RT Journal Article
SR Electronic
T1 Feasibility of Affibody-Based Bioorthogonal Chemistry–Mediated Radionuclide Pretargeting
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 431
OP 436
DO 10.2967/jnumed.115.162248
VO 57
IS 3
A1 Altai, Mohamed
A1 Perols, Anna
A1 Tsourma, Maria
A1 Mitran, Bogdan
A1 Honarvar, Hadis
A1 Robillard, Marc
A1 Rossin, Raffaella
A1 ten Hoeve, Wolter
A1 Lubberink, Mark
A1 Orlova, Anna
A1 Karlström, Amelie Eriksson
A1 Tolmachev, Vladimir
YR 2016
UL http://jnm.snmjournals.org/content/57/3/431.abstract
AB 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 111In and 177Lu. 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 pretreated 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 after injection, the tumor uptake of 111In-tetrazine and177Lu-tetrazine was approximately 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.