MIRANDA BEERS,1, 2 MELODY SAUERBORN,1 FRANCESCA GILLI,3 VERA BRINKS,1 HUUB SCHELLEKENS,1 WIM JISKOOT,2
1 Utrecht University, Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences (UIPS)
2 Leiden University, Division of Drug Delivery Technology Leiden/Amsterdam Centre for Drug Research (LACDR)
3 Regional Centre for Multiple Sclerosis (CReSM) and Clinical Neurobiology, AOU S. Luigi Gonzaga
PUBLICATION: Pharmaceutical Research. 27(9): 1812-1824. (2010)
DOI: 10.1007/s11095-010-0172-0
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 re-challenged 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 re-challenge.
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.
KEYWORDS: antibodies; immunogenicity; immunological memory; protein aggregates; recombinant human interferon beta
LINK TO ARTICLE: http://www.springerlink.com/content/85855l6412736242/
