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111In-Labeled chimeric monoclonal antibody, ch806, targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII)

[111In]-ch806
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: August 26, 2010.

Chemical name:111In-Labeled chimeric monoclonal antibody, ch806, targeting the epidermal growth factor receptor deletion variant de2-7 (EGFRvIII)
Abbreviated name:[111In]-ch806
Synonym:[111In]-CHX-A”-DTPA-ch806
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:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Human Studies
Structure not 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). The EGFR receptors are known to regulate the growth, survival, differentiation, and migration of cells through the activation of an associated intracellular tyrosine kinase (TK) signal transduction pathway, and they are overexpressed in many malignant epithelial tumors (1, 2). Overexpression of the EGFR in tumors has been attributed to gene amplification, and this phenomenon is believed to introduce mutations in the receptor (2, 4). Also, overexpression of the EGFR usually indicates a poor clinical prognosis for the patient (4). The most common mutation observed in the EGFR receptor is the deletion of a segment of the extracellular domain, including the ligand-binding region, which results in the generation of a variant known as the de2-7 EGFR or EGFRvIII (2, 4). The generation, structure, functions, and role of the EGFRvIII in tumor malignancy have been reviewed by Gan et al. (5). Although the EGFRvIII is nonresponsive to the ligand, it is constitutively active with a constantly operating downstream TK signaling pathway that appears to promote the development of a neoplastic phenotype, particularly for glioblastomas 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 (9) 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 125I and 111In, respectively, have been investigated by Perera et al. (8) and are described separately in MICAD (www.micad.nih.gov) (10, 11). The characterization and biodistribution (in nude mice bearing xenograft human glioblastoma cell tumors) of ch806 labeled with 125I ([125I]-ch806) or 111In ([111In]-ch806) have been investigated by Panousis et al. (9). 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 was investigated by Lee et al. (6) and has been described in another chapter in MICAD (12). This chapter describes the studies performed with [111In]-ch806. Studies performed with [125I]-ch806 are described in a separate chapter in MICAD (13).

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 Interactive Database)

Anti-EGFR antibodies in PubMed

EGFR tyrosine kinase inhibitors in PubMed

Related chapters in MICAD

Synthesis

[PubMed]

The production and labeling of ch806 to obtain [111In]-ch806 (as a 111In-labeled [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans(S,S)-cyclohexane-1,2-diethylenetriamine pentaacetic acid (CHX-A''-DTPA) conjugate of ch806; [111In]-CHX-A”-DTPA-ch806 or [111In]-ch806) is described elsewhere (9). The radiochemical purity of [111In]-chAb was reported to be 98.6% as determined with instant thin-layer chromatography. The specific activity of [111In]-ch806 was reported to be 0.0840–0.1221 MBq/6.6 pmol (~422 Ci/mmol). The final formulation, the number of CHX-A”-DTPA per ch806 and storage conditions of the radiolabeled chAb were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The stability of [111In]-ch806 was determined in healthy human donor serum at 37°C and was reported to maintain a radiochemical purity of >95% for up to 7 days (9). Under the same storage conditions and duration, immunoreactivity of the labeled chAb with U87MG.de2-7 cells (a human glioma cell line generated to overexpress the EGFRvIII) was determined to be >65%. Using various cell lines expressing or overexpressing the EGFRvIII or the wild-type EGFR, respectively, it was shown that ch806 and the parental mAb806 had a similar receptor-binding profile.

The receptor association constant for [111In]-ch806 was determined to be 1.36 × 109 M-1 compared with 1.1 × 109 M-1 for the parental mAb806 with the Lindmo assay using U87MG.de2-7 cells (9). The number of [111In]-ch806 molecules bound per cell was reported to be 6.0 × 105 compared with 4.7 × 105 for the [125I]-labeled ch806 (9).

In a clinical study using immunohistochemical techniques, 50% to 75% of cells in tumor samples from six of eight cancer patients were shown to bind ch806 (4). Cells of tumor samples obtained from the remaining two patients showed <10% binding of the chAb.

Animal Studies

Rodents

[PubMed]

The biodistribution patterns of [111In]-ch806 and [125I]-ch806 were studied in BALB/c nude mice respectively bearing xenograft U87MB.de2-7 and A431 cell tumors (of human epidermoid carcinoma origin; overexpress the EGFR and do not express the EGFR, respectively) (9). Nude mice bearing FaDu xenograft tumors (of human squamous cell carcinoma origin) were used as controls for this study. The animals (n = 3–5 animals/time point) were injected with the respectively labeled chAb through the tail vein and euthanized at predetermined time points ranging from 4 h to 312 h post-injection (p.i.) for the collection of tumors and all major organs (9). All data of radioactivity accumulated in the various organs were presented as percent of injected dose per gram tissue (% ID/g). In general, the uptake and retention of label by the tumors was significantly (P < 0.001) higher at all time points with [111In]-chAb806 (peaking at ~31.0% ID/g at 48 h) than with [125I]-ch806 (peaking at ~7.0% ID/g at 24 h). With [111In]-ch806, the accumulated radioactivity in the xenografts from 72 h to 168 h p.i. was observed to be more than six times higher than that with [125I]-ch806 in the same period (9). During the entire study period, the accumulation of radioactivity from [111In]-ch806 and [125I]-ch806 in all major organs was ~10.0% ID/g except for the kidneys and blood. The accumulation of radioactivity in these organs correlated to the level of tracer present in the blood pool of the animals. Lower uptake of the label and similar tracer biodistribution patterns were observed in all of the tissues from animals bearing the A431 or the FaDu xenograft tumors. No blocking studies using unlabeled ch806, mAb806, or another suitable anti-EGFR mAb were reported.

From serum samples obtained from the tracer-injected animals, the half-life times of [111In]-chAb806 and [125I]-ch806 were determined to be 3.42 ± 0.92 h and 2.85 ± 0.24 h, respectively (9). The total serum clearance for [111In]-chAb806 was reported to be 0.045 ± 0.005 ml/h; total serum clearance for [125I]-ch806 was 0.063 ± 0.0003 ml/h.

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

No references are currently available.

Human Studies

[PubMed]

Scott et al. investigated the tumor targeting, biodistribution, and pharmacokinetic properties of [111In]-chAb806 in an open-label, dose-escalating phase I study with eight patients having different cancerous lesions of the lungs (five patients), brain (one patient), lymph nodes (one patient), and supraglottis (one patient) (4). The objectives and patient inclusion or exclusion criteria for the study are described elsewhere (4). Each individual enrolled in the clinical trial received one of the four dose levels (5, 10, 20, or 40 mg/m2) of the unlabeled chAb.

To study the tumor uptake and biodistribution of the labeled chAb, whole-body gamma imaging was performed on the patients on different days, starting at day 0 for up to day 7, after an intravenous infusion of [111In]-chAb806. Blood clearance of the radioactivity from the patients was gradual at all dose levels, and the biological half-life of the labeled chAb was determined to be 948.6 ± 378.6 h. The tracer was observed to be cleared through the reticuloendothelial system during the 1-week period after the infusion. The accumulation of radioactivity in the targeted lesions, including in the brain, was apparent in all patients at the different dose levels of unlabeled ch806 (4).

For details of results obtained from the pharmacokinetic and dosimetry studies of [111In]-ch806, see Scott et al. (4). Briefly, the pharmacokinetic and dosimetry studies showed that no particular normal tissues could be saturated by ch806 and that there was no dose-dependent clearance of the labeled chAb from the organs or body of the patients. At the end of the 30-day study period, an assessment of the clinical response of patients at all dose levels of unlabeled ch806 indicated that five patients had stable disease and three patients had progressive disease. One patient at the 40 mg/m2-dose level showed some shrinkage of the lesion but was confirmed to have progressive disease by the RECIST criteria (response evaluation criteria in solid tumors) (14) at the end of the study.

From this study, the investigators concluded that ch806 had a very high selectivity to target the EGFR in tumors. Further evaluation of this chAb to treat cancers is ongoing (4).

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. 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. [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. 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.
Panousis C., Rayzman V.M., Johns T.G., Renner C., Liu Z., Cartwright G., Lee F.T., Wang D., Gan H., Cao D., Kypridis A., Smyth F.E., Brechbiel M.W., Burgess A.W., Old L.J., Scott A.M. Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR. Br J Cancer. 2005;92(6):1069–77. [PMC free article: PMC2361945] [PubMed: 15770208]
10.
Chopra, A., [125I]-Labeled monoclonal antibody 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: 20698072]
11.
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]
12.
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]
13.
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.
14.
Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., Dancey J., Arbuck S., Gwyther S., Mooney M., Rubinstein L., Shankar L., Dodd L., Kaplan R., Lacombe D., Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. [PubMed: 19097774]

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