An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia
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An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia. / 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.
In: LEUKEMIA, Vol. 31, No. 2, 02.2017, p. 459-469.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia
AU - Koerner, S P
AU - André, M C
AU - Leibold, J S
AU - Kousis, P C
AU - Kübler, A
AU - Pal, M
AU - Haen, S P
AU - Bühring, H-J
AU - Grosse-Hovest, L
AU - Jung, G
AU - Salih, H R
PY - 2017/2
Y1 - 2017/2
N2 - 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.
AB - 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.
KW - AC133 Antigen/immunology
KW - Animals
KW - Antibodies, Monoclonal/immunology
KW - Antibody-Dependent Cell Cytotoxicity
KW - Cell Degranulation/immunology
KW - Cytokines/metabolism
KW - Cytotoxicity, Immunologic/immunology
KW - Epitopes/immunology
KW - Heterografts
KW - Humans
KW - Immunoglobulin Fc Fragments/immunology
KW - Killer Cells, Natural/immunology
KW - Leukemia, Myeloid, Acute/immunology
KW - Lymphocyte Activation/immunology
KW - Mice
U2 - 10.1038/leu.2016.194
DO - 10.1038/leu.2016.194
M3 - SCORING: Journal article
C2 - 27435001
VL - 31
SP - 459
EP - 469
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 2
ER -