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TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond

Nature Reviews Rheumatology volume 19, pages 576–591 (2023)Cite this article

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Abstract

The cytokine TNF signals via two distinct receptors, TNF receptor 1 (TNFR1) and TNFR2, and is a central mediator of various immune-mediated diseases. Indeed, TNF-neutralizing biologic drugs have been in clinical use for the treatment of many inflammatory pathological conditions, including various rheumatic diseases, for decades. TNF has pleiotropic effects and can both promote and inhibit pro-inflammatory processes. The integrated net effect of TNF in vivo is a result of cytotoxic TNFR1 signalling and the stimulation of pro-inflammatory processes mediated by TNFR1 and TNFR2 and also TNFR2-mediated anti-inflammatory and tissue-protective activities. Inhibition of the beneficial activities of TNFR2 might explain why TNF-neutralizing drugs, although highly effective in some diseases, have limited benefit in the treatment of other TNF-associated pathological conditions (such as graft-versus-host disease) or even worsen the pathological condition (such as multiple sclerosis). Receptor-specific biologic drugs have the potential to tip the balance from TNFR1-mediated activities to TNFR2-mediated activities and enable the treatment of diseases that do not respond to current TNF inhibitors. Accordingly, a variety of reagents have been developed that either selectively inhibit TNFR1 or selectively activate TNFR2. Several of these reagents have shown promise in preclinical studies and are now in, or approaching, clinical trials.

Key points

  • TNF is an important pleotropic cytokine that triggers complex immune-regulatory circuits of crucial relevance in tissue homeostasis as well as in many inflammatory diseases and pathological conditions.

  • The clinically approved TNF blockers inhibit activation of both the pro-inflammatory and cytotoxic TNF receptor 1 (TNFR1) and the largely anti-inflammatory and tissue-protective TNF receptor 2 (TNFR2).

  • TNFR2 promotes the expansion of regulatory T cells and enhances the suppressive activity of these cells, and is thus a promising therapeutic target in the treatment of autoimmunity.

  • Biologic drugs that selectively and/or preferentially interfere with TNFR1 activation are in clinical trials and are effective in various preclinical disease models, including models of autoimmune disease.

  • Various ligand-based and antibody-based TNFR2 agonists are therapeutically effective in preclinical disease models including collagen-induced arthritis.

  • TNF receptor-targeting reagents with conditional and/or local activity are in early preclinical development and have the potential to expand the spectrum of applications of TNF receptor-regulating biologics in the future.

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Fig. 1: Model of TNFR1 and TNFR2 activation.
Fig. 2: The TNF–TNF receptor signalling network.
Fig. 3: Domain architecture of selected approved and experimental biologic drugs that target TNFR1 or TNFR2.
Fig. 4: Possible modes of action of anti-TNFR2-specific IgG antibodies.

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Acknowledgements

The research work of the authors is supported by the Deutsche Forschungsgemeinschaft grants DFG Si 1128/6–1 (to D.S.) and DFG WA 1025/33–1 and 324392634–TR221 (to H.W.).

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  1. Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany

    Daniela Siegmund & Harald Wajant

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  1. Daniela Siegmund
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The authors contributed equally to all aspects of the article.

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Correspondence to Harald Wajant.

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Competing interests

H.W. declares that he received consultancy fees from Dualyx NV regarding the targeting of Treg cells via TNF receptor 2 (TNFR2). D.S. declares no competing interests. The University of Würzburg has filed patent applications for “Novel TNFR2 binding molecules” and “Tumour necrosis factor (TNF) receptor superfamily (TNFRSF) receptor-activating antibody fusion proteins with FcγR-independent agonistic activity (TRAAFFIA)”, with H.W. as one of the inventors.

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Nature Reviews Rheumatology thanks D. Wallach and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Antibody-dependent cellular cytotoxicity

An antibody effector function by which antibody-opsonized cells are recognized and killed or lysed by immune cells that express appropriate Fcγ receptors (such as natural killers).

Antibody-dependent cellular phagocytosis

An antibody effector function by which antibody-opsonized cells are recognized and phagocytosed by macrophages.

Association rate constant

This constant describes the kinetics by which two components (such as a ligand and receptor) form a complex.

Auto-affinity

Affinity of proteins for self-assembly.

Complement-dependent cytotoxicity

An antibody effector function triggered by cell-bound IgG and IgM antibodies, which results in cell killing or lysis by the so-called membrane attack complex of the complement system.

Dissociation rate constant

This constant describes the kinetics of the dissociation of a two-component complex (such as a ligand–receptor complex) into the individual components.

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Siegmund, D., Wajant, H. TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond. Nat Rev Rheumatol 19, 576–591 (2023). https://doi.org/10.1038/s41584-023-01002-7

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