Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia

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 -