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

J Interferon Cytokine Res. 2000 Nov;20(11):971-82. doi: 10.1089/10799900050198417.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antiviral Agents / pharmacology*
  • Biological Assay
  • Cell Division
  • Cytotoxicity Tests, Immunologic
  • DNA-Binding Proteins / metabolism*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Interferon Type I / pharmacology*
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Janus Kinase 1
  • Killer Cells, Natural / immunology
  • Membrane Proteins
  • Phosphorylation
  • Phosphotyrosine
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / metabolism
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / immunology*
  • Receptors, Interferon / metabolism
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • STAT3 Transcription Factor
  • TYK2 Kinase
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Vesicular stomatitis Indiana virus / drug effects

Substances

  • Antibodies, Monoclonal
  • Antiviral Agents
  • DNA-Binding Proteins
  • Histocompatibility Antigens Class I
  • IFNAR1 protein, human
  • IRF9 protein, human
  • Interferon Type I
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Membrane Proteins
  • Proteins
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Transcription Factors
  • Receptor, Interferon alpha-beta
  • Phosphotyrosine
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1
  • TYK2 Kinase
  • TYK2 protein, human