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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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125I-Labeled monoclonal antibody PSA30

125I-PSA30
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: December 5, 2012.

Chemical name:125I-Labeled monoclonal antibody PSA30
Abbreviated name:125I-PSA30
Synonym:
Agent Category:Antibodies
Target:free, unbound form (fPSA) of prostate-specific antigen (PSA)
Target Category:Antigens
Method of detection:Single-photon emission computed tomography (SPECT); gamma planar imaging
Source of signal / contrast:125I
Activation:No
Studies:
  • Checkbox Rodents
No structure available.

Background

[PubMed]

125I-Labeled monoclonal antibody (mAb) PSA30, abbreviated as 125I-PSA30, was developed by Evans-Axelsson et al. for use in prostate cancer imaging by targeting the free, unbound form (fPSA) of prostate-specific antigen (PSA) (1).

The human kallikrein-related peptidases (KLKs) are a group of 15 secreted serine proteases with different expression patterns and physiological roles (2, 3). These KLKs exist as single-chain preproenzymes of 30–40 kDa and are overproduced in various malignancies, where they are involved in diverse cancer-related processes such as cell growth regulation, angiogenesis, invasion, and metastasis (2, 4). Several members of the KLKs have been shown to be useful as prognostic biomarkers in various malignancies, with PSA being the most widely accepted and broadly used in clinical practice (4).

PSA is encoded by the KLK3 gene and produced in abundance at almost all clinical stages and grades of prostate cancer (1, 2). An important finding is that, after synthesis in the cells, PSA is then released into the blood and exists in a noncatalytic form by forming stable covalent complexes (cPSA) with extracellular protease inhibitors, particularly a-1-antichymotrypsin (ACT) (5, 6). A smaller percentage (5%–40%) of the noncatalytic PSA in the blood also presents as a free, unbound form, which is unable to form complexes with inhibitors despite ~104-fold excess presence of inhibitors in the blood (1, 7). Because of its small size (28.4 kDa), fPSA is eliminated via glomerular filtration by the kidneys, with a half-life time of 12–18 h (7). In contrast, cPSA (~90 kDa) is eliminated very slowly, possibly via the liver. Measurements of the serum fPSA and cPSA are used for screening, diagnosis, and prognostic prediction of prostate cancer as well as for monitoring cancer recurrence.

Prostate cancer imaging with radiolabeled antibodies by targeting PSA was tested as early as 15–20 years ago (8-10). However, these studies were in general unable to delineate tumors with a good signal/noise ratio because of the high background activity. One reason for the failure might be the use of polyclonal antibodies as imaging agents, which not only cross-react with other antigens but also fail to discriminate fPSA from cPSA. Evans-Axelsson et al. hypothesized that in vivo imaging of prostate cancer, especially the disseminated cancer, might be feasible by targeting the fPSA based on the facts that fPSA, rather than cPSA, is present at high abundance in close proximity to its local site of production, and that fPSA is cleared rapidly from the blood by the kidneys (1). The investigators tested their hypothesis by radiolabeling the PSA30 mAb and imaging tumors in animal models of prostate cancer (1). PSA30 recognizes an epitope that is covered by the ACT and other inhibitors, but is accessible on fPSA (11, 12).

Synthesis

[PubMed]

Evans-Axelsson et al. labeled the PSA30 antibody with 125I using the Iodogen method (1). The labeling reaction was carried out for 15 min at room temperature. The radiochemical purity was 95% after gel filtration. Two metabolic probes, 2-18F-FDG and 18F-choline, were also produced with an in-house cyclotron. The radiochemical purity for both probes was >99%. The radiochemical yield and specific activity were not reported for the three imaging agents.

An immunoradiometric assay was used to estimate the binding quality of 125I-PSA30 (1). The estimation showed that 125I-PSA30 maintained 87% of the binding affinity of the unlabeled PSA30 antibody. No data for 125I-PSA30 binding affinity with either fPSA or cPSA were provided.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

No data are available.

Animal Studies

Rodents

[PubMed]

Biodistribution of 125I-PSA30 was studied in non–tumor-bearing mice (n = 14) and LNCaP tumor–bearing nude mice (n = 34) (1). Each mouse was administered ~10 MBq (27 μCi, 15 μg) 125I-PSA30 through the tail vein. The radioactive uptake in each organ was presented as decay-corrected percentage of injected activity per gram of tissue (% IA/g).

For studies in non–tumor-bearing mice, organs were collected, and the radioactivity in each organ was measured at 6, 24, 96, 168, and 312 h, respectively, after injection (n = 2–3 mice/group). A decrease of the radioactivity from the first measurement after injection was observed in all tested organs (except for the thyroid) and blood (Table 1). The decrease during the first 24 h ranged from 55% to 83% in the liver, kidney, and blood. The highest uptake was found in organs with high residual blood content. The organ/blood ratios in highly vascularized organs remained largely unchanged over time, which is in accordance with the fact that PSA is not expressed in non-primate species, including mice. The radioactivity in thyroid increased from 6 h to 168 h after injection, indicating dehalogenation.

Table 1: Biodistribution of 125I-PSA30 (percent of IA/g) in nontumor-bearing mice.

Tissue6 h (n = 3)24 h (n = 3)96 h (n = 3)168 h (n = 2)312 h (n = 3)
Blood13.12 ± 12.992.52 ± 2.263.76 ± 0.562.27 ± 0.401.32 ± 0.61
Kidneys4.04 ± 3.180.69 ± 0.631.04 ± 0.110.49 ± 0.230.28 ± 0.16
Liver1.64 ± 1.620.75 ± 0.790.85 ± 0.080.48 ± 0.140.24 ± 0.12
Prostate2.34 ± 2.080.55 ± 0.580.72 ± 0.160.66 ± 0.130.41 ± 0.11
Brain0.29 ± 0.220.07 ± 0.070.08 ± 0.010.05 ± 0.010.03 ± 0.01
Thyroida6.0 ± 5.814 ± 2226 ± 8.019 ± 3.025 ± 5.0

aThyroid data presented as % IA per whole organ.

For studies in LNCaP tumor–bearing nude mice, organs were collected, and the activity in each organ was measured at 4, 24, 72, 168, and 312 h, respectively, after injection (n = 5–8 mice/group). Similar to the findings in non–tumor-bearing mice, highly vascularized organs initially showed high activity levels, which rapidly decreased from the first measurement after injection (Table 2). The organ/blood ratios remained largely unchanged over time in most organs. LNCaP tumors had a higher uptake than most tested organs and peaked (4.32% IA/g) at 24 h, with a subsequent sharp decrease by 72 h after injection (Table 2). In comparison to non–tumor-bearing mice, the radioactive accumulation in thyroid was greatly augmented, and there was a sharp increase at 72 h after injection. This inverse correlation between tumor and thyroid radioactivity was considered to be due to dehalogenation.

Table 2: Biodistribution of 125I-PSA30 (percent of IA/g) in LNCaP tumor-bearing mice.

Tissue4 h (n = 8)24 h (n = 8)72 h (n = 8)168 h (n = 5)312 h (n = 5)
Tumor3.27 ± 3.354.32 ± 5.261.39 ± 1.260.56 ± 0.540.10 ± 0.13
Blood7.44 ± 3.865.56 ± 4.204.00 ± 2.241.19 ± 1.570.46 ± 0.62
Kidneys3.12 ± 3.781.66 ± 1.131.02 ± 0.670.39 ± 0.410.15 ± 0.20
Liver1.90 ± 1.191.66 ± 1.481.07 ± 0.680.35 ± 0.340.10 ± 0.14
Prostate1.07 ± 0.500.97 ± 0.660.71 ± 0.440.22 ± 0.280.14 ± 0.17
Brain0.28 ± 0.350.13 ± 0.110.09 ± 0.050.03 ± 0.030.01 ± 0.02
Thyroida23 ± 2131 ± 22104 ± 64105 ± 4848 ± 23

aThyroid data presented as % IA per whole organ.

The radioactive distribution within tumors was imaged with digital autoradiography of tumor sections. LNCaP tumor–bearing mice (n = 36) were first administered 125I-PSA30 (10 MBq, 27 μCi). In two mice, 18F-choline was then administered at 48 h after injection of 125I-PSA30, and in five mice 18F-FDG (n = 5) was administered at 24, 72, 168, and 312 h after injection of 125I-PSA30. Animals were euthanized 1 h after injection of the metabolic probes, and tumors were immediately removed and cut into 100-μm sections for imaging or into 20-μm sections for tumor pathology and PSA immunohistochemistry. Differences in both emission spectra and rate of decay were used to generate separate images of each radionuclide in animals injected with more than one radionuclide, in this case, 125I and 18F. Tumor section images showed uniform distribution of 125I-PSA30 in tumor areas containing densely packed viable cells. High activity of 125I-PSA30 was manifested in the proximity to blood vessels, capillaries, and areas with viable PSA-secreting tumor cells. Except for areas of necrosis, there was a close similarity between the distribution of PSA revealed by immunohistochemistry and high radioactivity of 125I-PSA30 on images, but there was little association between the high activity of 125I-PSA30 and the uptake of 18F-choline or 18F-FDG (1). No blocking studies were performed.

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

No references are currently available.

Human Studies

[PubMed]

No references are currently available.

References

1.
Evans-Axelsson S., Ulmert D., Orbom A., Peterson P., Nilsson O., Wennerberg J., Strand J., Wingardh K., Olsson T., Hagman Z., Tolmachev V., Bjartell A., Lilja H., Strand S.E. Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone. Cancer Biother Radiopharm. 2012;27(4):243–51. [PMC free article: PMC3353767] [PubMed: 22489659]
2.
Avgeris M., Mavridis K., Scorilas A. Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies. Biol Chem. 2010;391(5):505–11. [PubMed: 20302518]
3.
Papachristopoulou G., Avgeris M., Charlaftis A., Scorilas A. Quantitative expression analysis and study of the novel human kallikrein-related peptidase 14 gene (KLK14) in malignant and benign breast tissues. Thromb Haemost. 2011;105(1):131–7. [PubMed: 21057706]
4.
Lilja H., Ulmert D., Vickers A.J. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer. 2008;8(4):268–78. [PubMed: 18337732]
5.
Christensson A., Laurell C.B., Lilja H. Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem. 1990;194(3):755–63. [PubMed: 1702714]
6.
Lilja H., Christensson A., Dahlen U., Matikainen M.T., Nilsson O., Pettersson K., Lovgren T. Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem. 1991;37(9):1618–25. [PubMed: 1716536]
7.
Bruun L., Savage C., Cronin A.M., Hugosson J., Lilja H., Christensson A. Increase in percent free prostate-specific antigen in men with chronic kidney disease. Nephrol Dial Transplant. 2009;24(4):1238–41. [PMC free article: PMC2721427] [PubMed: 19028756]
8.
Dillman R.O., Beauregard J., Ryan K.P., Hagan P.L., Clutter M., Amox D., Frincke J.M., Bartholomew R.M., Burnett K.G., David G.S. et al. Radioimmunodetection of cancer with the use of indium-111-labeled monoclonal antibodies. NCI Monogr. 1987;(3):33–6. [PubMed: 3821917]
9.
Perala-Heape M., Vihko P., Pelkonen I., Laine A., Vihko R. Effect of conjugation on the biodistribution of 111In-labelled anti-PAP and anti-PSA monoclonal antibodies examined in nude mice with PC-82 human tumor xenografts. In Vivo. 1991;5(2):159–65. [PubMed: 1722716]
10.
Babaian R.J., Murray J.L., Lamki L.M., Haynie T.P., Hersh E.M., Rosenblum M.G., Glenn H.J., Unger M.W., Carlo D.J., von Eschenbach A.C. Radioimmunological imaging of metastatic prostatic cancer with 111indium-labeled monoclonal antibody PAY 276. J Urol. 1987;137(3):439–43. [PubMed: 3820371]
11.
Nilsson O., Peter A., Andersson I., Nilsson K., Grundstrom B., Karlsson B. Antigenic determinants of prostate-specific antigen (PSA) and development of assays specific for different forms of PSA. Br J Cancer. 1997;75(6):789–97. [PMC free article: PMC2063392] [PubMed: 9062397]
12.
Piironen T., Villoutreix B.O., Becker C., Hollingsworth K., Vihinen M., Bridon D., Qiu X., Rapp J., Dowell B., Lovgren T., Pettersson K., Lilja H. Determination and analysis of antigenic epitopes of prostate specific antigen (PSA) and human glandular kallikrein 2 (hK2) using synthetic peptides and computer modeling. Protein Sci. 1998;7(2):259–69. [PMC free article: PMC2143911] [PubMed: 9521101]

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