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Blockade of interleukin-13-mediated cell activation by a novel inhibitory antibody to human IL-13 receptor alpha1.

Abstract
Interleukin-13 (IL-13) is a cytokine with a crucial role in the development of allergic asthma. The IL-13 receptor shares the IL-4Ralpha subunit with the IL-4R system, but contains as a specific component the IL-13Ralpha1 chain. Blocking signal release by IL-13 without affecting IL-4 function is a potentially interesting therapeutical option for the treatment of asthma. Employing genetic immunization, we generated a set of novel monoclonal antibodies to the IL-13Ralpha1 receptor that proved very specific and efficient inhibitors of human IL-13 activity. Receptor binding antibodies were identified by their specific reactivity with both human monocytes and a murine pro-B cell line overexpressing human IL-13Ralpha1 by flow cytometry and cell ELISA. A luciferase reporter cell system based on STAT6-mediated promoter activation in murine Ba/F3 cells was employed to screen the antibodies for IL-13 antagonistic properties. Inhibitory antibody effects were quantified by interference with IL-13-dependent proliferation of TF-1 cells. The capability of blocking IL-13-driven responses of primary, inflammation-relevant cells was tested by Western blot analysis of STAT6 tyrosine phosphorylation and expression of 15-lipoxygenase in monocytes from fresh blood. The most potent inhibitory antibody identified, GM1E7, inhibited IL-13-driven gene activation and cell proliferation in immune cell lines with IC(50) values in the low nanomolar range. Both short-term (STAT6 activation) and long-term (15-LO induction) responses of primary human blood cells to IL-13 were almost entirely blocked, whereas IL-4 effects remained virtually unaffected. GM1E7 is superior to available agents interfering with IL-13 activity in terms of specificity and efficiency and offers potential novel therapeutic perspectives for the treatment of allergic asthma.
AuthorsSebastian Krause, Jochen Behrends, Andreas Borowski, Jens Lohrmann, Stefan Lang, Daniel Myrtek, Thomas Lorenzen, J Christian Virchow, Werner Luttmann, Karlheinz Friedrich
JournalMolecular immunology (Mol Immunol) Vol. 43 Issue 11 Pg. 1799-807 (Apr 2006) ISSN: 0161-5890 [Print] England
PMID16364441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • IL13RA1 protein, human
  • Interleukin-13
  • Interleukin-13 Receptor alpha1 Subunit
  • Receptors, Interleukin
  • Receptors, Interleukin-13
  • STAT6 Transcription Factor
  • Phosphotyrosine
  • Arachidonate 15-Lipoxygenase
Topics
  • Antibodies, Monoclonal (immunology)
  • Antibody Specificity (immunology)
  • Arachidonate 15-Lipoxygenase (metabolism)
  • Binding Sites, Antibody (immunology)
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Hybridomas
  • Inhibitory Concentration 50
  • Interleukin-13 (antagonists & inhibitors, immunology)
  • Interleukin-13 Receptor alpha1 Subunit
  • Monocytes (cytology, drug effects, enzymology, immunology)
  • Phosphotyrosine
  • Receptors, Interleukin (antagonists & inhibitors, metabolism)
  • Receptors, Interleukin-13
  • STAT6 Transcription Factor (metabolism)
  • Time Factors

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