The trimer to monomer transition of Tumor Necrosis Factor-Alpha is a dynamic process that is significantly altered by therapeutic antibodies
| Autor: | Bastian Groitl, Fjolla Ismajli, Lukas Traxler, Aymelt Itzen, Ulrich Rant, Herwin Daub |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Molecular biology medicine.medical_treatment Immunology Biophysics lcsh:Medicine Trimer Biosensing Techniques Certolizumab Article Etanercept 03 medical and health sciences Immunoglobulin Fab Fragments 0302 clinical medicine medicine Adalimumab lcsh:Science Multidisciplinary Chemistry Protein Stability Tumor Necrosis Factor-alpha Drug discovery lcsh:R Antibodies Monoclonal Receptor–ligand kinetics Golimumab Infliximab Molecular Imaging ddc 030104 developmental biology Cytokine Immobilized Proteins lcsh:Q Tumor necrosis factor alpha Protein Multimerization 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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