Development and validation of receptor occupancy pharmacodynamic assays used in the clinical development of the monoclonal antibody vedolizumab
Open Access
- 23 April 2015
- journal article
- research article
- Published by Wiley in Cytometry Part B: Clinical Cytometry
- Vol. 90 (2), 168-176
- https://doi.org/10.1002/cyto.b.21236
Abstract
Background Vedolizumab is a monoclonal antibody approved for use in ulcerative colitis and Crohn's disease. By specifically binding to α4β7 integrin, vedolizumab prevents trafficking of lymphocytes to the gut, thereby interfering with disease pathology. During the clinical development program, the pharmacodynamic effect of vedolizumab was evaluated by 2 flow cytometry receptor occupancy assays: act-1 (ACT-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Here we describe the development and validation of these assays. Methods The ACT-1 assay is a receptor occupancy free-site assay that uses a monoclonal antibody with the same binding epitope as vedolizumab to detect free (unbound) sites on α4β7 integrin. The MAdCAM-1 assay used a soluble version of the natural ligand for α4β7 integrin to detect free sites. The assays were validated using a fit-for-purpose approach throughout the clinical development of vedolizumab. Results Both the ACT-1 assay and the MAdCAM-1 assay demonstrated acceptable reproducibility and repeatability. The assays were sufficiently stable to allow for clinical use. During clinical testing the assays demonstrated that vedolizumab was able to saturate peripheral cells at all doses tested. Conclusions Two pharmacodynamic receptor occupancy assays were developed and validated to assess the effect of vedolizumab on peripheral blood cells. The results of these assays demonstrated the practical use of flow cytometry to examine pharmacodynamic response in clinical trials. © 2015 International Clinical Cytometry SocietyKeywords
Funding Information
- Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.)
- inVentiv Medical Communications
- Takeda Pharmaceuticals International, Inc
This publication has 13 references indexed in Scilit:
- Vedolizumab as Induction and Maintenance Therapy for Crohn's DiseaseThe New England Journal of Medicine, 2013
- Vedolizumab as Induction and Maintenance Therapy for Ulcerative ColitisThe New England Journal of Medicine, 2013
- Effect of Tumor Necrosis Factor-α Blockade on Mucosal Addressin Cell-adhesion Molecule-1 in Crohnʼs DiseaseInflammatory Bowel Diseases, 2013
- Vedolizumab for the Treatment of Active Ulcerative Colitis: A Randomized Controlled Phase 2 Dose-ranging StudyInflammatory Bowel Diseases, 2012
- Validation of a flow cytometry based G2M delay cell cycle assay for use in evaluating the pharmacodynamic response to Aurora A inhibitionJournal of Immunological Methods, 2011
- Recommendations for the validation of flow cytometric testing during drug development: II assaysJournal of Immunological Methods, 2011
- The Binding Specificity and Selective Antagonism of Vedolizumab, an Anti-α4β7Integrin Therapeutic Antibody in Development for Inflammatory Bowel DiseasesJournal of Pharmacology and Experimental Therapeutics, 2009
- Validation of a flow cytometry based chemokine internalization assay for use in evaluating the pharmacodynamic response to a receptor antagonistJournal of Translational Medicine, 2008
- α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1Cell, 1993
- MAdCAM-1 has homology to immunoglobulin and mucin-like adhesion receptors and to IgA1Nature, 1993