title: The efficacy of epidermal growth factor receptor-specific antibodies against glioma xenografts is influenced by receptor levels, activation status, and heterodimerization.
abstract: OBJECTIVE
  Factors affecting the efficacy of therapeutic monoclonal antibodies (mAb) directed to the epidermal growth factor receptor (EGFR) remain relatively unknown, especially in glioma.
  
  
  METHODS
  We examined the efficacy of two EGFR-specific mAbs (mAbs 806 and 528) against U87MG-derived glioma xenografts expressing EGFR variants. Using this approach allowed us to change the form of the EGFR while keeping the genetic background constant. These variants included the de2-7 EGFR (or EGFRvIII), a constitutively active mutation of the EGFR expressed in glioma.
  
  
  RESULTS
  The efficacy of the mAbs correlated with EGFR number; however, the most important factor was receptor activation. Whereas U87MG xenografts expressing the de2-7 EGFR responded to therapy, those exhibiting a dead kinase de2-7 EGFR were refractory. A modified de2-7 EGFR that was kinase active but autophosphorylation deficient also responded, suggesting that these mAbs function in de2-7 EGFR-expressing xenografts by blocking transphosphorylation. Because de2-7 EGFR-expressing U87MG xenografts coexpress the wild-type EGFR, efficacy of the mAbs was also tested against NR6 xenografts that expressed the de2-7 EGFR in isolation. Whereas mAb 806 displayed antitumor activity against NR6 xenografts, mAb 528 therapy was ineffective, suggesting that mAb 528 mediates its antitumor activity by disrupting interactions between the de2-7 and wild-type EGFR. Finally, genetic disruption of Src in U87MG xenografts expressing the de2-7 EGFR dramatically enhanced mAb 806 efficacy.
  
  
  CONCLUSIONS
  The effective use of EGFR-specific antibodies in glioma will depend on identifying tumors with activated EGFR. The combination of EGFR and Src inhibitors may be an effective strategy for the treatment of glioma.
authors.affiliation: Oncogenic Signalling Laboratory and Tumor Targeting Program, Ludwig Institute for Cancer Research, Melbourne Centre, Austin Hospital, Heidelberg, Melbourne, Australia. terry.johns@ludwig.edu.au
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Vernes
authors.forename: Angela A
authors.initials: AA
authors.lastname: Vitali
authors.forename: Diana X
authors.initials: DX
authors.lastname: Cao
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use*; D019281:Dimerization; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016233:Immunotherapy, Active; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D020033:Protein Isoforms; D066246:ErbB Receptors