Details

Autor(en) / Beteiligte

• Steeland, Sophie
• Puimège, Leen
• Vandenbroucke, Roosmarijn E.
• Van Hauwermeiren, Filip
• Haustraete, Jurgen
• Devoogdt, Nick
• Hulpiau, Paco
• Leroux-Roels, Geert
• Laukens, Debby
• Meuleman, Philip
• De Vos, Martine
• Libert, Claude

Titel

Generation and Characterization of Small Single Domain Antibodies Inhibiting Human Tumor Necrosis Factor Receptor 1

Ist Teil von

• The Journal of biological chemistry, 2015-02, Vol.290 (7), p.4022-4037

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• The cytokine TNF is a well known drug target for several inflammatory diseases such as Crohn disease. Despite the great success of TNF blockers, therapy could be improved because of high costs and side effects. Selective inhibition of TNF receptor (TNFR) 1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, thereby preserving the advantageous immunomodulatory signals mediated by TNFR2. We generated a selective human TNFR1 inhibitor based on Nanobody (Nb) technology. Two anti-human TNFR1 Nbs were linked with an anti-albumin Nb to generate Nb Alb-70-96 named “TNF Receptor-One Silencer” (TROS). TROS selectively binds and inhibits TNF/TNFR1 and lymphotoxin-α/TNFR1 signaling with good affinity and IC50 values, both of which are in the nanomolar range. Surface plasmon resonance analysis reveals that TROS competes with TNF for binding to human TNFR1. In HEK293T cells, TROS strongly reduces TNF-induced gene expression, like IL8 and TNF, in a dose-dependent manner; and in ex vivo cultured colon biopsies of CD patients, TROS inhibits inflammation. Finally, in liver chimeric humanized mice, TROS antagonizes inflammation in a model of acute TNF-induced liver inflammation, reflected in reduced human IL8 expression in liver and reduced IL6 levels in serum. These results demonstrate the considerable potential of TROS and justify the evaluation of TROS in relevant disease animal models of both acute and chronic inflammation and eventually in patients. Background: Several anti-TNF biologicals are available to treat autoimmune diseases. However, selective TNFR1 inhibition is advisable, thereby reducing the pro-inflammatory TNF/TNFR1 signaling, while the good immunomodulatory TNF/TNFR2 signaling is preserved. Results: We generated and characterized an anti-TNFR1 Nanobody, TNF Receptor-One Silencer (TROS). Conclusion: TROS inhibits inflammation in vitro, ex vivo, and in vivo. Significance: Anti-TNFR1 therapies are potential novel treatments against autoimmune diseases.