Radioimmunotherapy with α-Particle-Emitting Radionuclides

Seidl, Christof

doi:10.2217/imt.14.16

Cited by 62 publications

(51 citation statements)

References 163 publications

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“…The efficacy of targeted therapy with α-emitters has been demonstrated in an increasing number of preclinical and clinical studies [16-18]. Therefore, the aim of our study was to assay the efficacy of radioimmunoconjugates composed of the α-emitter 213 Bi coupled to the anti-CD38 MAb MOR03087 in targeted treatment of MM.…”

Section: Introductionmentioning

confidence: 99%

α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma

et al. 2014

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In spite of development of molecular therapeutics, multiple myeloma (MM) is fatal in most cases. CD38 is a promising target for selective treatment of MM. We tested radioimmunoconjugates consisting of the α-emitter 213Bi coupled to an anti-CD38 MAb in preclinical treatment of MM. Efficacy of 213Bi-anti-CD38-MAb was assayed towards different MM cell lines with regard to induction of DNA double-strand breaks, induction of apoptosis and initiation of cell cycle arrest. Moreover, mice bearing luciferase-expressing MM xenografts were treated with 213Bi-anti-CD38-MAb. Therapeutic efficacy was monitored by bioluminescence imaging, overall survival and histology. 213Bi-anti-CD38-MAb treatment induced DNA damage which did not result in activation of the G2 DNA-damage-response checkpoint, but instead in mitotic arrest and subsequent mitotic catastrophe. The anti-tumor effect of 213Bi-anti-CD38-MAb correlated with the expression level of CD38 in each MM cell line. In myeloma xenografts, treatment with 213Bi-anti-CD38-MAb suppressed tumor growth via induction of apoptosis in tumor tissue and significantly prolonged survival compared to controls. The major organ systems did not show any signs of 213Bi-induced toxicity. Preclinical treatment of MM with 213Bi-anti-CD38-MAb turned out as an effective therapeutic option.

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Section: Introductionmentioning

confidence: 99%

α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma

et al. 2014

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“…However, a-particles present significantly higher energies than b-particles (4-9 MeV vs. 0.1-2.2 MeV), which combined with short path lengths results in high linear energy transfer and a greater probability of generating DNA double-strand breaks on interaction with cell nuclei. This occurs independently of tissue oxygenation, dose rate, and cellular resistance to photon irradiation and chemotherapy (1)(2)(3)(4)(5). Therefore, a-particles are highly cytotoxic and promising candidates for targeted radiotherapy.…”

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confidence: 99%

α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colon Cancer Xenografts

et al. 2017

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Pretargeted radioimmunotherapy (PRIT) with the β-emitting radionuclide Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using α-emitting radionuclides such asBi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of Bi andLu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288. The in vitro binding characteristics ofBi-IMP288 were compared with those of Lu-IMP288. Tumor targeting ofBi-IMP288 and Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect ofBi-IMP288 (6, 12, or 17 MBq) and Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys. The in vitro binding characteristics of Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those ofLu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g).Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of Bi-IMP288 was comparable to that ofLu-IMP288. Mice treated with a single dose of Bi-IMP288 orLu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq Bi-IMP288, 12 MBqBi-IMP288, and 60 MBq Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBqBi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. To our knowledge, this study shows for the first time that PRIT with TF2 and Bi-IMP288 is feasible and at least as effective asLu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity.

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“…The cell killing capacity of low LET radiation is well characterized at high dose-rates given by external radiotherapy with photons (0.5 -2.0 Gy/min) but less is known when applied in targeted radionuclide therapy (0.01-1.0 Gy/h) [108][109][110][111]. Beta-particles have a LET in the range of 0.1-1.0 keV/μm [88,112].…”

Section: High Versus Low Let Radiation In Targeted Radionuclide Therapymentioning

confidence: 99%

Development of separation technology for the removal of radium-223 from decayed thorium-227 in drug formulations. Material screening and method development

Frenvik

Kristensen

Ryan

2015

Drug Development and Industrial Pharmacy

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Targeted thorium conjugates are currently being investigated as a new class of alpha-radiopharmaceuticals. The natural decay of thorium-227 ((227)Th) results in the ingrowth of radium-223 ((223)Ra). Consideration must, therefore, be given to define acceptable limits of (223)Ra in the drug product at the time of dose administration. By effective sequestration of (223)Ra, we aim to improve the radiochemical purity and extend the effective user window of drug products containing (227)Th. (223)Ra is the first progeny of (227)Th and the only one with a long half-life (days). We have, therefore, focused on the removal of this specific species since the progenies of (223)Ra will have a very limited lifetime in the formulation once (223)Ra is removed. In this study, we investigated a multitude of materials for their ability to reduce the (223)Ra level by: (1) passive diffusion or (2) by cartridge filtration on gravity columns. In addition, we probe the compatibility of these materials in the presence of antibody trastuzumab to assess the level of protein binding and estimate the quenching of radiolysis by binding of radionuclides. A screening matrix of organic and inorganic materials was established, i.e. strontium and calcium alginate gel beads, distearoyl phosphatidylglycerol (DSPG) liposomes, ceramic hydroxyapatite, Zeolite UOP type 4A and cation exchange resins AG50W-X8 and SOURCE 30S. First, passive diffusional uptake of (223)Ra by suspended materials present in the formulation was measured as a decrease in sample radioactivity after separation. Second, selected materials were packed on gravity columns in order to evaluate the efficiency of column separation versus diffusional adsorption. The retention of (223)Ra and (227)Th were characterized by measuring the radioactivity in the eluate and on the columns. Finally, the compatibility between trastuzumab, as a selected model antibody, and suspensions of the binding materials was analyzed during storage of the drug product in the presence of adsorbent. The formation of H2O2 was evaluated to measure the influence of radionuclide binding material on radiolysis in the formulation. All the materials bound (223)Ra by passive diffusional uptake ranging from 31% to 95% with DSPG liposomes demonstrating superiority at 95% efficiency. All materials suitable for assessment by gravity column filtration bound (223)Ra almost quantitatively (∼100%) and with minimal variation (relative standard deviation <1%). The uptake was significantly higher compared to passive diffusional uptake. Alginate gel beads, ceramic hydroxyapatite and SOURCE 30S reduced the antibody concentration in solution to 40-50% while the Zeolite UOP type 4A, AG50W-X8 resin and DSPG liposomes showed ≤10% reduction of antibody concentration. Ceramic hydroxyapatite significantly reduced H2O2 formed by radionuclide initiated radiolysis.

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Radioimmunotherapy with α-Particle-Emitting Radionuclides

Cited by 62 publications

References 163 publications

α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma

α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma

α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colon Cancer Xenografts

Development of separation technology for the removal of radium-223 from decayed thorium-227 in drug formulations. Material screening and method development

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