title: Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia.
abstract: 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.
authors.affiliation: Department of Immunology, Eberhard-Karls University, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hofmann
authors.forename: L
authors.initials: L
authors.lastname: Große-Hovest
authors.forename: T
authors.initials: T
authors.lastname: Nübling
authors.forename: E
authors.initials: E
authors.lastname: Pyż
authors.forename: M L
authors.initials: ML
authors.lastname: Bamberg
authors.forename: S
authors.initials: S
authors.lastname: Aulwurm
authors.forename: H-J
authors.initials: HJ
authors.lastname: Bühring
authors.forename: K
authors.initials: K
authors.lastname: Schwartz
authors.forename: S P
authors.initials: SP
authors.lastname: Haen
authors.forename: K
authors.initials: K
authors.lastname: Schilbach
authors.forename: H-G
authors.initials: HG
authors.lastname: Rammensee
authors.forename: H R
authors.initials: HR
authors.lastname: Salih
authors.forename: G
authors.initials: G
authors.lastname: Jung
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification* / Q000378:metabolism / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D001752:Blast Crisis; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D011961:Receptors, Fc / Q000276:immunology*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D011961:Receptors, Fc; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3