The trimer to monomer transition of Tumor Necrosis Factor-Alpha is a dynamic process that is significantly altered by therapeutic antibodies.

Scientific Reports
Herwin DaubUlrich Rant

Abstract

The cytokine tumor necrosis factor-alpha (TNF-α) readily forms homotrimers at sub-nM concentrations to promote inflammation. For the treatment of inflammatory diseases with upregulated levels of TNF-α, a number of therapeutic antibodies are currently used as scavengers to reduce the active TNF-α concentration in patients. Despite their clinical success, the mode-of-action of different antibody formats with regard to a stabilization of the trimeric state is not entirely understood. Here, we use a biosensor with dynamic nanolevers to analyze the monomeric and trimeric states of TNF-α together with the binding kinetics of therapeutic biologics. The intrinsic trimer-to-monomer decay rate k = 1.7 × 10-3 s-1 could be measured directly using a microfluidic system, and antibody binding affinities were analyzed in the pM range. Trimer stabilization effects are quantified for Adalimumab, Infliximab, Etanercept, Certolizumab, Golimumab for bivalent and monovalent binding formats. Clear differences in trimer stabilization are observed, which may provide a deeper insight into the mode-of-action of TNF-α scavengers.

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Citations

Sep 18, 2020·The Biochemical Journal·María Angélica ContrerasOliberto Sánchez
Mar 28, 2021·European Biophysics Journal : EBJ·Hanna Müller-Landau, Paloma Fernández Varela
Aug 4, 2021·Physical Chemistry Chemical Physics : PCCP·Fabian SoltermannPhilipp Kukura
Dec 22, 2021·Analytical Chemistry·Catherine Y TremblayRichard W Vachet

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Methods Mentioned

BETA
size exclusion chromatography
biosensor
equilibrium
FRET
Biosensors
fluorescence proximity
equilibrium titration

Software Mentioned

Origin
Hydropro
SLOW

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