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Blocking EGFR in the liver improves the tumor-to-liver uptake ratio of radiolabeled EGF
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
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2010 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 31, no 2, 79-87 p.Article in journal (Refereed) Published
Abstract [en]

Overexpression of epidermal growth factor receptor (EGFR) in several types of malignant tumors correlates with disease progression. EGFR could, therefore, be an excellent candidate for targeted radionuclide diagnostics. However, the high natural expression of EGFR in the liver may be problematic. The aim of this study was to improve the tumor-to-liver ratio of radiolabeled epidermal growth factor (EGF) by blocking its uptake by the liver with a nonradiolabeled EGFR-targeting molecule in tumorbearing mice. Intraperitoneally injected nonradiolabeled EGF was first evaluated as a blocking agent, preadministered at various time intervals before intravenous injection of 125I-labeled EGF. The anti-EGFR Affibody molecule (ZEGFR:955)2 was then assessed as a blocking agent of 111In-labeled EGF in a dual isotope study (50, 100, and 200μg, preadministered 30 or 60 min before 111In-EGF). The 30-min preadministration of nonradiolabeled EGF significantly decreased 125I-EGF uptake in the liver, whereas uptake in the tumor remained unchanged. Furthermore, preadministration of only 50μg (ZEGFR:955)2 as a blocking agent 30 min before the 111In-EGF decreased the uptake of 111In-EGF by the liver and increased its uptake by the tumor, thereby increasing the tumor-to-liver ratio sixfold. We conclude that the Affibody molecule (ZEGFR:955)2 shows promise as a blocking agent that could enhance the outcome of radionuclide-based EGFRexpressing tumor diagnostics and imaging.

Place, publisher, year, edition, pages
Springer , 2010. Vol. 31, no 2, 79-87 p.
Keyword [en]
Affibody molecule, EGF, EGFR, HNSCC, Imaging, Tumor-to-liver ratio
National Category
Cancer and Oncology
Research subject
Biomedical Radiation Science
Identifiers
URN: urn:nbn:se:uu:diva-156520DOI: 10.1007/s13277-009-0011-2ISI: 000278160700002PubMedID: 20358420OAI: oai:DiVA.org:uu-156520DiVA: diva2:432050
Available from: 2011-07-28 Created: 2011-07-28 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Radioimmunodiagnosis of Head and Neck Squamous Cell Carcinomas: Preclinical Studies
Open this publication in new window or tab >>Radioimmunodiagnosis of Head and Neck Squamous Cell Carcinomas: Preclinical Studies
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite improvements in treatment, the prognosis for patients with advanced head and neck squamous cell carcinomas (HNSCC) has only improved to a minor degree. To raise the success rate and minimize morbidity further developments in diagnostics are highly desired. Radioimmunodiagnosis could offer a more specific and sensitive diagnostic method. Herein, we have evaluated different radioimmunoconjugates directed against CD44v6 and epidermal growth factor receptor (EGFR) for imaging of HNSCC. The studies were performed in a murine HNSCC xenograft model.

Initially, the 111In-labeled anti CD44v6 chimeric monoclonal antibody U36 (cMAb U36) was evaluated. The novel radioimmunoconjugate showed high and accumulating tumor uptake. Since small molecules might be advantageous for imaging, due mainly to their shorter circulation half-life in the bloodstream, we then investigated antibody fragments F(ab’)2 and Fab’ derived from cMAb U36. The highest tumor-to-blood ratio was achieved with the dimeric antibody fragment F(ab’)2, compared with both the intact anti-body and monomeric Fab’.

Furthermore, the possibility of improving EGFR-targeted imaging was explored by pre-blocking EGFR. The liver uptake of injected labeled human epidermal growth factor (hEGF) was significantly reduced when an excess of unlabeled hEGF was injected 30 minutes in advance. However, as hEGF stimulates cell proliferation it may be inadvisable to treat cancer patients with large amounts. Alternatively, pre-blocking with an anti-EGFR Affibody molecule (ZEGFR:955)2 demonstrated similar decrease in liver uptake as unlabeled hEGF. Finally, (ZEGFR:955)2 was compared with other Affibody molecules with higher affinity to EGFR, ZEGFR:1907 and (ZEGFR:1907)2, as pre-blocking agents. In addition, a novel hEGF radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF was used for EGFR targeting. The dimeric (ZEGFR:1907)2 showed greatest reduction in non-tumor uptake, and highest tumor-to-organ ratio in EGFR expressing organs, when injected in advance of the radioimmunoconjugate.

To summarize, the results presented here demonstrate how different radioimmunoconjugates as well as pre-blocking EGFR can improve the radioimmunodiagnosis of head and neck squamous cell carcinomas.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 682
Keyword
Head and neck squamos cell carcinoma, radioimmunotargeting, radioimmunodiagnosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156523 (URN)978-91-554-8111-7 (ISBN)
Public defence
2011-09-16, Skoogsalen, Ing 78-79, Akademiska sjukhuset, Uppsala, 13:15 (Swedish)
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Available from: 2011-08-25 Created: 2011-07-28 Last updated: 2011-09-08Bibliographically approved

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Sandström, KarlAnniko, MattiNestor, Marika

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