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  Human IgG1 antibodies antagonizing activating receptor NKG2D on natural killer cells

Steigerwald, J., Raum, T., Pflanz, S., Cierpka, R., Mangold, S., Rau, D., et al. (2009). Human IgG1 antibodies antagonizing activating receptor NKG2D on natural killer cells. mAbs, 1(2), 115-127. doi:10.4161/mabs.1.2.7630.

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 Creators:
Steigerwald, Jutta1, Author
Raum , Tobias1, Author
Pflanz, Stefan2, Author
Cierpka, Ronny1, Author
Mangold , Susanne1, Author
Rau , Doris1, Author
Hoffmann, Patrick1, Author
Kvesic, Majk1, Author
Zube, Christina3, Author              
Linnerbauer, Stephanie4, Author
Lumsden, John1, Author
Sriskandarajah, Mirnaalini1, Author
Kufer, Peter1, Author
Baeuerle, Patrick A.1, Author
Volkland, Jörg1, Author
Affiliations:
1Micromet AG , ou_persistent22              
2Schering-Plough Biopharma , ou_persistent22              
3Department of Behavioral Physiology and Sociobiology, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, Germany, ou_67206              
4Clinical Cooperation Group, Helmholtz Center Munich and Children´s Clinic of the Technical University of Munich , ou_persistent22              

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 Abstract: NKG2D is a surface receptor expressed on NK cells but also on CD8+ T cells, γδ T cells, and auto-reactive CD4+/CD28- T cells of patients with rheumatoid arthritis. Various studies suggested that NKG2D plays a critical role in autoimmune diseases, e.g., in diabetes, celiac disease and rheumatoid arthritis (RA), rendering the activating receptor a potential target for antibody-based therapies. Here, we describe the generation and characteristics of a panel of human, high-affinity anti-NKG2D IgG1 monoclonal antibodies (mAbs) derived by phage display. The lead molecule mAb E4 bound with an affinity (KD) of 2.7 ± 1.4 x 10-11 M to soluble and membrane-bound human NKG2D, and cross-reacted with NKG2D from cynomolgus macaque, indicating potential suitability for studies in a relevant primate model. MAb E4 potently antagonized the cytolytic activity of NKL cells against BaF/3-MICA cells expressing NKG2D ligand, and blocked the NKG2D ligand-induced secretion of TNFα, IFNγ and GM-CSF, as well as surface expression of CRTAM by NK cells cultured on immobilized MICA or ULBP-1 ligands. The antibody did not show a detectable loss of binding to NKG2D after 7 days in human serum at 37°C, and resisted thermal inactivation up to 70°C. Based on these results, anti-human NKG2D mAb E4 provides an ideal candidate for development of a novel therapeutic agent antagonizing a key receptor of NK and cytotoxic T cells with implications in autoimmune diseases.

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Language(s): eng - English
 Dates: 2008-09-242008-12-112009-03-012009-03
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.4161/mabs.1.2.7630
PMID: 20061825
Other: Epub 2009
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Title: mAbs
Source Genre: Journal
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Pages: - Volume / Issue: 1 (2) Sequence Number: - Start / End Page: 115 - 127 Identifier: -