TY - JOUR T1 - Interleukin-13 Neutralization by Two Distinct Receptor Blocking Mechanisms Reduces Immunoglobulin E Responses and Lung Inflammation in Cynomolgus Monkeys JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 882 LP - 892 DO - 10.1124/jpet.108.136515 VL - 325 IS - 3 AU - Marion T. Kasaian AU - Xiang-Yang Tan AU - Macy Jin AU - Lori Fitz AU - Kimberly Marquette AU - Nancy Wood AU - Timothy A. Cook AU - Julie Lee AU - Angela Widom AU - Rita Agostinelli AU - Andrea Bree AU - Franklin J. Schlerman AU - Stephane Olland AU - Michael Wadanoli AU - Joseph Sypek AU - Davinder Gill AU - Samuel J. Goldman AU - Lioudmila Tchistiakova Y1 - 2008/06/01 UR - http://jpet.aspetjournals.org/content/325/3/882.abstract N2 - 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-13Rα1/IL-4Rα) 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-4Rα, and Ab02 blocks IL-13 interaction with IL-13Rα1. 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-4Rα-binding epitope or the IL-13Rα1-binding epitope. The American Society for Pharmacology and Experimental Therapeutics ER -