An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia

• Published in: Leukemia 2017-02, Vol.31 (2), p.459-469
• Main Authors: Koerner, S P, André, M C, Leibold, J S, Kousis, P C, Kübler, A, Pal, M, Haen, S P, Bühring, H-J, Grosse-Hovest, L, Jung, G, Salih, H R
• Format: Article
• Language: English
• Subjects: 13; 631/250/1619/382; 631/250/251; 631/61/51/1568; 631/67/1059/2325; 631/67/1990/283/1897; 82; 82/1; AC133 Antigen - immunology; Acute myeloid leukemia; Amino acids; Animals; Antibodies; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibody-Dependent Cell Cytotoxicity; Autografts; Cancer Research; Care and treatment; CD16 antigen; Cell Degranulation - immunology; Chronic myeloid leukemia; Cloning; Collaboration; Consortia; Critical Care Medicine; Cytokines - metabolism; Cytotoxicity; Cytotoxicity, Immunologic - immunology; Degranulation; Epitopes - immunology; Health aspects; Hematology; Hematopoietic stem cells; Heterografts; Humans; Immunoglobulin Fc Fragments - immunology; Immunology; Immunotherapy; Intensive; Internal Medicine; Killer cells; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Leukemia; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - metabolism; Lymphocyte Activation - immunology; Lysis; Medical research; Medicine; Medicine & Public Health; Mice; Minimal residual disease; Monoclonal antibodies; Myelocytic leukemia; Natural killer cells; Nonlymphoid leukemia; Oncology; original-article; Patients; Pediatrics; Physiological aspects; Progenitor cells; Stem cell transplantation; Stem cells; Testing; Toxicity; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.194

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.