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Comparative biodistribution of imaging agents for in vivo molecular profiling of disseminated prostate cancer in mice bearing prostate cancer xenografts: focus on (111)In- and (125)I-labeled anti-HER2 humanized monoclonal trastuzumab and ABY-025 Affibody
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, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
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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2011 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 38, no 8, 1093-1102 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Human epidermal growth factor receptor type 2 (HER2) overexpression supports proliferation of androgen-independent prostate cancer (PC). Radionuclide molecular imaging of HER2 expression in disseminated PC would aid in the selection of patients who are likely responders to HER2 targeting therapy. In this study, we evaluated whether ABY-025 Affibody molecule, a small (similar to 7-kDa) HER2-binding scaffold protein, produces superior tumor-to-nontumor ratios compared with those obtained through the use of radiolabeled humanized anti-HER2 antibody, trastuzumab. The influence of (111)In vs. (125)I radiolabel was evaluated for both tracers.

Methods: ABY-025 was labeled with (111)In using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid chelator, site-specifically coupled to the C-terminus via the maleimido derivative. Trastuzumab was labeled with (111)In using a CHX-A" diethylene triamine pentaacetic acid (DTPA) chelator. An indirect radioiodination with [(125)I]-N-succinimidyl-para-iodobenzoate was used for both targeting proteins. Biodistribution of all labeled targeting proteins was evaluated in mice bearing DU-145 PC xenografts.

Results: The use of residualizing (111)In-label facilitated better tumor uptake and better tumor-to-nontumor ratios for both targeting agents. [(111)In]-ABY-025 provided tumor uptake of 7.1 +/- 0.8% injected dose per gram of tissue (% ID/g) and tumor-to-blood ratio of 47 +/- 13 already at 6 h postinjection. The maximum tumor-to-nontumor ratios with [(111)In]-CHX-DTPA-trastuzumab were achieved at 72 h postinjection, whereas tumor uptake was 11 +/- 4% ID/g and tumor-to-blood ratio was 18 +/- 7. The biodistribution data were confirmed with gamma-camera imaging.

Conclusions: Radiolabeled ABY-025 Affibody molecule provides higher contrast in imaging of HER2-expressing PC xenografts than radiolabeled trastuzumab. Residualizing radiometal label for ABY-025 provides better contrast in imaging of HER2-expressing PC xenografts than nonresidualizing radiohalogen.

Place, publisher, year, edition, pages
2011. Vol. 38, no 8, 1093-1102 p.
Keyword [en]
HER2, Prostate cancer, Trastuzumab, Affibody molecule, Biodistribution, Radiolabeling
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-166866DOI: 10.1016/j.nucmedbio.2011.04.005ISI: 000298070400003PubMedID: 22137850OAI: oai:DiVA.org:uu-166866DiVA: diva2:478200
Available from: 2012-01-16 Created: 2012-01-16 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Preclinical Development of Imaging Agents for HER2 Expression in Prostate Cancer Using Radiolabeled Affibody Molecules
Open this publication in new window or tab >>Preclinical Development of Imaging Agents for HER2 Expression in Prostate Cancer Using Radiolabeled Affibody Molecules
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is focused on pre-clinical evaluation of in vivo detection of HER2-expression in prostate cancer (PCa) patients and on the possibility of using targeted molecular imaging to personalize treatment of disseminated PCa. The work is divided into three distinct parts: (1) the establishment of a preclinical model for further studies, (2) imaging of HER2 in a murine model of PCa and (3) exploration of new treatment regimes against PCa. The characterized cell line panel reflect the heterogeneity of PCa in a way that one cell line never could, and is crucial for a better understanding of different developmental stages during the progression toward androgen independence. The possibility of molecular detection of HER2 in PCa was determined in vitro using 111In-labeled CHX-A’’DTPA-trastuzumab and anti-HER2 ABY-025 affibody molecules. A novel real-time assay for radiolabeled tracer kinetics on living cells was evaluated, in an attempt to bring early developmental work a step closer to the target environment (imaging in living systems). The second part demonstrated the possibility of imaging PCa xenografts, despite the low expression levels, and that  ABY-025 is better adapted for this than the therapeutic anti-HER2 antibody trastuzumab. The study also demonstrated that a residualizing radiometal-label further improves imaging contrast. A comparative study of a HER2-binding affibody molecule N-terminally conjugated to DOTA, NOTA or NODAGA highlighted the influence of the chelator on biodistribution and emphasized the importance of taking into account potential metastatic sited during tracer development. The final study used the previously established in vitro model to explore the hypothesis of using molecular imaging of HER2 to identify PCa patients that may benefit from complemental treatment.

One conclusion from this thesis is that for imaging of PCa, molecular biological context and expression of the molecular target are equally important to consider. Another, that evaluation of response to treatment also need to consider the effect on the overall phenotypic profile, and consequently what this could mean for the efficacy of the treatment. The results of this thesis are in a larger perspective related to how the heterogeneity of tumors may affect the models used for diagnostics and monitoring of cancer in general.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 179
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science; Biomedical Radiation Science
Identifiers
urn:nbn:se:uu:diva-207256 (URN)978-91-554-8764-5 (ISBN)
Public defence
2013-11-08, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-10-17 Created: 2013-09-11 Last updated: 2014-01-23

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Malmberg, JennieSandström, MattiasWester, KennethTolmachev, VladimirOrlova, Anna

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