Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 5/2008

Open Access 01-05-2008 | Original article

[18F]FBEM-ZHER2:342-Affibody molecule—a new molecular tracer for in vivo monitoring of HER2 expression by positron emission tomography

Authors: Gabriela Kramer-Marek, Dale O. Kiesewetter, Lucia Martiniova, Elaine Jagoda, Sang Bong Lee, Jacek Capala

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 5/2008

Login to get access

Abstract

Purpose

The expression of human epidermal growth factor receptor-2 (HER2) receptors in cancers is correlated with a poor prognosis. If assessed in vivo, it could be used for selection of appropriate therapy for individual patients and for monitoring of the tumor response to targeted therapies. We have radiolabeled a HER2-binding Affibody molecule with fluorine-18 for in vivo monitoring of the HER2 expression by positron emission tomography (PET).

Materials and methods

The HER2-binding ZHER2:342-Cys Affibody molecule was conjugated with N-2-(4-[18F]fluorobenzamido)ethyl]maleimide ([18F]FBEM). The in vitro binding of the resulting radioconjugate was characterized by receptor saturation and competition assays. For in vivo studies, the radioconjugate was injected into the tail vein of mice bearing subcutaneous HER2-positive or HER2-negative tumors. Some of the mice were pre-treated with non-labeled ZHER2:342−Cys. The animals were sacrificed at different times post-injection, and the radioactivity in selected tissues was measured. PET images were obtained using an animal PET scanner.

Results

In vitro experiments indicated specific, high-affinity binding to HER2. PET imaging revealed a high accumulation of the radioactivity in the tumor as early as 20 min after injection, with a plateau being reached after 60 min. These results were confirmed by biodistribution studies demonstrating that, as early as 1 h post-injection, the tumor to blood concentration ratio was 7.5 and increased to 27 at 4 h. Pre-saturation of the receptors with unlabeled ZHER2:342-Cys lowered the accumulation of radioactivity in HER2-positive tumors to the levels observed in HER2-negative ones.

Conclusion

Our results suggest that the [18F]FBEM-ZHER2:342 radioconjugate can be used to assess HER2 expression in vivo.
Literature
1.
Ross JS, Fletcher JA, Bloom KJ, et al. HER-2/neu testing in breast cancer. Am J Clin Pathol 2003;120:S53-71.CrossRefPubMed
2.
Cooke T, Reeves J, Lanigan A, Stanton P. HER2 as a prognostic and predictive marker for breast cancer. Ann Oncol 2001;12(Suppl 1):S23-8.CrossRefPubMed
3.
Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003;22:6570-8.CrossRefPubMed
4.
Meric-Bernstam F, Hung MC. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res 2006;12:6326-30.CrossRefPubMed
5.
6.
Dowsett M, Cooke T, Ellis I, et al. Assessment of HER2 status in breast cancer: why, when and how? Eur J Cancer 2000;36:170-6.CrossRefPubMed
7.
Zidan J, Dashkovsky I, Stayerman C, Basher W, Cozacov C, Hadary A. Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer 2005;93:552-6.CrossRefPubMedPubMedCentral
8.
Carlsson J, Nordgren H, Sjostrom J, et al. HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. Br J Cancer 2004;90:2344-8.PubMedPubMedCentral
9.
Schrama D, Reisfeld RA, Becker JC. Antibody targeted drugs as cancer therapeutics. Nat Rev Drug Discov 2006;5:147-59.CrossRefPubMed
10.
Rueckert S, Ruehl I, Kahlert S, Konecny G, Untch M. A monoclonal antibody as an effective therapeutic agent in breast cancer: trastuzumab. Expert opinion on biological therapy 2005;5:853-66.CrossRefPubMed
11.
Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol 2007;18:977-84.CrossRefPubMed
12.
Pegram MD, Konecny GE, O’Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004;96:739-49.CrossRefPubMed
13.
Milenic DE, Garmestani K, Brady ED, et al. Targeting of HER2 antigen for the treatment of disseminated peritoneal disease. Clin Cancer Res 2004;10:7834-41.CrossRefPubMed
14.
Kobayashi H, Shirakawa K, Kawamoto S, et al. Rapid accumulation and internalization of radiolabeled herceptin in an inflammatory breast cancer xenograft with vasculogenic mimicry predicted by the contrast-enhanced dynamic MRI with the macromolecular contrast agent G6-(1B4M-Gd)(256). Cancer Res 2002;62:860-6.PubMed
15.
16.
Smith-Jones PM, Solit DB, Akhurst T, Afroze F, Rosen N, Larson SM. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol 2004;22:701-6.CrossRefPubMed
17.
Robinson MK, Doss M, Shaller C, et al. Quantitative immuno-positron emission tomography imaging of HER2-positive tumor xenografts with an iodine-124 labeled anti-HER2 diabody. Cancer Res 2005;65:1471-8.CrossRefPubMed
18.
Cai W, Olafsen T, Zhang X, et al. PET imaging of colorectal cancer in xenograft-bearing mice by use of an 18F-labeled T84.66 anti-carcinoembryonic antigen diabody. J Nucl Med 2007;48:304-10.CrossRefPubMed
19.
Tolmachev V, Orlova A, Nilsson FY, Feldwisch J, Wennborg A, Abrahmsen L. Affibody molecules: potential for in vivo imaging of molecular targets for cancer therapy. Expert Opin Biol Ther 2007;7:555-68.CrossRefPubMed
20.
Engfeldt T, Orlova A, Tran T, et al. Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the (99m)Tc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence. Eur J Nucl Med Mol Imaging 2007;34:722-33.CrossRefPubMed
21.
Tolmachev V, Nilsson FY, Widstrom C, et al. 111In-benzyl-DTPA-ZHER2:342, an affibody-based conjugate for in vivo imaging of HER2 expression in malignant tumors. J Nucl Med 2006;47:846-53.PubMed
22.
Orlova A, Tolmachev V, Pehrson R, et al. Synthetic affibody molecules: a novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors. Cancer Res 2007;67:2178-86.CrossRefPubMed
23.
24.
Innis RB, Cunningham VJ, Delforge J, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007;27:1533-9.CrossRefPubMed
25.
Delforge J, Mesangeau D, Dolle F, et al. In vivo quantification and parametric images of the cardiac beta-adrenergic receptor density. J Nucl Med 2002;43:215-26.PubMed
26.
Cai W, Chen K, Mohamedali KA, et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med 2006;47:2048-56.PubMed
27.
Lang L, Jagoda E, Schmall B, et al. Development of fluorine-18-labeled 5-HT1A antagonists. J Med Chem 1999;42:1576-86.CrossRefPubMed
28.
Kiesewetter DO, Jagoda EM, Kao CH, et al. Fluoro-, bromo-, and iodopaclitaxel derivatives: synthesis and biological evaluation. Nucl Med Biol 2003;30:11-24.CrossRefPubMed
29.
Seidel J. Resolution uniformity and sensitivity of the NIH atlas small animal PET scanner: comparison to simulated LSO scanners without depth-of-interaction capability. IEEE Trans Nucl Sci 2003;50:1347-57.CrossRef
30.
Olafsen T, Kenanova VE, Sundaresan G, et al. Optimizing radiolabeled engineered anti-p185HER2 antibody fragments for in vivo imaging. Cancer Res 2005;65:5907-16.CrossRefPubMedPubMedCentral
31.
Orlova A, Magnusson M, Eriksson TL, et al. Tumor imaging using a picomolar affinity HER2 binding affibody molecule. Cancer Res 2006;66:4339-48.CrossRefPubMed
32.
Steffen AC, Orlova A, Wikman M, et al. Affibody-mediated tumour targeting of HER-2 expressing xenografts in mice. Eur J Nucl Med Mol Imaging 2006;33:631-8.CrossRefPubMed
33.
Mume E, Orlova A, Larsson B, et al. Evaluation of ((4-hydroxyphenyl)ethyl)maleimide for site-specific radiobromination of anti-HER2 affibody. Bioconjug Chem 2005;16:1547-55.CrossRefPubMed
34.
Tran T, Engfeldt T, Orlova A, et al. In vivo evaluation of cysteine-based chelators for attachment of 99mTc to tumor-targeting Affibody molecules. Bioconjug Chem 2007;18:549-48.CrossRefPubMed
35.
De Lorenzo C, Cozzolino R, Carpentieri A, Pucci P, Laccetti P, D’Alessio G. Biological properties of a human compact anti-ErbB2 antibody. Carcinogenesis 2005;26:1890-5.CrossRefPubMed
36.
Olafsen T, Tan GJ, Cheung CW, et al. Characterization of engineered anti-p185HER-2 (scFv-CH3)2 antibody fragments (minibodies) for tumor targeting. Protein Eng Des Sel 2004;17:315-23.CrossRefPubMed
37.
Cobleigh M, Frame D. Is trastuzumab every three weeks ready for prime time? J Clin Oncol 2003;21:3900-01.CrossRefPubMed
38.
Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 2005;46:1023-7.PubMed
Metadata
Title
[18F]FBEM-ZHER2:342-Affibody molecule—a new molecular tracer for in vivo monitoring of HER2 expression by positron emission tomography
Authors
Gabriela Kramer-Marek
Dale O. Kiesewetter
Lucia Martiniova
Elaine Jagoda
Sang Bong Lee
Jacek Capala
Publication date
01-05-2008
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 5/2008
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-007-0658-0

Other articles of this Issue 5/2008

European Journal of Nuclear Medicine and Molecular Imaging 5/2008 Go to the issue

Original article

The diagnostic value of 124I-PET in patients with differentiated thyroid cancer

Original article

Dynamic bioluminescence imaging for quantitative tumour burden assessment using IV or IP administration of d-luciferin: effect on intensity, time kinetics and repeatability of photon emission

Letter to the Editor

Comments on profession and gender statistics of the EANM membership database 2007

Original article

Absolute quantitation of myocardial blood flow with 201Tl and dynamic SPECT in canine: optimisation and validation of kinetic modelling

Original article

Myocardial imaging with 18F-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis

Original article

13N-ammonia myocardial perfusion imaging with a PET/CT scanner: impact on clinical decision making and cost-effectiveness