Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules: Preparation and Preclinical Evaluation

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Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules : Preparation and Preclinical Evaluation

Ahlgren, Sara, 1979- (author): Uppsala universitet,Institutionen för medicinska vetenskaper

Tolmachev, Vladimir, Associate Professor (thesis advisor): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap

Orlova, Anna, Associate Professor (thesis advisor): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap

Hedenstierna, Göran, Professor (thesis advisor): Uppsala universitet,Klinisk fysiologi

Feldwisch, Joachim, Dr (thesis advisor): Affibody AB, Stockholm, Sweden

Reilly, Raymond, Professor (opponent): Leslie Dan Faculty of Pharmacy, University of Toronto, Canada

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(creator_code:org_t)

ISBN 9789155477875
Uppsala : Acta Universitatis Upsaliensis, 2010
English 70 s.
Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 553

Related links:: https://uu.diva-port... (primary) (Raw object); show more...; https://urn.kb.se/re...; show less...

Doctoral thesis (other academic/artistic)

Abstract Subject headings

Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours. Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection. Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial. Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule. It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)

Keyword

molecular radionuclide imaging
Affibody molecules
HER2
cancer detection
radiolabelling
technetium
indium
cobalt
SPECT
PET
Oncology
Onkologi
Diagnostic radiology
Diagnostisk radiologi
Radiation biology
Strålningsbiologi
Biomedical Radiation Science
Biomedicinsk strålningsvetenskap
Medicinsk vetenskap
Medical Science

Publication and Content Type

vet (subject category)
dok (subject category)

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