Padutsch et al. published in Front. Pharmacol.

November 20, 2019

Superior Treg-expanding properties of a novel dual-acting cytokine fusion protein

Tanja Padutsch, Sendetski Maksim, Carina Huber, Nathalie Peters, Klaus Pfizenmaier, John R. Bethea, Roland E. Kontermann and Roman Fischer

Abstract

Autoimmune diseases are caused by uncontrolled endogenous immune responses against healthy cells. They may develop due to an impaired function of regulatory T cells (Tregs), which normally suppress self-specific effector immune cells. Interleukin 2 (IL-2) and tumor necrosis factor (TNF) have been identified as key players that promote expansion, function and stability of Tregs. In vivo, both low-dose IL-2 therapy and TNF receptor 2 (TNFR2) agonism were shown to expand Tregs and alleviate autoimmunity. We here designed a novel dimeric dual-acting fusion cytokine, where mouse IL-2 is genetically linked to a TNFR2-selective single-chain TNF mutein (IL2-EHD2-sc-mTNFR2). IL2-EHD2-sc-mTNFR2 showed high affinity to TNFR2 and efficiently activated IL-2 and TNFR2-selective signaling pathways. Further, IL2-EHD2-sc-mTNFR2 promoted superior Treg expansion, with both the IL-2 and the TNFR2 agonist (sc-mTNFR2) component necessary for this biological response. Ultimately, we propose that IL2-EHD2-sc-mTNFR2 is a dual-acting cytokine that efficiently promotes Treg expansion and might have a superior therapeutic window than conventional IL-2-based drugs.

DOI: 10.3389/fphar.2019.01490

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