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| 3. |
- Garousi, Javad, et al.
(författare)
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Radionuclide therapy using ABD-fused ADAPT scaffold protein : Proof of Principle
- 2021
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Ingår i: Biomaterials. - : Elsevier. - 0142-9612 .- 1878-5905. ; 266
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Tidskriftsartikel (refereegranskat)abstract
- Molecular recognition in targeted therapeutics is typically based on immunoglobulins. Development of engineered scaffold proteins (ESPs) has provided additional opportunities for the development of targeted therapies. ESPs offer inexpensive production in prokaryotic hosts, high stability and convenient approaches to modify their biodistribution. In this study, we demonstrated successful modification of the biodistribution of an ESP known as ADAPT (Albumin-binding domain Derived Affinity ProTein). ADAPTs are selected from a library based on the scaffold of ABD (Albumin Binding Domain) of protein G. A particular ADAPT, the ADAPT6, binds to human epidermal growth factor receptor type 2 (HER2) with high affinity. Preclinical and early clinical studies have demonstrated that radiolabeled ADAPT6 can image HER2-expression in tumors with high contrast. However, its rapid glomerular filtration and high renal reabsorption have prevented its use in radionuclide therapy. To modify the biodistribution, ADAPT6 was genetically fused to an ABD. The non-covalent binding to the host's albumin resulted in a 14-fold reduction of renal uptake and appreciable increase of tumor uptake for the best variant, 177Lu-DOTA-ADAPT6-ABD035. Experimental therapy in mice bearing HER2-expressing xenografts demonstrated more than two-fold increase of median survival even after a single injection of 18 MBq 177Lu-DOTA-ADAPT6-ABD035. Thus, a fusion with ABD and optimization of the molecular design provides ADAPT derivatives with attractive targeting properties for radionuclide therapy.
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| 4. |
- Garousi, Javad, et al.
(författare)
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Radionuclide Therapy Using ABD-fused ADAPT Scaffold Protein: Proof of Principle
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The molecular recognition characteristics of targeted therapeutics is typically attributed to immunoglobulins. However, recent development of engineered scaffold proteins (ESPs) has provided additional opportunities for the improvement of these targeted therapies. ESPs offer inexpensive production in prokaryotic hosts and high molecular stability as well as convenient approaches to modify the biodistribution. In this study, we have demonstrated successful modification of the biodistribution of a particular ESP known as ADAPT (Albumin-binding domain Derived Affinity ProTein). These ADAPTs are generated through screening of combinatorial libraries based on the rigid scaffold of ABD (Albumin Binding Domain) of protein G. As one of these ADAPTs, ADAPT6 binds to human epidermal growth factor type 2 (HER2) with high affinity. Preclinical and early clinical studies have demonstrated that radiolabeled ADAPT6 can image HER2-expression in tumors with high contrast. However, its rapid glomerular filtration and high renal re-absorption have prevented its use in radionuclide therapy. To modify the biodistribution of ADAPT6 and allow for a therapeutic use, we present here an ADAPT6 genetically fused to ABD. The non-covalent binding of this fusion protein to the host albumin resulted in a 14-fold reduction of renal uptake and appreciable increase of tumor uptake for the best variant, 177Lu-DOTA-ADAPT6-ABD035. Experimental therapy in mice bearing HER2-expressing xenografts demonstrated more than two-fold increase of median survival even after a single injection of 18 MBq 177Lu-DOTA-ADAPT6-ABD035. The injections were not associated with any observable toxicity. Thus, a fusion with ABD and optimization of the molecular design provides ADAPT derivatives with attractive targeting properties for radionuclide therapy.
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- Gear, Jonathan I., et al.
(författare)
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EANM practical guidance on uncertainty analysis for molecular radiotherapy absorbed dose calculations
- 2018
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 45:13, s. 2456-2474
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Tidskriftsartikel (refereegranskat)abstract
- A framework is proposed for modelling the uncertainty in the measurement processes constituting the dosimetry chain that are involved in internal absorbed dose calculations. The starting point is the basic model for absorbed dose in a site of interest as the product of the cumulated activity and a dose factor. In turn, the cumulated activity is given by the area under a time–activity curve derived from a time sequence of activity values. Each activity value is obtained in terms of a count rate, a calibration factor and a recovery coefficient (a correction for partial volume effects). The method to determine the recovery coefficient and the dose factor, both of which are dependent on the size of the volume of interest (VOI), are described. Consideration is given to propagating estimates of the quantities concerned and their associated uncertainties through the dosimetry chain to obtain an estimate of mean absorbed dose in the VOI and its associated uncertainty. This approach is demonstrated in a clinical example.
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- Giammarile, Francesco, et al.
(författare)
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EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds
- 2011
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 38:7, s. 1393-1406
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Tidskriftsartikel (refereegranskat)abstract
- surgery (i.e. resection or liver transplantation), but only 10-20% of patients are candidates for this. In other patients, a variety of palliative treatments can be given, such as chemoembolization, radiofrequency ablation or recentlyPrimary liver cancers (i.e. hepatocellular carcinoma or cholangiocarcinoma) are worldwide some of the most frequent cancers, with rapidly fatal liver failure in a large majority of patients. Curative therapy consists of introduced tyrosine kinase inhibitors, e. g. sorafenib. Colorectal cancer is the second most lethal cancer in Europe and liver metastases are prevalent either at diagnosis or in follow-up. These patients are usually treated by a sequence of surgery, chemotherapy and antibody therapy [Okuda et al. (Cancer 56: 918-928, 1985); Schafer and Sorrell (Lancet 353: 1253-1257, 1999); Leong et al. (Arnold, London, 1999)]. Radioembolization is an innovative therapeutic approach defined as the injection of micron-sized embolic particles loaded with a radioisotope by use of percutaneous intra-arterial techniques. Advantages of the use of these intra-arterial radioactive compounds are the ability to deliver high doses of radiation to small target volumes, the relatively low toxicity profile, the possibility to treat the whole liver including microscopic disease and the feasibility of combination with other therapy modalities. Disadvantages are mainly due to radioprotection constraints mainly for I-131-labelled agents, logistics and the possibility of inadvertent delivery or shunting [Novell et al. (Br J Surg 78: 901-906, 1991)]. The Therapy, Oncology and Dosimetry Committees have worked together in order to revise the European Association of Nuclear Medicine (EANM) guidelines on the use of the radiopharmaceutical I-131-Lipiodol (Lipiocis (R), IBA, Brussels, Belgium) and include the newer medical devices with Y-90-microspheres. Y-90 is either bound to resin (SIR-Spheres (R), Sirtex Medical, Lane Cove, Australia) or embedded in a glass matrix (TheraSphere (R), MDS Nordion, Kanata, ON, Canada). Since Y-90-microspheres are not metabolized, they are not registered as unsealed sources. However, the microspheres are delivered in aqueous solution: radioactive contamination is a concern and microspheres should be handled, like other radiopharmaceuticals, as open sources. The purpose of this guideline is to assist the nuclear medicine physician in treating and managing patients undergoing such treatment. I-131-Lipiodol is a consolidated treatment option and the previous European Association of Nuclear Medicine (EANM) guidelines have been revised for its use. The newer Y-90-microsphere therapy is rapidly expanding throughout the nuclear medicine community. To date, published data on microspheres, particularly on dosimetry features and the characterization of the objective response, are still preliminary. Therefore, the aim of this part of the document is to set up a first basic procedure to guide nuclear medicine physicians in treatment with radiolabelled microspheres.
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- Liu, Yongsheng, et al.
(författare)
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Experimental Therapy of HER2-Expressing Xenografts Using the Second-Generation HER2-Targeting Affibody Molecule 188Re-ZHER2:41071
- 2022
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 14:5
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Tidskriftsartikel (refereegranskat)abstract
- HER2-targeted radionuclide therapy might be helpful for the treatment of breast, gastric, and ovarian cancers which have developed resistance to antibody and antibody-drug conjugate-based therapies despite preserved high HER2-expression. Affibody molecules are small targeting proteins based on a non-immunoglobulin scaffold. The goal of this study was to test in an animal model a hypothesis that the second-generation HER2-targeting Affibody molecule 188Re-ZHER2:41071 might be useful for treatment of HER2-expressing malignant tumors. ZHER2:41071 was efficiently labeled with a beta-emitting radionuclide rhenium-188 (188Re). 188Re-ZHER2:41071 demonstrated preserved specificity and high affinity (KD = 5 ± 3 pM) of binding to HER2-expressing cells. In vivo studies demonstrated rapid washout of 188Re from kidneys. The uptake in HER2-expressing SKOV-3 xenografts was HER2-specific and significantly exceeded the renal uptake 4 h after injection and later. The median survival of mice, which were treated by three injections of 16 MBq 188Re-ZHER2:41071 was 68 days, which was significantly longer (<0.0001 in the log-rank Mantel-Cox test) than survival of mice in the control groups treated with vehicle (29 days) or unlabeled ZHER2:41071 (27.5 days). In conclusion, the experimental radionuclide therapy using 188Re-ZHER2:41071 enabled enhancement of survival of mice with human tumors without toxicity to the kidneys, which is the critical organ.
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| 8. |
- Ljungberg, Michael, et al.
(författare)
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MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT applied for Dosimetry of Radiopharmaceutical Therapy.
- 2016
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 57:1, s. 151-162
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Tidskriftsartikel (refereegranskat)abstract
- Accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet No. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on 177-Lu (Lutetium) and its main application in radiopharmaceutical therapy.
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| 10. |
- Mitran, Bogdan, et al.
(författare)
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Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:12, s. 3347-3358
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Tidskriftsartikel (refereegranskat)abstract
- Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclidetherapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG2-RM26 for labeling with 177Lu and further determinedthe effect of treatment with 177Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in amurine model. The PEG2-RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-chelatorconjugates were labeled with 177Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC-3xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG2-RM26, (C) 177LuDOTAGA-PEG2-RM26, (D) trastuzumab or (E) 177Lu-DOTAGA-PEG2-RM26 in combination with trastuzumab. 177Lu-DOTAGA-PEG2-RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% ofradioligand remained when coinjected with phosphoramidon), high affinity to GRPR (KD = 0.4 0.2 nM), and favorablebiodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu-DOTAGAPEG2-RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorterthan for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantlyimproved survival. No treatment-related toxicity was observed. In conclusion, based on in vitro and in vivo characterization ofthe four 177Lu-labeled PEG2-RM26 analogs, we concluded that 177Lu-DOTAGA-PEG2-RM26 was the most promising analog forTRT. Radiotherapy using 177Lu-DOTAGA-PEG2-RM26 effectively inhibited tumor growth in vivo in a murine prostate cancermodel. Anti-HER2 therapy additionally improved survival.
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