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Interleukin-6: designing specific therapeutics for a complex cytokine

Abstract

Interleukin-6 (IL-6) is a pivotal cytokine with a diverse repertoire of physiological functions that include regulation of immune cell proliferation and differentiation. Dysregulation of IL-6 signalling is associated with inflammatory and lymphoproliferative disorders such as rheumatoid arthritis and Castleman disease, and several classes of therapeutics have been developed that target components of the IL-6 signalling pathway. So far, monoclonal antibodies against IL-6 or IL-6 receptor (IL-6R) and Janus kinases (JAK) inhibitors have been successfully developed for the treatment of autoimmune diseases such as rheumatoid arthritis. However, clinical trials of agents targeting IL-6 signalling have also raised questions about the diseases and patient populations for which such agents have an appropriate benefit–risk profile. Knowledge from clinical trials and advances in our understanding of the complexities of IL-6 signalling, including the potential to target an IL-6 trans-signalling pathway, are now indicating novel opportunities for therapeutic intervention. In this Review, we overview the roles of IL-6 in health and disease and analyse progress with several approaches of inhibiting IL-6-signalling, with the aim of illuminating when and how to apply IL-6 blockade.

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Figure 1: Three different modes of IL-6 signalling.
Figure 2: Important biological activities of IL-6.
Figure 3: Role of IL-6 in the differentiation of T cell subsets.
Figure 4: Therapeutic intervention to inhibit IL-6 signalling.

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Acknowledgements

T.K. was supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (TRR128, SFB1054-B07 and SyNergy), by the European Research Council (ERC) (EXODUS, CoG 647215) and the German Ministry of Education and Research (T-B interaction in neuromyelitis optica). C.G. was supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB877-A10 and Cluster of Excellence 'Inflammation at Interfaces'), and the German Ministry of Education and Research (grant “InTraSig”, project B). S.R.-J. was supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841-C01, SFB877-A1 and Cluster of Excellence 'Inflammation at Interfaces'), and the German Ministry of Education and Research (grant “InTraSig”, project B).

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Correspondence to Christoph Garbers or Thomas Korn or Stefan Rose-John.

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S.R.-J. has acted as a consultant and speaker for AbbVie, Chugai, Genentech Roche, Pfizer and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein olamkicept together with the company I-Mab. S.R.-J. has stock ownership in CONARIS. All other authors declare no competing interests.

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Multiple myeloma

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Castleman disease

A spectrum of heterogeneous lymphoproliferative disorders characterized by common lymph node histopathological features (including abnormal germinal centre architecture with prominent follicular dendritic cells) with interleukin-6 (IL-6) overproduction considered as a key mechanism,particularly for the entity multicentric Castleman disease.

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A systemic vasculitis of large and medium vessels with non-necrotizing granulomatous changes (activated macrophages forming multinucleated giant cells and T helper cell infiltration) that occur most frequently in the aorta and the extracranial branches of the external carotid arteries. It is a polygenic and multifactorial disease, and it is characterized by substantially elevated interleukin-6 (IL-6) serum levels.

Neuromyelitis optica

(NMO). An autoimmune disease of the central nervous system distinct from multiple sclerosis. In this disease, astrocytes, which express the water channel protein aquaporin 4 (AQP4), are targeted by an autoantibody to this protein.

Erdheim–Chester disease

Also known as non-Langerhans' cell histiocytosis. A rare, inflammatory myeloid neoplasia characterized by increased production of spumous histiocytes that infiltrate multiple tissues and organs (including bones, heart, lungs and brain) that are frequently surrounded by fibrosis.

Secondary demyelination

The destruction of astrocytes through anti-aquaporin 4 (AQP4) antibodies leads to secondary affection of oligodendrocytes through not entirely understood mechanisms. Oligodendrocytes produce the myelin sheath that surrounds axons in the central nervous system.

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(iNKT cells). Innate-like T lymphocytes expressing natural killer (NK) cell surface antigens and an invariant T cell receptor recognizing glycolipid antigens that, upon activation, secrete a variety of cytokines modulating dendritic cells, macrophages, neutrophils and NK cells as well as B and T lymphocytes, therefore orchestrating immune responses in autoimmunity, tumour surveillance and infections.

γδ T cells

Functionally distinct subsets of unconventional T lymphocytes with an invariant γδ T cell receptor that are localized in the liver or at epithelial (digestive tract, respiratory tract and reproductive tract) barriers and possess features of both innate and adaptive immune cells as they secrete various inflammatory cytokines (interferon-γ and interleukin-17) upon sensing of alarm signals (for example, via Toll-like receptors).

Lymphocytic choriomeningitis virus (LCMV) infection

A well-studied rodent viral infectious model that uses different strains to elicit acute or chronic disease. The LCMV model is used to analyse vigorous cytotoxic T cell effector functions, the interplay with other immune cells to eradicate the virus and the generation of immunological memory or T cell exhaustion.

ACR20

The American College of Rheumatology (ACR) clinical score used in patients with rheumatoid arthritis; the score includes physician and patient assessment items. An improvement of the score by 20% is referred to as ACR20; an improvement of the score by 50% is ACR50.

Nanobody

Also known as single-domain antibody. An antibody fragment consisting of a single monomeric variable domain (VH) naturally occurring in the Camelidae family or synthetically derived from the heavy chain of an antibody, combining high antigen affinity in the absence of complement-dependent or cell-mediated cytotoxicity due to the lack of a constant (Fc) region.

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Garbers, C., Heink, S., Korn, T. et al. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov 17, 395–412 (2018). https://doi.org/10.1038/nrd.2018.45

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