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Immunol Cell Biol. 2015 Apr;93(4):396-405. doi: 10.1038/icb.2014.102. Epub 2014 Dec 16.

A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway.

Author information

1
Biotest AG, Dreieich, Germany.
2
Condor Scientific Computing and Consulting, Sulzbach, Germany.
3
Division of Molecular Neuroimmunology, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
4
Department of Dermatology, Johannes Gutenberg University, Mainz, Germany.
5
Institute of Pharmaceutical Biology, Goethe University Frankfurt, Frankfurt, Germany.
6
Institute of Pharmacology and Toxicology, Clinic of the Goethe University, Frankfurt, Germany.

Abstract

CD4(+)CD25(+) regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor-independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing.

PMID:
25512343
PMCID:
PMC4407014
DOI:
10.1038/icb.2014.102
[Indexed for MEDLINE]
Free PMC Article

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