title: Characterization of a novel single-chain bispecific antibody for retargeting of T cells to tumor cells via the TCR co-receptor CD8.
abstract: There is currently growing interest in retargeting of effector T cells to tumor cells via bispecific antibodies (bsAbs). Usually, bsAbs are directed on the one hand to the CD3 complex of T cells and on the other hand to a molecule expressed on the surface of the target cell. A bsAb-mediated cross-linkage via CD3 leads to an activation of CD8+ T cells and consequently to killing of the target cells. In parallel, CD4+ T cells including TH1, TH2, TH17 cells and even regulatory T cells (Tregs) will be activated as well. Cytokines produced by CD4+ T cells can contribute to severe side effects e. g. life-threatening cytokine storms and, thinking of the immunosupressive function of Tregs, can even be counterproductive. Therefore, we asked whether or not it is feasible to limit retargeting to CD8+ T cells e. g. via targeting of the co-receptor CD8 instead of CD3. In order to test for proof of concept, a novel bsAb with specificity for CD8 and a tumor-associated surface antigen was constructed. Interestingly, we found that pre-activated (but not freshly isolated) CD8+ T cells can be retargeted via CD8-engaging bsAbs leading to an efficient lysis of target cells.
authors.affiliation: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Michalk
authors.affiliation: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Dresden, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Feldmann
authors.affiliation: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Koristka
authors.affiliation: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Arndt
authors.affiliation: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Dresden, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Cartellieri
authors.affiliation: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Ehninger
authors.affiliation: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Radioimmunology, Dresden, Germany; Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bachmann
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000302:isolation & purification; D017252:CD3 Complex / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002469:Cell Separation; D003432:Cross-Linking Reagents / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D016827:CD8 Antigens; D003432:Cross-Linking Reagents; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D057127:Single-Chain Antibodies
references.citation: Cancer Res. 2009 Jun 15;69(12):4941-4
references.pmid: 19509221
references.citation: Cancer Lett. 2006 May 18;236(2):229-38
references.pmid: 16046056
references.citation: Cancer Immunol Immunother. 2012 Oct;61(10):1869-75
references.pmid: 22976535
references.citation: MAbs. 2010 May-Jun;2(3):309-19
references.pmid: 20418662
references.citation: Blood. 2004 Nov 1;104(9):2840-8
references.pmid: 15238416
references.citation: Br J Haematol. 2013 Nov;163(3):315-25
references.pmid: 24033280
references.citation: J Immunol. 2003 Apr 15;170(8):4397-402
references.pmid: 12682277
references.citation: BioDrugs. 2010 Apr 1;24(2):89-98
references.pmid: 20199124
references.citation: Int J Cancer. 2005 May 20;115(1):98-104
references.pmid: 15688411
references.citation: Prostate. 2011 Jun 15;71(9):998-1011
references.pmid: 21541976
references.citation: PLoS One. 2011 Jan 21;6(1):e16315
references.pmid: 21283706
references.citation: Prostate. 2007 Jul 1;67(10):1121-31
references.pmid: 17492652
references.citation: Anal Biochem. 2012 Apr 15;423(2):261-8
references.pmid: 22274538
references.citation: J Autoimmun. 2013 May;42:105-16
references.pmid: 23352111
references.citation: Methods Mol Biol. 2012;869:465-9
references.pmid: 22585511
references.citation: Trends Biotechnol. 2013 Nov;31(11):621-32
references.pmid: 24094861
references.citation: Leukemia. 2011 Jun;25(6):1053-6
references.pmid: 21415850
references.citation: Methods Mol Biol. 2009;536:293-8
references.pmid: 19378068
references.citation: Nucl Med Biol. 2014 Jan;41(1):68-76
references.pmid: 24210808
references.citation: Leukemia. 2014 Jan;28(1):59-69
references.pmid: 23958923
references.citation: Leukemia. 2013 Apr;27(4):964-7
references.pmid: 23325142
references.citation: J Immunol. 2012 Sep 15;189(6):3249-59
references.pmid: 22875801
references.citation: Mol Immunol. 2006 Feb;43(6):763-71
references.pmid: 16360021
references.citation: Pharmacol Ther. 2012 Dec;136(3):334-42
references.pmid: 22940266