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Steffen, Ann-Charlott
Publications (3 of 3) Show all publications
Steffen, A.-C., Almqvist, Y., Chyan, M.-K., Lundqvist, H., Tolmachev, V., Wilbur, D. S. & Carlsson, J. (2007). Biodistribution of 211At labeled HER-2 binding affibody molecules in mice. Oncology Reports, 17(5), 1141-1147
Open this publication in new window or tab >>Biodistribution of 211At labeled HER-2 binding affibody molecules in mice
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2007 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 17, no 5, p. 1141-1147Article in journal (Refereed) Published
Abstract [en]

The size of affibody molecules makes them suitable as targeting agents for targeted radiotherapy with the alpha-emitter 211At, since their biokinetic properties match the short physical half-live of 211At. In this study, the potential for this approach was investigated in vivo. Two different HER-2 binding affibody molecules were radiolabeled with 211At using both the linker PAB (N-succinimidyl-para-astatobenzoate) and a decaborate-based linker, and the biodistribution in tumor-bearing nude mice was investigated. The influence of L-lysine and Na-thiocyanate on the 211At uptake in normal tissues was also studied. Based on the biokinetic information obtained, the absorbed dose was calculated for different organs. Compared with a previous biodistribution with 125I, the 211At biodistribution using the PAB linker showed higher uptake in lungs, stomach, thyroid and salivary glands, indicating release of free 211At. When the decaborate-based linker was used, the uptake in those organs was decreased, but instead, high uptake in kidneys and liver was found. The uptake, when using the PAB linker, could be significantly reduced in some organs by the use of L-lysine and/or Na-thiocyanate. In conclusion, affibody molecules have suitable blood-kinetics for targeted radionuclide therapy with 211At. However, the labeling chemistry affects the distribution in normal organs to a high degree and needs to be improved to allow clinical use.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-104494 (URN)000245855800025 ()17390057 (PubMedID)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
Nordberg, E., Steffen, A.-C., Persson, M., Sundberg, Å. L., Carlsson, J. & Glimelius, B. (2005). Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor.. European Journal of Nuclear Medicine and Molecular Imaging, 32(7), 771-7
Open this publication in new window or tab >>Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor.
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2005 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 32, no 7, p. 771-7Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The purpose of this study was to analyse whether non-radiolabelled epidermal growth factor (EGF) can modify the cellular uptake of 125I when delivered as [125I]trastuzumab. 125I was used as a marker for the diagnostically and therapeutically more interesting isotopes 123I (SPECT), 124I (PET) and 131I (therapy). METHODS: The cell-associated radioactivity was measured in squamous carcinoma A431 cells following addition of [125I]trastuzumab. Different concentrations of [125I]trastuzumab and unlabelled EGF were used, and the total, membrane-bound and internalised radioactivity was measured. We also analysed how EGF and trastuzumab affected the cell growth. RESULTS: It was generally found that the cellular 125I uptake was decreased by the addition of EGF when [125I]trastuzumab was added for short incubation times. However, if the incubation times were longer, EGF increased the 125I uptake. This shift came earlier when higher [125I]trastuzumab concentrations were applied. The addition of EGF also influenced cell proliferation, and concentrations above 10 ng/ml reduced cell growth by approximately 20% after 24 h of incubation. CONCLUSION: By adding unlabelled EGF, it was possible to modify the cellular uptake of [125I]trastuzumab. This points towards new approaches for the modification of radionuclide uptake in EGFR- and HER2-positive tumours.

Keywords
Antibodies; Monoclonal/*administration & dosage/chemistry, Antineoplastic Agents/*administration & dosage, Cell Line; Tumor, Cell Membrane/metabolism, Cell Proliferation, Dose-Response Relationship; Drug, Epidermal Growth Factor/*administration & dosage/metabolism, Humans, Iodine Radioisotopes/*pharmacokinetics, Ligands, Positron-Emission Tomography, Receptor; Epidermal Growth Factor/metabolism, Receptor; erbB-2/metabolism, Time Factors, Tomography; Emission-Computed; Single-Photon, Tumor Markers; Biological
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-80492 (URN)10.1007/s00259-005-1761-8 (DOI)15765233 (PubMedID)
Available from: 2007-02-12 Created: 2007-02-12 Last updated: 2017-12-14Bibliographically approved
Steffen, A.-C., Wikman, M., Tolmachev, V., Adams, G. P., Nilsson, F. Y., Ståhl, S. & Carlsson, J. (2005). In vitro characterization of a bivalent anti-HER-2 affibody with potential for radionuclide-based diagnostics. Cancer Biotherapy and Radiopharmaceuticals, 20(3), 239-248
Open this publication in new window or tab >>In vitro characterization of a bivalent anti-HER-2 affibody with potential for radionuclide-based diagnostics
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2005 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 20, no 3, p. 239-248Article in journal (Refereed) Published
Abstract [en]

The 185 kDa transmembrane glycoprotein human epidermal growth factor receptor 2 (HER-2) (p185/neu, c-ErbB-2) is overexpressed in breast and ovarian cancers. Overexpression in breast cancer correlates with poor patient prognosis, and visualization of HER-2 expression might provide valuable diagnostic information influencing patient management. We have previously described the generation of a new type of affinity ligand, a 58-amino-acid affibody (Z(HER2:4)) with specific binding to HER-2. In order to benefit from avidity effects, we have created a bivalent form of the affibody ligand, (Z(HER2:4))2. The monovalent and bivalent ligands were compared in various assays. The new bivalent affibody has a molecular weight of 15.6 kDa and an apparent affinity (K(D)) against HER-2 of 3 nM. After radioiodination, using the linker molecule N-succinimidyl p-(trimethylstannyl) benzoate (SPMB), in vitro binding assays showed specific binding to HER-2 overexpressing cells. Internalization of 125I was shown after delivery with both the monovalent and the bivalent affibody. The cellular retention of 125I was longer after delivery with the bivalent affibody when compared to delivery with the monovalent affibody. With approximately the same affinity as the monoclonal antibody trastuzumab (Herceptin) but only one tenth of the size, this new bivalent molecule is a promising candidate for radionuclide-based detection of HER-2 expression in tumors. 125I was used in this study as a surrogate marker for the diagnostically relevant radioisotopes 123I for single photon emission computed tomography (SPECT)/gamma-camera imaging and 124I for positron emission tomography (PET).

Keywords
Amino Acid Sequence, Antibodies; Bispecific/*immunology, Biological Transport, Cell Line; Tumor, Humans, Iodine Radioisotopes, Kinetics, Ligands, Microscopy; Confocal, Molecular Sequence Data, Molecular Weight, Neoplasms/immunology/*metabolism/*radionuclide imaging, Receptor; erbB-2/chemistry/immunology/*metabolism, Research Support; Non-U.S. Gov't, Sequence Alignment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-80490 (URN)15989469 (PubMedID)
Available from: 2007-02-12 Created: 2007-02-12 Last updated: 2017-12-14Bibliographically approved
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