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.