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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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89Zr-N-Succinyldesferal-chimeric monoclonal antibody G250

89Zr-Df-cG250
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: May 27, 2010.

Chemical name:89Zr-N-Succinyldesferalchimeric monoclonal antibody G250
Abbreviated name:89Zr-Df-cG250
Synonym:
Agent category:Antibody
Target:Carbonic anhydrase IX
Target category:Enzyme
Method of detection:Positron emission tomography (PET)
Source of signal:89Zr
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about human carbonic anhydrase IX.

Background

[PubMed]

In a variety of solid tumors, hypoxia was found to lead to tumor progression and the resistance of tumors to chemotherapy and radiotherapy (1-3). Tumor oxygenation is heterogeneously distributed within human tumors (4). Hypoxia in malignant tumors is thought to be a major factor limiting the efficacy of chemotherapy and radiotherapy. It would be beneficial to assess tumor oxygenation before and after therapy to provide an evaluation of tumor response to treatment and an insight into new therapeutic treatments (5). Tumor oxygenation is measured invasively using computerized polarographic oxygen-sensitive electrodes, which is regarded as the gold standard (6). Functional and non-invasive imaging of intratumoral hypoxia has been demonstrated to be feasible for the measurement of tumor oxygenation (7).

Chapman proposed the use of 2-nitroimidazoles for hypoxia imaging (8). 2-Nitroimidazole compounds are postulated to undergo reduction in hypoxic condition, forming highly reactive oxygen radicals that subsequently bind covalently to macromolecules inside the cells (9). [18F]Fluoromisonidazole ([18F]FMISO) is the most widely used positron emission tomography (PET) tracer for imaging tumor hypoxia (7). Carbonic anhydrase (CA) IX is one of the most overexpressed genes in cells under hypoxic conditions (10). It is a transmembrane glycoprotein with CA activity in the extracellular domain, and it is found to be overexpressed in renal cell, cervical, lung, and colorectal tumors. Murine monoclonal antibody G250 against CA IX has been developed for in vitro and in vivo localization of CA IX in cells (11-13). G250 is found to bind to >94% of human clear-cell renal carcinoma. A murine-human chimeric G250 (cG250) has been generated to be less immunogenic in humans. 124I-cG250 has been evaluated as a PET imaging agent for renal cell carcinoma in mice (14) and patients (15). Brouwers et al. (16) explored the use of a 89Zr positron emitter (half-life, 3.27 days) to radiolabel cG250. 89Zr was conjugated to a bifunctional derivative of desferrioxamine B (Df) to cG250 for PET imaging of CA IX expression in tumors. 89Zr-Df-cG250 has been evaluated as a PET imaging agent for renal cell carcinoma in rats.

Synthesis

[PubMed]

cG250 was coupled with N-SucDf via an amide linkage and labeled with 89Zr (16). Df-cG250 (2.4 nmol) was incubated with 165 MBq (4.5 mCi) 89Zr for 30 min at room temperature. 89Zr-Df-cG250 was purified by gel filtration. The radiochemical purity was >97% with >95% immunoreactivity. Maximum specific activity was 60 MBq/nmol (1.6 mCi/nmol). There was one N-SucDf group per cG250 molecule. 89Zr-Df-cG250 showed <10% loss of 89Zr in human serum for 4 d at 37°C.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Lawrentschuk et al. (17) performed binding experiments with124I-cG250 in SK-RC-52 human renal carcinoma cells. The dissociation constant (Kd ) was found to be 2.2 nM with 400,000 antibody molecules per cell.

Animal Studies

Rodents

[PubMed]

Brouwers et al. (16) studied ex vivo biodistribution of 89Zr-Df-cG250 in nude rats (n = 8) bearing SK-RC-52 tumors at 72 h after injection. The tracer accumulation in the tumors was 5.0 ± 2.4% injected dose per gram (ID/g). The liver, spleen, lung, intestines, muscle, blood, and kidneys had lower radioactivity levels than the tumors. The radioactivity in the blood was ~1.6% ID/g, and the tumor/blood ratio was 3.1. 111In-DTPA-cG250 exhibited a similar biodistribution pattern with a tumor/blood ratio of 2.9. No blocking experiment was performed. PET imaging with the 89Zr-Df-cG250 showed localization of radioactivity to the tumors and the abdomen area in the rats at 48 h and 72 h after injection.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Serkies K., Jassem J. Chemotherapy in the primary treatment of cervical carcinoma. Crit Rev Oncol Hematol. 2005;54(3):197–208. [PubMed: 15890269]
2.
Vaupel P., Mayer A. Hypoxia and anemia: effects on tumor biology and treatment resistance. Transfus Clin Biol. 2005;12(1):5–10. [PubMed: 15814285]
3.
Rajendran J.G., Krohn K.A. Imaging hypoxia and angiogenesis in tumors. Radiol Clin North Am. 2005;43(1):169–87. [PubMed: 15693655]
4.
Vaupel P., Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist. 2004;9 Suppl 5:4–9. [PubMed: 15591417]
5.
Dehdashti F., Grigsby P.W., Mintun M.A., Lewis J.S., Siegel B.A., Welch M.J. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys. 2003;55(5):1233–8. [PubMed: 12654432]
6.
Raleigh J.A., Dewhirst M.W., Thrall D.E. Measuring Tumor Hypoxia. Semin Radiat Oncol. 1996;6(1):37–45. [PubMed: 10717160]
7.
Foo S.S., Abbott D.F., Lawrentschuk N., Scott A.M. Functional imaging of intratumoral hypoxia. Mol Imaging Biol. 2004;6(5):291–305. [PubMed: 15380739]
8.
Chapman J.D. Hypoxic sensitizers--implications for radiation therapy. N Engl J Med. 1979;301(26):1429–32. [PubMed: 229413]
9.
Chapman J.D., Baer K., Lee J. Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. Cancer Res. 1983;43(4):1523–8. [PubMed: 6831401]
10.
Loncaster J.A., Harris A.L., Davidson S.E., Logue J.P., Hunter R.D., Wycoff C.C., Pastorek J., Ratcliffe P.J., Stratford I.J., West C.M. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 2001;61(17):6394–9. [PubMed: 11522632]
11.
Lam J.S., Pantuck A.J., Belldegrun A.S., Figlin R.A. G250: a carbonic anhydrase IX monoclonal antibody. Curr Oncol Rep. 2005;7(2):109–15. [PubMed: 15717944]
12.
Oosterwijk E., Debruyne F.M. Radiolabeled monoclonal antibody G250 in renal-cell carcinoma. World J Urol. 1995;13(3):186–90. [PubMed: 7550393]
13.
Grabmaier K., Vissers J.L., De Weijert M.C., Oosterwijk-Wakka J.C., Van Bokhoven A., Brakenhoff R.H., Noessner E., Mulders P.A., Merkx G., Figdor C.G., Adema G.J., Oosterwijk E. Molecular cloning and immunogenicity of renal cell carcinoma-associated antigen G250. Int J Cancer. 2000;85(6):865–70. [PubMed: 10709109]
14.
Lawrentschuk, N., F.T. Lee, G. Jones, A. Rigopoulos, A. Mountain, G. O'Keefe, A.T. Papenfuss, D.M. Bolton, I.D. Davis, and A.M. Scott, Investigation of hypoxia and carbonic anhydrase IX expression in a renal cell carcinoma xenograft model with oxygen tension measurements and (124)I-cG250 PET/CT. Urol Oncol, 2009. [PubMed: 19523858]
15.
Divgi C.R., Pandit-Taskar N., Jungbluth A.A., Reuter V.E., Gonen M., Ruan S., Pierre C., Nagel A., Pryma D.A., Humm J., Larson S.M., Old L.J., Russo P. Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial. Lancet Oncol. 2007;8(4):304–10. [PubMed: 17395103]
16.
Brouwers A., Verel I., Van Eerd J., Visser G., Steffens M., Oosterwijk E., Corstens F., Oyen W., Van Dongen G., Boerman O. PET radioimmunoscintigraphy of renal cell cancer using 89Zr-labeled cG250 monoclonal antibody in nude rats. Cancer Biother Radiopharm. 2004;19(2):155–63. [PubMed: 15186595]
17.
Ahlskog J.K., Schliemann C., Marlind J., Qureshi U., Ammar A., Pedley R.B., Neri D. Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours. Br J Cancer. 2009;101(4):645–57. [PMC free article: PMC2736829] [PubMed: 19623173]

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