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

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

doi:10.1074/jbc.m114.617787

Cited by 72 publications

(67 citation statements)

References 83 publications

(94 reference statements)

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“…Although we have not tested the hypothesis of dual inhibition in other psoriasis models and we lack information from clinical studies, our results show that it might be of interest to evaluate whether blocking both TNFR1 and IFNAR1 in psoriasis patients may achieve clinically superior results compared with TNF antagonists. Interestingly, therapeutic blocking tools for both IFNAR1 (62) and TNFR1 (63) are available.…”

Section: Discussionmentioning

confidence: 99%

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Grine

Dejager

Libert

et al. 2015

The Journal of Immunology

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Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.

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Section: Discussionmentioning

confidence: 99%

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Grine

Dejager

Libert

et al. 2015

The Journal of Immunology

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“…A similar approach was taken by Steeland et al [112], who generated a human TNFR1 selective inhibitor based on nanobody technology. Here two anti-human TNFR1 selective single domain antibodies (nanobodies) were fused to an anti-albumin nanobody to increase the in vivo half-life.…”

Section: Tnfr1-specific Antibodiesmentioning

confidence: 99%

“…The resulting protein, TROS (TNF receptor one silencer), competes with TNF for binding to TNFR1 and strongly inhibits TNF-induced gene expression (Table 1). Importantly, TROS inhibits acute TNF-induced liver inflammation in mice expressing human TNFR1 [112].…”

Section: Tnfr1-specific Antibodiesmentioning

confidence: 99%

Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy

2015

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Deregulation of the tumor necrosis factor (TNF) plays an important role in the initiation and perpetuation of chronic inflammation and has been implicated in the development of various autoimmune diseases. Accordingly, TNF-inhibitors are successfully used for the treatment of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, total inhibition of TNF can cause severe side effects such as an increased risk of inflammation and reactivation of tuberculosis. This is likely due to the different actions of the two TNF receptors. Whereas TNFR1 predominantly promotes inflammatory signaling pathways, TNFR2 mediates immune modulatory functions and promotes tissue homeostasis and regeneration. Therefore, the specific blockage of TNFR1 signaling, either by direct inhibition with TNFR1-selective antagonists or by targeting soluble TNF, which predominantly activates TNFR1, may prevent the detrimental effects associated with total TNF-inhibitors and constitute a next-generation approach to interfere with TNF.

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“…Thus the interaction of TNF–TNFR1 appears to be the main driver of proinflammatory pathways during the development of arthritis and cardiac abnormalities 4. Therefore, strategies to neutralise the detrimental effects of TNF through TNFR1-selective antibodies may be interesting alternate strategies of TNF blockade 20. Overall, the paper by Ntari et al shows a crucial contribution of the mesenchymal cells to the development of heart pathology in a TNF-driven mouse arthritis model with many similarities to human disease.…”

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confidence: 99%