Rapid and specific uptake of anti-Tac disulfide-stabilized Fv by interleukin-2 receptor-bearing tumors.
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 alpha). 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 alpha (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 (alpha t 1/2 = < 10 min; beta t 1/2 = approximately 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 = approximately 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.
Webber
K O
KO
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Kreitman
R J
RJ
Pastan
I
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D002277:Carcinoma / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000276:immunology*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D015375:Receptors, Interleukin-2