title: Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI x anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer.
abstract: A phase I study of the bispecific antibody MDX-H210 in combination with granulocyte colony-stimulating factor (G-CSF) was performed in stage IV breast carcinoma patients, overexpressing HER-2/neu. MDX-H210, constructed by crosslinking antigen binding fragments (F(ab') fragments) of monoclonal antibody (mAb) H22 to Fc gamma receptor I (FcgammaRI), and mAb 520C9 to HER-2/neu, respectively, mediates the lysis of tumour cells in vitro, and in human FcgammaRI transgenic mouse models. The proto-oncogene HER-2/neu is overexpressed in approximately 30% of breast cancer patients, and represents a promising target for antibody-based immunotherapy. Fc gamma receptor I (CD64) is an effective trigger molecule, which is expressed on monocytes/macrophages, immature dendritic cells, and G-CSF-primed polymorphonuclear cells (PMN). Patients received G-CSF (Filgrastim) for 8 consecutive days, and cohorts of three patients were treated on day 4 with escalating, single doses of MDX-H210. A total of 30 patients were included, and treatment was generally well tolerated, without reaching dose-limiting toxicity. Side effects consisted mainly of fever and short periods of chills, which were timely related to elevated plasma levels of interleukin 6 and tumour necrosis factor alpha. In the last two cohorts, MDX-H210 plasma levels exceeded 1 microg ml(-1), and on circulating myeloid cells >50% saturation of FcgammaRI was found until day 4. These effector cells were highly effective in antibody-dependent cell-mediated cytotoxicity. Immunohistochemical analyses of tumour biopsies in individual patients documented infiltration of monocytes and PMN after MDX-H210 infusion. Although the clinical course of the disease was not altered by the single dose of MDX-H210, a favourable toxicity profile--even at high doses--and remarkable biological effects were seen when combined with G-CSF. Therefore, the combination of G-CSF and MDX-H210 should be evaluated in further immunotherapeutical strategies.
authors.affiliation: Department of Medicine III, Division of Hematology/Oncology, University of Erlangen-Nürnberg, Krankenhausstrasse 12, Erlangen 91054, Germany. Roland.Repp@med3.imed.uni-erlangen.de
authors.forename: R
authors.initials: R
authors.lastname: Repp
authors.forename: H H
authors.initials: HH
authors.lastname: van Ojik
authors.forename: T
authors.initials: T
authors.lastname: Valerius
authors.forename: G
authors.initials: G
authors.lastname: Groenewegen
authors.forename: G
authors.initials: G
authors.lastname: Wieland
authors.forename: C
authors.initials: C
authors.lastname: Oetzel
authors.forename: B
authors.initials: B
authors.lastname: Stockmeyer
authors.forename: W
authors.initials: W
authors.lastname: Becker
authors.forename: M
authors.initials: M
authors.lastname: Eisenhut
authors.forename: H
authors.initials: H
authors.lastname: Steininger
authors.forename: Y M
authors.initials: YM
authors.lastname: Deo
authors.forename: G H
authors.initials: GH
authors.lastname: Blijham
authors.forename: J R
authors.initials: JR
authors.lastname: Kalden
authors.forename: J G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: M
authors.initials: M
authors.lastname: Gramatzki
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015331:Cohort Studies; D016207:Cytokines / Q000276:immunology; D005260:Female; D000069585:Filgrastim; D018734:Genes, erbB-2 / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins
chemical_list: D000276:Adjuvants, Immunologic; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016207:Cytokines; C000715470:MAS1 protein, human; C121360:MDX-H210 antibody; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim