Multistep tumor targeting in nude mice using bispecific antibodies and a Gallium chelate suitable for immunoscintigraphy with positron emission tomography

• Published in: Cancer research (Chicago, Ill.) Ill.), 1995, Vol.55 (1), p.115-123
• Main Authors: SCHUHMACHER, J, KLIVENYI, G, MATYS, R, STADLER, M, REGIERT, T, HAUSER, H, DOLL, J, MAIER-BORST, W, ZÖLLER, M
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bispecific - metabolism; Biological and medical sciences; Chelating Agents; Digestion. Liver. Biliary tract. Spleen. Pancreas; Female; Gallium Radioisotopes - metabolism; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mice; Mice, Nude; Neoplasms, Experimental - metabolism; Radionuclide investigations; Tomography, Emission-Computed - methods; Transferrin
• ISSN: 0008-5472; 1538-7445

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 (t1/2 = 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.