title: Interleukin-13 neutralization by two distinct receptor blocking mechanisms reduces immunoglobulin E responses and lung inflammation in cynomolgus monkeys.
abstract: 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-13Ralpha1/IL-4Ralpha) 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-4Ralpha, and Ab02 blocks IL-13 interaction with IL-13Ralpha1. 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-4Ralpha-binding epitope or the IL-13Ralpha1-binding epitope.
authors.affiliation: Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. mkasaian@wyeth.com
authors.forename: Marion T
authors.initials: MT
authors.lastname: Kasaian
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Tan
authors.forename: Macy
authors.initials: M
authors.lastname: Jin
authors.forename: Lori
authors.initials: L
authors.lastname: Fitz
authors.forename: Kimberly
authors.initials: K
authors.lastname: Marquette
authors.forename: Nancy
authors.initials: N
authors.lastname: Wood
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Cook
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Angela
authors.initials: A
authors.lastname: Widom
authors.forename: Rita
authors.initials: R
authors.lastname: Agostinelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Bree
authors.forename: Franklin J
authors.initials: FJ
authors.lastname: Schlerman
authors.forename: Stephane
authors.initials: S
authors.lastname: Olland
authors.forename: Michael
authors.initials: M
authors.lastname: Wadanoli
authors.forename: Joseph
authors.initials: J
authors.lastname: Sypek
authors.forename: Davinder
authors.initials: D
authors.lastname: Gill
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Goldman
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Tchistiakova
mesh_terms: D000818:Animals; D000909:Antibodies, Helminth / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology*; D001200:Ascaris / Q000276:immunology*; D001491:Basophils / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006636:Histamine Release / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood*; D007074:Immunoglobulin G / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D053660:Receptors, Interleukin-13 / Q000276:immunology*
chemical_list: D000909:Antibodies, Helminth; D000947:Antigens, Helminth; D000939:Epitopes; D007074:Immunoglobulin G; D018793:Interleukin-13; D053660:Receptors, Interleukin-13; D007073:Immunoglobulin E