title: The neutralization of type I IFN biologic actions by anti-IFNAR-2 monoclonal antibodies is not entirely due to inhibition of Jak-Stat tyrosine phosphorylation.
abstract: A panel of monoclonal antibodies (mAb) derived against human interferon-alpha/beta receptor-2 (IFNAR-2) was evaluated for their ability to antagonize the biologic effects of type 1 interferons (IFN-alpha1, IFN-alpha2a, and IFN-beta). Anti-IFNAR-2 mAb 117.7, 35.9, 53.2, and 51.44 neutralized type I IFN-mediated antiviral, antiproliferative, and major histocompatibility complex (MHC) class I upregulation functions. However, only mAb 51.44 neutralized IFN-alpha2a and IFN-beta-mediated natural killer (NK) cell cytotoxicity. In BIAcore and cell binding studies, only mAb 51.44 and 234.28 inhibited IFN-alpha2a and IFN-beta binding to its receptor. The receptor blockade by mAb 51.44 and 234.28 resulted in the inhibition of IFN-alpha2a and IFN-beta-induced tyrosine phosphorylation of Jak1, Tyk2, Stat1/2/3, and IFNAR-1/2 and inhibition of IFN-stimulated gene factor 3 (ISGF3) formation. mAb 117.7, 35.9, and 53.2, although antagonists of IFN's biologic activities, did not block the binding of IFN-alpha/beta to its receptor. The 117.7 mAb, representative of this class of receptor nonblocking mAb, induced hyper-tyrosine phosphorylation of IFNAR-2 in the presence of IFN-alpha/beta but did not inhibit IFN-alpha/beta-induced Jak-Stat tyrosine phosphorylation and ISGF3 complex formation. These results show that the neutralization of type I IFN biologic actions by anti-IFNAR-2 mAb cannot be entirely explained by inhibition of Jak-Stat tyrosine phosphorylation.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Novick
authors.forename: R R
authors.initials: RR
authors.lastname: Nabioullin
authors.forename: W
authors.initials: W
authors.lastname: Ragsdale
authors.forename: S
authors.initials: S
authors.lastname: McKenna
authors.forename: W
authors.initials: W
authors.lastname: Weiser
authors.forename: L
authors.initials: L
authors.lastname: Garone
authors.forename: C
authors.initials: C
authors.lastname: Burkins
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Rubinstein
authors.forename: M A
authors.initials: MA
authors.lastname: Tepper
authors.forename: A R
authors.initials: AR
authors.lastname: Arulanandam
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D001681:Biological Assay; D002455:Cell Division; D003601:Cytotoxicity Tests, Immunologic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D053613:Janus Kinase 1; D007694:Killer Cells, Natural / Q000276:immunology; D008565:Membrane Proteins; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C507964:IFNAR1 protein, human; C494227:IRF9 protein, human; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D008565:Membrane Proteins; D011506:Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D053633:Receptor, Interferon alpha-beta; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human