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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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111In-2-(4,7,10-Tris(carboxymethyl)-1,4,7,10-tetracyclododecan-1-yl)pentanedioic acid-Trastuzumab

111In-DOTAGA-Trastuzumab
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: September 13, 2012.

Chemical name:111In-2-(4,7,10-Tris(carboxymethyl)-1,4,7,10-tetracyclododecan-1-yl)pentanedioic acid-Trastuzumab
Abbreviated name:111In-DOTAGA-Trastuzumab
Synonym:
Agent category:Antibody
Target:Epidermal growth factor receptor (EGFR, HER2)
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar imaging
Source of signal:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about HER2.

Background

[PubMed]

Epidermal growth factor (EGF) is a growth factor composed of 53 amino acids (6.2 kDa), and it is secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors: EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2. However, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 and HER2 are overexpressed on many solid tumor cells such as breast, non-small cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with a poor patient prognosis because high levels are related to increased proliferation (7-10).

Trastuzumab is a humanized IgG1 monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant (Kd) of 0.1 nM (11). 111In-Trastuzumab, Cy5.5-trastuzumab, 89Zr-trastuzumab, and 68Ga-trastuzumab-F(ab')2 have been developed for imaging of human breast cancer (12-17). Moreau et al. (18) conjugated 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetracyclododecan-1-yl)pentanedioic acid (DOTAGA), which is a derivative of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), to trastuzumab and labeled it with 111In as 111In-DOTAGA-trastuzumab for single-photon emission computed tomography (SPECT) imaging of HER2 expression in tumors.

Synthesis

[PubMed]

Trastuzumab (20 nmol) was incubated with DOTAGA-anhydride (400 nmol) in phosphate-buffered saline (PBS) (pH, 7.4) for 30 min at 25°C (18). DOTAGA-Trastuzumab was isolated with ultrafiltration. There were 2.6 DOTAGA moieties per conjugate (148.9 kDa), as confirmed with mass spectroscopy. DOTAGA-Trastuzumab (0.83 nmol) was mixed with 125 MBq (3.4 mCi) 111InCl3 in ammonium acetate buffer (pH, 5.7) and incubated for 3 h at 37°C, with 66% labeling yield after removing free 111In3+ ions with ETDA treatment and isolation with ultrafiltration. The radiochemical purity was >97%. The specific activity was 150 MBq/nmol (4.1 mCi/nmol) at the end of synthesis. 111In-DOTAGA-Trastuzumab was >97% intact after incubation with 2,000-fold excess diethylenetriamine pentaacetic acid in PBS for up to 5 d.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Moreau et al. (18) performed saturation binding experiments with 111In-DOTAGA-trastuzumab using the HER2-positive HCC1954 breast tumor cell line. The binding affinity (Kd) value was 5.5 ± 0.6 nM. 111In-DOTAGA-Trastuzumab exhibited an immunoreactivity of 65%.

Animal Studies

Rodents

[PubMed]

Moreau et al. (18) performed SPECT imaging scans in female nude mice (n = 4) bearing BT-474 human breast tumors at 24, 48, and 72 h after injection of 15 MBq (0.41 mCi) 111In-DOTAGA-trastuzumab (0.17 nmol). The tumors were clearly visualized at these time points. Region of interest analysis showed that the tumor accumulation of radioactivity was 11.0 ± 5.6% injected dose (ID), 13.1 ± 7.6% ID, and 14.0 ± 8.1% ID at 24, 48, and 72 h after injection, respectively. The radioactivity was located mainly in the rim of the tumor, with a lower radioactivity in the necrotic center of the tumor. The effective half-life (radioactive decay of 111In and biological excretion) of 111In-DOTAGA-trastuzumab in the mice was found with the image analysis to be 53.5 ± 4.0 h. The biological half-life (biological excretion) was calculated to be 268 ± 92 h. Ex vivo tissue biodistribution study was performed at 72 h after the last SPECT scan. Tumor accumulation was 66.9 ± 0.9% ID/g or 13.2 ± 8.2% ID. The highest radioactivity level was in the blood (10.0% ID/g), followed by the ovary (8.0% ID/g), spleen (6.9% ID/g), kidney (6.3% ID/g), lung (5.6% ID/g), liver (4.3% ID/g), heart (3.6% ID/g), and gastrointestinal tract (1.8% ID/g). Co-injection with 100-fold excess unlabeled trastuzumab reduced tumor accumulation by 73% at 72 h after injection, with little effect on the blood radioactivity.

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

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Carpenter G., Cohen S. Epidermal growth factor. J Biol Chem. 1990;265(14):7709–12. [PubMed: 2186024]
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Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37 Suppl 4:S3–8. [PubMed: 11597398]
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Rubin I., Yarden Y. The basic biology of HER2. Ann Oncol. 2001;12 Suppl 1:S3–8. [PubMed: 11521719]
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Grunwald V., Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst. 2003;95(12):851–67. [PubMed: 12813169]
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Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibodies as potential anti-cancer agents. J Steroid Biochem Mol Biol. 1990;37(6):889–92. [PubMed: 2285602]
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Yasui W., Sumiyoshi H., Hata J., Kameda T., Ochiai A., Ito H., Tahara E. Expression of epidermal growth factor receptor in human gastric and colonic carcinomas. Cancer Res. 1988;48(1):137–41. [PubMed: 2446740]
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Costa S., Stamm H., Almendral A., Ludwig H., Wyss R., Fabbro D., Ernst A., Takahashi A., Eppenberger U. Predictive value of EGF receptor in breast cancer. Lancet. 1988;2(8622):1258. [PubMed: 2903994]
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Ethier S.P. Growth factor synthesis and human breast cancer progression. J Natl Cancer Inst. 1995;87(13):964–73. [PubMed: 7629883]
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Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61 Suppl 2:1–13. [PubMed: 11694782]
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Carter P., Presta L., Gorman C.M., Ridgway J.B., Henner D., Wong W.L., Rowland A.M., Kotts C., Carver M.E., Shepard H.M. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992;89(10):4285–9. [PMC free article: PMC49066] [PubMed: 1350088]
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Perik P.J., Lub-De Hooge M.N., Gietema J.A., van der Graaf W.T., de Korte M.A., Jonkman S., Kosterink J.G., van Veldhuisen D.J., Sleijfer D.T., Jager P.L., de Vries E.G. Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2006;24(15):2276–82. [PubMed: 16710024]
13.
Lub-de Hooge M.N., Kosterink J.G., Perik P.J., Nijnuis H., Tran L., Bart J., Suurmeijer A.J., de Jong S., Jager P.L., de Vries E.G. Preclinical characterisation of 111In-DTPA-trastuzumab. Br J Pharmacol. 2004;143(1):99–106. [PMC free article: PMC1575276] [PubMed: 15289297]
14.
Garmestani K., Milenic D.E., Plascjak P.S., Brechbiel M.W. A new and convenient method for purification of 86Y using a Sr(II) selective resin and comparison of biodistribution of 86Y and 111In labeled Herceptin. Nucl Med Biol. 2002;29(5):599–606. [PubMed: 12088731]
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Smith-Jones P.M., Solit D., Afroze F., Rosen N., Larson S.M. Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET. J Nucl Med. 2006;47(5):793–6. [PMC free article: PMC3193602] [PubMed: 16644749]
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Smith-Jones P.M., Solit D.B., Akhurst T., Afroze F., Rosen N., Larson S.M. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol. 2004;22(6):701–6. [PubMed: 15133471]
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Dijkers E.C., Oude Munnink T.H., Kosterink J.G., Brouwers A.H., Jager P.L., de Jong J.R., van Dongen G.A., Schroder C.P., Lub-de Hooge M.N., de Vries E.G. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87(5):586–92. [PubMed: 20357763]
18.
Moreau, M., O. Raguin, J.M. Vrigneaud, B. Collin, C. Bernhard, X. Tizon, F. Boschetti, O. Duchamp, F. Brunotte, and F. Denat, DOTAGA-Trastuzumab. A New Antibody Conjugate Targeting HER2/Neu Antigen for Diagnostic Purposes. Bioconjug Chem, 2012. [PubMed: 22519915]

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