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Rapid and Specific Uptake of Anti-Tac Disulfide-stabilized Fv by Interleukin-2 Receptor-bearing Tumors

Laboratory of Molecular Biology, Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, NIH, Bethesda, Maryland 20892

The disulfide-stabilized Fv (dsFv) is a novel form of a variable-region fragment (Fv) of an antibody which is stabilized by an interchain disulfide bond. As a consequence, it is more stable than its Fv analogue. Anti-Tac(dsFv) is derived from anti-Tac(IgG) which specifically binds to the p55 subunit of the interleukin-2 receptor (IL2R). The receptor is found in large numbers on activated T cells and many T-cell leukemias. The biodistribution patterns of ¹²⁵I-anti-Tac(dsFv) and ¹²⁵I-anti-Tac(IgG) were determined in athymic nude mice bearing two s.c. tumors, one expressing a stably transfected plasmid encoding IL2R (ATAC4) and one composed of parental untransfected A431 epidermoid carcinoma cells. Anti-Tac(dsFv), which has a molecular weight of 25,000, was specifically captured by the ATAC4 tumors but not by control A431 tumors. The antigen-specific tumors accumulated >2% of the injected dose/g within 15–45 min after i.v. injection. The level of radioactivity in the ATAC4 tumors was maintained at >1% of the injected dose/g for nearly 6 h, at which time the ATAC4 tumors contained 11-fold more ¹²⁵I-anti-Tac(dsFv) than did the A431 tumors. Unbound ¹²⁵I-anti-Tac(dsFv) was rapidly cleared from the blood with apparently biphasic pharmacokinetics (t_1/2 = <10 min; ßt_1/2 = 5.5 h). Initially, the bulk of the ¹²⁵I-anti-Tac(dsFv) appeared in the kidneys. In contrast, ¹²⁵I-anti-Tac(IgG) showed no tumor- or tissue-specific uptake over the 24-h time course of the experiments and remained primarily in the blood stream (blood clearance t_1/2 = 12 h).

This is the first report of the biodistribution of a dsFv fragment. Because of its rapid uptake by IL2 receptor-bearing tumors, short serum half-life, and increased stability, radiolabeled anti-Tac(dsFv) may be useful for the imaging and therapy of neoplasias expressing the IL2 receptor.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Biology, Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, NIH, 9000 Rockville Pike, Building 37, Room 4E16, Bethesda, MD 20892.

Received 5/23/94. Accepted 11/ 8/94.

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