Aggregated Recombinant Human Interferon Beta Induces Antibodies but No Memory in Immune-Tolerant Transgenic Mice

ABSTRACT Purpose To study the influence of protein aggregation on the immunogenicity of recombinant human interferon beta (rhIFNβ) in wild-type mice and transgenic, immune-tolerant mice, and to evaluate the induction of immunological memory. Methods RhIFNβ-1b and three rhIFNβ-1a preparations with di...

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Bibliographic Details
Published in:Pharmaceutical research 2010-09, Vol.27 (9), p.1812-1824
Main Authors: van Beers, Miranda M. C., Sauerborn, Melody, Gilli, Francesca, Brinks, Vera, Schellekens, Huub, Jiskoot, Wim
Format: Article
Language:English
Subjects:
Animals
Antibodies, Neutralizing - blood
Binding Sites, Antibody
Biochemistry
Biological and medical sciences
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Blotting, Western
Chromatography, Gel
Electrophoresis, Polyacrylamide Gel
Enzyme-Linked Immunosorbent Assay
General pharmacology
Humans
Immune Tolerance - genetics
Immunologic Memory - genetics
Immunology
Interferon
Interferon Type I - adverse effects
Interferon Type I - genetics
Interferon Type I - immunology
Light
Medical Law
Medical sciences
Mice
Mice, Transgenic
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Pharmacology/Toxicology
Pharmacy
Proteins
Recombinant Proteins
Research Paper
Rodents
Scattering, Radiation
Spectrometry, Fluorescence
Transgenic animals
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Summary:ABSTRACT Purpose To study the influence of protein aggregation on the immunogenicity of recombinant human interferon beta (rhIFNβ) in wild-type mice and transgenic, immune-tolerant mice, and to evaluate the induction of immunological memory. Methods RhIFNβ-1b and three rhIFNβ-1a preparations with different aggregate levels were injected intraperitoneally in mice 15× during 3 weeks, and the mice were rechallenged with rhIFNβ-1a. The formation of binding (BABs) and neutralizing antibodies (NABs) was monitored. Results Bulk rhIFNβ-1a contained large, mainly non-covalent aggregates and stressed rhIFNβ-1a mainly covalent, homogeneous (ca. 100 nm) aggregates. Reformulated rhIFNβ-1a was essentially aggregate-free. All products induced BABs and NABs in wild-type mice. Immunogenicity in the transgenic mice was product dependent. RhIFNβ-1b showed the highest and reformulated rhIFNβ-1a the lowest immunogenicity. In contrast with wild-type mice, transgenic mice did not show NABs, nor did they respond to the rechallenge. Conclusions The immunogenicity of the products in transgenic mice, unlike in wild-type mice, varied. In the transgenic mice, neither NABs nor immunological memory developed. The immunogenicity of rhIFNβ in a model reflecting the human immune system depends on the presence and the characteristics of aggregates.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-010-0172-0