Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn's Disease.
J Crohns Colitis
; 12(1): 77-86, 2018 Jan 05.
Article
em En
| MEDLINE
| ID: mdl-28961803
ABSTRACT
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, ß7-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 ß7+ 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 ß7+ effector memory T cells [placebo, 8%; PF-00547659, 84-138%] and ß7+ 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 ß7+ 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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Imunoglobulinas
/
Linfócitos T
/
Doença de Crohn
/
Receptores CCR
/
Anticorpos Monoclonais Humanizados
/
Transcriptoma
/
Mucoproteínas
Tipo de estudo:
Clinical_trials
Limite:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
J Crohns Colitis
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos