Integrin alphavbeta3-targeted radioimmunotherapy of glioblastoma multiforme.
OBJECTIVE
Abegrin is a monoclonal antibody to human integrin alphavbeta3, 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 90Y-Abegrin radioimmunotherapeutic agent in murine xenograft glioblastoma models with noninvasive in vivo molecular imaging modalities.


METHODS
A s.c. U87MG human glioblastoma xenograft model was used to determine maximum tolerated dose (MTD), biodistribution, dose response, and efficacy of 90Y-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 microCi per mouse as appropriate treatment dose with hepatic clearance and no organ toxicity. 90Y-Abegrin-treated U87MG tumor mice showed partial regression of tumor volume, with increased tumor volumes in 90Y-IgG, Abegrin, and saline groups. 18F-FDG imaging revealed a reduction of cell proliferation and metabolic activity whereas 18F-FLT reflected decreased DNA synthesis in the 90Y-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 90Y-Abegrin animals. CD31 and 4',6-diamidino-2-phenylindole staining showed increased vascular fragmentation and dysmorphic vessel structure in 90Y-Abegrin animals only. Orthotopic U87MG tumors treated with 90Y-Abegrin displayed reduced tumor volume. HT-29 tumors showed no significant difference among the various groups.


CONCLUSIONS
Radioimmunotherapy with 90Y-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.
Veeravagu
Anand
A
Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.
Liu
Zhaofei
Z
Niu
Gang
G
Chen
Kai
K
Jia
Bing
B
Cai
Weibo
W
Jin
Cunjing
C
Hsu
Andrew R
AR
Connolly
Andrew J
AJ
Tse
Victor
V
Wang
Fan
F
Chen
Xiaoyuan
X
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D039302:Integrin alphaVbeta3 / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; C112567:etaracizumab