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 (hIFNbeta). METHODS: A transgenic mouse model immune tolerant for hIFNbeta was developed by making C57Bl/6 mice transgenic for the hIFNbeta gene. To evaluate the model, both wild-type and transgenic mice were immunized with recombinant human interferon beta 1a (rhIFNbeta-1a) and recombinant human interferon beta 1b (rhIFNbeta-1b). Serum antibodies against rhIFNbeta were detected by ELISA. RESULTS: The genetically modified mice were shown to be immune tolerant for mammalian cell-derived rhIFNbeta-1a, which has a relative low immunogenicity in patients. However, Escherichia coli-derived rhIFNbeta-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 hIFNbeta and test new formulations before going into clinical trials. The model also provides the first evidence that the rhIFNbetas differ in the immunological mechanisms responsible for the development of antibodies.
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 humaninterferon beta (hIFNbeta). METHODS: A transgenic mouse model immune tolerant for hIFNbeta was developed by making C57Bl/6 mice transgenic for the hIFNbeta gene. To evaluate the model, both wild-type and transgenic mice were immunized with recombinant humaninterferon beta 1a (rhIFNbeta-1a) and recombinant humaninterferon beta 1b (rhIFNbeta-1b). Serum antibodies against rhIFNbeta were detected by ELISA. RESULTS: The genetically modified mice were shown to be immune tolerant for mammalian cell-derived rhIFNbeta-1a, which has a relative low immunogenicity in patients. However, Escherichia coli-derived rhIFNbeta-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 hIFNbeta and test new formulations before going into clinical trials. The model also provides the first evidence that the rhIFNbetas differ in the immunological mechanisms responsible for the development of antibodies.
Authors: L Runkel; W Meier; R B Pepinsky; M Karpusas; A Whitty; K Kimball; M Brickelmaier; C Muldowney; W Jones; S E Goelz Journal: Pharm Res Date: 1998-04 Impact factor: 4.200
Authors: C Ross; K M Clemmesen; M Svenson; P S Sørensen; N Koch-Henriksen; G L Skovgaard; K Bendtzen Journal: Ann Neurol Date: 2000-11 Impact factor: 10.422
Authors: P Perini; A Facchinetti; P Bulian; A R Massaro; D D Pascalis; A Bertolotto; G Biasi; P Gallo Journal: Eur Cytokine Netw Date: 2001-03 Impact factor: 2.737
Authors: J L Ottesen; P Nilsson; J Jami; D Weilguny; M Dührkop; D Bucchini; S Havelund; J M Fogh Journal: Diabetologia Date: 1994-12 Impact factor: 10.122
Authors: Miranda M C van Beers; Melody Sauerborn; Francesca Gilli; Vera Brinks; Huub Schellekens; Wim Jiskoot Journal: Pharm Res Date: 2011-05-05 Impact factor: 4.200
Authors: Miranda M C van Beers; Melody Sauerborn; Francesca Gilli; Vera Brinks; Huub Schellekens; Wim Jiskoot Journal: Pharm Res Date: 2010-05-25 Impact factor: 4.200
Authors: Christine Lenk; Sabine Unterthurner; Maria Schuster; Markus Weiller; Gerhard Antoine; Mantas Malisauskas; Friedrich Scheiflinger; Hans-Peter Schwarz; Maurus de la Rosa; Birgit M Reipert Journal: Pharm Res Date: 2013-06-18 Impact factor: 4.200
Authors: Melody Sauerborn; Miranda M C van Beers; Wim Jiskoot; Grzegorz M Kijanka; Louis Boon; Huub Schellekens; Vera Brinks Journal: J Clin Immunol Date: 2012-09-04 Impact factor: 8.317
Authors: Wim Jiskoot; Grzegorz Kijanka; Theodore W Randolph; John F Carpenter; Atanas V Koulov; Hanns-Christian Mahler; Marisa K Joubert; Vibha Jawa; Linda O Narhi Journal: J Pharm Sci Date: 2016-04-01 Impact factor: 3.534