Pretargeted radioimmunotherapy of human colorectal xenografts with bispecific antibody and I-131-labeled bivalent hapten

We have developed a pretargeting strategy, called the affinity enhancement system (AES), which uses bispecific antibodies to target radiolabeled bival ent haptens to tumor cells. The aim of this study was to evaluate the poten tial of the AES for the radioimmunotherapy (RIT) of LS174T colorectal xenog rafts in comparison with RIT with directly labeled F(ab')(2) fragment. Meth ods: A total of 6 groups of tumor-bearing mice were treated using anticarci noembryonic antigen (CEA) x anti-diethylenetriamine pentaacetic acid (DTPA) -In bispecific antibody (BsF(ab')(2)) and I-131-labeled di-DTPA-ln bivalent hapten. Three groups of mice were injected with various activities of I-13 1-labeled bivalent hapten (75, 96, and 112 MBq) 20 h after administration o f BsF(ab)'(2) Three other groups were injected with an almost constant acti vity of labeled hapten (102 MBq) at 3 time periods (15, 30, and 48 h) after BsF(ab'), administration. For conventional RIT, mice were treated with 96 MBq I-131-labeled anti-CEA F(ab')(2). Control groups were left untreated. T oxicity and tumor growth were monitored at weekly intervals. Results: Doses used for conventional RIT induced severe toxicity and resulted in death of several treated animals. Nevertheless, all surviving animals treated with I-131-labeled anti-CEA F(ab'), relapsed shortly after treatment (tumor grow th delay = 48 +/- 13 d). For animals treated with the AES reagents, toxicit y Varied with the pretargeting time interval and the administered activity. For 20-h pretargeting time, the maximum tolerated dose was 96 MBq. For all AES RIT except 1 (with 48-h pretargeting time interval and growth delay of 82 +/- 26 d), no tumor growth was observed over a period of 8 mo. Furtherm ore, based on clinical and histologic criteria, 33% of the treated mice wer e considered cured. Conclusion: High cure rates of LS174T colon carcinoma w ere achieved with the AES, and the flexibility of the pretargeting approach allowed the control of hematologic toxicity, which is the main limitation to dose escalation with conventional RIT.