Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the biodistribution, pharmacokinetics, and generation of catabolites of an 18F- and 125I-labeled anti-Tac disulfide-stabilized Fv fragment (dsFv) in tumor-bearing nude mice. This dsFv is genetically engineered from a murine monoclonal antibody that recognizes the alpha subunit of the interleukin 2 (IL-2 alpha) receptor. Labeling was performed with 18F using N-succinimidyl 4-([18F]fluoromethyl)benzoate or with 125I using the Iodo-Gen method. The immunoreactivities of the radiolabeled anti-Tac dsFv were > 82%. The biodistribution was evaluated (at 15, 45, and 90 min and 6 h) in athymic nude mice (approximately five/group) bearing s.c. tumor xenografts. Cell line A431 served as the IL-2 receptor-negative control tumor, whereas the ATAC4 cell line served as our IL-2 receptor-positive tumor. Animals received injections of 18F-labeled anti-Tac dsFv (0.7-1.4 megabecquerels/1.5-3 micrograms) and 125I-labeled anti-Tac dsFv (0.1-0.4 megabecquerels/0.9-1 microgram). Blood clearance for both preparations was rapid, with < 10% retained in the blood by 15 min. Maximum accumulation in ATAC4 tumors occurred between 45 and 90 min and peaked at a mean of 4.2% injected dose/g (18F) and 5.6% of injected dose/g (125I). At 6 h, the ATAC4 tumors contained 11 times more 18F and 3 times more 125I than did the A431 tumors. The ATAC4 tumor:blood ratios for the 18F and 125I were > 12:1 and > 1.4:1 at 6 h, respectively, whereas the ratios for the antigen-negative A431 tumor were less than 1. The kidneys were the major route of elimination. Catabolites appeared quickly and were identified as [125I]iodide and predominantly N-epsilon-[18F]4-fluoromethylbenzoyl(alpha-N-acetyl) lysine. This is the first study to evaluate the biodistribution of an 18F-labeled Fv fragment in vitro and in vivo. In vivo, the dsFv was taken up rapidly by the kidneys, producing lysine-containing catabolites for 18F-labeled dsFv and [125I]iodide for 125I-labeled dsFv.
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PMID:Biodistribution of 18F- and 125I-labeled anti-Tac disulfide-stabilized Fv fragments in nude mice with interleukin 2 alpha receptor-positive tumor xenografts. 758 95

The anti-Tac disulfide-bonded variable region fragment (dsFv) is a genetically engineered, 25 kDa, murine monoclonal antibody fragment that recognizes the alpha subunit of the interleukin-2 receptor (IL-2Ralpha). The dsFv radiolabeled with the tetrafluorophenyl ester (TFP) of [99mTc]mercaptoacetyltriglycine ([99mTc]MAG3-TFP) showed rapid tumor uptake and fast blood clearance in mice, resulting in high tumor-to-nontumor background ratios. However, its high renal uptake was a problem. In this study, we tested the effect of lowering the isoelectric point (pI) of dsFv to <9.3 on renal and tumor uptake. To lower the pI, dsFv was acylated simultaneously with both [99mTc]MAG3-TFP and TFP-glycolate. The acylation of dsFv decreased its pI and its immunoreactivity inversely proportional to the molar ratio of TFP-glycolate to dsFv, whereas the conjugation of [99mTc]MAG3-TFP alone did not. When biodistribution studies were performed in nude mice, the effect of the lowered pI was reflected primarily in decreased kidney uptake and whole-body retention, with its highest effect seen at the earliest time point (15 min) after injection. In tumor-bearing nude mice, glycolated [99mTc]MAG3-dsFv with a pI range of 4.9 to 6.5 accumulated selectively into IL-2 receptor-positive SP2/Tac tumor similar to that of the control [125I]dsFv labeled by the Iodo-Gen method, whereas its renal uptake was 25% of [125I]dsFv at 15 min. At 90 min, the ratios of tumor to receptor-negative SP2/0 tumor, liver, kidney, stomach, and blood had peaked at 10.9, 8.5, 0.3, 5.0, and 6.2, respectively, for the glycolated [99mTc]MAG3-dsFv. The corresponding ratios for [125I]dsFv were 3.7, 5.0, 0.1, 1.5, and 2.1, respectively.
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PMID:Chemical modification to reduce renal uptake of disulfide-bonded variable region fragment of anti-Tac monoclonal antibody labeled with 99mTc. 1034 77