Protein engineering of a stable and potent anti-inflammatory IL-37-Fc fusion with enhanced therapeutic potential

Alexander Bujotzek, Georg Tiefenthaler, Laurent Lariviere, Laura D'Andrea, Elsa A. Marquez, Ina Rudloff, Steven Cho, Nadia Deen, Wolfgang Richter, Franziska Regenass-Lechner, Alexander Poehler, James Whisstock, Jasmin Sydow-Anderson, Xaver Reiser, Sabine Schuster, Jeannette Neubauer, Sebastian Hoepfl, Kirsten Richter, Marcel Nold, Claudia Nold-PetryFelix Schumacher, Andrew M. Ellisdon

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1-11.e1–e4
Number of pages15
JournalCell Chemical Biology
Volume29
DOIs
Publication statusPublished - 17 Mar 2022

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