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

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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.