RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 882
OP 892
DO 10.1124/jpet.108.136515
VO 325
IS 3
A1 Marion T. Kasaian
A1 Xiang-Yang Tan
A1 Macy Jin
A1 Lori Fitz
A1 Kimberly Marquette
A1 Nancy Wood
A1 Timothy A. Cook
A1 Julie Lee
A1 Angela Widom
A1 Rita Agostinelli
A1 Andrea Bree
A1 Franklin J. Schlerman
A1 Stephane Olland
A1 Michael Wadanoli
A1 Joseph Sypek
A1 Davinder Gill
A1 Samuel J. Goldman
A1 Lioudmila Tchistiakova
YR 2008
UL http://jpet.aspetjournals.org/content/325/3/882.abstract
AB 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