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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Interleukin-13 Neutralization by Two Distinct Receptor Blocking Mechanisms Reduces Immunoglobulin E Responses and Lung Inflammation in Cynomolgus Monkeys

Departments of Inflammation (M.T.K., L.F., N.W., T.A.C., J.L., A.B., F.J.S., J.S., S.J.G.) and Biological Technologies (X.-Y.T., M.J., K.M., A.W., R.A., S.O., D.G., L.T.), Wyeth Research, Cambridge, Massachusetts; and Department of Bioresources, Wyeth Research, Andover, Massachusetts (M.W.)

Interleukin (IL)-13 is a key cytokine driving allergic and asthmatic responses and contributes to airway inflammation in cynomolgus monkeys after segmental challenge with Ascaris suum antigen. IL-13 bioactivity is mediated by a heterodimeric receptor (IL-13R1/IL-4R) and can be inhibited in vitro by targeting IL-13 interaction with either chain. However, in cytokine systems, in vitro neutralization activity may not always predict inhibitory function in vivo. To address the efficacy of two different IL-13 neutralization mechanisms in a primate model of atopic disease, two humanized monoclonal antibodies to IL-13 were generated, with highly homologous properties, differing in epitope recognition. Ab01 blocks IL-13 interaction with IL-4R, and Ab02 blocks IL-13 interaction with IL-13R1. In a cynomolgus monkey model of IgE responses to A. suum antigen, both Ab01 and Ab02 effectively reduced serum titers of Ascaris-specific IgE and diminished ex vivo Ascaris-triggered basophil histamine release, assayed 8 weeks after a single administration of antibody. The two antibodies also produced comparable reductions in pulmonary inflammation after lung segmental challenge with Ascaris antigen. Increased serum levels of IL-13, lacking demonstrable biological activity, were seen postchallenge in animals given either anti-IL-13 antibody but not in control animals given human IgG of irrelevant specificity. These findings demonstrate a potent effect of IL-13 neutralization on IgE-mediated atopic responses in a primate system and show that IL-13 can be efficiently neutralized by targeting either the IL-4R-binding epitope or the IL-13R1-binding epitope.

Address correspondence to: Dr. Marion T. Kasaian, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140. E-mail: mkasaian{at}wyeth.com