucosa; Intestines; Leukocytes; Literature; Lymphocyte; Magnetic Resonance Imaging; Measures; Mediating; Methods; Morbidity - disease rate; Mucositis; Mus; Outcome; Patients; Peptides; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Recurrence; Relapse; Research; Risk; Sampling; Serine Protease; Serious Adverse Event; Site; Small Intestines; Societies; Specificity; Specimen; Stains; TNF gene; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Translations; Ulcerative Colitis; White Blood Cell Count procedure; Withholding Treatment; Work; anatomic imaging; base; biomarker evaluation; clinical care; cost; cytokine; cytotoxic; drug development; early detection biomarkers; effector T cell; extracellular; human tissue; imaging agent; imaging modality; improved outcome; indexing; ineffective therapies; inflammatory disease of the intestine; inflammatory marker; insight; leukocyte activation; molecular imaging; molecular marker; mouse model; nervous system disorder; novel; novel diagnostics; personalized approach; personalized medicine; point-of-care diagnostics; predicting response; prevent; rapid detection; rapid test; reduce symptoms; response; side effect; standard of care; stool sample; targeted treatment; temporal measurement; treatment response; uptake

Project Summary/Abstract Inflammatory bowel disease (IBD) is a group of inflammatory disorders associated with significant morbidity and cost to the patients and society. With the absence of a cure, therapy is directed at control of intestinal inflammation using anti-inflammatory and immunosuppressive agents, which have been shown to vastly improve the outcomes and reduce complications. The use of these therapies, however, should only be limited to those with active disease due to high cost and risk of serious adverse events such as serious infections, neurologic disorders, heart failure, and hematologic malignancies. Endoscopy is currently the preferred method of disease activity assessment due to high correlation with clinical outcomes. However, repeated use of endoscopy is limited by its invasiveness, difficult administration, and restricted access to small bowel. Anatomical imaging is helpful in detection of active disease but has limited utility in early response assessment, differentiation of fibrostenotic disease from active inflammation or prediction of disease recurrence. Molecular imaging is currently of unclear clinical value in IBD due to suboptimal specificity and lack of correlation with clinical indices. A biomarker of leukocyte activity may prove to be ideal marker of intestinal inflammation and predictive of response to therapy. Such biomarker can significantly advance IBD management by identifying subclinical inflammation to prevent disease associated complications and reducing the cost and side effects associated with ineffective treatments. Granzyme B (GzmB) is a marker of cytotoxic lymphocyte activity which strongly correlates with disease activity in IBD. It is secreted in the extracellular matrix by activated lymphocytes and can mount a robust inflammatory response by processing proinflammatory cytokines. We have developed a peptide-based PET-imaging agent, 68Ga-NOTA-GZP, with high affinity and specificity for active GzmB and a favorable biodistribution for imaging intestinal inflammation. We have shown in our preliminary data that GZP PET uptake correlates with intestinal inflammation in mouse models and can differentiate vehicle or anti-TNF treated mice. In human tissue specimens of active Crohn’s disease our humanized GZP (hGZP) probe strongly stained the sites of inflammation, while in the normal subjects and quiescent disease did not. Thus, GZP PET imaging offers a unique insight into assessment of active inflammation and early response, not currently possible using other techniques. We propose this study to assess and optimize a novel diagnostic method for assessment of disease activity and early treatment response in IBD. To validate the findings in mouse models for human translation, we will correlate the ex vivo hGZP staining of human tissue specimens with conventional histopathology. Additionally, we will optimize a point of care diagnostic assay for rapid detection of GzmB in stool samples in mouse models and validate in human specimens. We believe non-invasive assessment of active GzmB represents a novel method for repeat assessment of disease activity and early treatment response in IBD with potential to advance care and research in the near future.

项目概要/摘要 炎症性肠病（IBD）是一组与显着发病率相关的炎症性疾病 以及患者和社会的成本。由于无法治愈，治疗的目的是控制肠道 使用抗炎药和免疫抑制剂治疗炎症，已被证明可以大大改善 结果并减少并发症。然而，这些疗法的使用应仅限于那些 由于高成本和严重不良事件（例如严重感染、神经系统疾病）的风险而患有活动性疾病 疾病、心力衰竭和血液系统恶性肿瘤。内窥镜检查是目前疾病的首选方法 由于与临床结果高度相关，因此进行活动评估。然而，内窥镜的重复使用受到限制 由于其侵入性、给药困难以及进入小肠的限制。解剖成像有帮助 用于检测活动性疾病，但在早期反应评估、纤维狭窄分化方面作用有限 来自活动性炎症的疾病或疾病复发的预测。分子影像目前尚不清楚 由于特异性欠佳且缺乏与临床指标的相关性，因此在 IBD 中具有临床价值。的生物标志物 白细胞活性可能被证明是肠道炎症的理想标志并预测治疗反应。 这种生物标志物可以通过识别亚临床炎症来预防炎症，从而显着推进 IBD 管理。 疾病相关的并发症，并减少与无效治疗相关的成本和副​​作用。 颗粒酶 B (GzmB) 是细胞毒性淋巴细胞活性的标志物，与疾病活动密切相关 在炎症性肠病中。它由活化的淋巴细胞分泌在细胞外基质中，可以产生强烈的炎症反应。 通过处理促炎细胞因子做出反应。我们开发了一种基于肽的 PET 成像剂， 68Ga-NOTA-GZP，对活性 GzmB 具有高亲和力和特异性，并且具有良好的成像生物分布 肠道炎症。我们的初步数据表明，GZP PET 摄取与肠道相关 小鼠模型中的炎症，并且可以区分载体或抗 TNF 治疗的小鼠。在人体组织标本中 在活动性克罗恩病的研究中，我们的人源化 GZP (hGZP) 探针对炎症部位进行了强烈染色，而在 正常受试者和静止期疾病则没有。因此，GZP PET 成像提供了独特的见解 评估活动性炎症和早期反应，目前无法使用其他技术。 我们提出这项研究是为了评估和优化一种新的诊断方法，用于评估疾病活动度和 IBD 的早期治疗反应。为了验证用于人类翻译的小鼠模型中的发现，我们将关联 使用常规组织病理学对人体组织标本进行离体 hGZP 染色。此外，我们将 优化护理点诊断测定，以快速检测小鼠模型粪便样本中的 GzmB，以及 在人体样本中进行验证。我们相信活性 GzmB 的非侵入性评估代表了一种新方法 用于重复评估 IBD 的疾病活动性和早期治疗反应，有可能促进护理 并在不久的将来进行研究。