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Feasibility of affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. (Vladimir Tolmachev)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. (Vladimir Tolmachev)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. (Anna Orlova)
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2016 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 3, 431-436 p.Article in journal (Refereed) Published
Abstract [en]

Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal re-absorption of affibody molecules prevents the use of residualizing radiometals, including a number of promising low energy beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys.

Methods:

TCO was conjugated to the anti-HER2 affibody molecule Z2395. DOTA-tetrazine was labeled with indium-111 and lutetium-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts.

Results:

125I-Z2395-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45±16 pM. 111In-tetrazine bound specifically and selectively to Z2395-TCO pre-treated cells. In vivo studies demonstrated HER2-specific 125I-Z2395-TCO accumulation in xenografts. TCO-mediated 111In-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z2395-TCO. At 1 h post injection, the tumor uptake of 111In-tetrazine and 177Lu-tetrazine was ca. 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of 111In in comparison with direct targeting.

Conclusion:

The feasibility of affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pretargeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.

Place, publisher, year, edition, pages
2016. Vol. 57, no 3, 431-436 p.
National Category
Clinical Medicine Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-273543DOI: 10.2967/jnumed.115.162248ISI: 000371371800037PubMedID: 26659353OAI: oai:DiVA.org:uu-273543DiVA: diva2:894793
Funder
Swedish Cancer Society, 2012/354Swedish Research Council, 521-2012-2228Swedish Research Council, 621-2013-5135
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2017-11-30Bibliographically approved

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Altai, MohamedMitran, BogdanHonarvar, HadisLubberink, MarkOrlova, AnnaTolmachev, Vladimir

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