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17AAG-induced internalisation of HER2- specific Affibody molecules
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
Univ Gothenburg, Sahlgrenska Acad, Dept Radiat Phys, SE-41345 Gothenburg, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Swedish Radiat Safety Author, SE-17116 Stockholm, Sweden.
2016 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 12, no 4, 2574-2580 p.Article in journal (Refereed) Published
Abstract [en]

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) is known to induce internalisation and degradation of the otherwise internalisation-resistant human epidermal growth factor receptor 2 (HER2) receptor. In the present study, 17-AAG was used to increase internalisation of the HER2-specific Affibody molecule ABY-025. The cellular redistribution of halogen-labelled At-211-ABY-025 and radiometal-labelled In-111-ABY-025 following treatment with 17-AAG was studied. 17-AAG treatment of SKOV-3 human ovarian carcinoma and SKBR-3 human breast carcinoma cells to some extent shifted the localisation of In-111-ABY-025 from the cell surface to intracellular compartments in the two cell lines. ABY-025 labelled with the high-linear energy transfer emitter At-211 was also internalised to a higher degree; however, due to its physiological properties, this nuclide was excreted faster. The results indicate that 17-AAG may be used to facilitate cell-specific intracellular localisation of a suitable cytotoxic or radioactive agent coupled to ABY-025 in HER2-overexpressing cells.

Place, publisher, year, edition, pages
2016. Vol. 12, no 4, 2574-2580 p.
Keyword [en]
HER2; 17-AAG; Affibody molecule; radiometal; radiohalogen
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-279516DOI: 10.3892/ol.2016.4990ISI: 000385579200050PubMedID: 27698830OAI: oai:DiVA.org:uu-279516DiVA: diva2:908287
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2017-11-30Bibliographically approved
In thesis
1. Cellular Studies of HER-family Specific Affibody Molecules
Open this publication in new window or tab >>Cellular Studies of HER-family Specific Affibody Molecules
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human epidermal growth-factor like receptor (HER) family of receptor tyrosine kinases are important targets for cancer therapy. The family consists of four members - EGFR, HER2, HER3 and HER4 - that normally transfer stimulatory signals from extracellular growth factors to the intracellular signalling network. Over-activation of these receptors leads to uncontrolled cell proliferation and is seen in several types of tumours. The aim of the studies reported in this thesis was to study the uptake and effects of affibody molecules against EGFR, HER2 and HER3 in cultured cells. Affibody molecules are affinity proteins originally derived from one of the domains of protein A, and their small size and robust structure make them suitable agents for tumour targeting and therapy.

Papers I and II of this thesis concern EGFR-specific affibody molecules, which were shown to be more similar to the antibody cetuximab than the natural ligand EGF in terms of cellular uptake, binding site and internalisation rate. In addition, fluorescence-based methods for the quantification of internalisation were evaluated.

In the studies reported in papers III and IV, HER2-specific affibody molecules were utilised as carriers of radionuclides. Paper III reports that different cell lines exhibit different radiosensitivities to 211At-labelled affibody molecules; radiosensitivity was found to correlate with cell geometry and the rate of internalisation. Paper IV discusses the use of 17-AAG, an agent that induces HER2 internalisation and degradation, to force the internalisation of 211At- and 111In-labelled affibody molecules.

Papers V and VI describe the selection and maturation of HER3-specific affibody molecules, which were found to compete with the receptor’s natural ligand, heregulin, for receptor binding. These affibody molecules were demonstrated to inhibit heregulin-induced HER3 activation and cell proliferation.

The studies summarised in this paper will hopefully contribute to a better understanding of these affibody molecules and bring them one step closer to being helpful tools in the diagnosis and treatment of cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 688
Keyword
EGFR, HER2, HER3, Affibody, internalisation, tumour targeting
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-156730 (URN)978-91-554-8119-3 (ISBN)
Public defence
2011-09-24, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 10:15 (Swedish)
Opponent
Supervisors
Available from: 2011-09-02 Created: 2011-08-08 Last updated: 2016-11-22Bibliographically approved

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