TY  - JOUR
AU  - Beyer, GJ
AU  - Miederer, M
AU  - Vranješ-Đurić, Sanja
AU  - Čomor, Jožef J.
AU  - Kunzi, G
AU  - Hartley, O
AU  - Senekowitsch-Schmidtke, R
AU  - Soloviev, D
AU  - Buchegger, F
PY  - 2004
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/2757
AB  - This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10(6) Daudi cells resulted in tumour-free survival for GT 120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 mug unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%+/-4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%+/-2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with Tb-149 is worthy of consideration as a new-generation radio-immunotherapeutic approach.
T2  - European Journal of Nuclear Medicine and Molecular Imaging
T1  - Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using Tb-149-rituximab
VL  - 31
IS  - 4
SP  - 547
EP  - 554
DO  - 10.1007/s00259-003-1413-9
ER  - 

@article{
author = "Beyer, GJ and Miederer, M and Vranješ-Đurić, Sanja and Čomor, Jožef J. and Kunzi, G and Hartley, O and Senekowitsch-Schmidtke, R and Soloviev, D and Buchegger, F",
year = "2004",
abstract = "This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10(6) Daudi cells resulted in tumour-free survival for GT 120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 mug unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%+/-4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%+/-2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with Tb-149 is worthy of consideration as a new-generation radio-immunotherapeutic approach.",
journal = "European Journal of Nuclear Medicine and Molecular Imaging",
title = "Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using Tb-149-rituximab",
volume = "31",
number = "4",
pages = "547-554",
doi = "10.1007/s00259-003-1413-9"
}

Beyer, G., Miederer, M., Vranješ-Đurić, S., Čomor, J. J., Kunzi, G., Hartley, O., Senekowitsch-Schmidtke, R., Soloviev, D.,& Buchegger, F.. (2004). Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using Tb-149-rituximab. in European Journal of Nuclear Medicine and Molecular Imaging, 31(4), 547-554.
https://doi.org/10.1007/s00259-003-1413-9

Beyer G, Miederer M, Vranješ-Đurić S, Čomor JJ, Kunzi G, Hartley O, Senekowitsch-Schmidtke R, Soloviev D, Buchegger F. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using Tb-149-rituximab. in European Journal of Nuclear Medicine and Molecular Imaging. 2004;31(4):547-554.
doi:10.1007/s00259-003-1413-9 .

Beyer, GJ, Miederer, M, Vranješ-Đurić, Sanja, Čomor, Jožef J., Kunzi, G, Hartley, O, Senekowitsch-Schmidtke, R, Soloviev, D, Buchegger, F, "Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using Tb-149-rituximab" in European Journal of Nuclear Medicine and Molecular Imaging, 31, no. 4 (2004):547-554,
https://doi.org/10.1007/s00259-003-1413-9 . .

TY  - JOUR
AU  - Miederer, M
AU  - Seidl, C
AU  - Beyer, GJ
AU  - Charlton, DE
AU  - Vranješ-Đurić, Sanja
AU  - Čomor, Jožef J.
AU  - Huber, R
AU  - Nikula, T
AU  - Apostolidis, C
AU  - Schuhmacher, C
AU  - Becker, KF
AU  - Senekowitsch-Schmidtke, R
PY  - 2003
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/2630
AB  - We investigated the effects of the a-particle emitters Tb-149 and Bi-213 coupled to a tumor-specific antibody targeting the mutated delta 9 E-cadherin (d9 E-Cad) on single cells and cell pellets. The d9 mutation of the adhesion molecule E-cadherin is found in 10% of diffuse-type gastric cancers and is not expressed in normal tissue. Human breast cancer cells (MDA-MB-435S) transfected with d9 E-Cad or the wild-type E-cadherin gene were used to study the effects of anti-d9 E-Cad MAb coupled to Tb-149 and Bi-213 (Tb-149-d9 MAb and Bi-213-d9 MAb). The density of binding sites determined on transfected MDA tumor cells by Scatchard analysis and flow cytometry varied from 4 x 10(4) to 6 x 10(4) antigens per cell. Internalization of radioimmunoconjugates by cells expressing d9 E-Cad was less than 10% of bound antibody within 240 min. The effect of the radioimmunoconjugates on cell suspensions and cell pellets was quantified by [H-3]thymidine incorporation, and the dose to the cell nuclei was determined using microdosimetric calculations. Tb-149 and Bi-213 immunoconjugates affected cells in suspension similarly. Significant differences in the proliferation capacity of d9 E-cadherin- and wildtype E-cadherin-expressing cells were observed at activity concentrations around 185 kBq/ml, corresponding to antibody concentrations between 200 ng/ml and 1000 ng/ml. Proliferation after incubation with Bi-213-d9 MAb was 50% greater in pelleted wild-type E-Cad-expressing cells compared to wildtype E-Cad cells in suspension. In contrast, the proliferation of pelleted d9 E-Cad cells was similar to that of d9 E-Cad cells in suspension. For Tb-149-d9 MAb, no significant difference was found between pelleted cells and cells in suspension for low activity concentrations. However, at high activity concentrations, Tb-149-d9 MAb had only a small effect on pelleted cells. These in vitro studies demonstrate different effects of Tb-149 and Bi-213 conjugated to a tumor-specific antibody toward single cells and tumor cell pellets. Microdosimetric simulation of single cell survival after a-particle irradiation modeled the experimental results with reasonable accuracy. (C) 2003 by Radiation Research Society.
T2  - Radiation Research
T1  - Comparison of the radiotoxicity of two alpha-particle-emitting immunoconjugates, terbium-149 and bismuth-213, directed against a tumor-specific, exon 9 deleted (d9) E-cadherin adhesion protein
VL  - 159
IS  - 5
SP  - 612
EP  - 620
DO  - 10.1667/0033-7587(2003)159[0612:COTROT]2.0.CO;2
ER  - 

@article{
author = "Miederer, M and Seidl, C and Beyer, GJ and Charlton, DE and Vranješ-Đurić, Sanja and Čomor, Jožef J. and Huber, R and Nikula, T and Apostolidis, C and Schuhmacher, C and Becker, KF and Senekowitsch-Schmidtke, R",
year = "2003",
abstract = "We investigated the effects of the a-particle emitters Tb-149 and Bi-213 coupled to a tumor-specific antibody targeting the mutated delta 9 E-cadherin (d9 E-Cad) on single cells and cell pellets. The d9 mutation of the adhesion molecule E-cadherin is found in 10% of diffuse-type gastric cancers and is not expressed in normal tissue. Human breast cancer cells (MDA-MB-435S) transfected with d9 E-Cad or the wild-type E-cadherin gene were used to study the effects of anti-d9 E-Cad MAb coupled to Tb-149 and Bi-213 (Tb-149-d9 MAb and Bi-213-d9 MAb). The density of binding sites determined on transfected MDA tumor cells by Scatchard analysis and flow cytometry varied from 4 x 10(4) to 6 x 10(4) antigens per cell. Internalization of radioimmunoconjugates by cells expressing d9 E-Cad was less than 10% of bound antibody within 240 min. The effect of the radioimmunoconjugates on cell suspensions and cell pellets was quantified by [H-3]thymidine incorporation, and the dose to the cell nuclei was determined using microdosimetric calculations. Tb-149 and Bi-213 immunoconjugates affected cells in suspension similarly. Significant differences in the proliferation capacity of d9 E-cadherin- and wildtype E-cadherin-expressing cells were observed at activity concentrations around 185 kBq/ml, corresponding to antibody concentrations between 200 ng/ml and 1000 ng/ml. Proliferation after incubation with Bi-213-d9 MAb was 50% greater in pelleted wild-type E-Cad-expressing cells compared to wildtype E-Cad cells in suspension. In contrast, the proliferation of pelleted d9 E-Cad cells was similar to that of d9 E-Cad cells in suspension. For Tb-149-d9 MAb, no significant difference was found between pelleted cells and cells in suspension for low activity concentrations. However, at high activity concentrations, Tb-149-d9 MAb had only a small effect on pelleted cells. These in vitro studies demonstrate different effects of Tb-149 and Bi-213 conjugated to a tumor-specific antibody toward single cells and tumor cell pellets. Microdosimetric simulation of single cell survival after a-particle irradiation modeled the experimental results with reasonable accuracy. (C) 2003 by Radiation Research Society.",
journal = "Radiation Research",
title = "Comparison of the radiotoxicity of two alpha-particle-emitting immunoconjugates, terbium-149 and bismuth-213, directed against a tumor-specific, exon 9 deleted (d9) E-cadherin adhesion protein",
volume = "159",
number = "5",
pages = "612-620",
doi = "10.1667/0033-7587(2003)159[0612:COTROT]2.0.CO;2"
}

Miederer, M., Seidl, C., Beyer, G., Charlton, D., Vranješ-Đurić, S., Čomor, J. J., Huber, R., Nikula, T., Apostolidis, C., Schuhmacher, C., Becker, K.,& Senekowitsch-Schmidtke, R.. (2003). Comparison of the radiotoxicity of two alpha-particle-emitting immunoconjugates, terbium-149 and bismuth-213, directed against a tumor-specific, exon 9 deleted (d9) E-cadherin adhesion protein. in Radiation Research, 159(5), 612-620.
https://doi.org/10.1667/0033-7587(2003)159[0612:COTROT]2.0.CO;2

Miederer M, Seidl C, Beyer G, Charlton D, Vranješ-Đurić S, Čomor JJ, Huber R, Nikula T, Apostolidis C, Schuhmacher C, Becker K, Senekowitsch-Schmidtke R. Comparison of the radiotoxicity of two alpha-particle-emitting immunoconjugates, terbium-149 and bismuth-213, directed against a tumor-specific, exon 9 deleted (d9) E-cadherin adhesion protein. in Radiation Research. 2003;159(5):612-620.
doi:10.1667/0033-7587(2003)159[0612:COTROT]2.0.CO;2 .

Miederer, M, Seidl, C, Beyer, GJ, Charlton, DE, Vranješ-Đurić, Sanja, Čomor, Jožef J., Huber, R, Nikula, T, Apostolidis, C, Schuhmacher, C, Becker, KF, Senekowitsch-Schmidtke, R, "Comparison of the radiotoxicity of two alpha-particle-emitting immunoconjugates, terbium-149 and bismuth-213, directed against a tumor-specific, exon 9 deleted (d9) E-cadherin adhesion protein" in Radiation Research, 159, no. 5 (2003):612-620,
https://doi.org/10.1667/0033-7587(2003)159[0612:COTROT]2.0.CO;2 . .

TY  - JOUR
AU  - Beyer, GJ
AU  - Čomor, Jožef J.
AU  - Dakovic, M
AU  - Soloviev, D
AU  - Tamburella, C
AU  - Hagebo, E
AU  - Allan, B
AU  - Dmitriev, SN
AU  - Zaitseva, NG
AU  - Starodub, GY
AU  - Molokanova, LG
AU  - Vranješ, Sanja
AU  - Miederer, M
AU  - ISOLDE Collaboration
PY  - 2002
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/2520
AB  - The partial alpha emitting lanthanide isotope Tb-149 seems to have a great potential in systemic radioimmuno therapy (RIT), especially when single cells in transit or circulation are targeted. The isotope Tb-149 has a half life of 4.118h and decays by alpha emission (3.97MeV, 17%) EC-process (76%) and beta(+)-emission (7%). In this paper. we analyze the possible production routes: light- and heavy ion induced nuclear reactions and p-induced spallation. The excitation functions for light- and heavy ion induced reactions have been calculated using the ALICE91 code. The direct nuclear reaction Gd-152 (p, 4n) Tb-149 was found to be the most promising production path. Alternatively, the indirect reaction Nd-142 (C-12 5n) Dy-149 -- GT Tb-149 seems to be much more suitable compared to the reaction on the mono-isotopic target element Pr-141 (C-12, 4n) Tb-149. In this case, both, the production yield of Tb-149 and the radionuclidic purity are considerably lower, compared to the (p, 4n)-reaction. In preliminary experiments we produced Tb-149 via the indirect reaction Nd (C-12, 5n) Dy-149 -- GT Tb-149 (108 MeV C-12(+6) ions and 1 particle-muA) at the U-200 heavy ion cyclotron at the FLNR of the JINR Dubna. From a 1.25 It irradiation of a 12 mg/cm(2) (Nd2O3)-Nd-nat target, we obtained 2.7 MBq of Tb-149 (70 muCi) at 20 min EOB. This allows the conclusion, that a dedicated cyclotron equipped with a modem ECR-ion source, providing high ion currents would allow the continuous production of batches of the order of 10-20 GBq of Tb-149 for routine RI-therapy. The lower cross section of the spallation process can be compensated by using very thick targets. On-line mass separation technique provides high purity isotopically clean Tb-149 preparations, independently on the production route chosen. At the ISOLDE facility at CERN, we prepared batches of up to 500 MBq Tb-149 by combining on-line mass separation process followed by a cation exchange chromatography process using alpha-HIBA as eluent. The obtained Tb-149 preparations showed excellent behavior in labeling of chelated monoclonal antibodies.
T2  - Radiochimica Acta
T1  - Production routes of the alpha emitting Tb-149 for medical application
VL  - 90
IS  - 5
SP  - 247
EP  - 252
DO  - 10.1524/ract.2002.90.5_2002.247
ER  - 

@article{
author = "Beyer, GJ and Čomor, Jožef J. and Dakovic, M and Soloviev, D and Tamburella, C and Hagebo, E and Allan, B and Dmitriev, SN and Zaitseva, NG and Starodub, GY and Molokanova, LG and Vranješ, Sanja and Miederer, M and ISOLDE Collaboration",
year = "2002",
abstract = "The partial alpha emitting lanthanide isotope Tb-149 seems to have a great potential in systemic radioimmuno therapy (RIT), especially when single cells in transit or circulation are targeted. The isotope Tb-149 has a half life of 4.118h and decays by alpha emission (3.97MeV, 17%) EC-process (76%) and beta(+)-emission (7%). In this paper. we analyze the possible production routes: light- and heavy ion induced nuclear reactions and p-induced spallation. The excitation functions for light- and heavy ion induced reactions have been calculated using the ALICE91 code. The direct nuclear reaction Gd-152 (p, 4n) Tb-149 was found to be the most promising production path. Alternatively, the indirect reaction Nd-142 (C-12 5n) Dy-149 -- GT Tb-149 seems to be much more suitable compared to the reaction on the mono-isotopic target element Pr-141 (C-12, 4n) Tb-149. In this case, both, the production yield of Tb-149 and the radionuclidic purity are considerably lower, compared to the (p, 4n)-reaction. In preliminary experiments we produced Tb-149 via the indirect reaction Nd (C-12, 5n) Dy-149 -- GT Tb-149 (108 MeV C-12(+6) ions and 1 particle-muA) at the U-200 heavy ion cyclotron at the FLNR of the JINR Dubna. From a 1.25 It irradiation of a 12 mg/cm(2) (Nd2O3)-Nd-nat target, we obtained 2.7 MBq of Tb-149 (70 muCi) at 20 min EOB. This allows the conclusion, that a dedicated cyclotron equipped with a modem ECR-ion source, providing high ion currents would allow the continuous production of batches of the order of 10-20 GBq of Tb-149 for routine RI-therapy. The lower cross section of the spallation process can be compensated by using very thick targets. On-line mass separation technique provides high purity isotopically clean Tb-149 preparations, independently on the production route chosen. At the ISOLDE facility at CERN, we prepared batches of up to 500 MBq Tb-149 by combining on-line mass separation process followed by a cation exchange chromatography process using alpha-HIBA as eluent. The obtained Tb-149 preparations showed excellent behavior in labeling of chelated monoclonal antibodies.",
journal = "Radiochimica Acta",
title = "Production routes of the alpha emitting Tb-149 for medical application",
volume = "90",
number = "5",
pages = "247-252",
doi = "10.1524/ract.2002.90.5_2002.247"
}

Beyer, G., Čomor, J. J., Dakovic, M., Soloviev, D., Tamburella, C., Hagebo, E., Allan, B., Dmitriev, S., Zaitseva, N., Starodub, G., Molokanova, L., Vranješ, S., Miederer, M.,& ISOLDE Collaboration. (2002). Production routes of the alpha emitting Tb-149 for medical application. in Radiochimica Acta, 90(5), 247-252.
https://doi.org/10.1524/ract.2002.90.5_2002.247

Beyer G, Čomor JJ, Dakovic M, Soloviev D, Tamburella C, Hagebo E, Allan B, Dmitriev S, Zaitseva N, Starodub G, Molokanova L, Vranješ S, Miederer M, ISOLDE Collaboration. Production routes of the alpha emitting Tb-149 for medical application. in Radiochimica Acta. 2002;90(5):247-252.
doi:10.1524/ract.2002.90.5_2002.247 .

Beyer, GJ, Čomor, Jožef J., Dakovic, M, Soloviev, D, Tamburella, C, Hagebo, E, Allan, B, Dmitriev, SN, Zaitseva, NG, Starodub, GY, Molokanova, LG, Vranješ, Sanja, Miederer, M, ISOLDE Collaboration, "Production routes of the alpha emitting Tb-149 for medical application" in Radiochimica Acta, 90, no. 5 (2002):247-252,
https://doi.org/10.1524/ract.2002.90.5_2002.247 . .