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Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease
OBJECTIVE: To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn’s disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. METHODS: In this Phase 2, randomised, double-blind, controlled stud...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881777/ https://www.ncbi.nlm.nih.gov/pubmed/28961803 http://dx.doi.org/10.1093/ecco-jcc/jjx121 |
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author | Hassan-Zahraee, Mina Banerjee, Anindita Cheng, John B Zhang, Weidong Ahmad, Alaa Page, Karen von Schack, David Zhang, Baohong Martin, Steven W Nayak, Satyaprakash Reddy, Padma Xi, Li Neubert, Hendrik Fernandez Ocana, Mireia Gorelick, Ken Clare, Robert Vincent, Michael Cataldi, Fabio Hung, Kenneth |
author_facet | Hassan-Zahraee, Mina Banerjee, Anindita Cheng, John B Zhang, Weidong Ahmad, Alaa Page, Karen von Schack, David Zhang, Baohong Martin, Steven W Nayak, Satyaprakash Reddy, Padma Xi, Li Neubert, Hendrik Fernandez Ocana, Mireia Gorelick, Ken Clare, Robert Vincent, Michael Cataldi, Fabio Hung, Kenneth |
author_sort | Hassan-Zahraee, Mina |
collection | PubMed |
description | OBJECTIVE: To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn’s disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. METHODS: In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12. Soluble MAdCAM [sMAdCAM] was measured by mass spectrometry, β7-expressing T cells by flow cytometry, and gene transcriptome by RNA sequencing. RESULTS: A slight increase in sMAdCAM was measured in the placebo group from baseline to Week 12 [6%], compared with significant decreases in all PF-00547659 groups [–87% to –98%]. A slight increase from baseline to Week 12 was observed in frequency and molecules of equivalent soluble fluorochrome for β7+ central memory T cells in the placebo group [4%], versus statistically significant increases in the active treatment groups [48% to 81%]. Similar trends were seen for β7+ effector memory T cells [placebo, 8%; PF-00547659, 84–138%] and β7+ naïve T cells [8%; 13–50%]. CCR9 gene expression had statistically significant up-regulation [p = 1.09e-06; false discovery rate < 0.1] with PF-00547659 treatment, and was associated with an increase in β7+ T cells. CONCLUSIONS: Results of the OPERA study demonstrate positive pharmacology and dose-dependent changes in pharmacodynamic biomarker measurements in blood, including changes in cellular composition of lymphocytes and corresponding CCR9 gene expression changes. |
format | Online Article Text |
id | pubmed-5881777 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58817772018-04-06 Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease Hassan-Zahraee, Mina Banerjee, Anindita Cheng, John B Zhang, Weidong Ahmad, Alaa Page, Karen von Schack, David Zhang, Baohong Martin, Steven W Nayak, Satyaprakash Reddy, Padma Xi, Li Neubert, Hendrik Fernandez Ocana, Mireia Gorelick, Ken Clare, Robert Vincent, Michael Cataldi, Fabio Hung, Kenneth J Crohns Colitis Original Articles OBJECTIVE: To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn’s disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. METHODS: In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12. Soluble MAdCAM [sMAdCAM] was measured by mass spectrometry, β7-expressing T cells by flow cytometry, and gene transcriptome by RNA sequencing. RESULTS: A slight increase in sMAdCAM was measured in the placebo group from baseline to Week 12 [6%], compared with significant decreases in all PF-00547659 groups [–87% to –98%]. A slight increase from baseline to Week 12 was observed in frequency and molecules of equivalent soluble fluorochrome for β7+ central memory T cells in the placebo group [4%], versus statistically significant increases in the active treatment groups [48% to 81%]. Similar trends were seen for β7+ effector memory T cells [placebo, 8%; PF-00547659, 84–138%] and β7+ naïve T cells [8%; 13–50%]. CCR9 gene expression had statistically significant up-regulation [p = 1.09e-06; false discovery rate < 0.1] with PF-00547659 treatment, and was associated with an increase in β7+ T cells. CONCLUSIONS: Results of the OPERA study demonstrate positive pharmacology and dose-dependent changes in pharmacodynamic biomarker measurements in blood, including changes in cellular composition of lymphocytes and corresponding CCR9 gene expression changes. Oxford University Press 2018-01 2017-09-07 /pmc/articles/PMC5881777/ /pubmed/28961803 http://dx.doi.org/10.1093/ecco-jcc/jjx121 Text en © The Author 2017. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Hassan-Zahraee, Mina Banerjee, Anindita Cheng, John B Zhang, Weidong Ahmad, Alaa Page, Karen von Schack, David Zhang, Baohong Martin, Steven W Nayak, Satyaprakash Reddy, Padma Xi, Li Neubert, Hendrik Fernandez Ocana, Mireia Gorelick, Ken Clare, Robert Vincent, Michael Cataldi, Fabio Hung, Kenneth Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease |
title | Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease |
title_full | Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease |
title_fullStr | Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease |
title_full_unstemmed | Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease |
title_short | Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease |
title_sort | anti-madcam antibody increases ß7+ t cells and ccr9 gene expression in the peripheral blood of patients with crohn’s disease |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881777/ https://www.ncbi.nlm.nih.gov/pubmed/28961803 http://dx.doi.org/10.1093/ecco-jcc/jjx121 |
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