| 1. |
- Chouin, Nicolas, et al.
(författare)
-
Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique.
- 2013
-
Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 54:8, s. 1347-1353
-
Tidskriftsartikel (refereegranskat)abstract
- Targeted α-therapy (TAT) appears to be an ideal therapeutic technique for eliminating malignant circulating, minimal residual, or micrometastatic cells. These types of malignancies are typically infraclinical, complicating the evaluation of potential treatments. This study presents a method of ex vivo activity quantification with an α-camera device, allowing measurement of the activity taken up by tumor cells in biologic structures a few tens of microns. METHODS: We examined micrometastases from a murine model of ovarian carcinoma after injection of a radioimmunoconjugate labeled with (211)At for TAT. At different time points, biologic samples were excised and cryosectioned. The activity level and the number of tumor cells were determined by combined information from 2 adjacent sections: one exposed to the α-camera and the other stained with hematoxylin and eosin. The time-activity curves for tumor cell clusters, comprising fewer than 10 cells, were derived for 2 different injected activities (6 and 1 MBq). RESULTS: High uptake and good retention of the radioimmunoconjugate were observed at the surface of tumor cells. Dosimetric calculations based on the measured time-integrated activity indicated that for an injected activity of 1 MBq, isolated tumor cells received at least 12 Gy. In larger micrometastases (≤100 μm in diameter), the activity uptake per cell was lower, possibly because of hindered penetration of radiolabeled antibodies; however, the mean absorbed dose delivered to tumor cells was above 30 Gy, due to cross-fire irradiation. CONCLUSION: Using the α-camera, we developed a method of ex vivo activity quantification at the cellular scale, which was further applied to characterize the behavior of a radiolabeled antibody administered in vivo against ovarian carcinoma. This study demonstrated a reliable measurement of activity. This method of activity quantification, based on experimentally measured data, is expected to improve the relevance of small-scale dosimetry studies and thus to accelerate the optimization of TAT.
|
|
| 2. |
|
|
| 3. |
- Elgqvist, Jörgen, 1963, et al.
(författare)
-
The Potential and Hurdles of Targeted Alpha Therapy - Clinical Trials and Beyond.
- 2014
-
Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 3
-
Forskningsöversikt (refereegranskat)abstract
- This article presents a general discussion on what has been achieved so far and on the possible future developments of targeted alpha (α)-particle therapy (TAT). Clinical applications and potential benefits of TAT are addressed as well as the drawbacks, such as the limited availability of relevant radionuclides. Alpha-particles have a particular advantage in targeted therapy because of their high potency and specificity. These features are due to their densely ionizing track structure and short path length. The most important consequence, and the major difference compared with the more widely used β(-)-particle emitters, is that single targeted cancer cells can be killed by self-irradiation with α-particles. Several clinical trials on TAT have been reported, completed, or are on-going: four using (213)Bi, two with (211)At, two with (225)Ac, and one with (212)Pb/(212)Bi. Important and conceptual proof-of-principle of the therapeutic advantages of α-particle therapy has come from clinical studies with (223)Ra-dichloride therapy, showing clear benefits in castration-resistant prostate cancer.
|
|
| 4. |
- Frost, Sofia, 1981, et al.
(författare)
-
Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models.
- 2015
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
-
Tidskriftsartikel (refereegranskat)abstract
- Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.
|
|
| 5. |
- Frost, Sofia, 1981, et al.
(författare)
-
Comparison of (211)At-PRIT and (211)At-RIT of Ovarian Microtumors in a Nude Mouse Model.
- 2013
-
Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 28:2, s. 108-14
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Purpose: Pretargeted radioimmunotherapy (PRIT) against intraperitoneal (i.p.) ovarian microtumors using avidin-conjugated monoclonal antibody MX35 (avidin-MX35) and (211)At-labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PL(suc)) was compared with conventional radioimmunotherapy (RIT) using (211)At-labeled MX35 in a nude mouse model. Methods: Mice were inoculated i.p. with 1×10(7) NIH:OVCAR-3 cells. After 3 weeks, they received PRIT (1.0 or 1.5MBq), RIT (0.9MBq), or no treatment. Concurrently, 10 additional animals were sacrificed and examined to determine disease progression at the start of therapy. Treated animals were analyzed with regard to presence of tumors and ascites (tumor-free fraction; TFF), 8 weeks after therapy. Results: Tumor status at baseline was advanced: 70% of sacrificed animals exhibited ascites. The TFFs were 0.35 (PRIT 1.0MBq), 0.45 (PRIT 1.5MBq), and 0.45 (RIT). The 1.5-MBq PRIT group exhibited lower incidence of ascites and fewer tumors >1mm than RIT-treated animals. Conclusions: PRIT was as effective as RIT with regard to TFF; however, the size distribution of tumors and presence of ascites indicated that 1.5-MBq PRIT was more efficient. Despite advanced disease in many animals at the time of treatment, PRIT demonstrated good potential to treat disseminated ovarian cancer.
|
|
| 6. |
- Frost, Sofia, 1981, et al.
(författare)
-
In vitro evaluation of avidin antibody pretargeting using 211At-labeled and biotinylated poly-L-lysine as effector molecule.
- 2010
-
Ingår i: Cancer. - : Wiley. - 0008-543X. ; 116:4 Suppl, s. 1101-10
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pretargeting is an approach for enhancing the therapeutic index of radioimmunotherapy by separating the administrations of tumor-targeting substance and radiolabel. In this study, a pretargeting model system of avidin-conjugated monoclonal antibody trastuzumab and biotinylated, (211)At-labeled poly-L-lysine was constructed and analyzed in vitro. METHODS: Avidin activated by 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxysuccinimide ester sodium salt (sulfo-SMCC) and thiolated trastuzumab were incubated overnight at 4 degrees C. The monomeric fraction was extracted using size exclusion fast protein liquid chromatography (FPLC) and further purified on an iminobiotin affinity column. Poly-L-lysine was biotinylated with succinimidyl-6-(biotinamido)hexanoate (NHS-LC-biotin), followed by direct (211)At-labeling with N-succinimidyl-3-(trimethylstannyl)benzoate (m-MeATE), and succinylation with succinic anhydride. The avidin-trastuzumab conjugate was characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and FPLC, together with cell-binding and biotin-binding analyses. The labeled poly-L-lysine conjugate was assessed in terms of radiochemical purity and avidin binding. Furthermore, the full pretargeting system was evaluated in a tumor cell binding assay. RESULTS: The estimated size of the pretargeting molecule was 220 kDa, which corresponds to that of the expected avidin-trastuzumab monomer. Neither cell-binding ability (64%) nor biotin-binding ability (85%-95%) indicated any severe adverse effects from the chemical modifications. The radiochemical purity of the effector molecule was 92%-97%, and the avidin binding capacity was 91%-93%. The complete pretargeting assay resulted in a binding of 75.3 +/- 6.2% of added effector molecules to cells. CONCLUSIONS: The high binding of effector molecules to cells demonstrates a proof of concept for the synthesized molecules and pretargeting system, which will be further evaluated in vivo in future studies.
|
|
| 7. |
- Frost, Sofia, 1981, et al.
(författare)
-
In Vivo Distribution of Avidin-Conjugated MX35 and (211)At-Labeled, Biotinylated Poly-l-Lysine for Pretargeted Intraperitoneal ?-Radioimmunotherapy.
- 2011
-
Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 26:6
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Purpose: Avidin-coupled monoclonal antibody MX35 (avidin-MX35) and astatine-211?labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PL(suc)) were administered in mice to assess potential efficacy as an intraperitoneal (i.p.) therapy for microscopic tumors. We aimed to establish a timeline for pretargeted radioimmunotherapy using these substances, and estimate the maximum tolerable activity. Methods: (125)I-avidin-MX35 and (211)At-B-PL(suc) were administered i.p. in nude mice. Tissue distributions were studied at various time points and mean absorbed doses were estimated from organ uptake of (211)At-B-PL(suc). Studies of myelotoxicity were performed after administration of different activities of (211)At-B-PL(suc). Results: We observed low blood content of both (125)I-avidin-MX35 and (211)At-B-PL(suc), indicating fast clearance. After sodium perchlorate blocking, the highest (211)At uptake was found in kidneys. Red bone marrow (RBM) accumulated some (211)At activity. Mean absorbed doses of special interest were 2.3 Gy/MBq for kidneys, 0.4 Gy/MBq for blood, and 0.9 Gy/MBq for RBM. An absorbed dose of 0.9 Gy to the RBM was found to be safe. These values suggested that RBM would be the key dose-limiting organ in the proposed pretargeting scheme, and that blood data alone was not sufficient for predicting its absorbed dose. Conclusions: To attain a favorable distribution of activity and avoid major toxicities, at least 1.0?MBq of (211)At-B-PL(suc) can be administered 24 hours after an i.p. injection of avidin-MX35. These results provide a basis for future i.p. therapy studies in mice of microscopic ovarian cancer.
|
|
| 8. |
|
|
| 9. |
- Frost, Sofia, 1981, et al.
(författare)
-
α-Imaging Confirmed Efficient Targeting of CD45-Positive Cells After 211At-Radioimmunotherapy for Hematopoietic Cell Transplantation.
- 2015
-
Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 56:11, s. 1766-1773
-
Tidskriftsartikel (refereegranskat)abstract
- Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-211 ((211)At)-radioimmunotherapy, extending the analysis to include intra-organ (211)At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining.
|
|
| 10. |
- Green, Damian J, et al.
(författare)
-
Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model.
- 2015
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 125:13, s. 2111-9
-
Tidskriftsartikel (refereegranskat)abstract
- α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, (211)At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to (211)At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of (211)At-labeled anti-CD20 mAb ([(211)At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with (211)At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [(211)At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail.
|
|
| 11. |
|
|
| 12. |
- Lindegren, Sture, 1960, et al.
(författare)
-
Direct procedure for the production of 211At-labeled antibodies with an epsilon-lysyl-3-(trimethylstannyl)benzamide immunoconjugate.
- 2008
-
Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 49:9, s. 1537-45
-
Tidskriftsartikel (refereegranskat)abstract
- (211)At-labeled tumor-specific antibodies have long been considered for the treatment of disseminated cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. METHODS: The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. RESULTS: The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%-81%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0+/-0.06 (mean+/-SD), 0.44+/-0.06, and 0.29+/-0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. CONCLUSION: The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
|
|
| 13. |
- Lindegren, Sture, 1960, et al.
(författare)
-
Pretargeted Radioimmunotherapy with α-Particle Emitting Radionuclides.
- 2011
-
Ingår i: Current radiopharmaceuticals. - 1874-4729. ; 4:3, s. 248-60
-
Tidskriftsartikel (refereegranskat)abstract
- Alpha-particle emitting radionuclides are attractive for targeted cancer therapies due to their physicochemical properties. Their high linear energy transfer (LET) and short particle range makes them particularly toxic at a microscopic level, which is ideal for treating disseminated micrometastases. However, their cytotoxic properties also place special demands on the pharmacokinetics of the tumor specific carrier vector, where high tumor-to-normal-tissue ratios are a prerequisite. Tumor specific antibodies are perhaps the most common vector for targeted therapy, but due to pharmacokinetics considerations antibodies will generally not meet the standard for α-particle radioimmunotherapy. However, the tumor specificity of monoclonal antibodies may be used in pretargeting techniques, strategies used to increase the selectivity of the radioactivity. The basic concept of pretargeting relies on a separate administration of a modified antibody and a radioactive ligand. The modified antibody is first injected and allowed to localize on the tumor. Then, the radiolabeled ligand is injected, which is a small molecule that rapidly localizes the modified antibody on tumor cells while non-localized ligand rapidly clears from the circulation, preferably through renal filtration. Several pretargeting strategies have been developed, in particular the avidin-biotin system and bispecific antibodies. Approaches under evaluation are the use of complementary DNA, morpholinos, and the use of infinite antigen binding. Preclinical and clinical studies of pretargeting have shown that favorable distribution of the radioactivity can be achieved, which may increase dose to the tumor as compared with the dose from directly labeled antibodies, and most important decrease the dose to normal tissues. This survey describes different pretargeting strategies, and includes a review of pretargeting with α emitting radionuclides.
|
|
| 14. |
- Palm, Stig, 1964, et al.
(författare)
-
Therapeutic efficacy of astatine-211-labeled trastuzumab on radioresistant SKOV-3 tumors in nude mice.
- 2007
-
Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier BV. - 0360-3016. ; 69:2, s. 572-9
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To investigate the potential use of astatine-211 (211At)-labeled trastuzumab for the treatment of HER-2-positive, radioresistant ovarian carcinoma. METHODS AND MATERIALS: Four-week-old nude mice were inoculated intraperitoneally with 5 . 10(6) SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and 211At-labeled antibody was evaluated. RESULTS: Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between 211At activity (0-400 kBq on Day 7) and therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq 211At-trastuzumab, and different groups received 5, 50, or 500 microg trastuzumab on Day 7. The increase from 5 to 50 microg trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 microg trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq 211At-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24% less tumor weight than the corresponding controls. CONCLUSION: The combination of 500 microg trastuzumab and 400 kBq 211At-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model.
|
|
