Interleukin-13 neutralization by two distinct receptor blocking mechanisms reduces immunoglobulin E responses and lung inflammation in cynomolgus monkeys.
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.
Kasaian
Marion T
MT
Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. mkasaian@wyeth.com
Tan
Xiang-Yang
XY
Jin
Macy
M
Fitz
Lori
L
Marquette
Kimberly
K
Wood
Nancy
N
Cook
Timothy A
TA
Lee
Julie
J
Widom
Angela
A
Agostinelli
Rita
R
Bree
Andrea
A
Schlerman
Franklin J
FJ
Olland
Stephane
S
Wadanoli
Michael
M
Sypek
Joseph
J
Gill
Davinder
D
Goldman
Samuel J
SJ
Tchistiakova
Lioudmila
L
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*
D000909:Antibodies, Helminth; D000947:Antigens, Helminth; D000939:Epitopes; D007074:Immunoglobulin G; D018793:Interleukin-13; D053660:Receptors, Interleukin-13; D007073:Immunoglobulin E