title: Molecular targeting and treatment of composite EGFR and EGFRvIII-positive gliomas using boronated monoclonal antibodies.
abstract: OBJECTIVE
  The purpose of the present study was to evaluate the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98(EGFR)) or mutant receptors(F98(npEGFRvIII)).
  
  
  METHODS
  A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats. Biodistribution studies were carried out by administering (125)I-labeled bioconjugates via convection-enhanced delivery (CED), and for therapy studies, nonradiolabeled bioconjugates were used for BNCT. This was carried out 14 days after tumor implantation and 24 h after CED at the Massachusetts Institute of Technology nuclear reactor.
  
  
  RESULTS
  Following CED of a mixture of (125)I-BD-C225 and (125)I-BD-L8A4 to rats bearing composite tumors, 61.4% of the injected dose per gram (ID/g) was localized in the tumor compared with 30.8% ID/g for (125)I-BD-L8A4 and 34.7% ID/g for (125)I-BD-C225 alone. The corresponding calculated tumor boron values were 24.4 mug/g for rats that received both mAbs, and 12.3 and 13.8 mug/g, respectively, for BD-L8A4 or BD-C225 alone. The mean survival time of animals bearing composite tumors, which received both mAbs, was 55 days (P < 0.0001) compared with 36 days for BD-L8A4 and 38 days for BD-C225 alone, which were not significantly different from irradiated controls.
  
  
  CONCLUSIONS
  Both EGFRvIII and wild-type EGFR tumor cell populations must be targeted using a combination of BD-cetuximab and BD-L8A4. Although in vitro C225 recognized both receptors, in vivo it was incapable of delivering the requisite amount of (10)B for BNCT of EGFRvIII-expressing gliomas.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Gong
authors.initials: G
authors.lastname: Wu
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Michele R
authors.initials: MR
authors.lastname: Swindall
authors.forename: Achintya K
authors.initials: AK
authors.lastname: Bandyopadhyaya
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
authors.forename: Kevin
authors.initials: K
authors.lastname: Tordoff
authors.forename: Melvin
authors.initials: M
authors.lastname: Moeschberger
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sferra
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Binns
authors.forename: Kent J
authors.initials: KJ
authors.lastname: Riley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciesielski
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenstermaker
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Wikstrand
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001666:Binding Sites, Antibody; D001895:Boron / Q000032:analysis* / Q000276:immunology; D001932:Brain Neoplasms / Q000532:radiotherapy*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000032:analysis*; D005910:Glioma / Q000532:radiotherapy*
chemical_list: D000911:Antibodies, Monoclonal; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D001895:Boron