Stimulation of TNF receptor type 2 expands regulatory T cells and ameliorates established collagen-induced arthritis in mice

Lamontain, Vanessa; Schmid, Tobias; Weber-Steffens, Dorothea; Zeller, David; Jenei-Lanzl, Zsuzsa; Wajant, Harald; Straub, Rainer H.; Männel, Daniela N.

doi:10.1038/cmi.2017.138

Cited by 42 publications

(37 citation statements)

References 39 publications

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“…This drug protected against graft-versus-host disease (GVHD) via host Treg expansion [357]. Lamontain and colleagues recently confirmed that stimulation with TNCscTNF80 effectively leads to expansion of Tregs and ameliorates established CIA in mice [358]. Another TNFR2-selective TNF mutein EHD2-scTNFR2 consists of a covalently stabilized human TNFR2-selective single-chain TNF fused to the dimerization domain EHD2 derived from the heavy chain domain of IgEs [167].…”

Section: Selective Tnfr2 Targetingmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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Section: Selective Tnfr2 Targetingmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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“…Interestingly, expression of TNFR2 defines a maximally suppressive subset of mouse Tregs (Chen et al, 2008), indicating that TNFR2 activation regulates suppressive activity of Tregs. Indeed, it was shown that exogenous activation of TNFR2 leads to expansion of Tregs, alleviates arthritic disease and protects from acute graft versus host disease (Chopra et al, 2016;Fischer et al, 2018;Lamontain et al, 2018). Our published data indicate that presence of IL-2 dramatically increases TNFR2-dependent Treg expansion in vitro (Fischer et al, 2017;Fischer et al, 2018).…”

Section: Introductionmentioning

confidence: 62%

“…We and others have shown that exogenous TNFR2 activation promotes the expansion of Tregs in vitro and in vivo (Okubo et al, 2013;Chopra et al, 2016;Okubo et al, 2016;Fischer et al, 2017;Fischer et al, 2018;Lamontain et al, 2018) and that TNFR2 and IL-2 synergistically promote Treg expansion (Fischer et al, 2018). We therefore genetically fused mouse IL-2 to a TNFR2-selective TNF mutein resulting in IL2-EHD2-sc-mTNF R2 , a fusion protein that efficiently activated both IL-2 and TNFR2 signaling.…”

Section: Discussionmentioning

confidence: 99%

Superior Treg-Expanding Properties of a Novel Dual-Acting Cytokine Fusion Protein

et al. 2019

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Autoimmune diseases are caused by uncontrolled endogenous immune responses against healthy cells. They may develop due to an impaired function of regulatory T cells (Tregs), which normally suppress self-specific effector immune cells. Interleukin 2 (IL-2) and tumor necrosis factor (TNF) have been identified as key players that promote expansion, function, and stability of Tregs. In vivo, both low-dose IL-2 therapy and TNF receptor 2 (TNFR2) agonism were shown to expand Tregs and alleviate autoimmunity. We here designed a novel dimeric dual-acting fusion cytokine, where mouse IL-2 is genetically linked to a TNFR2-selective single-chain TNF mutein (IL2-EHD2-sc-mTNF R2). IL2-EHD2sc-mTNF R2 showed high affinity to TNFR2 and efficiently activated IL-2 and TNFR2selective signaling pathways. Further, IL2-EHD2-sc-mTNF R2 promoted superior Treg expansion, with both the IL-2 and the TNFR2 agonist (sc-mTNF R2) component necessary for this biological response. Ultimately, we propose that IL2-EHD2-sc-mTNF R2 is a dualacting cytokine that efficiently promotes Treg expansion and might have a superior therapeutic window than conventional IL-2-based drugs.

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“…This drug protected against graft-versus-host disease (GVHD) via host T reg expansion [ 369 ]. Lamontain and colleagues recently confirmed that stimulation with TNCscTNF80 effectively leads to expansion of T regs and ameliorates established CIA in mice [ 370 ]. Another TNFR2-selective TNF mutein EHD2-scTNFR2 consists of a covalently stabilized human TNFR2-selective single-chain TNF fused to the dimerization domain EHD2 derived from the heavy chain domain of IgEs [ 174 ].…”

Section: A New Chapter Of Inventive Tnf Manipulating Approachesmentioning

confidence: 99%

A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

IJMS

104

View full text Add to dashboard Cite

The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases.

show abstract

Stimulation of TNF receptor type 2 expands regulatory T cells and ameliorates established collagen-induced arthritis in mice

Cited by 42 publications

References 39 publications

A New Venue of TNF Targeting

A New Venue of TNF Targeting

Superior Treg-Expanding Properties of a Novel Dual-Acting Cytokine Fusion Protein

A New Venue of TNF Targeting

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