Feasibility of Affibody-Based Bioorthogonal Chemistry Mediated Radionuclide Pretargeting
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) PublishedText
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 reabsorption of Affibody molecules prevents the use of residualizing radiometals, including several 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-human epidermal growth factor receptor 2 (HER2) Affibody molecule Z(2395). DOTA-tetrazine was labeled with In-111 and Lu-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: I-125-Z(2395)-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45 +/- 16 pM. In-111-tetrazine bound specifically and selectively to Z(2325)-TCO pretreated cells. In vivo studies demonstrated HER2-specific I-125-Z(2395)-TCO accumulation in xenografts. TCO-mediated In-111-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z(2395)-TCO. At 1 h after injection, the tumor uptake of In-111-tetrazine and Lu-177-tetrazine was approximately 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of In-111 in comparison with direct targeting. Conclusion: The feasibility of Affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pre-targeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.
Place, publisher, year, edition, pages
SOC NUCLEAR MEDICINE , 2016. Vol. 57, no 3, 431-436 p.
affibody, tetrazine, trans-cyclooctene, radionuclide pretargeting, engineered scaffold protein, radionuclide therapy
Radiology, Nuclear Medicine and Medical Imaging
IdentifiersURN: urn:nbn:se:kth:diva-184961DOI: 10.2967/jnumed.115.162248ISI: 000371371800037PubMedID: 26659353ScopusID: 2-s2.0-84960118391OAI: oai:DiVA.org:kth-184961DiVA: diva2:917811
FunderSwedish Research Council, 521-2012-2228; 621-2013-5135
QC 201604072016-04-072016-04-072016-04-07Bibliographically approved