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Development of a Syngeneic Rat Brain Tumor Model Expressing EGFRvIII and Its Use for Molecular Targeting Studies with Monoclonal Antibody L8A4

¹ Department of Pathology, The Ohio State University, Columbus, Ohio; ² Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York; ³ Department of Radiology, University of Michigan, Ann Arbor, Michigan; and ⁴ Department of Pathology, Duke University, Durham, North Carolina

Requests for reprints: Rolf F. Barth, Department of Pathology, Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. Phone: 614-292-2177; Fax: 614-292-7072; E-mail: barth.1{at}osu.edu.

Purpose: The goals of the present study were 2-fold: (a) to develop and characterize a rat brain tumor model that could be used for studies of molecular targeting of EGFRvIII and (b) to study the tumor localizing properties of radiolabeled monoclonal antibody (mAb) L8A4, specifically directed against EGFRvIII, following systemic, i.t., and convection enhanced delivery to brain tumor–bearing rats.

Experimental Design and Results: F98 wild-type (F98_WT) rat glioma cells were transfected with a gene encoding human EGFRvIII, and following selection and cloning, a cell line, designated F98_npEGFRvIII, was identified, which expressed a nonconstitutively phosphorylated form of the receptor. As determined by a radioligand binding assay, there were 1.2x10⁵ EGFRvIII sites per cell compared with an undetectable number on F98_WT cells. The tumorigenicity of the F98_npEGFRvIIIglioma was studied following i.c. implantation of 10³, 10⁴, or 10⁵ cells into CD-Fischer rats. Mean survival times were 23, 17, and 13 days, respectively, which were equivalent to those obtained with F98_EGFR and F98_WT cells. As determined by magnetic resonance imaging, the mean doubling times for the F98_WT and F98_npEGFRvIII gliomas were similar (59.8 ± 4.8 versus 52 ± 3.3 hours). Following i.v. administration to glioma-bearing rats, mAb L8A4 specifically targeted the F98_npEGFRvIII glioma, and at 24 hours, 7.7% of the injected dose per gram (ID/g) localized in the tumor. This increased 5-fold to 39.5% ID/g following i.t. injection and 7-fold to 59.8% ID/g at 24 hours following convection enhanced delivery.

Conclusions: Based on these data, we have concluded that the F98_npEGFRvIII glioma should be a valuable animal model for therapy studies focusing on molecular targeting of EGFRvIII by receptor specific mAbs.

Key Words: EGFRvIII-expressing rat glioma • monoclonal antibody L8A4 • biodistribution following i.v. and i.t. injection • convection enhanced delivery

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