The Intratumoral Distribution of Radiolabeled 177Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model
Journal of Nuclear Medicine
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 177 Lu-DOTA-BR96 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 177 Lu-DOTA-BR96 i.v. and
... OTA-BR96 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 3 initial uptake regions after the elimination of tumor cells and formation of granulation tissue. Further studies using these techniques could aid in determining the effects of the intratumoral activity distribution on overall therapeutic efficacy.