The Intratumoral Distribution of Radiolabeled 177Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon

The therapeutic effect of radioimmunotherapy depends on the distribution of the absorbed dose in relation to viable cancer cells within the tumor, which in turn is a function of the activity distribution. The aim of this study was to investigate the distribution of Lu-DOTABR96 monoclonal antibodies (mAbs) targeting the Lewis Y antigen over 7 days using a syngeneic rat model of colon carcinoma. Methods: 38 tumor bearing rats were given 25 or 50 MBq/kg body weight Lu-DOTABR96 i.v. and were sacrificed 2, 8, 24, 48, 72, 96, 120, or 168 h post-injection (p.i.) with activity measured in blood and tumor samples. Adjacent cryosections of each tumor were analyzed in three ways: imaging using a silicon-strip detector for digital autoradiography, staining for histological characterization, or staining to determine the distribution of the antigen, vasculature and proliferating cells using immunohistochemistry. Absorbed-dose rate distribution images at the moment of sacrifice were calculated using the activity distribution and a point-dose kernel. The correlations between antigen expression and both activity uptake and absorbed-dose rate were calculated for several regions of interest in each tumor. Nine additional animals with tumors were given unlabeled antibody to evaluate possible immunological effects. Results: At 2-8 h p.i. the activity was found in the tumor margins, at 24 h p.i. in viable antigen-expressing areas within the tumor, and at 48 h p.i. and later increasingly in antigennegative areas of granulation tissue. The correlation between antigen expression and both the mean activity and absorbed-dose rate in regions of interest, changed from positive to negative after 24 h p.i. Antigen-negative areas also increased over time in animals injected with unlabeled BR96 compared to untreated tumors. Conclusion: The results indicate that viable Lewis Y-expressing tumor cells are most efficiently treated during the initial uptake period. The activity then seems to remain in these