Characterization of a powerful high affinity antagonist that inhibits biological activities of human interleukin-13

Interleukin-13 (IL-13), a predominantly Th2-derived cytokine, appears to pl ay a central pathological role in asthma, atopic dermatitis, allergic rhini tis, some parasitic infections, and cancer. We hypothesized that an IL-13 a ntagonist may have profound therapeutic utility in these conditions. We, th erefore, mutagenized human IL-13 in which Glu at position 13 was substitute d by a Lys residue. This highly purified recombinant IL-13 variant, IL-13E1 3K, bound with 4-fold higher affinity to the IL-13 receptor than wild-type IL-13 but retained no detectable proliferative activity on the TF-1 hematop oietic cell line. IL-13E13K competitively inhibited IL-13- and IL-4-depende nt TF-1 proliferation. It also inhibited IL13-induced STAT-B (signal transd uction and activator of transducer-6) activation in immune cells and cancer cells and reversed IL-13-induced inhibition of CD14 expression on human pr imary monocytes. These results demonstrate that high affinity binding and s ignal generation can be uncoupled efficiently in a ligand receptor interact ion. These results also suggest that IL-13E13K may be a useful antagonist f or the treatment of allergic, inflammatory, and parasitic diseases or even malignancies in which IL-13 plays a central role.