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

作者：van Beers Miranda M C^*; Sauerborn Melody; Gilli Francesca; Brinks Vera; Schellekens Huub; Jiskoot Wim

来源：Pharmaceutical Research, 2010, 27(9): 1812-1824.

DOI：10.1007/s11095-010-0172-0

• antibodies
• immunogenicity
• immunological memory
• protein aggregates
• recombinant human interferon beta

Purpose To study the influence of protein aggregation on the immunogenicity of recombinant human interferon beta (rhIFN beta) in wild-type mice and transgenic, immune-tolerant mice, and to evaluate the induction of immunological memory.
Methods RhIFN beta-1b and three rhIFN beta-1a preparations with different aggregate levels were injected intraperitoneally in mice 15x during 3 weeks, and the mice were rechallenged with rhIFN beta-1a. The formation of binding (BABs) and neutralizing antibodies (NABs) was monitored.
Results Bulk rhIFN beta-1a contained large, mainly non-covalent aggregates and stressed rhIFN beta-1a mainly covalent, homogeneous (ca. 100 nm) aggregates. Reformulated rhIFN beta-1a was essentially aggregate-free. All products induced BABs and NABs in wild-type mice. Immunogenicity in the transgenic mice was product dependent. RhIFN beta-1b showed the highest and reformulated rhIFN beta-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 rhIFN beta in a model reflecting the human immune system depends on the presence and the characteristics of aggregates.

• 出版日期2010-9