Journal
CELL CHEMICAL BIOLOGY
Volume 29, Issue 4, Pages 586-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2021.10.004
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Funding
- National Health and Medical Research Council Investigator Grant Leadership 1 [1173584]
- National Heart Foundation of Australia [CF14/3517]
- Operational Infrastructure Support Program of the Victorian Government
- Fielding Foundation
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This article presents the engineering of the unstable cytokine IL-37 into an anti-inflammatory molecule with excellent therapeutic properties. The use of site-directed mutagenesis, the addition of a non-native disulfide bond, and the engineering of IL-37 as an Fc-fusion protein overcame its poor pharmacokinetic and manufacturing profile. These findings provide a platform for preclinical testing of IL-37 Fc-fusion proteins and can be applied to convert similar short-acting cytokines into therapeutics.
Harnessing the immunomodulatory activity of cytokines is a focus of therapies targeting inflammatory disease. The interleukin (IL)-1 superfamily contains pro-inflammatory and anti-inflammatory members that help orchestrate the immune response in adaptive and innate immunity. Of these molecules, IL-37 has robust anti-inflammatory activity across a range of disease models through inhibition of pro-inflammatory signaling cascades downstream of tumor necrosis factor, IL-1, and toll-like receptor pathways. We find that IL-37 is unstable with a poor pharmacokinetic and manufacturing profile. Here, we present the engineering of IL-37 from an unstable cytokine into an anti-inflammatory molecule with an excellent therapeutic likeness. We overcame these shortcomings through site-directed mutagenesis, the addition of a non-native disulfide bond, and the engineering of IL-37 as an Fc-fusion protein. Our results provide a platform for preclinical testing of IL-37 Fc-fusion proteins. The engineering approaches undertaken herein will apply to the conversion of similar potent yet short-acting cytokines into therapeutics.
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