Abstract:
:The aim of this study was to determine the sensitivity of transgenic immune tolerant mice for the type and level of aggregation of recombinant human interferon alpha2b (rhIFNalpha2b). RhIFNalpha2b was aggregated by metal-catalyzed oxidation or by incubation at elevated temperature and various pHs. Native rhIFNalpha2b was mixed with oxidized rhIFNalpha2b at different ratios to obtain samples with different aggregation levels. The preparations were characterized by UV and fluorescence spectroscopy, gel permeation chromatography (GPC), dynamic light scattering (DLS), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting, and ELISA. The immunogenicity was evaluated in wild-type mice and transgenic mice immune tolerant for hIFNalpha2. Sera were analyzed by ELISA for the presence of rhIFNalpha2b-specific antibodies. The oxidized and aged preparations widely differed regarding the level and nature of aggregates. All preparations containing aggregates increased the immune response in the wild-type mice as compared to native rhIFNalpha2b and were able to break the tolerance of the transgenic mice. The more native-like the conformation of the aggregated proteins, the more immunogenic the preparations were in the transgenic mice. The native-like aggregates prepared via metal catalysis induced a dose-dependent loss of tolerance in the transgenic mice. In conclusion, the transgenic mouse model can be used to screen rhIFNalpha2b formulations for low levels of immunogenic aggregates obtained under accelerated storage conditions.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Hermeling S,Schellekens H,Maas C,Gebbink MF,Crommelin DJ,Jiskoot Wdoi
10.1002/jps.20599subject
Has Abstractpub_date
2006-05-01 00:00:00pages
1084-96issue
5eissn
0022-3549issn
1520-6017pii
S0022-3549(16)32006-8journal_volume
95pub_type
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