Integrin αvβ3-Targeted Radioimmunotherapy of Glioblastoma Multiforme

Purpose: Abegrin is a monoclonal antibody to human integrin (alpha(v)beta(3), a cell adhesion molecule highly expressed on actively angiogenic endothelium and glioblastoma multiforme tumor cells. The purpose of this study was to evaluate the efficacy of a novel Y-90-Abegrin radioimmunotherapeutic agent in murine xenograft glioblastoma models with noninvasive in vivo molecular imaging modalities. Experimental Design: A s.c. U87MG human glioblastoma xenograft model was used to determine maximum tolerated dose (MTD), biodistribution, dose response, and efficacy of Y-90-Abegrin. Antitumor efficacy was also characterized in an orthotopic U87MG and in a HT-29 colorectal cancer model, a low integrin-expressing carcinoma. Small-animal positron emission tomography imaging was used to correlate histologic findings of treatment efficacy. Results: MTD and dose response analysis revealed 200 mu Ci per mouse as appropriate treatment dose with hepatic clearance and no organ toxicity. Y-90-Abegrin-treated U87 MG tumor mice showed partial regression of tumor volume, with increased tumor volumes in Y-90-IgG, Abegrin, and saline groups. F-18-FDG imaging revealed a reduction of cell proliferation and metabolic activity whereas F-18-FLT reflected decreased DNA synthesis in the Y-90-Abegrin group. Ki67 analysis showed reduced proliferative index and quantitative terminal deoxynucleotidyl transferase dUTP nick-end labeling - positive analysis revealed increased DNA fragmentation and apoptosis in Y-90-Abegrin animals. CD31 and 4',6-diamidino-2-phenylindole staining showed increased vascular fragmentation and dysmorphic vessel structure in Y-90-Abegrin animals only. Orthotopic U87MG tumors treated with Y-90-Abegrin displayed reduced tumor volume. HT-29 tumors showed no significant difference among the various groups. Conclusion: Radioimmunotherapy with Y-90-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.