TY  - THES
A1  - Heim, Katharina Julia
T1  - High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
N2  - 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 2b in clinical trials in patients suffering from rheumatoid arthritis (RA). 
A pharmacokinetic-pharmacodynamic model, which is based on clinical data from RA and healthy subjects, used the cell surface CD4-down-modulation as marker of the antibodies' activity. This model surprisingly revealed a stronger effect of Tregalizumab in healthy subjects compared to RA patients. This thesis presents a series of experiments performed to understand this phenomenon. 
To counteract oxidative stress, which is strongly associated with RA pathophysiology, the organism employs the small oxidoreductase thioredoxin-1 (Trx1). Therefore, augmented expression and secretion of Trx1 was seen in many studies the synovial fluid and plasma of RA patients. Moreover, the binding site of Tregalizumab is in close proximity to a disulfide bond in domain 2 (D2) of CD4, which is a known target for a reduction by Trx1. So, this thesis also evaluated the influence of Trx1 on binding of Tregalizumab to its target CD4. 
With the experiments reported herein, it was possible to demonstrate that specific reduction of the D2 disulfide bond of CD4 by Trx1 led to diminished binding of Tregalizumab to recombinant human soluble CD4 (rh sCD4) and membrane-bound CD4 on T cells from a human leukemia cell line and peripheral blood mononuclear cells (PBMC). Moreover, the experiments revealed that this caused changes in the Tregalizumab-induced CD4 signalling pathway via the lymphocyte-specific protein tyrosine kinase p56Lck.
In summary, this thesis provides evidence that high Trx1 levels in RA patients compared to healthy subjects are a potential valid reason for diminished binding of Tregalizumab to CD4-positive T cells and offers an explanation for the observed decreased CD4 down-modulation in RA patients in comparison with healthy subjects. It emphasizes that binding of Tregalizumab is impaired in a particular way in RA patients.
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44145
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-441453
CY  - Frankfurt am Main
ER  -