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Two-Step Targeting of Xenografted Colon Carcinoma Using a Bispecific Antibody and ¹⁸⁸Re-Labeled Bivalent Hapten: Biodistribution and Dosimetry Studies

Institut de Biologie, Institut National de la Santé et de la Recherche Médicale, Nantes; Hopital St. Antoine, Institut National de la Santé et de la Recherche Médicale, Paris; and Immunotech, Marseille, France

Radioimmunotherapy (RIT) is currently being considered for the treatment of solid tumors. Although results have been encouraging for pretargeted ¹³¹I RIT with the affinity enhancement system (AES), the radionuclide used is not optimal because of its long half-life, strong emission, poor specific activity, and low ß particle energy. ¹⁸⁸Re, though unsuitable for direct antibody labeling, could be used with the AES two-step targeting technique. The purpose of this study was to compare the distribution and dosimetry of a bivalent hapten labeled with ¹⁸⁸Re or ¹²⁵I. For dosimetry calculations and biodistribution data, ¹²⁵I was substituted for ¹³¹I. Methods: After preliminary injection of a bispecific anticarcinoembryonic antigen (CEA) or antihapten antibody (Bs-mAb F6-679), AG 8.1 or AG 8.0 hapten radiolabeled with ¹⁸⁸Re or ¹²⁵I was injected into a nude mouse model grafted subcutaneously with a human colon carcinoma cell line (LS-174-T) expressing CEA. A dosimetry study was performed for each animal from the concentration of radioactivity in tumor and different tissues. Results: Radiolabeling of AG 8.1 with ¹²⁵I afforded a 40% yield with a specific activity of 11.1 MBq/nmol after purification. Radiolabeling of AG 8.0 with ¹⁸⁸Re afforded a 72% yield with a specific activity of 31.82 MBq/nmol. In all experiments, the percentage of tumor uptake of ¹²⁵I-AG 8.1 was always significantly greater than that of ¹⁸⁸Re-AG 8.0. The corresponding tumor-to-tissue ratios reflected uptake values. The least favorable tumor-to-normal tissue ratios in the dosimetry study were 8.1 and 8.5 for ¹³¹I (tumor-to-blood ratio and tumor-to-kidney ratio, respectively) and 2.3 for ¹⁸⁸Re (tumor-to-intestine ratio). Conclusion: This study indicates that ¹⁸⁸Re can be used for radiolabeling of hapten in two-step radioimmunotherapy protocols with the AES technique. ¹⁸⁸Re has a greater range than ¹³¹I, which should allow the treatment of solid tumors around 1 cm in diameter. Although the method used for hapten radiolabeling did not provide optimal tumor uptake, the use of a bifunctional chelating agent associated with AG 8.1 should solve this problem.

Key Words: ¹⁸⁸Re • radioimmunotherapy • bispecific antibody • pretargeting

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