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High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab

The humanized non-depleting anti-CD4 monoclonal antibody Tregalizumab (BT-061) is able to selectively activate the suppressive function of regulatory T cells and has been investigated up to phase IIb in clinical trials in patients suffering from rheumatoid arthritis (RA). A pharmacokinetic–pharmacod...

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Autores principales: Heim, Katharina, Dälken, Benjamin, Faust, Stefanie, Rharbaoui, Faiza, Engling, Andre, Wallmeier, Holger, Dingermann, Theodor, Radeke, Heinfried H, Schüttrumpf, Jörg, Gutscher, Marcus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192061/
https://www.ncbi.nlm.nih.gov/pubmed/28090323
http://dx.doi.org/10.1038/cti.2016.69
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author Heim, Katharina
Dälken, Benjamin
Faust, Stefanie
Rharbaoui, Faiza
Engling, Andre
Wallmeier, Holger
Dingermann, Theodor
Radeke, Heinfried H
Schüttrumpf, Jörg
Gutscher, Marcus
author_facet Heim, Katharina
Dälken, Benjamin
Faust, Stefanie
Rharbaoui, Faiza
Engling, Andre
Wallmeier, Holger
Dingermann, Theodor
Radeke, Heinfried H
Schüttrumpf, Jörg
Gutscher, Marcus
author_sort Heim, Katharina
collection PubMed
description The humanized non-depleting anti-CD4 monoclonal antibody Tregalizumab (BT-061) is able to selectively activate the suppressive function of regulatory T cells and has been investigated up to phase IIb in clinical trials in patients suffering from rheumatoid arthritis (RA). A pharmacokinetic–pharmacodynamic model based on clinical data from RA and healthy volunteers, which used the cell surface CD4 downmodulation as marker of activity, confirmed a stronger effect in healthy volunteers compared with RA patients. We tried to understand this phenomenon and evaluated the influence of the small oxidoreductase thioredoxin-1 (Trx1). To counteract oxidative stress that is strongly associated with RA pathophysiology, the organism employs Trx1. Therefore, increased expression and secretion of Trx1 is found in the synovial fluid and plasma of RA patients. Moreover, the binding site of Tregalizumab is in close proximity to a disulphide bond in domain 2 (D2) of CD4, which is a known target for a reduction by oxidoreductase Trx1. With the experiments reported herein, we demonstrated that specific reduction of the D2 disulphide bond by Trx1 led to diminished binding of Tregalizumab to recombinant human soluble CD4 and membrane-bound CD4 on T cells. Moreover, we showed that this caused changes in the Tregalizumab-induced CD4 signalling pathway via the lymphocyte-specific protein tyrosine kinase p56(Lck) and CD4 downmodulation. In summary, we provide evidence that high Trx1 levels in RA patients compared with healthy subjects are a potential reason for diminished binding of Tregalizumab to CD4-positive T cells and offer an explanation for the observed decreased CD4 downmodulation in RA patients in comparison to healthy subjects.
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spelling pubmed-51920612017-01-13 High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab Heim, Katharina Dälken, Benjamin Faust, Stefanie Rharbaoui, Faiza Engling, Andre Wallmeier, Holger Dingermann, Theodor Radeke, Heinfried H Schüttrumpf, Jörg Gutscher, Marcus Clin Transl Immunology Original Article The humanized non-depleting anti-CD4 monoclonal antibody Tregalizumab (BT-061) is able to selectively activate the suppressive function of regulatory T cells and has been investigated up to phase IIb in clinical trials in patients suffering from rheumatoid arthritis (RA). A pharmacokinetic–pharmacodynamic model based on clinical data from RA and healthy volunteers, which used the cell surface CD4 downmodulation as marker of activity, confirmed a stronger effect in healthy volunteers compared with RA patients. We tried to understand this phenomenon and evaluated the influence of the small oxidoreductase thioredoxin-1 (Trx1). To counteract oxidative stress that is strongly associated with RA pathophysiology, the organism employs Trx1. Therefore, increased expression and secretion of Trx1 is found in the synovial fluid and plasma of RA patients. Moreover, the binding site of Tregalizumab is in close proximity to a disulphide bond in domain 2 (D2) of CD4, which is a known target for a reduction by oxidoreductase Trx1. With the experiments reported herein, we demonstrated that specific reduction of the D2 disulphide bond by Trx1 led to diminished binding of Tregalizumab to recombinant human soluble CD4 and membrane-bound CD4 on T cells. Moreover, we showed that this caused changes in the Tregalizumab-induced CD4 signalling pathway via the lymphocyte-specific protein tyrosine kinase p56(Lck) and CD4 downmodulation. In summary, we provide evidence that high Trx1 levels in RA patients compared with healthy subjects are a potential reason for diminished binding of Tregalizumab to CD4-positive T cells and offer an explanation for the observed decreased CD4 downmodulation in RA patients in comparison to healthy subjects. Nature Publishing Group 2016-12-23 /pmc/articles/PMC5192061/ /pubmed/28090323 http://dx.doi.org/10.1038/cti.2016.69 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Heim, Katharina
Dälken, Benjamin
Faust, Stefanie
Rharbaoui, Faiza
Engling, Andre
Wallmeier, Holger
Dingermann, Theodor
Radeke, Heinfried H
Schüttrumpf, Jörg
Gutscher, Marcus
High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
title High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
title_full High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
title_fullStr High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
title_full_unstemmed High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
title_short High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
title_sort high thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody tregalizumab
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192061/
https://www.ncbi.nlm.nih.gov/pubmed/28090323
http://dx.doi.org/10.1038/cti.2016.69
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