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Cytometry B Clin Cytom. 2016 Mar;90(2):141-9. doi: 10.1002/cyto.b.21339. Epub 2016 Feb 22.

Recommendations for the development and validation of flow cytometry-based receptor occupancy assays.

Author information

1
Amgen, Inc, 1 Amgen Center Drive, Mailstop 30E-3-C, Thousand Oaks, California, 91320.
2
Flow Contract Site Laboratory, LLC, 13029 NE 126th PL, Unit A229, Kirkland, Washington, 98034.
3
Novo Nordisk a/S, Novo Nordisk Park, Måløv, DK, 2760, Denmark.
4
Laboratory Corporation of America® Holdings, LabCorp Clinical Trials, 201 Summit View Dr, Suite 200, Brentwood, Tennessee, 37027.
5
Medimmune, LLC, 319 North Bernardo Avenue, Mountain View, California, 94043.
6
Alnylam Pharmaceuticals, Bioanalytical Sciences, 300 Third Street, Cambridge, Massachusetts, 02142.
7
BioCytex, 140 Chemin De L'armée D'afrique, Marseille, 13010, France.
8
7 Rue Moïse-Marcinhes, Geneva, Meyrin, 1217, Switzerland.
9
ICON Laboratory Services, 123 Smith Street, Farmingdale, New York, 11735.
10
PRA Healthsciences, Amerikaweg 18, Assen, TK, 9407, The Netherlands.
11
Charles River Laboratories International, Inc, 6995 Longley Lane, Reno, Nevada, 89511.
12
Eurofins Pharma Bioanalysis Services UK Limited, 91 Park Drive, Milton Park Abingdon, OX14 4RY, United Kingdom.
13
Takeda Pharmaceuticals, 35 Landsdown St, Cambridge, Massachusetts, 02139.
14
Covance Central Laboratory Services, 8211 SciCor Dr, Indianapolis, Indiana, 46214.

Abstract

Receptor occupancy measurements demonstrate the binding of a biotherapeutic agent to its extra-cellular target and represent an integral component of the pharmacodynamic (PD) portfolio utilized to advance the development and commercialization of a therapeutic agent. Coupled with traditional pharmacokinetic (PK) assessments derived from serum drug concentration, receptor occupancy data can be used to model PK/PD relationships and validate dose selection decisions throughout the drug development lifecycle. Receptor occupancy assays can be even more challenging to develop than other flow cytometric methods (e.g. surface immunophenotyping). In addition to typical considerations regarding stability of the cell type of interest, stability of the target-bound therapeutic agent and stability of the target receptor must be taken into account. Reagent selection is also challenging as reagents need to be evaluated for the potential to compete with the therapeutic agent and bind with comparable affinity. This article provides technical guidance for the development and validation of cytometry-based receptor occupancy assays.

KEYWORDS:

biotherapeutic; flow cytometry; pharmacodynamic biomarker; pharmacokinetics; receptor occupancy; target binding

PMID:
26566147
DOI:
10.1002/cyto.b.21339
[Indexed for MEDLINE]
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