DELIVERY OF THERAPEUTIC DOSES OF RADIOIODINE USING BISPECIFIC ANTIBODY-TARGETED BIVALENT HAPTENS

Two-step pretargeting strategies have been designed to deliver radiois otopes 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. Methods: 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 b ivalent DTPA derivatives labeled with iodine. The biodistribution of i odine in nude mice grafted with the LS174T human colorectal carcinoma was monitored in time and used for calculating radiation doses. Result s: In agreement with earlier studies, the IgG was more effective for d elivering 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 re spect 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 tum or. Using a nM-affinity DTPA-ln bivalent hapten, the two-step protocol was optimized by varying the dosage of the BsF(ab')(2), the stoichiom etry of the reagents and the pretargeting time. The saturation of the tumor was obtained by injecting 5 nmol (500 mu g) of BsF(ab')(2). The pretargeted BsF(ab')(2) was saturated by the injection of 0.5 mol of b ivalent hapten per mole of antibody. With a 48-hr pretargeting time, t he selectivity of the irradiation of the tumor was optimized (tumor:bl ood 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 mu M-affinity DTPA-Y bivalent hapt en or by chasing excess circulating radiolabeled hapten with an excess of unlabeled hapten also reduced tumor exposure. The use of a monoval ent 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 les s than 9 Gy to the blood in tumor-bearing mice. Conclusion: Radioimmun otherapy with AES is predicted to be as efficient and with lower hemat ological toxicity than direct targeting.