title: An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia.
abstract: Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE). In vitro, treatment with 293C3-SDIE significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by allogeneic and autologous NK cells as compared with its wild-type counterpart. In line with the observed lower expression levels of CD133 on healthy cells compared with malignant hematopoietic cells, 293C3-SDIE caused no relevant toxicity towards committed hematopoietic progenitor cells. In a NOD.Cg-PrkdcscidIL2rgtmWjl/Sz xenotransplantation model, 293C3-SDIE facilitated elimination of patient AML cells by human NK cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for elimination of minimal residual disease in the context of allogeneic stem cell transplantation in AML.
authors.affiliation: Department for Internal Medicine II, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Tuebingen, Germany.|Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: S P
authors.initials: SP
authors.lastname: Koerner
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University, Tuebingen, Germany.|Department of Pediatric Intensive Care, University Children's Hospital, Basel, Switzerland.
authors.forename: M C
authors.initials: MC
authors.lastname: André
authors.affiliation: Department for Immunology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: J S
authors.initials: JS
authors.lastname: Leibold
authors.affiliation: Department for Internal Medicine II, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Tuebingen, Germany.|Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: P C
authors.initials: PC
authors.lastname: Kousis
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University, Tuebingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kübler
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University, Tuebingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pal
authors.affiliation: Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.|Department for Immunology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: S P
authors.initials: SP
authors.lastname: Haen
authors.affiliation: Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Bühring
authors.affiliation: Department for Immunology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Grosse-Hovest
authors.affiliation: Department for Immunology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Jung
authors.affiliation: Department for Internal Medicine II, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Tuebingen, Germany.|Department of Hematology and Oncology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: H R
authors.initials: HR
authors.lastname: Salih
mesh_terms: D000071916:AC133 Antigen / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D015550:Cell Degranulation / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D064593:Heterografts; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice
chemical_list: D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal; D016207:Cytokines; D000939:Epitopes; D007141:Immunoglobulin Fc Fragments