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Emerging principles of cytokine pharmacology and therapeutics

Nature Reviews Drug Discovery volume 22, pages 21–37 (2023)Cite this article

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Abstract

Cytokines are secreted signalling proteins that play essential roles in the initiation, maintenance and resolution of immune responses. Although the unique ability of cytokines to control immune function has garnered clinical interest in the context of cancer, autoimmunity and infectious disease, the use of cytokine-based therapeutics has been limited. This is due, in part, to the ability of cytokines to act on many cell types and impact diverse biological functions, resulting in dose-limiting toxicity or lack of efficacy. Recent studies combining structural biology, protein engineering and receptor pharmacology have unlocked new insights into the mechanisms of cytokine receptor activation, demonstrating that many aspects of cytokine function are highly tunable. Here, we discuss the pharmacological principles underlying these efforts to overcome cytokine pleiotropy and enhance the therapeutic potential of this important class of signalling molecules.

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Fig. 1: Mechanism of cytokine signalling and sources of pleiotropy.
Fig. 2: Tunable parameters in cytokine receptor pharmacology.
Fig. 3: Tuning cytokine function by controlling receptor affinity.
Fig. 4: Tuning cytokine function by controlling receptor geometry.
Fig. 5: Nanobody-based surrogate cytokines.
Fig. 6: Tuning cytokine function by controlling receptor composition.

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Acknowledgements

K.C.G. is an investigator of the Howard Hughes Medical Institute (HHMI). This work was supported by National Institutes of Health (NIH) grant R01-AI51321 (K.C.G.) as well as funding from the Helen Hay Whitney Foundation (R.A.S.).

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  1. These authors contributed equally: Robert A. Saxton, Caleb R. Glassman.

Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA

    Robert A. Saxton, Caleb R. Glassman & K. Christopher Garcia

  2. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA

    Robert A. Saxton, Caleb R. Glassman & K. Christopher Garcia

  3. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA

    Robert A. Saxton & K. Christopher Garcia

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Correspondence to K. Christopher Garcia.

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K.C.G. is the founder of Synthekine Therapeutics. R.A.S., C.R.G. and K.C.G. are inventors on patents relating to molecules discussed in this Review that are being commercialized.

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Glossary

Receptor tyrosine kinases

(RTKs). Cell surface receptors with intrinsic tyrosine kinase activity.

Janus kinases

(JAKs). A family of cytosolic tyrosine kinases that associate with cytokine receptor intracellular domains.

EC50

The ligand concentration that induces half-maximal response.

E max

The maximal response elicited by saturating ligand concentrations.

Regulatory T cells

(Treg cells). A subpopulation of immunosuppressive T cells important for maintaining self-tolerance and homeostasis.

Cellular pleiotropy

Pleiotropy arising from the ability of one molecule to stimulate multiple distinct cell types or tissues.

Functional pleiotropy

Pleiotropy arising from the ability of one molecule to activate multiple signalling pathways and, thereby, induce multiple functional responses on a target cell type.

G proteins

Guanine nucleotide binding proteins that mediate signal transduction in a GTP-dependent manner.

Diamond–Blackfan anaemia

A genetic disorder resulting in reduced production of red blood cells.

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Saxton, R.A., Glassman, C.R. & Garcia, K.C. Emerging principles of cytokine pharmacology and therapeutics. Nat Rev Drug Discov 22, 21–37 (2023). https://doi.org/10.1038/s41573-022-00557-6

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