IgG-single-chain TRAIL fusion proteins for tumour therapy

Scientific Reports
Martin SiegemundRoland E Kontermann

Abstract

Single-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225. The binding specificity to EGFR and death receptors was retained in all IgG-scTRAIL formats and translated into high antigen-specific bioactivity on EGFR-positive Colo205, HCT116 and WM1366 tumour cell lines, with or without sensitization to apoptosis by bortezomib. In vivo, therapeutic potential was assessed for one of the targeted variants, HC-scTRAIL, compared to the non-targeted Fc-scTRAIL. Both molecules showed a significant reduction of tumour volume and synergism with a Smac mimetic in a Colo205 xenograft tumour model. The IgG-scTRAIL format allows directing a defined, h...Continue Reading

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Citations

Nov 13, 2018·NPJ Systems Biology and Applications·Greta Del MistroDagmar Kulms
Jun 13, 2020·Frontiers in Pharmacology·Franziska HartungLuis A Pardo
Jun 13, 2020·Frontiers in Cell and Developmental Biology·Roman FischerKlaus Pfizenmaier
May 21, 2020·Molecular Cancer Therapeutics·Alexander RauRoland E Kontermann
Apr 3, 2021·Science·Robby DivineDavid Baker
Feb 17, 2020·Antibody Therapeutics·Siwei NieJijie Gu

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Methods Mentioned

BETA
size-exclusion chromatography
size exclusion chromatography
flow cytometry
ELISA
differential scanning calorimetry
xenograft
PCR
transfection
gel filtration
FACS

Software Mentioned

Excel
GraphPad
Prism
MS

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