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Feasibility of Affibody-Based Bioorthogonal Chemistry-Mediated Radionuclide Pretargeting.

AbstractUNLABELLED:
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 β- and α-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 Z2395. DOTA-tetrazine was labeled with (111)In and (177)Lu. 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:
(125)I-Z2395-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45 ± 16 pM. (111)In-tetrazine bound specifically and selectively to Z2395-TCO pretreated cells. In vivo studies demonstrated HER2-specific (125)I-Z2395-TCO accumulation in xenografts. TCO-mediated (111)In-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z2395-TCO. At 1 h after injection, the tumor uptake of (111)In-tetrazine and (177)Lu-tetrazine was approximately 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of (111)In 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.
AuthorsMohamed Altai, Anna Perols, Maria Tsourma, Bogdan Mitran, Hadis Honarvar, Marc Robillard, Raffaella Rossin, Wolter ten Hoeve, Mark Lubberink, Anna Orlova, Amelie Eriksson Karlström, Vladimir Tolmachev
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 57 Issue 3 Pg. 431-6 (Mar 2016) ISSN: 1535-5667 [Electronic] United States
PMID26659353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
Chemical References
  • Radioisotopes
  • Radiopharmaceuticals
  • ERBB2 protein, human
  • Receptor, ErbB-2
Topics
  • Animals
  • Cell Line, Tumor
  • Drug Delivery Systems (methods)
  • Feasibility Studies
  • Female
  • Humans
  • Kidney Neoplasms (radiotherapy)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms (radiotherapy)
  • Radioisotopes (therapeutic use)
  • Radiopharmaceuticals (administration & dosage, therapeutic use)
  • Receptor, ErbB-2 (chemistry)
  • Tomography, Emission-Computed, Single-Photon
  • Xenograft Model Antitumor Assays

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