16. Oktober 2017

Hutt et al. accepted for publication in Molecular Cancer Therapeutics

Superior properties of Fc-comprising scTRAIL fusion proteins

 

Superior properties of Fc-comprising scTRAIL fusion proteins.

Hutt M, Marquardt L, Seifert O, Siegemund M, Müller I, Kulms D, Pfizenmaier K, Kontermann RE.

Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In the present study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of epidermal growth factor receptor (EGFR)-targeting dimeric scTRAIL fusion proteins (Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL) as well as two non-targeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on anti-tumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro, exceeding the activity of the respective non-targeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent anti-tumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable anti-tumor activities were found for the EGFR-targeting scFv-Fc-scTRAIL and the non-targeting Fc-scTRAIL in vivo.

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