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Multistep Tumor Targeting in Nude Mice Using Bispecific Antibodies and a Gallium Chelate Suitable for Immunoscintigraphy with Positron Emission Tomography¹

Department of Diagnostic and Therapeutic Radiology (FS5) [J. S., G. K., R. M., M. S., T. R., H. H., J. D., W. M-B.] and Department of Diagnostic and Experimental Therapy (FS4) [M. Z.], German Cancer Research Center, Im Neuenheimer Feld 280, 69009 Heidelberg, Germany

To improve tumor:tissue ratios in immunoscintigraphy, a three-step targeting method has been developed. The reagents used were (a) a radioactive, low molecular weight chelate prepared from ionic gallium and a phenolic polyaminocarboxylic acid, which can be labeled either with the single-photon emitter ⁶⁷Ga or with the short-lived positron emitter ⁶⁸GA(t = 68 min); (b) a bispecific monoclonal antibody (bs-mAb) synthesized from the F(ab)₂ fragment of the 1.1ASML antibody specific for the glycoprotein CD44v associated with a rat pancreas carcinoma cell line and the F(ab') fragment of an antibody specific for the gallium chelate; and (c) the nonradioactive gallium chelate covalently coupled to transferrin, which served as a high molecular weight blocker to prevent binding of the radioactive gallium chelate to bs-mAbs in the circulation. Targeting experiments in tumor-bearing nude mice with different doses of bs-mAbs, blocker, and ⁶⁷Ga chelate were adjusted to maximize tumor to tissue contrasts and tumor uptake. Compared with the biodistribution of the ¹³¹I-labeled, native 1.1ASML antibody 24 h postinjection, a schedule using 100 pmol bs-mab 24 h later 100 pmol blocker, 15 min later 16 pmol ⁶⁷Ga chelate, 1 h later examination, increased tumor:blood and tumor:liver ratios by a factor of 5 while keeping the localization of radioactivity in the tumor constant (10.1% injected dose/g). High-contrast images using either ⁶⁷Ga or ⁶⁸Ga were obtained within 1 h. The targeting method described enables the use of the short-lived positron emitter ⁶⁸Ga and thus allows the combination of an improved immunoscintigraphy and positron emission tomography.

¹ These studies were supported by grants from the Tumor-Zentrum Heidelberg/Mannheim and the Dr. Mildred Scheel Stiftung für Krebsforschung.

² To whom requests for reprints should be addressed.

Received 7/ 6/94. Accepted 10/31/94.

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