| Autor: |
Berry LM; UCB, 216 Bath Road, Slough, Berkshire SL14EN, United Kingdom., Adams R, Airey M, Bracher MG, Bourne T, Carrington B, Cross AS, Davies GC, Finney HM, Foulkes R, Gozzard N, Griffin RA, Hailu H, Lamour SD, Lawson AD, Lightwood DJ, McKnight AJ, O'Dowd VL, Oxbrow AK, Popplewell AG, Shaw S, Stephens PE, Sweeney B, Tomlinson KL, Uhe C, Palframan RT |
| Jazyk: |
angličtina |
| Zdroj: |
International immunopharmacology [Int Immunopharmacol] 2009 Feb; Vol. 9 (2), pp. 201-6. Date of Electronic Publication: 2008 Nov 27. |
| DOI: |
10.1016/j.intimp.2008.11.001 |
| Abstrakt: |
Interleukin-13 (IL-13) sequentially binds to IL-13Ralpha1 and IL-4Ralpha forming a high affinity signalling complex. This receptor complex is expressed on multiple cell types in the airway and signals through signal transducer and activator of transcription factor-6 (STAT-6) to stimulate the production of chemokines, cytokines and mucus. Antibodies have been generated, using the UCB Selected Lymphocyte Antibody Method (UCB SLAM), that block either binding of murine IL-13 (mIL-13) to mIL-13Ralpha1 and mIL-13Ralpha2, or block recruitment of mIL-4Ralpha to the mIL-13/mIL-13Ralpha1 complex. Monoclonal antibody (mAb) A was shown to bind to mIL-13 with high affinity (K(D) 11 pM) and prevent binding of mIL-13 to mIL-13Ralpha1. MAb B, that also bound mIL-13 with high affinity (K(D) 8 pM), was shown to prevent recruitment of mIL-4Ralpha to the mIL-13/mIL-13Ralpha1 complex. In vitro, mAbs A and B similarly neutralised mIL-13-stimulated STAT-6 activation and TF-1 cell proliferation. In vivo, mAbs A and B demonstrated equipotent, dose-dependent inhibition of eotaxin generation in mice stimulated by intraperitoneal administration of recombinant mIL-13. In an allergic lung inflammation model in mice, mAbs A and B equipotently inhibited muc5ac mucin mRNA upregulation in lung tissue measured two days after intranasal allergen challenge. These data support the design of therapeutics for the treatment of allergic airway disease that inhibits assembly of the high affinity IL-13 receptor signalling complex, by blocking the binding of IL-13 to IL-13Ralpha1 and IL-13Ralpha2, or the subsequent recruitment of IL-4Ralpha. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
Full Text from ScienceDirect