Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab

Gong Wu, Weilian Yang, Rolf F. Barth, Shinji Kawabata, Michele Swindall, Achintya K. Bandyopadhyaya, Werner Tjarks, Behrooz Khorsandi, Thomas E. Blue, Amy K. Ferketich, Ming Yang, Gregory A. Christoforidis, Thomas J. Sferra, Peter J. Binns, Kent J. Riley, Michael J. Ciesielski, Robert A. Fenstermaker

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Purpose: 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 F98EGFR. Experimental Design: 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 F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR 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 μg/g, respectively, with normal brain and blood boron values <0.05 μg/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.

Original languageEnglish (US)
Pages (from-to)1260-1268
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number4
DOIs
StatePublished - Feb 15 2007
Externally publishedYes

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Epidermal Growth Factor Receptor
Glioma
Boron Neutron Capture Therapy
Convection
Monoclonal Antibodies
Boron
Therapeutics
Injections
erbB-1 Genes
Cetuximab
Dendrimers
Inbred F344 Rats
Brain
Epidermal Growth Factor
Brain Neoplasms
Survivors
Research Design
Survival Rate
Molecular Weight
Technology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wu, G., Yang, W., Barth, R. F., Kawabata, S., Swindall, M., Bandyopadhyaya, A. K., ... Fenstermaker, R. A. (2007). Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. Clinical Cancer Research, 13(4), 1260-1268. https://doi.org/10.1158/1078-0432.CCR-06-2399

Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. / Wu, Gong; Yang, Weilian; Barth, Rolf F.; Kawabata, Shinji; Swindall, Michele; Bandyopadhyaya, Achintya K.; Tjarks, Werner; Khorsandi, Behrooz; Blue, Thomas E.; Ferketich, Amy K.; Yang, Ming; Christoforidis, Gregory A.; Sferra, Thomas J.; Binns, Peter J.; Riley, Kent J.; Ciesielski, Michael J.; Fenstermaker, Robert A.

In: Clinical Cancer Research, Vol. 13, No. 4, 15.02.2007, p. 1260-1268.

Research output: Contribution to journalArticle

Wu, G, Yang, W, Barth, RF, Kawabata, S, Swindall, M, Bandyopadhyaya, AK, Tjarks, W, Khorsandi, B, Blue, TE, Ferketich, AK, Yang, M, Christoforidis, GA, Sferra, TJ, Binns, PJ, Riley, KJ, Ciesielski, MJ & Fenstermaker, RA 2007, 'Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab', Clinical Cancer Research, vol. 13, no. 4, pp. 1260-1268. https://doi.org/10.1158/1078-0432.CCR-06-2399
Wu, Gong ; Yang, Weilian ; Barth, Rolf F. ; Kawabata, Shinji ; Swindall, Michele ; Bandyopadhyaya, Achintya K. ; Tjarks, Werner ; Khorsandi, Behrooz ; Blue, Thomas E. ; Ferketich, Amy K. ; Yang, Ming ; Christoforidis, Gregory A. ; Sferra, Thomas J. ; Binns, Peter J. ; Riley, Kent J. ; Ciesielski, Michael J. ; Fenstermaker, Robert A. / Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 4. pp. 1260-1268.
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abstract = "Purpose: 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 F98EGFR. Experimental Design: 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 F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR 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 μg/g, respectively, with normal brain and blood boron values <0.05 μg/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.",
author = "Gong Wu and Weilian Yang and Barth, {Rolf F.} and Shinji Kawabata and Michele Swindall and Bandyopadhyaya, {Achintya K.} and Werner Tjarks and Behrooz Khorsandi and Blue, {Thomas E.} and Ferketich, {Amy K.} and Ming Yang and Christoforidis, {Gregory A.} and Sferra, {Thomas J.} and Binns, {Peter J.} and Riley, {Kent J.} and Ciesielski, {Michael J.} and Fenstermaker, {Robert A.}",
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T1 - Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab

AU - Wu, Gong

AU - Yang, Weilian

AU - Barth, Rolf F.

AU - Kawabata, Shinji

AU - Swindall, Michele

AU - Bandyopadhyaya, Achintya K.

AU - Tjarks, Werner

AU - Khorsandi, Behrooz

AU - Blue, Thomas E.

AU - Ferketich, Amy K.

AU - Yang, Ming

AU - Christoforidis, Gregory A.

AU - Sferra, Thomas J.

AU - Binns, Peter J.

AU - Riley, Kent J.

AU - Ciesielski, Michael J.

AU - Fenstermaker, Robert A.

PY - 2007/2/15

Y1 - 2007/2/15

N2 - Purpose: 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 F98EGFR. Experimental Design: 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 F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR 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 μg/g, respectively, with normal brain and blood boron values <0.05 μg/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.

AB - Purpose: 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 F98EGFR. Experimental Design: 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 F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR 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 μg/g, respectively, with normal brain and blood boron values <0.05 μg/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.

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