title: Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system.
abstract: Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: C
authors: C
authors: Arndt
authors: 1] Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany [2] Helmholtz-Zentrum Dresden-Rossendorf, Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.
authors: A
authors: A
authors: Feldmann
authors: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: M
authors: M
authors: von Bonin
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: M
authors: M
authors: Cartellieri
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: E-M
authors: EM
authors: Ewen
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: S
authors: S
authors: Koristka
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: I
authors: I
authors: Michalk
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: S
authors: S
authors: Stamova
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: N
authors: N
authors: Berndt
authors: Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: A
authors: A
authors: Gocht
authors: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: M
authors: M
authors: Bornhäuser
authors: Medical Clinic and Polyclinic I, University Hospital 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: G
authors: G
authors: Ehninger
authors: 1] Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany [2] Center for Regenerative Therapies Dresden, 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: M
authors: M
authors: Schmitz
authors: 1] Institute of Immunology, Medical Faculty 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany [2] Helmholtz-Zentrum Dresden-Rossendorf, Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany [3] Center for Regenerative Therapies Dresden, 'Carl Gustav Carus', Technical University Dresden, Dresden, Germany.
authors: M
authors: M
authors: Bachmann
mesh_terms: D000818:Animals; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D063268:Sialic Acid Binding Ig-like Lectin 3
references: Leukemia. 2013 Apr;27(5):1107-15
references: 23178753
references: Int J Cancer. 2002 Aug 20;100(6):690-7
references: 12209608
references: J Immunother. 2012 Jun;35(5):418-29
references: 22576347
references: Science. 2008 Aug 15;321(5891):974-7
references: 18703743
references: J Immunol. 2003 Apr 15;170(8):4397-402
references: 12682277
references: Blood. 2000 Aug 1;96(3):870-7
references: 10910899
references: Mol Immunol. 2006 Feb;43(6):763-71
references: 16360021
references: Eur J Haematol. 2008 Oct;81(4):281-8
references: 18573171
references: Clin Ther. 2009;31 Pt 2:2349-70
references: 20110045
references: J Immunother. 2009 Jun;32(5):452-64
references: 19609237
references: Cancer Res. 1992 Jun 15;52(12):3402-8
references: 1596900
references: Anal Biochem. 2012 Apr 15;423(2):261-8
references: 22274538
references: J Autoimmun. 2013 May;42:105-16
references: 23352111
references: Blood. 2011 Jun 30;117(26):7174-84
references: 21540460
references: Blood. 2009 Mar 5;113(10):2245-55
references: 18988867
references: Cancer Lett. 2006 May 18;236(2):229-38
references: 16046056
references: Cancer Immunol Immunother. 2006 May;55(5):503-14
references: 16032400
references: Leukemia. 2011 Jun;25(6):1053-6
references: 21415850
references: J Immunol. 2012 Feb 1;188(3):1551-8
references: 22184723
references: Nat Biotechnol. 2005 Sep;23(9):1126-36
references: 16151406
references: Exp Hematol. 2008 Apr;36(4):486-94
references: 18249062
references: Nat Biotechnol. 2013 Jan;31(1):71-5
references: 23242161
references: Prostate. 2011 May;71(6):588-96
references: 20945402
references: BioDrugs. 2010 Apr 1;24(2):89-98
references: 20199124
references: Leukemia. 2013 Apr;27(4):964-7
references: 23325142
references: J Immunol. 2012 Sep 15;189(6):3249-59
references: 22875801
references: Int J Cancer. 2005 May 20;115(1):98-104
references: 15688411
references: Blood. 1986 Apr;67(4):1048-53
references: 2937468
references: Immunobiology. 2009;214(6):441-53
references: 19157637
references: J Clin Oncol. 2011 Jun 20;29(18):2493-8
references: 21576633
references: Mol Immunol. 2011 Dec;49(3):474-82
references: 22014687
references: J Immunother. 2009 May;32(4):341-52
references: 19342971
references: Prostate. 2011 Jun 15;71(9):998-1011
references: 21541976
references: Exp Cell Res. 2011 May 15;317(9):1255-60
references: 21419116
references: Exp Cell Res. 1989 Nov;185(1):73-85
references: 2530103
references: Cytotherapy. 2010 Dec;12(8):1056-62
references: 20735170
references: Blood. 2012 Jun 28;119(26):6226-33
references: 22592608
references: Cancer Immunol Immunother. 2010 Dec;59(12):1839-49
references: 20814675