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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 (mAb) 806 targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII)

[125I]-mAb806
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: August 5, 2010.

Chemical name:125I-Labeled monoclonal antibody (mAb) 806 targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII)
Abbreviated name:[125I]-mAb806
Synonym:
Agent Category:Antibody
Target:Epidermal growth factor receptor deletion variant de2-7 (EGFRvIII)
Target Category:Receptor
Method of detection:Single-photon emission tomography (SPECT); gamma planar imaging
Source of signal / contrast:125I
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
No structure information available in PubChem.

Background

[PubMed]

The biological characteristics, activating ligands, and functioning of the different members of the transmembrane epidermal growth factor receptor (EGFR) family are described elsewhere (1-3). These receptors are known to regulate the growth, survival, differentiation, and migration of cells through the activation of an associated intracellular tyrosine kinase (TK) signaling pathway, and they are overexpressed in many malignant epithelial tumors (1, 2). In addition, overexpression of the EGFR usually indicates a poor clinical prognosis for the patient (4). Overexpression of the EGFR in the tumors has been attributed to gene amplification, and this phenomenon is believed to introduce mutations in the receptor (2, 4). The most common mutation observed in the EGFR receptor is the deletion of a segment of the EGFR extracellular domain, including the ligand-binding region, which results in the generation of an EGFR variant known as the de2-7 EGFR or EGFRvIII (2, 4). The generation, structure, functions, and role of EGFRvIII in tumor malignancy have been reviewed by Gan et al. (5). Although EGFRvIII is nonresponsive to the ligand, it is constitutively active with a constantly operating downstream TK signal transduction pathway that appears to promote the development of a neoplastic phenotype, particularly for glioblastoma and to some extent for other cancers such as those of the prostate and the breast (2, 6).

Because the EGFR promotes and helps maintain the cancerous state of cells, several antibodies that inhibit the receptor activity and small molecules that block the downstream TK signaling pathway have been developed and have been approved by the United States Food and Drug Administration (FDA) for the treatment of certain cancers (2). The antibodies are directed toward the extracellular domain of the receptor, block ligand binding, and inhibit activation of the TK signal transduction pathway, which ultimately results in downregulation of the EGFR on the cell surface. However, because the EGFRvIII lacks the ligand-binding region on the extracellular domain, these antibodies cannot obstruct the constitutive mutant receptor activity (2). As a consequence, the monoclonal antibody (mAb) 806, which specifically targets the EGFRvIII, was generated and characterized in preclinical studies (7, 8). Subsequently, a chimeric form of the mAb (chAb), designated as ch806, was developed and evaluated in a phase I clinical trial with patients having cancerous tumors overexpressing the EGFRvIII (4). Results obtained from this trial indicated that ch806 could be a good biotherapeutic agent for the treatment of cancers expressing the ch806 antigen (4). In addition, several other clinical trials approved by the FDA are in progress to evaluate the targeting of EGFRvIII as a treatment against various cancers.

The internalization, intracellular trafficking, and biodistribution (in nude mice bearing xenograft human epidermoid carcinoma cell tumors) of mAb806 labeled with 111In ([111In]-mAb806) and 125I ([125I]-mAb806) have been investigated by Perera et al. (8). The characterization and biodistribution (in nude mice bearing xenograft human glioblastoma cell tumors) of ch806 labeled with 125I and 111In, respectively, are described in separate chapters in MICAD (www.micad.nih.gov) (9, 10). Another chapter describes the use of 124I-labeled ch806 for the detection of EGFRvIII-expressing xenograft human glioblastoma tumors in nude mice with an immuno–positron emission tomography (PET) technique (11). This chapter describes the studies performed with [125I]-mAb806. Studies performed with [111In]-mAb806 are described in a separate chapter in MICAD (12).

Other sources of information

Human EGFR Gene (Gene ID: 1956)

Protein and mRNA sequence of human EGFR variant 1

EGFR in OMIM (Online Mendelian Inheritance in Man)

EGFR signaling pathways (NCI-Nature Pathways Interaction Database)

Anti-EGFR antibodies in PubMed

EGFR tyrosine kinase inhibitors in PubMed

Related chapters in MICAD

Synthesis

[PubMed]

The labeling of mAb806 with 125I was done using a modified chloramine-T method as described by Perera et al. (8). The radiochemical purity of the 125I-labeled mAb was reported to be 99.6% as determined with instant thin-layer chromatography. The yield of the radiolabeling reaction was not reported. The specific activity of [125I]-mAb806 was reported to be ~37.0 kBq/6.6 pmol (151.5 Ci/mmol). The final formulation and storage conditions of the labeled mAb were not reported.

For use as a control, another isotype-matched mAb, 100-310 (directed against the human A33 antigen), was labeled with 125I in a similar manner (8).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The immunoreactivity of [125I]-mAb806 was determined using A431 cells (a human epidermoid carcinoma cell line that expresses the EGFRvIII receptor) (8). The number of labeled mAb molecules bound per cell was reported to be 3.14 × 105, which is similar to the number determined for [111In]-mAb806 (3.89 × 105/cell) (8). The isotype-matched 125I-labeled mAb 100-310 did not bind to the A431 cells under the same study conditions.

In another study, the internalization and trafficking of a fluorescent dye (Cy-3)–tagged mAb806 (mAb806-Cy3) was investigated using A431 cells (8). This study revealed that mAb806-Cy3 was internalized by the cells through a dynamin-dependent, clathrin-mediated, endocytotic process. The mAb was initially localized in the endosomes and later trafficked to and accumulated in the lysosomes (8).

Animal Studies

Rodents

[PubMed]

The biodistribution of [125I]-mAb806 was studied in BALB/c nude mice bearing xenograft A431 cell tumors (8). The animals were injected with the labeled mAb through the tail vein, and the mice were euthanized at predetermined time points (n = 4 animals/time point) for the collection of all major organs, including the tumors (6). In general, the uptake of label from [125I]-mAb806 by the tumors was lower than that from the [111In]-mAb806 at all time points (8). With [125I]-mAb806, the accumulation of radioactivity in the tumors decreased from 13.7 ± 3.3% injected dose per gram tissue (% ID/g) at 4 h post-injection (p.i.) to 9.9 ± 3.5% ID/g at 48 h and reduced to 2.5 ± 6.3% ID/g by 168 h p.i. During the same time period, radioactivity in the blood from [125I]-mAb806 was observed to reduce from 29.8 ± 1.7% ID/g at 4 h p.i. to 12.5 ± 1.7% ID/g at 48 h p.i., and to further reduce to 4.7 ± 1.6 at 168 h p.i. To compare the accumulation of radioactivity from [125I]-mAb806 and [111In]-mAb806, respectively, in the tumors and blood of the animals, the reader is referred to Table 1 in Perera et al. (8). All major organs were reported to have an accumulation of <10% ID/g radioactivity from [125I]-mAb806 at all time points. No blocking studies using unlabeled mAb806 or another suitable anti-EGFR mAb were reported.

On the basis of results obtained from these studies, the investigators concluded that [111In]-mAb806 would be a better candidate than [125I]-mAb806 for development as a cancer detection or therapeutic agent (8).

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.

Supplemental Information

[Disclaimers]

No information is currently available.

References

1.
Spector N.L., Blackwell K.L. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009;27(34):5838–47. [PubMed: 19884552]
2.
Pines G., Kostler W.J., Yarden Y. Oncogenic mutant forms of EGFR: lessons in signal transduction and targets for cancer therapy. FEBS Lett. 2010;584(12):2699–706. [PMC free article: PMC2892754] [PubMed: 20388509]
3.
Hasselbalch, B., U. Lassen, H.S. Poulsen, and M.T. Stockhausen, Cetuximab Insufficiently Inhibits Glioma Cell Growth Due to Persistent EGFR Downstream Signaling. Cancer Invest. 2010. [PubMed: 20504227]
4.
Scott A.M., Lee F.T., Tebbutt N., Herbertson R., Gill S.S., Liu Z., Skrinos E., Murone C., Saunder T.H., Chappell B., Papenfuss A.T., Poon A.M., Hopkins W., Smyth F.E., MacGregor D., Cher L.M., Jungbluth A.A., Ritter G., Brechbiel M.W., Murphy R., Burgess A.W., Hoffman E.W., Johns T.G., Old L.J. A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors. Proc Natl Acad Sci U S A. 2007;104(10):4071–6. [PMC free article: PMC1805701] [PubMed: 17360479]
5.
Gan H.K., Kaye A.H., Luwor R.B. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci. 2009;16(6):748–54. [PubMed: 19324552]
6.
Lee F.T., O'Keefe G.J., Gan H.K., Mountain A.J., Jones G.R., Saunder T.H., Sagona J., Rigopoulos A., Smyth F.E., Johns T.G., Govindan S.V., Goldenberg D.M., Old L.J., Scott A.M. Immuno-PET quantitation of de2-7 epidermal growth factor receptor expression in glioma using 124I-IMP-R4-labeled antibody ch806. J Nucl Med. 2010;51(6):967–72. [PubMed: 20484439]
7.
Jungbluth A.A., Stockert E., Huang H.J., Collins V.P., Coplan K., Iversen K., Kolb D., Johns T.J., Scott A.M., Gullick W.J., Ritter G., Cohen L., Scanlan M.J., Cavenee W.K., Old L.J. A monoclonal antibody recognizing human cancers with amplification/overexpression of the human epidermal growth factor receptor. Proc Natl Acad Sci U S A. 2003;100(2):639–44. [PMC free article: PMC141049] [PubMed: 12515857]
8.
Perera R.M., Zoncu R., Johns T.G., Pypaert M., Lee F.T., Mellman I., Old L.J., Toomre D.K., Scott A.M. Internalization, intracellular trafficking, and biodistribution of monoclonal antibody 806: a novel anti-epidermal growth factor receptor antibody. Neoplasia. 2007;9(12):1099–110. [PMC free article: PMC2134906] [PubMed: 18084617]
9.
Chopra, A., [111In]-Labeled CHX-A"-DTPA conjugated chimeric antibody 806 (ch806) targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII). Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current. [PubMed: 20698071]
10.
Chopra, A., [125I]-Labeled chimeric antibody 806 (ch806) targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII). Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current.
11.
Chopra, A., [124I]-Labeled residulizing ligand IMP-R4 conjugated chimeric monoclonal antibody ch806 targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII). Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current. [PubMed: 20698075]
12.
Chopra, A., [111In]-Labeled CHX-A"-DTPA conjugated monoclonal antibody 806 (mAb 806) targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII). Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current. [PubMed: 20698071]

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