Development of a Transgenic Mouse Model Immune Tolerant for Human Interferon Beta

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 immuneresponse. 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 (hIFNβ). Methods. A transgenic mouse model immune tolerant for hIFNβ was developed by making C57B1/6 mice transgenic for the hIFNβ gene. To evaluate the model, both wild-type and transgenic mice were immunized with recombinant human interferon beta la (rhIFNβ-1a) and recombinant human interferon beta 1b (rhIFNβ-1b). Serum antibodies against rhIFNβ were detected by ELISA. Results. The genetically modified mice were shown to be immune tolerant for mammalian cell-derived rhIFNβ-1a, which has a relative low immunogenicity in patients. However, Escherichia coli-derived rhIFNβ-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 hIFNβ and test new formulations before going into clinical trials. The model also provides the first evidence that the rhIFNβs differ in the immunological mechanisms responsible for the development of antibodies.