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Two-step pretargeting strategies have been designed to deliver radioisotopes to tumors more selectively than directly labeled antibodies or fragments. In this article, we compare quantitatively the potential of these strategies for the radioimmunotherapy of solid tumors.Direct targeting was performed using iodine-labeled IgG and F(ab')2. As two-step strategies, we used the sequential injection of anti-CEA x anti-DTPA-In bispecific F(ab')2 (BsF(ab')2) and monovalent and bivalent DTPA derivatives labeled with iodine. The biodistribution of iodine in nude mice grafted with the LS174T human colorectal carcinoma was monitored in time and used for calculating radiation doses.In agreement with earlier studies, the IgG was more effective for delivering a radiation dose to the tumor than the F(ab')2 (7.8 versus 0.76 Gy/MBq, respectively) and both were moderately selective with respect to normal tissues (tumor:blood of 2.9 and 1.7, respectively). At their MTD, they should deliver 86 and 34 Gy, respectively, to the tumor. Using a nM-affinity DTPA-In bivalent hapten, the two-step protocol was optimized by varying the dosage of the BsF(ab')2, the stoichiometry of the reagents and the pretargeting time. The saturation of the tumor was obtained by injecting 5 nmol (500 microg) of BsF(ab')2. The pretargeted BsF(ab')2 was saturated by the injection of 0.5 mol of bivalent hapten per mole of antibody. With a 48-hr pretargeting time, the selectivity of the irradiation of the tumor was optimized (tumor:blood of 7.8) but only at the price of a lower efficiency (0.35 versus 0.86 Gy/MBq, 48-hr and 20-hr pretargeting time, respectively). Attempts to increase selectivity by using a microM-affinity DTPA-Y bivalent hapten or by chasing excess circulating radiolabeled hapten with an excess of unlabeled hapten also reduced tumor exposure. The use of a monovalent hapten resulted in both lower efficiency and selectivity. However, the two-step pretargeting of high-affinity bivalent hapten (Affinity Enhancement System, AES) should deliver 30-60 Gy to the tumor with less than 9 Gy to the blood in tumor-bearing mice.Radioimmunotherapy with AES is predicted to be as efficient and with lower hematological toxicity than direct targeting.