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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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111In-Diethylenetriamine pentaacetic acid-anti-epithelial glycoprotein-1 hRS7 humanized monoclonal antibody

111In-DTPA-hRS7
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: April 19, 2012.

Chemical name:111In-Diethylenetriamine pentaacetic acid-anti-epithelial glycoprotein-1 hRS7 humanized monoclonal antibody
Abbreviated name:111In-DTPA-hRS7
Synonym:
Agent category:Antibody
Target:Epithelial glycoprotein-1 (EGP-1, also known as TROP2)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar imaging
Source of signal/ contrast:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about EGP-1

Background

[PubMed]

Epithelial glycoprotein-1 (EGP-1, also known as TROP2) is a transmembrane glycoprotein (46 kDa) identified with murine IgG1 monoclonal antibody (mAb) RS7 raised against human non-small cell lung carcinoma (1). EGP-1 is also present in human carcinomas of the stomach, bladder, breast, ovary, uterus, and prostate, but it is not expressed in most normal tissues. EGP-1 is expressed at low levels in glandular cells in the bronchus, breast, prostate, skin, and pancreas. EGP-1 activates intracellular calcium mobilization (2) and protein kinase C (3) after binding with RS7. EGP-1 is a cell-surface receptor with unknown physiological ligand and cellular functions. However, EGP-1 has been implicated in the activation of the ERK/MAPK pathway, leading to downstream alterations in cellular proliferation, migration, invasion, and survival of cancer cells (4). EGP-1 overexpression has been associated with increased tumor invasiveness and decreased overall survival rates in multiple types of human carcinomas (5, 6). van Rij et al. (7) evaluated 111In-diethylenetriamine pentaacetic acid-hRS7 (111In-DTPA-hRS7) as a 111In-based single-photon emission computed tomography (SPECT) agent in human prostate PC-3 tumors in nude mice.

Synthesis

[PubMed]

DTPA-hRS7 was prepared by conjugation of p-isothiocyanatobenzyl-DTPA to hRS7 at a molar ratio of 50:1 (pH 9.5) for 60 min at 25°C (7). DTPA-hRS7 was purified with dialysis. There were two DTPA moieties per mAb. DTPA-hRS7 was incubated with 111InCl3 in 0.25 M NH4Ac buffer (pH 5.4) for 60 min at 25°C. 111In-DTPA-hRS7 was purified with column chromatography. The specific activity was estimated to be 606 MBq/nmol (16.4 mCi/nmol). No radiochemical yield or radiochemical purity was reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Immunostaining of PC-3 tumor sections with hRS7 showed the expression of EGP-1 in the membranes and cytosol of PC-3 tumor cells (7). Immunochemical analysis of three human primary prostate tumor sections showed high homogeneous and consistent expression of EGP-1 in all three tumors and metastases in a lymph node and in the liver. The immunoreactivity of 111In-DTPA-hRS7 was >80%.

Animal Studies

Rodents

[PubMed]

van Rij et al. (7) injected 0.4 MBq (0.011 mCi, 0.66 pmol) 111In-DTPA-hRS7 into male nude mice (n = 5/group) bearing the EGP-1–positive PC-3 human prostate tumors for ex vivo biodistribution studies. Ex vivo tumor accumulation was 61 ± 15% injected dose/gram (ID/g) at 3 d after injection. The tumor/blood ratio was 7.2. The radioactivity levels in the other organs were <10% ID/g. Co-injection of excess hRS7 (0.66 nmol) inhibited the accumulation in the tumors to 22 ± 7% ID/g and the tumor/blood ratio to 3.0 at 3 d after injection. Little inhibition was observed in the other organs.

van Rij et al. (7) performed ex vivo biodistribution and SPECT imaging studies in male nude mice (n = 5/group) bearing orthotopic PC-3 xenografts (17 d after tumor inoculation) at 3 d after injection of 37 MBq (1 mCi, 0.066 nmol)) 111In-DTPA-hRS7. Prostate tumor accumulation was 32 ± 13% ID/g. The radioactivity levels in the other organs were <7% ID/g, with <4% ID/g in the normal prostate. Co-injection of excess hRS7 (3.3 nmol) inhibited accumulation in the tumors to 6.1 ± 1.7% ID/g. Little inhibition was observed in the other organs. SPECT imaging showed that the tumors were clearly visualized in the prostate of all mice. The tumor/liver ratio was 7.3.

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.
Stein R., Chen S., Sharkey R.M., Goldenberg D.M. Murine monoclonal antibodies raised against human non-small cell carcinoma of the lung: specificity and tumor targeting. Cancer Res. 1990;50(4):1330–6. [PubMed: 2153458]
2.
Ripani E., Sacchetti A., Corda D., Alberti S. Human Trop-2 is a tumor-associated calcium signal transducer. Int J Cancer. 1998;76(5):671–6. [PubMed: 9610724]
3.
Basu A., Goldenberg D.M., Stein R. The epithelial/carcinoma antigen EGP-1, recognized by monoclonal antibody RS7-3G11, is phosphorylated on serine 303. Int J Cancer. 1995;62(4):472–9. [PubMed: 7635574]
4.
Cubas R., Zhang S., Li M., Chen C., Yao Q. Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer. 2010;9:253. [PMC free article: PMC2946292] [PubMed: 20858281]
5.
Varughese J., Cocco E., Bellone S., de Leon M., Bellone M., Todeschini P., Schwartz P.E., Rutherford T.J., Pecorelli S., Santin A.D. Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Cancer. 2011;117(14):3163–72. [PMC free article: PMC3128671] [PubMed: 21246534]
6.
Bignotti E., Todeschini P., Calza S., Falchetti M., Ravanini M., Tassi R.A., Ravaggi A., Bandiera E., Romani C., Zanotti L., Tognon G., Odicino F.E., Facchetti F., Pecorelli S., Santin A.D. Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients. Eur J Cancer. 2010;46(5):944–53. [PubMed: 20060709]
7.
van Rij C.M., Sharkey R.M., Goldenberg D.M., Frielink C., Molkenboer J.D., Franssen G.M., van Weerden W.M., Oyen W.J., Boerman O.C. Imaging of prostate cancer with immuno-PET and immuno-SPECT using a radiolabeled anti-EGP-1 monoclonal antibody. J Nucl Med. 2011;52(10):1601–7. [PubMed: 21865288]

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