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Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
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2013 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no Suppl. 2, S219-S220 p.Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1±0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172±32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

Place, publisher, year, edition, pages
2013. Vol. 40, no Suppl. 2, S219-S220 p.
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-211592DOI: 10.1007/s00259-013-2535-3ISI: 000325853400417OAI: oai:DiVA.org:uu-211592DiVA: diva2:675388
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Lyon 19-23 oktober 2013.
Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Tumour Targeting using Radiolabelled Affibody Molecules: Influence of Labelling Chemistry
Open this publication in new window or tab >>Tumour Targeting using Radiolabelled Affibody Molecules: Influence of Labelling Chemistry
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Affibody molecules are promising candidates for targeted radionuclide-based imaging and therapy applications. Optimisation of targeting properties would permit the in vivo visualization of cancer-specific surface receptors with high contrast. In therapy, this may increase the ratio of radioactivity uptake between tumour and normal tissues.  This thesis work is based on 5 original research articles (papers I-V) and focuses on optimisation of targeting properties of anti-HER2 affibody molecules by optimising the labelling chemistry.

Paper I and II report the comparative evaluation of the anti-HER2 ZHER2:2395 affibody molecule site specifically labelled with 111In (suitable for SPECT imaging) and 68Ga (suitable for PET imaging) using the thiol reactive derivatives of DOTA and NODAGA as chelators. The incorporation of different macrocyclic chelators and labelling with different radionuclides modified the biodistribution properties of affibody molecules. This indicates that the labelling strategy may have a profound effect on the targeting properties of radiotracers and must be carefully optimized.

Paper III reports the study of the mechanism of renal reabsorption of anti-HER2 ZHER2:2395 affibody molecule. An unknown receptor (not HER2) is suspected to be responsible for the high reabsorption of ZHER2:2395 molecules in the kidneys.

Paper IV reports the optimization and development of in vivo targeting properties of 188Re-labelled anti-HER2 affibody molecules. By using an array of peptide based chelators, it was found that substitution of one amino acid by another or changing its position can have a dramatic effect on the biodistribution properties of 188Re-labelled affibody molecules. This permitted the selection of –GGGC chelator whichdemonstrated the lowest retention of radioactivity in kidneys compared to other variants and showed excellent tumour targeting properties.

Paper V reports the preclinical evaluation of 188Re-ZHER2:V2 as a potential candidate for targeted radionuclide therapy of HER2-expressing tumours. In vivo experiments in mice along with dosimetry assessment in both murine and human models revealed that future human radiotherapy studies using 188Re-ZHER2:V2 may be feasible.

It would be reasonable to believe that the results of optimisation of anti-HER2 affibody molecules summarized in this thesis can be of importance for the development of other scaffold protein-based targeting agents.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1013
Keyword
HER2, Affibody molecule, Radionuclide molecular maging, Targeted radionuclide therapy, Labeling chemistry
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-229090 (URN)978-91-554-8983-0 (ISBN)
Public defence
2014-09-20, Rudbecksalen, DagHammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-08-28 Created: 2014-07-29 Last updated: 2014-09-08

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Altai, MohamedHonarvar, HadisStrand, JoannaVarasteh, ZohrehOrlova, AnnaSandström, MattiasRosestedt, MariaTolmachev, Vladimir

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Biomedical Radiation SciencesPreclinical PET PlatformDepartment of Radiology, Oncology and Radiation Science
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European Journal of Nuclear Medicine and Molecular Imaging
Radiology, Nuclear Medicine and Medical Imaging

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