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: 10641731
• 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/10641731
• 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; Prediction of Response to Therapy; Recurrence; Recurrent disease; 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; access restrictions; anatomic imaging; biomarker evaluation; clinical care; cost; cytokine; cytotoxic; drug development; early detection biomarkers; effector T cell; efficacy evaluation; extracellular; gut inflammation; human tissue; imaging agent; imaging modality; improved outcome; indexing; ineffective therapies; 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; 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.

项目摘要/摘要 炎症性肠病（IBD）是一组与明显发病率相关的炎症性疾病 并为患者和社会成本。由于缺乏治疗，治疗针对肠道控制 使用抗炎和免疫抑制剂的炎症，已证明可以大大改善 结果并减少并发症。但是，这些疗法的使用仅应限于 由于高成本和严重不良事件的风险，例如严重感染，神经系统疾病 疾病，心力衰竭和血液学恶性肿瘤。内窥镜检查是目前首选的疾病方法 由于与临床结局的高相关性，活动评估。但是，反复使用内镜是有限的 由于其侵入性，艰难的管理和限制进入小肠的机会。解剖成像很有帮助 在检测活性疾病但在早期反应评估中的效用有限，纤维雌激素分化 活跃的炎症或疾病复发的疾病。分子成像目前尚不清楚 IBD的临床价值由于特异性次优，并且与临床指数缺乏相关性。一个生物标志物 白细胞活性可能被证明是肠道炎症和对治疗反应的预测的理想标志。 这种生物标志物可以通过识别亚临床炎症来大大提高IBD管理 疾病相关并发症，并降低与无效治疗相关的成本和副​​作用。 Granzyme B（GZMB）是细胞毒性淋巴细胞活性的标记，与疾病活性密切相关 在IBD中。它是通过活化的淋巴细胞在细胞外基质中分泌的，可以安装强大的炎症 通过处理促炎细胞因子的反应。我们已经开发了基于肽的宠物成像剂， 68GA-NOTA-GZP，具有高亲和力和针对活性GZMB的特异性和成像的有利生物分布 肠炎。我们在初步数据中显示了GZP PET的吸收与肠道相关 在小鼠模型中的人体组织标本中，可以区分媒介物或抗TNF处理的小鼠。 在活跃的克罗恩病中，我们人源化的GZP（HGZP）探测炎症部位的强烈染色，而在 正常的受试者和静止疾病没有。那就是GZP PET成像提供了独特的见解 评估主动感染和早期反应，目前无法使用其他技术。 我们建议这项研究评估和优化一种新型诊断方法，以评估疾病活动和 IBD的早期治疗反应。为了验证鼠标模型中的发现结果，我们将相关 人体组织标本的离体HGZP染色具有常规组织病理学。此外，我们会的 优化一种护理点诊断测定方法，以快速检测小鼠模型中的粪便样品中的GZMB和 在人类标本中进行验证。我们认为，主动GZMB的非侵入性评估代表了一种新方法 为了重复评估IBD的疾病活动和早期治疗反应，并有可能提高护理 和不久的将来的研究。