title: A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo.
abstract: OBJECTIVE
  Expression of the receptor tyrosine kinase c-Met and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly increased in glioblastomas, where they promote tumor proliferation, migration, invasion, and angiogenesis. We used a novel one-armed anti-c-Met antibody to inhibit glioblastoma growth in vivo.
  
  
  METHODS
  U87 glioblastoma cells (c-Met and SF/HGF positive) or G55 glioblastoma cells (c-Met positive and SF/HGF negative) were used to generate intracranial orthotopic xenografts in nude mice. The one-armed 5D5 (OA-5D5) anti-c-Met antibody was infused intratumorally using osmotic minipumps. Following treatment, tumor volumes were measured and tumors were analyzed histologically for extracellular matrix (ECM) components and proteases relevant to tumor invasion. Microarray analyses were done to determine the effect of the antibody on invasion-related genes.
  
  
  RESULTS
  U87 tumor growth, strongly driven by SF/HGF, was inhibited > 95% with OA-5D5 treatment. In contrast, G55 tumors, which are not SF/HGF driven, did not respond to OA-5D5, suggesting that the antibody can have efficacy in SF/HGF-activated tumors. In OA-5D5-treated U87 tumors, cell proliferation was reduced > 75%, microvessel density was reduced > 90%, and apoptosis was increased > 60%. Furthermore, OA-5D5 treatment decreased tumor cell density > 2-fold, with a consequent increase in ECM deposition and increased immunoreactivity for laminin, fibronectin, and tenascin. Microarray studies showed no increase in these ECM factors, rather down-regulation of urokinase-type plasminogen activator and matrix metalloproteinase 16 in glioblastoma cells treated with OA-5D5.
  
  
  CONCLUSIONS
  Local treatment with OA-5D5 can almost completely inhibit intracerebral glioblastoma growth when SF/HGF is driving tumor growth. The mechanisms of tumor inhibition include antiproliferative, antiangiogenic, and proapoptotic effects.
authors.affiliation: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Martens
authors.forename: Nils-Ole
authors.initials: NO
authors.lastname: Schmidt
authors.forename: Carmen
authors.initials: C
authors.lastname: Eckerich
authors.forename: Regina
authors.initials: R
authors.lastname: Fillbrandt
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Ralph
authors.initials: R
authors.lastname: Schwall
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000276:immunology* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D019859:Proto-Oncogene Proteins c-met