Molecular Profiling of Ulcerative Colitis Subjects from the TURANDOT Trial Reveals Novel Pharmacodynamic/Efficacy Biomarkers
| العنوان: | Molecular Profiling of Ulcerative Colitis Subjects from the TURANDOT Trial Reveals Novel Pharmacodynamic/Efficacy Biomarkers |
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| المؤلفون: | Mina Hassan-Zahraee, Michael S. Vincent, Julie Lee, Mateusz Maciejewski, Vivek Pradhan, Shanrong Zhao, Yutian Zhan, David von Schack, Huanyu Zhou, Kenneth J. Gorelick, Zachary S. Stewart, Lori Fitz, Shawn P. O'Neil, Ying Zhang, Austin Huang, Li Xi, Karen Page, Kenneth E. Hung, Daniel Ziemek, Fabio Cataldi, Baohong Zhang |
| المصدر: | Journal of Crohn's & Colitis |
| بيانات النشر: | Oxford University Press (OUP), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Proteomics, 0301 basic medicine, Colon, CCR9, Antibodies, Monoclonal, Humanized, Inflammatory bowel disease, Vedolizumab, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, inflammatory bowel disease, Biopsy, medicine, Addressin, MAdCAM-1, Humans, Dose-Response Relationship, Drug, biology, medicine.diagnostic_test, business.industry, PF-00547659, Gene Expression Profiling, Cell Adhesion Molecule-1, Gastroenterology, Oncostatin M, biomarkers, Original Articles, General Medicine, medicine.disease, Ulcerative colitis, Treatment Outcome, 030104 developmental biology, Immunology, biology.protein, Colitis, Ulcerative, 030211 gastroenterology & hepatology, business, medicine.drug |
| الوصف: | Background and Aims To define pharmacodynamic and efficacy biomarkers in ulcerative colitis [UC] patients treated with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody, in the TURANDOT study. Methods Transcriptome, proteome and immunohistochemistry data were generated in peripheral blood and intestinal biopsies from 357 subjects in the TURANDOT study. Results In peripheral blood, C-C motif chemokine receptor 9 [CCR9] gene expression demonstrated a dose-dependent increase relative to placebo, but in inflamed intestinal biopsies CCR9 gene expression decreased with increasing PF-00547659 dose. Statistical models incorporating the full RNA transcriptome in inflamed intestinal biopsies showed significant ability to assess response and remission status. Oncostatin M [OSM] gene expression in inflamed intestinal biopsies demonstrated significant associations with, and good accuracy for, efficacy, and this observation was confirmed in independent published studies in which UC patients were treated with infliximab or vedolizumab. Compared with the placebo group, intestinal T-regulatory cells demonstrated a significant increase in the intermediate 22.5-mg dose cohort, but not in the 225-mg cohort. Conclusions CCR9 and OSM are implicated as novel pharmacodynamic and efficacy biomarkers. These findings occur amid coordinated transcriptional changes that enable the definition of surrogate efficacy biomarkers based on inflamed biopsy or blood transcriptomics data. ClinicalTrials.gov identifier NCT01620255 |
| تدمد: | 1876-4479 1873-9946 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d78295909580def005dec0596bf95fb5 https://doi.org/10.1093/ecco-jcc/jjy217 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d78295909580def005dec0596bf95fb5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18764479 18739946 |
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