title: Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab.
abstract: OBJECTIVE
  The purpose of the present study was to evaluate the anti-epidermal growth factor monoclonal antibody (mAb) cetuximab (IMC-C225) as a delivery agent for boron neutron capture therapy (BNCT) of a human epidermal growth factor receptor (EGFR) gene-transfected rat glioma, designated as F98(EGFR).
  
  
  METHODS
  A heavily boronated polyamidoamine dendrimer was chemically linked to cetuximab by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)-propionate and N-(k-maleimido undecanoic acid)-hydrazide. The bioconjugate, designated as BD-C225, was specifically taken up by F98(EGFR) glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 microg/g). For in vivo biodistribution studies, F98(EGFR) cells were implanted stereotactically into the brains of Fischer rats, and 14 days later, BD-C225 was given intracerebrally by either convection enhanced delivery (CED) or direct intratumoral (i.t.) injection.
  
  
  RESULTS
  The amount of boron retained by F98(EGFR) gliomas 24 h following CED or i.t. injection was 77.2 and 50.8 microg/g, respectively, with normal brain and blood boron values <0.05 mug/g. Boron neutron capture therapy was carried out at the Massachusetts Institute of Technology Research Reactor 24 h after CED of BD-C225, either alone or in combination with i.v. boronophenylalanine (BPA). The corresponding mean survival times (MST) were 54.5 and 70.9 days (P = 0.017), respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls, respectively, were 30.3 and 26.3 days. In a second study, the combination of BD-C225 and BPA plus sodium borocaptate, given by either i.v. or intracarotid injection, was evaluated and the MSTs were equivalent to that obtained with BD-C225 plus i.v. BPA.
  
  
  CONCLUSIONS
  The survival data obtained with BD-C225 are comparable with those recently reported by us using boronated mAb L8A4 as the delivery agent. This mAb recognizes the mutant receptor, EGFRvIII. Taken together, these data convincingly show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA and provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus 43210, USA.
authors.forename: Gong
authors.initials: G
authors.lastname: Wu
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Shinji
authors.initials: S
authors.lastname: Kawabata
authors.forename: Michele
authors.initials: M
authors.lastname: Swindall
authors.forename: Achintya K
authors.initials: AK
authors.lastname: Bandyopadhyaya
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
authors.forename: Behrooz
authors.initials: B
authors.lastname: Khorsandi
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Blue
authors.forename: Amy K
authors.initials: AK
authors.lastname: Ferketich
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Christoforidis
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
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001896:Boron Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D000068818:Cetuximab; D003131:Combined Modality Therapy; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology; D008279:Magnetic Resonance Imaging / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001896:Boron Compounds; D050091:Dendrimers; D018796:Immunoconjugates; D066246:ErbB Receptors; D000068818:Cetuximab