Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia
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Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia. / Hofmann, M; Große-Hovest, L; Nübling, T; Pyż, E; Bamberg, M L; Aulwurm, S; Bühring, H-J; Schwartz, K; Haen, S P; Schilbach, Karin; Rammensee, H-G; Salih, H R; Jung, G.
In: LEUKEMIA, Vol. 26, No. 6, 06.2012, p. 1228-37.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia
AU - Hofmann, M
AU - Große-Hovest, L
AU - Nübling, T
AU - Pyż, E
AU - Bamberg, M L
AU - Aulwurm, S
AU - Bühring, H-J
AU - Schwartz, K
AU - Haen, S P
AU - Schilbach, Karin
AU - Rammensee, H-G
AU - Salih, H R
AU - Jung, G
PY - 2012/6
Y1 - 2012/6
N2 - The therapeutic efficacy of humanized or chimeric second-generation antitumor antibodies is clearly established, but often limited. In recent years, defined modifications of the glycosylation pattern or the amino-acid sequence of the human immunoglobulin G1 Fc part have resulted in the development of third-generation antibodies with improved capability to recruit Fc receptor-bearing effector cells. The first antibodies of this kind, currently evaluated in early clinical trials, are directed against lymphoma-associated antigens. Fc-engineered antibodies targeting myeloid leukemia are not yet available. We here report on the generation and preclinical characterization of an Fc-optimized antibody directed to the FMS-related tyrosine kinase 3 (FLT3), an antigen expressed on the leukemic blasts of all investigated patients with acute myeloid leukemia (AML). This antibody, termed 4G8SDIEM, mediated markedly enhanced cellular cytotoxicity against FLT3-expressing cell lines as well as blasts of AML patients. FLT3 expression levels on AML cells varied between 300 and 4600 molecules/cell and, in most cases, were substantially higher than those detected on normal hematopoietic precursor cells and dendritic cells (approximately 300 molecules/cell). Antibody-mediated cytotoxicity against these normal cells was not detectable. 4G8SDIEM has been produced in pharmaceutical quality in a university-owned production unit and is currently used for the treatment of leukemia patients.
AB - The therapeutic efficacy of humanized or chimeric second-generation antitumor antibodies is clearly established, but often limited. In recent years, defined modifications of the glycosylation pattern or the amino-acid sequence of the human immunoglobulin G1 Fc part have resulted in the development of third-generation antibodies with improved capability to recruit Fc receptor-bearing effector cells. The first antibodies of this kind, currently evaluated in early clinical trials, are directed against lymphoma-associated antigens. Fc-engineered antibodies targeting myeloid leukemia are not yet available. We here report on the generation and preclinical characterization of an Fc-optimized antibody directed to the FMS-related tyrosine kinase 3 (FLT3), an antigen expressed on the leukemic blasts of all investigated patients with acute myeloid leukemia (AML). This antibody, termed 4G8SDIEM, mediated markedly enhanced cellular cytotoxicity against FLT3-expressing cell lines as well as blasts of AML patients. FLT3 expression levels on AML cells varied between 300 and 4600 molecules/cell and, in most cases, were substantially higher than those detected on normal hematopoietic precursor cells and dendritic cells (approximately 300 molecules/cell). Antibody-mediated cytotoxicity against these normal cells was not detectable. 4G8SDIEM has been produced in pharmaceutical quality in a university-owned production unit and is currently used for the treatment of leukemia patients.
KW - Animals
KW - Antibodies, Monoclonal/isolation & purification
KW - Antibodies, Neoplasm/immunology
KW - Antibody-Dependent Cell Cytotoxicity
KW - Blast Crisis
KW - Cells, Cultured
KW - Dendritic Cells/immunology
KW - Flow Cytometry
KW - Humans
KW - Leukemia, Myeloid/immunology
KW - Mice
KW - Receptors, Fc/immunology
KW - fms-Like Tyrosine Kinase 3/genetics
U2 - 10.1038/leu.2011.372
DO - 10.1038/leu.2011.372
M3 - SCORING: Journal article
C2 - 22289926
VL - 26
SP - 1228
EP - 1237
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 6
ER -