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Differences in sensitivity for 211At-(ZHER2:4)2 treatment between three HER-2 overexpressing cell lines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
2006 (English)In: Radiation Research, ISSN 0033-7587Article in journal (Refereed) Submitted
Place, publisher, year, edition, pages
URN: urn:nbn:se:uu:diva-94187OAI: oai:DiVA.org:uu-94187DiVA: diva2:167952
Available from: 2006-03-30 Created: 2006-03-30 Last updated: 2010-07-20Bibliographically approved
In thesis
1. Radiolabeled HER-2 Binding Affibody Molecules for Tumor Targeting: Preclinical Studies
Open this publication in new window or tab >>Radiolabeled HER-2 Binding Affibody Molecules for Tumor Targeting: Preclinical Studies
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Conventional cancer treatment based on radiotherapy or chemotherapy affects all dividing cells. By directing the therapy specifically to the tumor cells, normal cells can be spared. Tumor targeting molecules carrying a cytotoxic moiety is then an attractive approach.

In this thesis, an affibody molecule with high affinity for the protein HER-2, that is strongly associated with aggressive forms of breast cancer, was selected. After radiolabeling with 125I, the affibody molecule, in monovalent and bivalent form, was tested in vitro in HER-2 overexpressing tumor cells and in transplanted tumors in mice.

It was shown that the HER-2 targeting affibody molecule bound its target in a specific manner, both in vitro and in vivo. The small size of the affibody molecule resulted in fast clearance through the kidneys. An impressive tumor-to-blood ratio of 10 eight hours post injection was achieved and the tumors could easily be visualized in a gamma camera.

The biologic effects of the bivalent affibody molecule and a monovalent affinity maturated version was measured and compared with the effects of the monoclonal antibody trastuzumab. It was found that although all molecules target the same protein, the effects differed greatly.

The affibody molecule was also labeled with the alpha-emitting radionuclide 211At. Specific decrease in survival was seen in HER-2 overexpressing cells receiving the 211At labeled affibody molecule. The sensitivity to the treatment differed between cell lines, probably as a result of differences between the cell lines in internalization and nuclear size. The 211At labeled affibody molecules were also tested in vivo, where stability of the 211At label was a problem. To circumvent this problem, more stable conjugation chemistry was tested, as well as strategies to prevent uptake of released 211At by normal organs.

This thesis describes the selection and optimization of affibody molecules for medical use for the first time.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 127
Biomedicine, HER-2, affibody, 211At, tumor targeting, targeted radiotherapy, molecular imaging, Biomedicin
National Category
Microbiology in the medical area
urn:nbn:se:uu:diva-6678 (URN)91-554-6503-X (ISBN)
Public defence
2006-04-22, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskölds väg 20, UPPSALA, 09:15
Available from: 2006-03-30 Created: 2006-03-30Bibliographically approved

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