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

Abstract

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 [125 I]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 Ag/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 (f40 Ag

Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated Cetuximab

“…or intracarotid administration of BPA and BSH. The present data, and those recently reported by us in other studies using boronated L8A4 (17) and EGF (13), establish proof of principle that gliomas expressing either EGFR or EGFRvIII can be selectively targeted with boronated mAbs or EGF, given by either i.t. injection or CED, and that a significant therapeutic gain can be obtained following BNCT.…”

“…These were produced by Dr. Frank Furnari (Ludwig Institute for Cancer Research, La Jolla, CA), who generously provided them to us. Five million F98 wild-type (F98 WT ), F98 fEGFR , or F98 npEGFRvIII (17) glioma cells were seeded into T-150 flasks with DMEM containing 10% fetal bovine serum (Life Technologies, Inc., Rockville, MD) supplemented with 100 units/mL penicillin and 100 Ag/mL streptomycin. After incubation for 24 h at 37jC, the medium was replaced with DMEM containing 1.68 mg BD-C225 (90 Ag boron), and the cells were incubated for an additional 2 h at 37jC.…”

“…Neutron irradiations for these experiments were identical to those reported previously by us using the boronated mAb L8A4 (17). BNCT was done 14 days following stereotactic implantation of 10 3 F98 EGFR glioma cells.…”

“…We have investigated molecular targeting of EGFR or EGFRvIII using EGF (11 -13), or the monoclonal antibodies (mAb) cetuximab (14,15) and L8A4 (16,17), which have been linked to a heavily boronated polyamidoamine dendrimer. Cetuximab (Erbitux), known previously as IMC-C225, is a chimeric mouse-human mAb that originally was produced in the laboratory of Dr. John Mendelsohn (University of Texas M. D. Anderson Cancer Center, Houston, TX; ref.…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…They can be formulated non-ocovalently with biological agents, such as DNA or conjugated with pro-drug or imaging agents and thus can be used as delivery vehicles for drug therapy or molecular imaging [250][251][252][253][254][255]. To the best of our knowledge dendrimers have not been evaluated so far for CNS delivery except for few studies on intratumoral delivery of dendrimer conjugates with anti-cancer agents to treat glioma [256,257]. However, transport of dendrimers in another barrier cell model, intestine epithelial cells (Caco-2) was studied recently [258].…”