Avidin-biotin system pretargeting radioimmunoimaging and radioimmunotherapy and its application in mouse model of human colon carcinoma

摘要

AIM: To evaluate the multi-step pretargeting radioimmunoimaging (RII) and radioimmunotherapy (RIT) in nude mice bearing human colon carcinoma with avidin-biotin system labeled with ~(153)Sm. METHODS: Two- and three-step strategies for avidin-biotin system pretargeting techniques were established. In a three-step procedure, human colon carcinoma bearing nude mice were first injected with biotinylated monoclonal antibody (McAb-Bt) followed by cold avidin (Av) 48 h later and then ~(153)Sm-DB_2 24 h thereafter; whereas the two-step procedure consisted of injection of ~(153)Sm-SA 48 h after pretargeting with biotinylated anti-CEA monoclonal antibody (CEA McAb-Bt). SPECT imaging and biodistribution were performed at 4, 24, 48, or 72 h after injection of ~(153)Sm-labeled compounds. Five groups of nude mice subcutaneously grafted with human colon carcinoma were treated 3 d after grafting. One group received the injection with 100 μg CEA McAb-Bt followed by cold avidin (80 μg) after 2 d and 11.1 MBq ~(153)Sm-DB_2 after 1 d. Four control groups were treated respectively with 11.1 MBq ~(153)Sm-CEA McAb, 11.1 MBq ~(153)Sm-nmIgG, 11.1 MBq ~(153)Sm-DB_2, 100 μL normal saline. Toxicity was evaluated by changes of leukocyte count, and the efficacy by variation in tumor volume. Histological analyses of tumors were performed. RESULTS: The three-step procedure allowed faster blood clearance and yielded higher tumor blood ratios (5.76 at 4 h and 12.94 at 24 h) of the ~(153)Sm-DB_2. The tumor was clearly visualized at 4 h in γ-imaging after the injection of ~(153)Sm-DB_2, while a significant accumulation of ~(153)Sm-SA in the tumor was observed only 24 h after the injection and tumor blood ratios at 4 and 24 h were 1.00 and 2.03, respectively, in the two-step procedure. Pretargeting RIT and ~(153)Sm-CEA McAb had a strong tumor-inhibiting effect. The tumor inhibitory rate was 80.67% and 78.44%, respectively, five weeks after therapy. Histopathological evidence also indicated radioactive damage in tumor tissues as necrosis of tumor cells, while in the other organs such as liver and kidney no radioactive damage was observed. Leukocyte counts showed significant decrease after treatment in groups of ~(153)Sm-CEA McAb and ~(153)Sm-nmIgG. CONCLUSION: The two kinds of pretargeting strategies can elevate the target-to-nontarget ratio, decrease the blood background and shorten the imaging time compared to ~(153)Sm-CEA McAb. Three-step pretargeting RIT is as efficient as ~(153)Sm-CEA McAb, but markedly less toxic. This study provides experimental evidence for the clinical application of pretargeting RII and RIT.