| 1. |
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| 2. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Intraperitoneal alpha-Emitting Radioimmunotherapy with At-211 in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations
- 2019
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 60:8, s. 1073-1079
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Tidskriftsartikel (refereegranskat)abstract
- Eliminating microscopic residual disease with alpha-particle radiation is theoretically appealing. After extensive preclinical work with alpha-particle-emitting At-211, we performed a phase I trial with intraperitoneal alpha-particle therapy in epithelial ovarian cancer using At-211 conjugated to MX35, the antigen-binding fragments-F(ab')(2)-of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of At-211-MX35 F(ab')(2). Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the alpha-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion: No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity.
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| 3. |
- Albertsson, Per, 1964, et al.
(författare)
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Astatine-211 based radionuclide therapy: Current clinical trial landscape
- 2023
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Astatine-211 (At-211) has physical properties that make it one of the top candidates for use as a radiation source for alpha particle-based radionuclide therapy, also referred to as targeted alpha therapy (TAT). Here, we summarize the main results of the completed clinical trials, further describe ongoing trials, and discuss future prospects.
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| 4. |
- Aneheim, Emma, 1982, et al.
(författare)
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Automated astatination of biomolecules--a stepping stone towards multicenter clinical trials.
- 2015
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- To facilitate multicentre clinical studies on targeted alpha therapy, it is necessary to develop an automated, on-site procedure for conjugating rare, short-lived, alpha-emitting radionuclides to biomolecules. Astatine-211 is one of the few alpha-emitting nuclides with appropriate chemical and physical properties for use in targeted therapies for cancer. Due to the very short range of the emitted α-particles, this therapy is particularly suited to treating occult, disseminated cancers. Astatine is not intrinsically tumour-specific; therefore, it requires an appropriate tumour-specific targeting vector, which can guide the radiation to the cancer cells. Consequently, an appropriate method is required for coupling the nuclide to the vector. To increase the availability of astatine-211 radiopharmaceuticals for targeted alpha therapy, their production should be automated. Here, we present a method that combines dry distillation of astatine-211 and a synthesis module for producing radiopharmaceuticals into a process platform. This platform will standardize production of astatinated radiopharmaceuticals, and hence, it will facilitate large clinical studies focused on this promising, but chemically challenging, alpha-emitting radionuclide. In this work, we describe the process platform, and we demonstrate the production of both astaine-211, for preclinical use, and astatine-211 labelled antibodies.
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| 5. |
- Aneheim, Emma, 1982, et al.
(författare)
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Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates
- 2016
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1520-4812 .- 1043-1802. ; 27:3, s. 688-97
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Tidskriftsartikel (refereegranskat)abstract
- Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 μm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies.
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| 6. |
- Bäck, Tom, 1964, et al.
(författare)
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Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated alpha-Radioimmunotherapy with At-211-MX35-F(ab')(2): Influence of Absorbed Tumor Dose and Effect on Long-Term Survival
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:4, s. 598-604
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Tidskriftsartikel (refereegranskat)abstract
- The goal of this study was to investigate whether targeted a-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of alpha-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm(3), NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with At-211-MX35-F (ab')(2) at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from bio-distribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated alpha-radioimmunotherapy with 211At-MX35-F(ab')(2) was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after a-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted alpha-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.
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| 7. |
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| 8. |
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| 9. |
- Bäck, Tom, 1964, et al.
(författare)
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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors
- 2020
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Ingår i: Ejnmmi Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic alpha-radioimmunotherapy (alpha-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the alpha-particle emitter At-211-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. Methods PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of alpha-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (100-200 mu m; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. Results Tumor targeting of At-211-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 +/- 0.003 mm(3) versus 3.79 +/- 1.24 mm(3) (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). Conclusion Evaluating fractionated alpha-RIT with At-211-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of At-211-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of alpha-RIT or by altering the size of the targeting vector.
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| 10. |
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| 11. |
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| 12. |
- Chouin, Nicolas, et al.
(författare)
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Ex Vivo Activity Quantification in Micrometastases at the Cellular Scale Using the α-Camera Technique.
- 2013
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 54:8, s. 1347-1353
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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.
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| 13. |
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| 14. |
- Dekempeneer, Y., et al.
(författare)
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Labeling of Anti-HER2 Nanobodies with Astatine-211: Optimization and the Effect of Different Coupling Reagents on Their in Vivo Behavior
- 2019
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 16:8, s. 3524-3533
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Tidskriftsartikel (refereegranskat)abstract
- The use of nanobodies (Nbs) as vehicles in targeted alpha therapy (TAT) has gained great interest because of their excellent properties. They combine high in vivo affinity and specificity of binding with fast kinetics. This research investigates a novel targeted therapy that combines the alpha-particle emitter astatine-211 (At-211) and the anti-HER2 Nb 2Rs15d to selectively target HER2+ cancer cells. Two distinctive radiochemical methodologies are investigated using three different coupling reagents. The first method uses the coupling reagents, N-succinimidyl 4-(1,2-bis-tert-butoxycarbonyl)guanidinomethyl-3-(trimethylstannyl)benzo ate (Boc(2)-SGMTB) and N-succinimidyl-3-(trimethylstannyl)-benzoate (m-MeATE), which are both directed to amino groups on the Nb, resulting in random conjugation. The second method aims at obtaining a homogeneous tracer population, via a site-specific conjugation of the N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide (MSB) reagent onto the carboxyl-terminal cysteine of the Nb. The resulting radioconjugates are evaluated in vitro and in vivo. 2Rs15d is labeled with At-211 using Boc(2)-SGMTB, m-MeATE, and MSB. After astatination and purification, the binding specificity of the radioconjugates is validated on HER2+ cells, followed by an in vivo biodistribution assessment in SKOV-3 xenografted mice. alpha-camera imaging is performed to determine uptake and activity distribution in kidneys/tumors. 2Rs15d astatination resulted in a high radiochemical purity >95% for all radioconjugates. The biodistribution studies of all radioconjugates revealed comparable tumor uptake (higher than 8% ID/g at 1 h). [At-211]SAGMB-2Rs15d showed minor uptake in normal tissues. Only in the kidneys, a higher uptake was measured after 1 h, but decreased rapidly after 3 h. Astatinated Nbs consisting of m-MeATE or MSB reagents revealed elevated uptake in lungs and stomach, indicating the presence of released At-211. alpha-Camera imaging of tumors revealed a homogeneous activity distribution. The radioactivity in the kidneys was initially concentrated in the renal cortex, while after 3 h most radioactivity was measured in the medulla, confirming the fast washout into urine. Changing the reagents for Nb astatination resulted in different in vivo biodistribution profiles, while keeping the targeting moiety identical. Boc(2)-SGMTB is the preferred reagent for Nb astatination because of its high tumor uptake, its low background signals, and its fast renal excretion. We envision [At-211]SAGMB-2Rs15d to be a promising therapeutic agent for TAT and aim toward efficacy evaluation.
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| 15. |
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| 16. |
- Gustafsson-Lutz, Anna, 1981, et al.
(författare)
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Therapeutic efficacy of alpha-radioimmunotherapy with different activity levels of the Bi-213-labeled monoclonal antibody MX35 in an ovarian cancer model
- 2017
-
Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to compare the therapeutic efficacy of two different activity levels of the Bi-213-labeled monoclonal antibody MX35 in an ovarian cancer model. Sixty female BALB/c (nu/nu) mice were inoculated intraperitoneally with human ovarian cancer cells (OVCAR-3). Two weeks later, 40 mice were injected intraperitoneal (i.p.) with 1 ml of Bi-213-MX35, 3 MBq/mL (n = 20), or 9 MBq/mL (n = 20). An additional 20 mice received unlabeled MX35. Incidence of tumors and ascites was investigated 8 weeks after therapy. Body weight and white blood cell counts were monitored after treatment for possible signs of toxicity. Results: The tumor-free fraction of the animals treated with 3 MBq/mL of Bi-213-MX35 was 0.55, whereas that of animals treated with 9 MBq/mL of Bi-213-MX35 was 0.78. The control group treated with unlabeled MX35 had a tumor-free fraction of 0.15. No significant reduction in white blood cell counts or weight loss was observed. Conclusions: Tumor growth after i.p. treatment with Bi-213-MX35 was significantly reduced compared to treatment with unlabeled MX35. Treatment with 9 MBq/mL of Bi-213-MX35 resulted in higher tumor-free fraction compared with 3 MBq/mL of Bi-213-MX35, but this difference was not statistically significant. No signs of toxicity were observed in the treated animals.
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| 17. |
- Hultborn, Ragnar, 1946, et al.
(författare)
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Radiosensitivity: Gender and Order of Administration of G-CSF, An Experimental Study in Mice
- 2019
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Ingår i: Radiation Research. - : Radiation Research Society. - 0033-7587. ; 191:4, s. 335-341
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the potential influence of stimulating bone marrow before cell-cycle-dependent irradiation, we sought to determine overall survival in mice receiving total-body irradiation (TBI) when administered granulocyte stimulating factor (G-CSF) at different time points. Gender differences were also studied. C57/BL/6J mice, aged 9-14 weeks, received 8 Gy TBI in a perspex cage using a linear accelerator. In each of five different experiments, three groups were studied: 1. one control group receiving TBI only; 2. one group treated with filgrastim [500 mu g/kg subcutaneously/intraperitoneally (s.c./i.p.)] the day before TBI, followed by daily filgrastim injections postirradiation (1-5 days); and 3. one group treated with daily filgrastim injections only post-TBI (1-5 days). Each experimental group included male and female mice. Survival of the mice was monitored daily, and mice were euthanized when their condition deteriorated. A total of 293 mice were monitored for at least 37 days post-TBI. Control mice that received 8 Gy TBI showed a significant gender difference, with a median survival of 22 days in females and 17 days in males. Addition of G-CSF, irrespective of pre- or postirradiation, significantly improved survival, but in males the improvement was significantly better when G-CSF was not given before TBI. Improved survival in females was independent of the order of administration of G-CSF. Multiple filgrastim injections were more effective than a single injection, and s.c. administration was not better than i.p. In conclusion, these findings indicate that male mice are more sensitive to TBI than females. Filgrastim improved survival in both genders irrespective of whether given pre- orpostirradiation, but in males the improvement was significantly less if an injection was given before irradiation. These results suggest that, to prevent toxicity most effectively, G-CSF should not be given before cytotoxic therapy. While a completely different experimental model was used here, these results may also be extrapolated to indicate that endocrine cell-cycle suppression therapy should not be given before or during cytotoxic therapy of hormone-dependent tumors (e.g., breast and prostate cancer), thus a reduction in the efficacy of cell-cycle-dependent therapy can be prevented. (C) 2019 by Radiation Research Society
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| 18. |
- Leidermark, Erik, 1981, et al.
(författare)
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Estimating the risk for secondary cancer following targeted alpha therapy with astatine-211 intraperitoneal radioimmunotherapy.
- 2022
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 64:1, s. 165-172
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Tidskriftsartikel (refereegranskat)abstract
- Intraperitoneal 211At-based targeted alpha therapy (TAT) may hold most promise as an adjuvant therapy following surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought whether to justify the treatment. Methods: Baseline data for risk estimates of alpha-particle irradiation were collected from published studies on excess cancer induction and mortality for subjects exposed to either 224Ra treatments or Thorotrast contrast agent (25% ThO2 colloid, containing 232Th). Organ dosimetry for 224Ra and Thorotrast irradiation were taken from the literature. These organ-specific risks were then applied for our previously reported dosimetry for intraperitoneal (i.p.) 211At-TAT patients. Results: Risk could be estimated for 10 different organ or organ groups. The calculated excess relative risk per Gray (ERR/Gy) could be sorted into two groups. In the lower ERR/Gy group, up to approx. 5, were: Trachea, bronchus and lung 0.52 (CI 95% 0.21-0.82), Stomach 1.4 (CI 95% -5.0-7.9), Lymphoid and hematopoietic system 2.17 (CI 95% 1.7-2.7), Bone and articular cartilage 2.6 (CI 95% 2.0-3.3), Breast 3.45 (CI 95% -10-17) and Colon 4.5 (CI 95% -3.5-13). In the higher ERR/Gy group, ranging from approx. 10 to 15 were: Urinary bladder 10.1 (CI 95% 1.4-23), Liver 14.2 (CI 95% 13-16), Kidney 14.9 (CI 95% 3.9-26) and Lip, oral cavity and pharynx 15.20 (CI 95% 2.73-27.63). Applying a typical candidate patient (female, age 65 years) and correcting for reference population mortality rate, a total estimated excess mortality of an i.p. 211At-mAb treatment amounted to 1.13 per 100 treated. More than half of this excess originated from urinary bladder and kidney, 0.29 and 0.34 respectively. Depending on various adjustments in calculation and assumptions on competing risks excess mortality could range from 0.11 - 1.84 per 100 treated. Conclusion: Published epidemiological data on life-long detriment following alpha-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer following 211At-based i.p. TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from 211At-mAb based i.p. TAT.
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| 19. |
- Lindegren, Sture, 1960, et al.
(författare)
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Astatine-211: The Chemistry Infrastructure.
- 2019
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Ingår i: Journal of Medical Imaging and Radiation Sciences. - 1939-8654.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 20. |
- Lindegren, Sture, 1960, et al.
(författare)
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Binding Affinity, Specificity and Comparative Biodistribution of the Parental Murine Monoclonal Antibody MX35 (Anti-NaPi2b) and Its Humanized Version Rebmab200.
- 2015
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovarian cancer with 211At-Rebmab200. Here, the biodistribution of 211At-Rebmab200 was evaluated, as was the utility of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its in-vitro capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were similar between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and in-vivo tumor binding. We also demonstrated that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics.
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| 21. |
- Lindegren, Sture, 1960, et al.
(författare)
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Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure
- 2020
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 35:6, s. 425-436
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Tidskriftsartikel (refereegranskat)abstract
- Despite the consensus around the clinical potential of the alpha-emitting radionuclide astatine-211 (At-211), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing(211)At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of(211)At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with(211)At depend on custom systems for recovering(211)At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of(211)At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between(211)At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing(211)At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with(211)At.
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| 22. |
- Palm, Stig, 1964, et al.
(författare)
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Biokinetic modeling and dosimetry for optimizing intraperitoneal radioimmunotherapy of ovarian cancer microtumors.
- 2016
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 57:4, s. 594-600
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Tidskriftsartikel (refereegranskat)abstract
- A biokinetic model was constructed to evaluate and optimize various intraperitoneal (i.p.) radioimmunotherapies for micrometastatic tumors. The model was used to calculate the absorbed dose to both anticipated microtumors and critical healthy organs and demonstrates how i.p. targeted radiotherapy can be optimized to achieve a maximum ratio between them.
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| 23. |
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| 24. |
- Palm, Stig, 1964, et al.
(författare)
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Evaluation of therapeutic efficacy of 211At-labeled farletuzumab in an intraperitoneal mouse model of disseminated ovarian cancer
- 2021
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Ingår i: Translational Oncology. - : Elsevier BV. - 1936-5233. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i.p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of 211At-farletuzumab in in-vitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170 kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200 MBq/L). Methods: For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either 211At-farletuzumab (n = 16); or with a combination of 125I-farletuzumab and 211At-MX35 (n = 12). At 1, 3, 10 and 22 h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2 × 106 NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by 211At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either 211At-labeled rituximab which is unspecific for OVCAR-3 (group B; n = 22, 170 kBq/mL), non-radiolabeled farletuzumab (group C; n = 11) or PBS only (group D; n = 8). Results: The biodistribution of 211At-farletuzumab was similar to that with 125I as radiolabel, and also to that of 211At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific 211At-rituximab 14%). TFF following treatment with 211At-farletuzumab was 91%. Conclusion: The current investigation of intraperitoneal therapy with 211At-farletuzumab, delivered at clinically relevant 211At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing. © 2020 The Authors
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| 25. |
- Palm, Stig, 1964, et al.
(författare)
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Model of Intraperitoneal Targeted α-Particle Therapy Shows That Posttherapy Cold-Antibody Boost Enhances Microtumor Radiation Dose and Treatable Tumor Sizes.
- 2018
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 59:4, s. 646-651
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Tidskriftsartikel (refereegranskat)abstract
- Intraperitoneally administered radiolabeled monoclonal antibodies (mAbs) have been tested in several clinical trials, often with promising results, but have never proven curative. Methods: We have previously presented simulations of clinically relevant amounts of intraperitoneal 90Y-mAbs for treatment of minimal disease and shown that such treatments are unlikely to eradicate microtumors. Our previous model simulated the kinetics of intraperitoneally infused radiolabeled mAbs in humans and showed the benefit of instead using α-emitters such as 211At. In the current work, we introduce penetration of mAbs into microtumors with radii of up to 400 μm. Calculations were performed using dynamic simulation software. To determine the radiation dose distribution in nonvascularized microtumors of various sizes after intraperitoneal 211At-radioimmunotherapy, we used an in-house-developed Monte Carlo program for microdosimetry. Our aim was to find methods that optimize the therapy for as wide a tumor size range as possible. Results: Our results show that high-specific-activity radiolabeled mAbs that are bound to a tumor surface will penetrate slowly compared with the half-lives of 211At and shorter-lived radionuclides. The inner-core cells of tumors with radii exceeding 100 μm may therefore not be sufficiently irradiated. For lower specific activities, the penetration rate and dose distribution will be more favorable for such tumors, but the dose to smaller microtumors and single cells will be low. Conclusion: Our calculations show that the addition of a boost with unlabeled mAb 1-5 h after therapy results in sufficient absorbed doses both to single cells and throughout microtumors up to approximately 300 μm in radius. This finding should also hold for other high-affinity mAbs and short-lived α-emitters.
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