This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yang, W. Articles by Wikstrand, C. J. PubMed PubMed Citation Articles by Yang, W. Articles by Wikstrand, C. J.

Molecular Targeting and Treatment of Composite EGFR and EGFRvIII-Positive Gliomas Using Boronated Monoclonal Antibodies

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

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

Purpose: The purpose of the present study was to evaluate the anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98_EGFR) or mutant receptors(F98_npEGFRvIII).

Experimental Design: A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats. Biodistribution studies were carried out by administering ¹²⁵I-labeled bioconjugates via convection-enhanced delivery (CED), and for therapy studies, nonradiolabeled bioconjugates were used for BNCT. This was carried out 14 days after tumor implantation and 24 h after CED at the Massachusetts Institute of Technology nuclear reactor.

Results: Following CED of a mixture of ¹²⁵I-BD-C225 and ¹²⁵I-BD-L8A4 to rats bearing composite tumors, 61.4% of the injected dose per gram (ID/g) was localized in the tumor compared with 30.8% ID/g for ¹²⁵I-BD-L8A4 and 34.7% ID/g for ¹²⁵I-BD-C225 alone. The corresponding calculated tumor boron values were 24.4 µg/g for rats that received both mAbs, and 12.3 and 13.8 µg/g, respectively, for BD-L8A4 or BD-C225 alone. The mean survival time of animals bearing composite tumors, which received both mAbs, was 55 days (P < 0.0001) compared with 36 days for BD-L8A4 and 38 days for BD-C225 alone, which were not significantly different from irradiated controls.

Conclusions: Both EGFRvIII and wild-type EGFR tumor cell populations must be targeted using a combination of BD-cetuximab and BD-L8A4. Although in vitro C225 recognized both receptors, in vivo it was incapable of delivering the requisite amount of ¹⁰B for BNCT of EGFRvIII-expressing gliomas.