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Interleukin-6: designing specific therapeutics for a complex cytokine

Nature Reviews Drug Discovery volume 17, pages 395–412 (2018)Cite this article

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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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Authors and Affiliations

  1. Institute of Biochemistry, Kiel University, Kiel, Germany

    Christoph Garbers & Stefan Rose-John

  2. Department of Neurology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany

    Sylvia Heink & Thomas Korn

  3. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany

    Thomas Korn

Authors
  1. Christoph Garbers
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  2. Sylvia Heink
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  3. Thomas Korn
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  4. Stefan Rose-John
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Correspondence to Christoph Garbers, Thomas Korn or Stefan Rose-John.

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Competing interests

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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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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