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- Altai, Mohamed, et al.
(författare)
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188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors : preclinical assessment
- 2014
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:11, s. 8-1842
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.
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| 2. |
- Altai, Mohamed, et al.
(författare)
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Feasibility of Affibody-Based Bioorthogonal Chemistry Mediated Radionuclide Pretargeting
- 2016
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Ingår i: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:3, s. 431-436
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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