Received for publication January 14, 2008.
Revised March 10, 2008.
Accepted for publication March 11, 2008.

IL-13 Neutralization by Two Distinct Receptor Blocking Mechanisms Reduces IgE Responses and Lung Inflammation in Cynomolgus Monkeys

Abstract

Interleukin-13 (IL-13) is a key cytokine driving allergic and asthmatic responses, and contributes to airway inflammation in cynomolgus monkeys following 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. In cytokine systems, however, 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 homolgous 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 Ascaris suum antigen, both Ab01 and Ab02 effectively reduced serum titers of Ascaris-specific IgE, and dimished ex vivo Ascaris-triggered basophil histamine release, assayed 8 weeks following a single administration of antibody. The two antibodies also produced comparable reductions in pulmonary inflammation following lung segmental challenge with Ascaris antigen. Increased serum levels of IL-13, lacking demonstrable biological activity, were seen post-challenge 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.

Key words: IgE, airway, cytokine, humanized antibody, inflammation, nonhuman primate