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

TITLE=Superior Treg-Expanding Properties of a Novel Dual-Acting Cytokine Fusion Protein

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01490

DOI=10.3389/fphar.2019.01490

ISSN=1663-9812

ABSTRACT=<p>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. <italic>In vivo</italic>, 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-mTNF<sub>R2</sub>). IL2-EHD2-sc-mTNF<sub>R2</sub> showed high affinity to TNFR2 and efficiently activated IL-2 and TNFR2-selective signaling pathways. Further, IL2-EHD2-sc-mTNF<sub>R2</sub> promoted superior Treg expansion, with both the IL-2 and the TNFR2 agonist (sc-mTNF<sub>R2</sub>) component necessary for this biological response. Ultimately, we propose that IL2-EHD2-sc-mTNF<sub>R2</sub> is a dual-acting cytokine that efficiently promotes Treg expansion and might have a superior therapeutic window than conventional IL-2-based drugs.</p>