Development of a transgenic mouse model immune tolerant for human interferon beta

Publication Type:

Journal Article

Source:

Pharmaceutical Research, Volume 22, Number 6, pp. 847-851 (2005)

ISBN:

0724-8741

DOI Name (links to online publication)

10.1007/s11095-005-4578-z

Keywords:

immune tolerance; immunogenicity; protein formulations; recombinant human interferon beta; transgenic mice; multiple-sclerosis patients; site-specific mutagenesis; neutralizing antibodies; polycytidylic acid; cross-reactivity; ifn-beta; immunogenicity; mi

Abstract:

Purpose. Therapeutic proteins may induce antibodies that inhibit their efficacy or have other serious biological effects. There is a great need for strategies to predict whether a certain formulation will induce an immune response. In principle, conventional animals develop an immune response against all human proteins no matter how they are formulated, which restricts their use. The aim of this study was to develop a mouse model immune tolerant for human interferon beta (hIFN beta).Methods. A transgenic mouse model immune tolerant for hIFN beta was developed by making C57Bl/6 mice transgenic for the hIFNb gene. To evaluate the model, both wild-type and transgenic mice were immunized with recombinant human interferon beta 1a ( rhIFN beta-1a) and recombinant human interferon beta 1b ( rhIFN beta-1b). Serum antibodies against rhIFN beta were detected by ELISA.Results. The genetically modified mice were shown to be immune tolerant for mammalian cell-derived rhIFN beta-1a, which has a relative low immunogenicity in patients. However, Escherichia coli-derived rhIFN beta-1b, known to have a relatively high immunogenicity in patients, was shown not only to be immunogenic in the wild-type mice but could also break the immune tolerance of the genetically modified mice.Conclusions. This animal model offers the possibility to study the many factors influencing the immunogenicity of hIFN beta and test new formulations before going into clinical trials. The model also provides the first evidence that the rhIFN beta s differ in the immunological mechanisms responsible for the development of antibodies.

28/10/2009