Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

Oncoimmunology
Sina Fellermeier-KopfRoland Kontermann

Abstract

Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell - antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines). By linking the TNFSF ligands 4-1BBL, OX40L and CD27L in all possible combinations, cis-acting Duokines were generated that act on the same or adjacent T cells, while combining CD40L with 4-1BBL, OX40L and CD27L resulted in trans-acting Duokines acting simultaneously on APCs and T cells. In vitro, co-stimulation of T cells was seen for cis- and trans-acting Duokines and scDuokines in an antigen-independent as well as antigen-specific setting. Trans-acting molecules furthermore activated B cells, which represent a subclass of APCs. In a ...Continue Reading

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Citations

Aug 14, 2019·Human Vaccines & Immunotherapeutics·David M RichardsChristian Merz
Apr 22, 2020·Cellular & Molecular Immunology·Heliang LiErwei Song

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Methods Mentioned

BETA
ELISA
flow cytometry
density gradient centrifugation
electrophoresis
gel filtration

Software Mentioned

TreeStar
FlowJo
Graphpad Prism

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