Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

Beyer, G.J.; Miederer, Matthias; Vranješ-Đurić, Sanja; Čomor, Jožef J.; Künzi, G.; Hartley, Oliver; Senekowitsch–Schmidtke, Reingard; Soloviev, D.; Buchegger, Franz

doi:10.1007/s00259-003-1413-9

Cited by 101 publications

(92 citation statements)

References 19 publications

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“…So far, there is only a single preclinical therapy study reported in the literature, in which 149 Tb has been successfully used for a-therapy in a leukemia mouse model with an antibody as a targeting agent (1). The present work demonstrated for the first time the successful therapeutic application of 161 Tb in vivo.…”

Section: Discussionmentioning

confidence: 54%

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A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β⁻-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

et al. 2012

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Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: 149 Tb, 152 Tb, 155 Tb, and 161 Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET ( 152 Tb) and SPECT diagnosis ( 155 Tb) and for a-( 149 Tb) and b 2 -particle ( 161 Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent. Methods: 161 Tb was produced by irradiation of 160 Gd targets with neutrons at Paul Scherrer Institute or Institut LaueLangevin. After neutron capture, the short-lived 161 Gd decays to 161 Tb. 149 Tb, 152 Tb, and 155 Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA-folate conjugate cm09, which binds to folate receptor (FR)-positive KB tumor cells. Therapy experiments with 149 Tb-cm09 and 161 Tb-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/ CT ( 152 Tb-cm09) and SPECT/CT ( 155 Tb-cm09 and 161 Tbcm09) studies were performed in the same tumor mouse model. Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for 149 Tb) to approximately 15 GBq (for 161 Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% 6 2.5% at 4 h after injection, 22.0% 6 4.4% at 24 h after injection, and 18.4% 6 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ;15; tumor to liver, ;5.9; and tumor to kidney, ;0.8) allowed the visualization of tumors in mice using PET ( 152 Tb-cm09) and SPECT ( 155 Tb-cm09 and 161 Tb-cm09). Compared with no therapy, a-( 149 Tb-cm09) and b 2 -particle therapy ( 161 Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for 149 Tb-cm09 and 80% for 161 Tb-cm09) and a significantly increased survival. Conclusion: Because of its physical half-lives (T 1/2 ), decay properties, and energies, the lanthanide terbium is one of the few elements that features 4 clinically interesting radioisotopes (Table 1). 149 Tb has a half-life of 4.12 h and emits shortrange a-particles at an energy (E a ) of 3.967 MeV with an intensity of 17%. It is the only a-emitter among radiolanthanides with a suitable half-life for application in radionuclide therapy. 152 Tb (T 1/2 , 17.5 h) emits positrons of an average energy of 1.080 MeV with an intensity of 17%. The radionuclide would be useful for patient-specific dosimetry using PET before the application of therapeutic radiolanthanides. 155 Tb (T 1/2 , 5.32 d) decays by electron cap...

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Section: Discussionmentioning

confidence: 54%

“…161 Tb emits low-energy b 2 -particles of an average energy (E b 2 average ) of 0.154 MeV and with an intensity of 100%. In addition, it emits also Auger electrons and 149 Tb-labeled rituximab in a mouse model carrying human xenografts expressing the CD20 antigen (1). The same group has proposed 152 Tb as a radioisotope for kinetics studies with PET (2).…”

mentioning

confidence: 99%

A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β⁻-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

et al. 2012

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“…Besides the approved radiopharmaceuticals, 131 I-rituximab has been used in low-and high-dose RIT [9][10][11]. First in vitro and in vivo alpha-radiation therapy experiments using DTPA-rituximab, labelled with 213 Bi and 149 Tb, have also been reported [12,13]. Both approved RITs are based on the injection of a single therapeutic dose of radiolabelled mouse MAb that may be preceded by the injection of a dosimetric dose of MAb, labelled with 111 In in the case of Zevalin and with 131 I in that of Bexxar.…”

Section: Introductionmentioning

confidence: 99%

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Antonescu

Delaloye

Kosinski

et al. 2005

Eur J Nucl Med Mol Imaging

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Abstract. Purpose: It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post 131 I-rituximab injection prior to the second and third injections, respectively. Results: A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T 1/2 β, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T 1/2 of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48-0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver. Conclusion: These results show that the biodistribution and tissue kinetics of 131 I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.

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“…This can serve for direct comparison of the radiobiological effectiveness of alpha versus beta radiation (of 161 Tb or chemically similar 177 Lu). First preclinical studies have been reported [Bey04,Mue12] but so far this interesting isotope is only available at the ISOL facilities ISOLDE (CERN) and ISAC (TRIUMF).…”

Section: Radium: Diffusion Makes the Differencementioning

confidence: 99%

Ion and Neutron Beams Discover New Facts from History

Macková

Kučera

Kameník

et al. 2017

Nuclear Physics News

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Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

Cited by 101 publications

References 19 publications

A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β⁻-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β⁻-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Ion and Neutron Beams Discover New Facts from History

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Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

Cited by 101 publications

References 19 publications

A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β−-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β−-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Ion and Neutron Beams Discover New Facts from History

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Product

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A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β⁻-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β⁻-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative