Cited by 309Cytokine Signaling Pathways and InteractionsMonoclonal and Polyclonal Antibodies ResearchReceptor Mechanisms and Signaling

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Insights into Cytokine–Receptor Interactions from Cytokine Engineering

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Spangler, Jamie B., Moraga, Ignacio, Mendoza, Juan L., Garcia, K. Christopher·2015·Annual Review of Immunology

DOI 10.1146/annurev-immunol-032713-120211PMC PMC4445396

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Abstract

Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine–receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.

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Authors: Spangler, J. B., Moraga, I., Mendoza, J. L., & Garcia, K. C.
Affiliations: Howard Hughes Medical Institute (US)
Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305;, , ,
ORCID: Spangler, Jamie B.
Moraga, Ignacio
Mendoza, Juan L.
Venue: Annual Review of Immunology
Publisher: Annual Reviews
Published: 2015-03-21
Volume: 33
Issue: 1
Pages: 139-167
ISSN: 0732-0582 (ISSN-L)
1545-3278
DOI: 10.1146/annurev-immunol-032713-120211
PMC: PMC4445396
OpenAlex: W2098212097
Cited by: 304
References: 202
Citations by year: 2026: 19 · 2025: 30 · 2024: 38 · 2023: 32 · 2022: 48 · 2021: 48 · 2020: 24 · 2019: 16 · 2018: 18 · 2017: 18 · 2016: 6 · 2015: 7
FWCI: 1.17
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Annual Review of Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health
National Cancer Institute (K01CA175127)
National Institute of Allergy and Infectious Diseases (R01 AI51321, R37AI051321, R01AI051321)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: cytokine engineering, cytokine-cytokine receptor interaction, cytokine signaling, structure-based protein engineering, cytokine antagonists, target cell specificity, cytokine toxicity, immunotherapy, interferon, interleukin-2, IL-4
MeSH terms: Animals, Extracellular Space, Genetic Engineering, Humans, Protein Binding, Signal Transduction, Cytokines, Receptors, Cytokine, Protein Transport, Intracellular Space

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Insights into Cytokine–Receptor Interactions from Cytokine Engineering

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