Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Emerging principles of cytokine pharmacology and therapeutics

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Akdis, M. et al. Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J. Allergy Clin. Immunol. 127, 701–721.e1–e70 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Rider, P., Carmi, Y. & Cohen, I. Biologics for targeting inflammatory cytokines, clinical uses, and limitations. Int. J. Cell Biol. 2016, 9259646 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Donnelly, R. P., Young, H. A. & Rosenberg, A. S. An overview of cytokines and cytokine antagonists as therapeutic agents. Ann. N. Y. Acad. Sci. 1182, 1–13 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pires, I. S., Hammond, P. T. & Irvine, D. J. Engineering strategies for immunomodulatory cytokine therapies — challenges and clinical progress. Adv. Ther. https://doi.org/10.1002/adtp.202100035 (2021).

    Article  Google Scholar 

  5. Holder, P. G. et al. Engineering interferons and interleukins for cancer immunotherapy. Adv. Drug Deliv. Rev. 182, 114112 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Cunningham, B. C. et al. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science 254, 821–825 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Watowich, S. S., Hilton, D. J. & Lodish, H. F. Activation and inhibition of erythropoietin receptor function: role of receptor dimerization. Mol. Cell Biol. 14, 3535–3549 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kossiakoff, A. A. & De Vos, A. M. Structural basis for cytokine hormone-receptor recognition and receptor activation. Adv. Protein Chem. 52, 67–108 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Brooks, A. J. et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344, 1249783 (2014).

    Article  PubMed  CAS  Google Scholar 

  10. Wilmes, S. et al. Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science 367, 643–652 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Glassman, C. R. et al. Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation. Science 376, 163–169 (2022).

    Article  CAS  PubMed  Google Scholar 

  12. Ihle, J. N., Witthuhn, B. A., Quelle, F. W., Yamamoto, K. & Silvennoinen, O. Signaling through the hematopoietic cytokine receptors. Annu. Rev. Immunol. 13, 369–398 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. O’Shea, J. J. & Plenge, R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36, 542–550 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Levy, D. E. & Darnell, J. E. Jr. Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3, 651–662 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Morris, R., Kershaw, N. J. & Babon, J. J. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 27, 1984–2009 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wells, J. A. & de Vos, A. M. Hematopoietic receptor complexes. Annu. Rev. Biochem. 65, 609–634 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Wang, X., Lupardus, P., Laporte, S. L. & Garcia, K. C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27, 29–60 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Rickert, M., Wang, X., Boulanger, M. J., Goriatcheva, N. & Garcia, K. C. The structure of interleukin-2 complexed with its α receptor. Science 308, 1477–1480 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Boulanger, M. J. & Garcia, K. C. Shared cytokine signaling receptors: structural insights from the gp130 system. Adv. Protein Chem. 68, 107–146 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. van Boxel-Dezaire, A. H., Rani, M. R. & Stark, G. R. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25, 361–372 (2006).

    Article  PubMed  CAS  Google Scholar 

  21. Donnelly, R. P. & Kotenko, S. V. Interferon-λ: a new addition to an old family. J. Interferon Cytokine Res. 30, 555–564 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Lai, Y. & Dong, C. Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases. Int. Immunol. 28, 181–188 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Metcalf, D. Hematopoietic cytokines. Blood 111, 485–491 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Borden, E. C. et al. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug Discov. 6, 975–990 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gillis, S. & Smith, K. A. Long term culture of tumour-specific cytotoxic T cells. Nature 268, 154–156 (1977).

    Article  CAS  PubMed  Google Scholar 

  27. Morgan, D. A., Ruscetti, F. W. & Gallo, R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193, 1007–1008 (1976).

    Article  CAS  PubMed  Google Scholar 

  28. Rosenberg, S. A., Yang, J. C., White, D. E. & Steinberg, S. M. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann. Surg. 228, 307–319 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McDermott, D. F. & Atkins, M. B. Application of IL-2 and other cytokines in renal cancer. Expert Opin. Biol. Ther. 4, 455–468 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Legha, S. S., Gianan, M. A., Plager, C., Eton, O. E. & Papadopoulous, N. E. Evaluation of interleukin-2 administered by continuous infusion in patients with metastatic melanoma. Cancer 77, 89–96 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Waldhauer, I. et al. Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy. MAbs 13, 1913791 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Ptacin, J. L. et al. An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism. Nat. Commun. 12, 4785 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Arellano, M. & Lonial, S. Clinical uses of GM-CSF, a critical appraisal and update. Biologics 2, 13–27 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ng, T., Marx, G., Littlewood, T. & Macdougall, I. Recombinant erythropoietin in clinical practice. Postgrad. Med. J. 79, 367–376 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tahtinen, S. et al. Favorable alteration of tumor microenvironment by immunomodulatory cytokines for efficient T-cell therapy in solid tumors. PLoS ONE 10, e0131242 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Liu, B. L. et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 10, 292–303 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Andtbacka, R. H. I. et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte–macrophage colony-stimulating factor in unresectable stage III–IV melanoma. J. Immunother. Cancer 7, 145 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Pegram, H. J. et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zitvogel, L. et al. Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts. J. Immunol. 155, 1393–1403 (1995).

    CAS  PubMed  Google Scholar 

  40. Hsu, E. J. et al. A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy. Nat. Commun. 12, 2768 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Momin, N. et al. Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaw2614 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Pasche, N., Wulhfard, S., Pretto, F., Carugati, E. & Neri, D. The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel. Clin. Cancer Res. 18, 4092–4103 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Mansurov, A. et al. Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours. Nat. Biomed. Eng. 4, 531–543 (2020).

    Article  CAS  PubMed  Google Scholar 

  44. Neri, D. & Sondel, P. M. Immunocytokines for cancer treatment: past, present and future. Curr. Opin. Immunol. 40, 96–102 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mock, J. et al. An engineered 4-1BBL fusion protein with “activity on demand”. Proc. Natl Acad. Sci. USA 117, 31780–31788 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pogue, S. L. et al. Targeting attenuated interferon-α to myeloma cells with a CD38 antibody induces potent tumor regression with reduced off-target activity. PLoS ONE 11, e0162472 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Xu, Y. et al. An engineered IL15 cytokine mutein fused to an anti-PD1 improves intratumoral T-cell function and antitumor immunity. Cancer Immunol. Res. 9, 1141–1157 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. O’Shea, J. J. & Murray, P. J. Cytokine signaling modules in inflammatory responses. Immunity 28, 477–487 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Regis, G., Pensa, S., Boselli, D., Novelli, F. & Poli, V. Ups and downs: the STAT1:STAT3 seesaw of interferon and gp130 receptor signalling. Semin. Cell Dev. Biol. 19, 351–359 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Rosenbaum, D. M., Rasmussen, S. G. & Kobilka, B. K. The structure and function of G-protein-coupled receptors. Nature 459, 356–363 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schioth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Weis, W. I. & Kobilka, B. K. The molecular basis of G protein-coupled receptor activation. Annu. Rev. Biochem. 87, 897–919 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wingler, L. M. & Lefkowitz, R. J. Conformational basis of G protein-coupled receptor signaling versatility. Trends Cell Biol. 30, 736–747 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wootten, D., Christopoulos, A., Marti-Solano, M., Babu, M. M. & Sexton, P. M. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 19, 638–653 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Wacker, D., Stevens, R. C. & Roth, B. L. How ligands illuminate GPCR molecular pharmacology. Cell 170, 414–427 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tan, H. S. & Habib, A. S. Oliceridine: a novel drug for the management of moderate to severe acute pain — a review of current evidence. J. Pain. Res. 14, 969–979 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Gonzalez-Navajas, J. M., Lee, J., David, M. & Raz, E. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 12, 125–135 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jaitin, D. A. et al. Inquiring into the differential action of interferons (IFNs): an IFN-α2 mutant with enhanced affinity to IFNAR1 is functionally similar to IFN-β. Mol. Cell Biol. 26, 1888–1897 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wilmes, S. et al. Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling. J. Cell Biol. 209, 579–593 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Thomas, C. et al. Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146, 621–632 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Jaks, E., Gavutis, M., Uze, G., Martal, J. & Piehler, J. Differential receptor subunit affinities of type I interferons govern differential signal activation. J. Mol. Biol. 366, 525–539 (2007). This work demonstrates that differences in IFNAR1/2 affinity and complex stability enable distinct functions of type 1 interferons.

    Article  CAS  PubMed  Google Scholar 

  62. Khabar, K. S. et al. Expressed gene clusters associated with cellular sensitivity and resistance towards anti-viral and anti-proliferative actions of interferon. J. Mol. Biol. 342, 833–846 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Zurawski, S. M., Vega, F. Jr, Huyghe, B. & Zurawski, G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 12, 2663–2670 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ozaki, K. & Leonard, W. J. Cytokine and cytokine receptor pleiotropy and redundancy. J. Biol. Chem. 277, 29355–29358 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Spangler, J. B., Moraga, I., Mendoza, J. L. & Garcia, K. C. Insights into cytokine-receptor interactions from cytokine engineering. Annu. Rev. Immunol. 33, 139–167 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Kalie, E., Jaitin, D. A., Abramovich, R. & Schreiber, G. An interferon α2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitumor activities. J. Biol. Chem. 282, 11602–11611 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Mendoza, J. L. et al. The IFN-λ–IFN-λ–R1-IL-10Rβ complex reveals structural features underlying type III IFN functional plasticity. Immunity 46, 379–392 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Levin, A. M. et al. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 484, 529–533 (2012). This work presents the first use of yeast display to engineer a super agonist variant of IL-2 (super-2).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rao, B. M., Girvin, A. T., Ciardelli, T., Lauffenburger, D. A. & Wittrup, K. D. Interleukin-2 mutants with enhanced α-receptor subunit binding affinity. Protein Eng. 16, 1081–1087 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Junttila, I. S. et al. Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nat. Chem. Biol. 8, 990–998 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Martinez-Fabregas, J. et al. Kinetics of cytokine receptor trafficking determine signaling and functional selectivity. eLife https://doi.org/10.7554/eLife.49314 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Saxton, R. A. et al. Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science https://doi.org/10.1126/science.abc8433 (2021). This work presents insights from the cryo-electron microscopy structure of the IL-10R complex that enable the design of myeloid selective anti-inflammatory IL-10 variants with diminished immunostimulatory effects.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Gorby, C. et al. Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses. Sci. Signal. https://doi.org/10.1126/scisignal.abc0653 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Moraga, I. et al. Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency. Sci. Signal. 8, ra114 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Saxton, R. A. et al. The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design. Immunity 54, 660–672 e669 (2021). This work presents the rational design of STAT3-biased IL-22 variants that drive tissue protection without inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Piehler, J., Thomas, C., Garcia, K. C. & Schreiber, G. Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation. Immunol. Rev. 250, 317–334 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 6, 595–601 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. McKay, D. B. Response. Science 257, 412–413 (1992).

    Article  CAS  PubMed  Google Scholar 

  79. Ren, J. et al. Interleukin-2 superkines by computational design. Proc. Natl Acad. Sci. USA 119, e2117401119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Silva, D. A. et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature 565, 186–191 (2019). This work is the first example of a de novo designed cytokine therapeutic (neo-2/15), now in phase I clinical trials (NL-201, developed by Neoleukin).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hecht, J. R. et al. Randomized phase III study of FOLFOX alone or with pegilodecakin as second-line therapy in patients with metastatic pancreatic cancer that progressed after gemcitabine (SEQUOIA). J. Clin. Oncol. 39, 1108–1118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mitra, S. et al. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity 42, 826–838 (2015). This work designs high-affinity partial agonist variants of IL-2 with increased affinity for IL-2Rβ and reduced affinity for γc.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mo, F. et al. An engineered IL-2 partial agonist promotes CD8+ T cell stemness. Nature 597, 544–548 (2021). This work identifies a partial agonist variant of IL-2 that selectively expands stem-like CD8+ T cells ex vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Mendoza, J. L. et al. Structure of the IFNγ receptor complex guides design of biased agonists. Nature 567, 56–60 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    Article  CAS  PubMed  Google Scholar 

  89. Sadlack, B. et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053–3059 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).

    Article  CAS  PubMed  Google Scholar 

  91. Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody–cytokine immune complexes. Science 311, 1924–1927 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Spangler, J. B. et al. Antibodies to interleukin-2 elicit selective T cell subset potentiation through distinct conformational mechanisms. Immunity 42, 815–825 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Peterson, L. B. et al. A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease. J. Autoimmun. 95, 1–14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Khoryati, L. et al. An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice. Sci. Immunol. https://doi.org/10.1126/sciimmunol.aba5264 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Glassman, C. R. et al. Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist. eLife https://doi.org/10.7554/eLife.65777 (2021). This work identifies partial agonist IL-2 variants that selectively expand Treg cells.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Arenas-Ramirez, N. et al. Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2. Sci. Transl. Med. 8, 367ra166 (2016).

    Article  PubMed  CAS  Google Scholar 

  99. Sahin, D. et al. An IL-2-grafted antibody immunotherapy with potent efficacy against metastatic cancer. Nat. Commun. 11, 6440 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Spangler, J. B. et al. Engineering a single-agent cytokine/antibody fusion that selectively expands regulatory T cells for autoimmune disease therapy. J. Immunol. 201, 2094–2106 (2018).

    Article  CAS  PubMed  Google Scholar 

  101. Junttila, I. S. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front. Immunol. 9, 888 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Junttila, I. S. et al. Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Rα, IL-13α1, and γc regulates relative cytokine sensitivity. J. Exp. Med. 205, 2595–2608 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Woytschak, J. et al. Type 2 interleukin-4 receptor signaling in neutrophils antagonizes their expansion and migration during infection and inflammation. Immunity 45, 172–184 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Impellizzieri, D. et al. IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation. J. Allergy Clin. Immunol. 144, 267–279.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M. & O’Garra, A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol. 147, 3815–3822 (1991).

    CAS  PubMed  Google Scholar 

  106. Fujii, S., Shimizu, K., Shimizu, T. & Lotze, M. T. Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ. Blood 98, 2143–2151 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Brunda, M. J. et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J. Exp. Med. 178, 1223–1230 (1993).

    Article  CAS  PubMed  Google Scholar 

  109. Carson, W. E. et al. Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-γ production and STAT-mediated signal transduction. Blood 96, 1465–1473 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Glassman, C. R. et al. Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. Cell 184, 983–999 e924 (2021). This work presents the dtructure-based design of T cell selective IL-12 variants.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kim, A. R. et al. Functional selectivity in cytokine signaling revealed through a pathogenic EPO mutation. Cell 168, 1053–1064 e1015 (2017). This work discusses the discovery of a natural cytokine variant that elicits biased receptor signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Dudakov, J. A., Hanash, A. M. & van den Brink, M. R. Interleukin-22: immunobiology and pathology. Annu. Rev. Immunol. 33, 747–785 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22–IL-22R1 system. Nat. Rev. Drug Discov. 13, 21–38 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Ouyang, W. & O’Garra, A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity 50, 871–891 (2019).

    Article  CAS  PubMed  Google Scholar 

  115. Mantovani, A., Locati, M., Vecchi, A., Sozzani, S. & Allavena, P. Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. Trends Immunol. 22, 328–336 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Dinarello, C. A., Novick, D., Kim, S. & Kaplanski, G. Interleukin-18 and IL-18 binding protein. Front. Immunol. 4, 289 (2013).

    PubMed  PubMed Central  Google Scholar 

  117. Srivastava, S., Salim, N. & Robertson, M. J. Interleukin-18: biology and role in the immunotherapy of cancer. Curr. Med. Chem. 17, 3353–3357 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Zhou, T. et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 583, 609–614 (2020). This work presents the directed evolution of an IL-18 variant that is no longer inhibited by the soluble decoy receptor IL-18BP, displaying superior antitumour effects in mouse models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Harris, K. E. et al. A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells. Sci. Rep. 11, 10592 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yea, K. et al. Agonist antibody that induces human malignant cells to kill one another. Proc. Natl Acad. Sci. USA 112, E6158–E6165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nakano, K. et al. Effective screening method of agonistic diabodies based on autocrine growth. J. Immunol. Methods 347, 31–35 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Moraga, I. et al. Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. Cell 160, 1196–1208 (2015). This work demonstrates that altering the receptor geometry and orientation can influence downstream signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yen, M. et al. Facile discovery of surrogate cytokine agonists. Cell 185, 1414–1430.e19 (2022). This work presents a platform for the identification of nanobody-based surrogate cytokine receptor agonists.

    Article  CAS  PubMed  Google Scholar 

  124. Pluckthun, A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu. Rev. Pharmacol. Toxicol. 55, 489–511 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Mohan, K. et al. Topological control of cytokine receptor signaling induces differential effects in hematopoiesis. Science https://doi.org/10.1126/science.aav7532 (2019). This work uses synthetic DARPins to systematically control cytokine receptor geometry, yielding partial and biased agonism.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Moraga, I. et al. Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers. eLife https://doi.org/10.7554/eLife.22882 (2017). This work demonstrates that induced dimerization of non-natural cytokine receptor pairs can drive JAK/STAT signalling.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Engelowski, E. et al. Synthetic cytokine receptors transmit biological signals using artificial ligands. Nat. Commun. 9, 2034 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Kallen, K. J. et al. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. J. Biol. Chem. 274, 11859–11867 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Findeisen, M. et al. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature 574, 63–68 (2019).

    Article  CAS  PubMed  Google Scholar 

  130. Yang, J. C. et al. The use of polyethylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2. Cancer 76, 687–694 (1995).

    Article  CAS  PubMed  Google Scholar 

  131. Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167, 419–432.e16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang, B. et al. Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells. Nat. Biomed. Eng. 5, 1288–1305 (2021).

    Article  PubMed  CAS  Google Scholar 

  133. Casadevall, N. et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469–475 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Ettinger, M. P. et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA 289, 1826–1832 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Hermeling, S., Crommelin, D. J., Schellekens, H. & Jiskoot, W. Structure–immunogenicity relationships of therapeutic proteins. Pharm. Res. 21, 897–903 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Andreatta, M. & Nielsen, M. Gapped sequence alignment using artificial neural networks: application to the MHC class I system. Bioinformatics 32, 511–517 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. Liu, D. V., Maier, L. M., Hafler, D. A. & Wittrup, K. D. Engineered interleukin-2 antagonists for the inhibition of regulatory T cells. J. Immunother. 32, 887–894 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kuziel, W. A., Ju, G., Grdina, T. A. & Greene, W. C. Unexpected effects of the IL-2 receptor α subunit on high affinity IL-2 receptor assembly and function detected with a mutant IL-2 analog. J. Immunol. 150, 3357–3365 (1993).

    CAS  PubMed  Google Scholar 

  139. Rath, T. et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit. Rev. Biotechnol. 35, 235–254 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K. Christopher Garcia.

Ethics declarations

Competing interests

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saxton, R.A., Glassman, C.R. & Garcia, K.C. Emerging principles of cytokine pharmacology and therapeutics. Nat Rev Drug Discov (2022). https://doi.org/10.1038/s41573-022-00557-6

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41573-022-00557-6

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing