title: A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway.
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.
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Helling
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: König
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dälken
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Engling
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Krömer
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Heim
authors.affiliation: Condor Scientific Computing and Consulting, Sulzbach, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Wallmeier
authors.affiliation: Division of Molecular Neuroimmunology, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.affiliation: Division of Molecular Neuroimmunology, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wildemann
authors.affiliation: Division of Molecular Neuroimmunology, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fritz
authors.affiliation: Department of Dermatology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
authors.affiliation: Department of Dermatology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kubach
authors.affiliation: Institute of Pharmaceutical Biology, Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Theodor
authors.initials: T
authors.lastname: Dingermann
authors.affiliation: Institute of Pharmacology and Toxicology, Clinic of the Goethe University, Frankfurt, Germany.
authors.forename: Heinfried H
authors.initials: HH
authors.lastname: Radeke
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Osterroth
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Uherek
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Czeloth
authors.affiliation: Biotest AG, Dreieich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schüttrumpf
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015704:CD4 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D018985:Epitopes, B-Lymphocyte / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C561371:BT-061; D015704:CD4 Antigens; D018985:Epitopes, B-Lymphocyte; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta