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Clin Transl Immunology. 2016 Dec 23;5(12):e121. doi: 10.1038/cti.2016.69. eCollection 2016 Dec.

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

Author information

1
Biotest AG , Dreieich, Germany.
2
Condor Scientific Computing and Consulting , Sulzbach, Germany.
3
Institute of Pharmaceutical Biology, Goethe University Frankfurt , Frankfurt, Germany.
4
Institute of Pharmacology and Toxicology/ZAFES, Clinic of the Goethe University , Frankfurt, Germany.

Abstract

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.

Conflict of interest statement

K.H., Dr M.G., Dr B.D., Dr A.E., Dr S.F., Dr F.R. and Dr J.S. are employed by Biotest AG. Dr H.W. obtained a grant from Biotest AG. The other authors declare no conflict of interest.

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