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Molecular Targeting and Treatment of EGFRvIII-Positive Gliomas Using Boronated Monoclonal Antibody L8A4

Authors' Affiliations: Departments of ¹ Pathology and ² Pediatrics and Children's Research Institute, ³ College of Pharmacy, and ⁴ School of Public Health, The Ohio State University, Columbus, Ohio; ⁵ Nuclear Reactor Laboratory and ⁶ Department of Nuclear Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; ⁷ Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York; and ⁸ Department of Pathology, Duke University, Durham, North Carolina

Requests for reprints: Rolf F. Barth, Department of Pathology, The Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. Phone: 614-292-2177; Fax: 614-292-7072; E-mail: rolf.barth{at}osumc.edu.

Purpose: The purpose of the present study was to evaluate a boronated EGFRvIII-specific monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive rat glioma, F98_npEGFRvIII.

Experimental Design: A heavily boronated polyamido amine (PAMAM) dendrimer (BD) was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies, F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive F98_npEGFRvIII glioma cells were implanted i.c. into the brains of Fischer rats. Biodistribution studies were initiated 14 days later. Animals received [¹²⁵I]BD-L8A4 by either convection enhanced delivery (CED) or direct i.t. injection and were euthanized 6, 12, 24, or 48 hours later.

Results: At 6 hours, equivalent amounts of the bioconjugate were detected in receptor-positive and receptor-negative tumors, but by 24 hours the amounts retained by receptor-positive gliomas were 60.1% following CED and 43.7% following i.t. injection compared with 14.6% ID/g by receptor-negative tumors. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (<0.5 µg/g) at the corresponding times. Based on these favorable biodistribution data, BNCT studies were initiated at the Massachusetts Institute of Technology Research Reactor-II. Rats received BD-L8A4 (40 µg ¹⁰B/750 µg protein) by CED either alone or in combination with i.v. boronophenylalanine (BPA; 500 mg/kg). BNCT was carried out 24 hours after administration of the bioconjugate and 2.5 hours after i.v. injection of BPA for those animals that received both agents. Rats that received BD-L8A4 by CED in combination with i.v. BPA had a mean ± SE survival time of 85.5 ± 15.5 days with 20% long-term survivors (>6 months) and those that received BD-L8A4 alone had a mean ± SE survival time of 70.4 ± 11.1 days with 10% long-term survivors compared with 40.1 ± 2.2 days for i.v. BPA and 30.3 ± 1.6 and 26.3 ± 1.1 days for irradiated and untreated controls, respectively.

Conclusions: These data convincingly show the therapeutic efficacy of molecular targeting of EGFRvIII using either boronated monoclonal antibody L8A4 alone or in combination with BPA and should 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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