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Journal Article

Human IgG1 antibodies antagonizing activating receptor NKG2D on natural killer cells

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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.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0012-0F78-3
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.