Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Radioimmunodiagnosis of Head and Neck Squamous Cell Carcinomas: Preclinical Studies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
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 [en]
Head and neck squamos cell carcinoma, radioimmunotargeting, radioimmunodiagnosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-156523ISBN: 978-91-554-8111-7 (print)OAI: oai:DiVA.org:uu-156523DiVA: diva2:432054
Public defence
2011-09-16, Skoogsalen, Ing 78-79, Akademiska sjukhuset, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2011-08-25 Created: 2011-07-28 Last updated: 2011-09-08Bibliographically approved
List of papers
1. Targeting CD44v6 expressed in head and neck squamous cell carcinoma: preclinical characterization of an 111In-labeled monoclonal antibody
Open this publication in new window or tab >>Targeting CD44v6 expressed in head and neck squamous cell carcinoma: preclinical characterization of an 111In-labeled monoclonal antibody
Show others...
2008 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 29, no 3, 137-144 p.Article in journal (Refereed) Published
Abstract [en]

In patients with head and neck squamous cell carcinoma (HNSCC) radioimmunodiagnosis could offer a more specific and sensitive tumor diagnostic method.Our aim was to evaluate the labeling and biodistribution of the novel radioimmunoconjugate (111)In-cMAb U36. In this study cMAb U36, targeting CD44v6, and huA33, as a negative control, were labeled with indium-111, using the chelator CHXA''-DTPA. Immunoreactivity assays and binding studies were performed in vitro. Biodistribution and tumor imaging were conducted after intravenous injection of the radioimmunoconjugate to nude mice bearing HNSCC xenografts expressing CD44v6. The immunoreactive fraction was very high and the binding was CD44v6-specific. In vivo results demonstrated a promising biodistribution, with tumors clearly accumulating radioactivity with time. At 168 h postinjection (p.i.) the tumor uptake was 54.7 +/- 16.6% injected dose/g. The cMAb U36 had significantly (p < 0.05) higher uptake in tumors 72 h p.i. compared to huA33. We produced a novel radioimmunoconjugate targeting CD44v6 for possible use in the detection of HNSCC. The conjugate demonstrates no adverse effects from labeling and a favorable biodistribution.

Keyword
CD44v6, Indium-111, HNSCC, Imaging, Antibody
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-104611 (URN)10.1159/000143399 (DOI)000258412400001 ()18612218 (PubMedID)
Available from: 2009-05-29 Created: 2009-05-29 Last updated: 2017-12-13Bibliographically approved
2. A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio.
Open this publication in new window or tab >>A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio.
Show others...
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-156522 (URN)
Available from: 2011-07-28 Created: 2011-07-28 Last updated: 2011-08-26
3. Blocking EGFR in the liver improves the tumor-to-liver uptake ratio of radiolabeled EGF
Open this publication in new window or tab >>Blocking EGFR in the liver improves the tumor-to-liver uptake ratio of radiolabeled EGF
Show others...
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
Keyword
Affibody molecule, EGF, EGFR, HNSCC, Imaging, Tumor-to-liver ratio
National Category
Cancer and Oncology
Research subject
Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-156520 (URN)10.1007/s13277-009-0011-2 (DOI)000278160700002 ()20358420 (PubMedID)
Available from: 2011-07-28 Created: 2011-07-28 Last updated: 2017-12-08Bibliographically approved
4. Improved Tumor-to-Organ Ratios of a Novel 67Ga-Human Epidermal Growth Factor Radionuclide Conjugate with Preadministered Antiepidermal Growth Factor Receptor Affibody Molecules
Open this publication in new window or tab >>Improved Tumor-to-Organ Ratios of a Novel 67Ga-Human Epidermal Growth Factor Radionuclide Conjugate with Preadministered Antiepidermal Growth Factor Receptor Affibody Molecules
Show others...
2011 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 26, no 5, 593-601 p.Article in journal (Refereed) Published
Abstract [en]

The over-expression of the epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis. Targeted nuclear imaging of the EGFR expression could improve the diagnostics in patients with HNSCC. However, the high expression of EGFR in normal organs may conceal the tumor uptake and therefore limit the use.

In this study, we have assessed the biodistribution of a novel hEGF radionuclide conjugate after pre-injection with anti-EGFR Affibody molecules. hEGF was conjugated with p-SCN-Bn-NOTA and labeled with 67Ga. The biodistribution of [67Ga]Ga-NOTA-Bn-NCS-hEGF in nude mice with EGFR-expressing xenografts was evaluated either alone or 45 minutes after pre-injection with one of the anti-EGFR Affibody molecules ZEGFR:1907, (ZEGFR:1907)2 or (ZEGFR:955)2.

The novel radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF demonstrated high stability in vitro and specific binding to hEGF in vitro and in vivo. Pre-injection with anti-EGFR Affibody molecules improved the tumor-to-organ ratio in the liver, salivary glands and colon. Overall, the dimeric high affinity Affibody molecule (ZEGFR:1907)2 exhibited the best results.

These findings show that pre-blocking with an anti-EGFR Affibody molecule is a promising tool that could improve the outcome of radionuclide-based imaging of EGFR-expressing tumors.

Keyword
EGFR, Gallium, Affibody molecule, Head and neck cancer, Molecular imaging, Tumor-to-organ ratio
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156521 (URN)10.1089/cbr.2011.0981 (DOI)000296087300009 ()21834651 (PubMedID)
Available from: 2011-07-28 Created: 2011-07-28 Last updated: 2017-12-08Bibliographically approved

Open Access in DiVA

Fulltext(2099 kB)393 downloads
File information
File name FULLTEXT01.pdfFile size 2099 kBChecksum SHA-512
4427921ec9193e9ead32c8298c910e8ff8df5aabc62253e8f17b0ed8d2a75c665692ac4ec2926e9e75c0ce1ea5ee5cc441d4d067dcd07e7bad83a687e84f4b57
Type fulltextMimetype application/pdf
Buy this publication >>

By organisation
Otolaryngology and Head and Neck Surgery
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 393 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 655 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf