Journal
ANNUAL REVIEW OF IMMUNOLOGY VOL 33
Volume 33, Issue -, Pages 139-+Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-immunol-032713-120211
Keywords
protein design; ligand-receptor interaction; immune signaling; immunotherapeutics; interferon; interleukin
Categories
Funding
- NATIONAL CANCER INSTITUTE [K01CA175127] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R37AI051321, R01AI051321] Funding Source: NIH RePORTER
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [K01CA175127, K01 CA175127] Funding Source: Medline
- NIAID NIH HHS [R37 AI051321, R01 AI051321, R01-AI51321] Funding Source: Medline
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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 cytokiine 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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