Rationale for Translational Research on Targeted Alpha Therapy in Japan —Renaissance of Radiopharmaceuticals Utilizing Astatine-211 and Actinium-225
We wish to herewith report safety evaluations, microdosimetry, and clinical requirements for first-in-human (FIH) study for handling of targeted alpha therapy (TAT) drug products labelled by 211At and 225Ac. 1) The safety evaluation method is proposed including delayed toxicity using the histopathol...
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| Published in | RADIOISOTOPES Vol. 69; no. 10; pp. 329 - 340 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Japan Radioisotope Association
15.10.2020
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| ISSN | 0033-8303 1884-4111 |
| DOI | 10.3769/radioisotopes.69.329 |
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| Abstract | We wish to herewith report safety evaluations, microdosimetry, and clinical requirements for first-in-human (FIH) study for handling of targeted alpha therapy (TAT) drug products labelled by 211At and 225Ac. 1) The safety evaluation method is proposed including delayed toxicity using the histopathological examination. The biodistribution study using PET or SPECT corresponding to alpha nuclides is also proposed. 2) Two scales of microdosimetry are proposed for the TAT design; one is the organ-microstructure scales and the other is the cellular and subcellular scales. Recently, the stochastic microdosimetric kinetic model was developed by the cellular-scale particle transport simulation using PHITS. 3) The dose of TAT drug for FIH study can be considered in the amount of radioactivity and mass, and radioactivity would often be a more important determining factor than mass. 4) In Japan, Medical Device system for regulatory approval of the synthesizer itself has been adopted as well as Medical Drug system for delivery of radiopharmaceuticals. We propose to start an automatic synthesis device at an early stage and to establish manufacturing process, quality control and GMP evaluations. The need for radiation shielding based on the calculation by effective dose rate coefficients for alpha particles is also introduced. The argument is concluded that the operation in hot cell used at many PET centers is sufficient. |
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| AbstractList | We wish to herewith report safety evaluations, microdosimetry, and clinical requirements for first-in-human (FIH) study for handling of targeted alpha therapy (TAT) drug products labelled by 211At and 225Ac. 1) The safety evaluation method is proposed including delayed toxicity using the histopathological examination. The biodistribution study using PET or SPECT corresponding to alpha nuclides is also proposed. 2) Two scales of microdosimetry are proposed for the TAT design; one is the organ-microstructure scales and the other is the cellular and subcellular scales. Recently, the stochastic microdosimetric kinetic model was developed by the cellular-scale particle transport simulation using PHITS. 3) The dose of TAT drug for FIH study can be considered in the amount of radioactivity and mass, and radioactivity would often be a more important determining factor than mass. 4) In Japan, Medical Device system for regulatory approval of the synthesizer itself has been adopted as well as Medical Drug system for delivery of radiopharmaceuticals. We propose to start an automatic synthesis device at an early stage and to establish manufacturing process, quality control and GMP evaluations. The need for radiation shielding based on the calculation by effective dose rate coefficients for alpha particles is also introduced. The argument is concluded that the operation in hot cell used at many PET centers is sufficient. |
| Author | Watabe, Tadashi Fujii, Hirofumi Sato, Tatsuhiko Yonekura, Yoshiharu Hasegawa, Koki Kabayama, Kazuya Fukase, Koichi Tatsumi, Mitsuaki Yano, Tsuneo Kadonaga, Yuichiro Hirabayashi, Yoko Hachisuka, Akiko |
| Author_xml | – sequence: 1 fullname: Yonekura, Yoshiharu organization: Institute for Radiation Sciences, Osaka University – sequence: 1 fullname: Fukase, Koichi organization: Department of Chemistry, Graduate School of Science, Osaka University – sequence: 1 fullname: Hirabayashi, Yoko organization: Center for Biological Safety & Research, National Institute of Health Sciences – sequence: 1 fullname: Tatsumi, Mitsuaki organization: Department of Radiology, Osaka University Hospital – sequence: 1 fullname: Hachisuka, Akiko organization: Division of Biochemistry, National Institute of Health Sciences – sequence: 1 fullname: Yano, Tsuneo organization: QiSS-Targeted Alpha Therapy Research, Research Center for Nuclear Physics, Osaka University – sequence: 1 fullname: Watabe, Tadashi organization: Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University – sequence: 1 fullname: Fujii, Hirofumi organization: Division of Functional Imaging, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center – sequence: 1 fullname: Kadonaga, Yuichiro organization: Institute for Radiation Sciences, Osaka University – sequence: 1 fullname: Sato, Tatsuhiko organization: Nuclear Science and Engineering Center, Japan Atomic Energy Agency – sequence: 1 fullname: Hasegawa, Koki organization: Center for Instrumental Analysis, Kyoto Pharmaceutical University – sequence: 1 fullname: Kabayama, Kazuya organization: Department of Chemistry, Graduate School of Science, Osaka University |
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| Cites_doi | 10.2967/jnumed.116.178673 10.1007/s12149-018-1317-1 10.1088/0031-9155/57/10/3207 10.1093/rpd/ncw103 10.1088/0031-9155/57/13/4403 10.1074/jbc.273.37.23629 10.2174/1874471011666180416161908 10.1186/s41181-017-0025-9 10.1158/1078-0432.CCR-18-1650 10.2967/jnumed.118.222638 10.1080/00223131.2017.1419890 10.1021/bc060345s 10.1038/s41598-017-18871-0 10.1056/NEJMoa1213755 |
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| References | 4) Yano, T., Hasegawa, K., Sato, T., Tatsumi, M., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 4—, —First-in-Human Clinical Requirements—, Pharma. Med. Device Regula. Sci., 51, 364–377 (2020 6) Hosono, M., Ikebuchi, H., Nakamura, Y., Kinuya, S., et al., Introduction of the targeted alpha therapy (with Radium-223) into clinical practice in Japan: Learnings and implementation, Ann. Nucl. Med., 33, 211–221 (2019 11) Henderson Robertson, A. K., Ramogida, C. F., Schaffer, P. and Radchenko, V., Development of 225Ac Radiopharmaceuticals: TRIUMF Perspectives and Experiences, Curr. Radiopharm., 11, 156–172 (2018 12) Goddu, S. M., Howell, R. W., Bouchet, L. G., Bolch, W. E., et al., MIRD Cellular S values: Self-Absorbed Dose per Unit Cumulated Activity for Selected Radionuclides and Monoenergetic Electron and Alpha Particle Emitters Incorporated into Different Cell Compartments. Reston, VA: Society of Nuclear Medicine and Molecular Imaging, (1997 2) Yano, T., Hasegawa, K., Sato, T., Hirabayashi, Y., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 2—, Pharma. Med. Device Regula. Sci., 50, 118–130 (2019 7) Kratochwil, C., Bruchertseifer, F., Giesel, F. L., Morgenstern, A., et al., 225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer, J. Nucl. Med., 57, 1941–1944 (2016 8) Watabe, T., Kaneda-Nakashima, K., Liu, Y., Shirakami, Y., et al., Enhancement of 211At Uptake via the Sodium Iodide Symporter by the Addition of Ascorbic Acid in Targeted alpha-Therapy of Thyroid Cancer, J. Nucl. Med., 60, 1301–1307 (2019 24) Todde, S., Kolenc, P., Elsinga, P. P., Koziorowski, J., et al., Guidance on validation and qualification of processes and operations involving radiopharmaceuticals, Eur. J. Nucl. Med. Mol. Imaging, Radiopharm. Chem, 2, 8 (2017 1) Yano, T., Hasegawa, K., Hachisuka, A., Hirabayashi, Y., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 1—, Pharma. Med. Device Regula. Sci., 49, 676–684 (2018 16) Akabani, G., Kennel, S. J. and Zalutsky, M. R., Microdosimetric analysis of alpha-particle-emitting targeted radiotherapeutics using histological images, J. Nucl. Med., 44, 792–805 (2003 19) Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., et al., Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98), J. Biol. Chem., 273, 23629–23632 (1998 9) U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry-Pharmacology/Toxicology, August 2019, https://www.fda.gov/media/129547/download (accessed 2020-3-10 13) Hobbs, R. F., Song, H., Watchman, C. J., Sgouros, G., et al., A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy, Phys. Med. Biol., 57, 3207–3222 (2012 14) Hobbs, R. F., Song, H., Huso, D. L., Sgouros, G., et al., A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry, Phys. Med. Biol., 57, 4403–4424 (2012 3) Yano, T., Hasegawa, K., Kadonaga, Y., Fukase, K., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 3—, Pharma. Med. Device Regula. Sci., 50, 750–764 (2019 17) Sato, T., Masunaga, S., Kumada, H. and Hamada, N., Microdosimetric Modeling of Biological Effectiveness for Boron Neutron Capture Therapy Considering Intra- and Intercellular Heterogeneity in 10B Distribution, Sci. Rep., 8, 988 (2018 21) Poty, S., Carter, L. M., Mandleywala, K., Lewis, J., et al., Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma, Clin. Cancer Res., 25, 868–880 (2019 15) Goddu, S. M., Howell, R. W. and Rao, D. V., Cellular dosimetry: Absorbed fractions for monoenergetic electron and alpha particle sources and S-values for radionuclides uniformly distributed in different cell compartments, J. Nucl. Med., 35, 303–316 (1994 5) Parker, C., Nilsson, S., Heinrich, D., O’Sullivan, J. M., et al., Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer, N. Engl. J. Med., 369, 213–223 (2013 22) Poty, S., Mandleywala, K., Carter, L. and Lewis, J., Leveraging 225Ac-pretargeted radioimmunotherapy for application in pancreatic ductal adenocarcinoma therapy, J. Nucl. Med., 59(supplement 1), 540 (2018 18) Sato, T., Iwamoto, Y., Hashimoto, S., Ogawa, T., et al., Features of Particle and Heavy Ion Transport Code System PHITS Version 3.02, J. Nucl. Sci. Technol., 55, 684–690 (2018 20) Wilbur, D. S., Chyan, M. K., Hamlin, D. K., Vessella, R. L., et al., Reagents for astatination of biomolecules. 2. Conjugation of anionic boron cage pendant groups to a protein provides a method for direct labeling that is stable to in vivo deastatination, Bioconjug. Chem., 18, 1226–1240 (2007 10) European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), Draft Guideline on the non-clinical requirements for radiopharmaceuticals—First version, November 22, 2018, https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-non-clinical-requirements-radiopharmaceuticals-first-version_en.pdf (accessed 2020-3-10 23) Bellamy, M. B., Veinot, K. G., Hiller, M. M., Manger, R., et al., Effective Dose Rate Coefficients for Immersions in Radioactive Air and Water, Radiat. Prot. Dosimetry, 174, 275–286 (2017 11 22 12 23 13 24 14 15 16 17 18 19 1 2 3 4 5 6 7 8 9 20 10 21 |
| References_xml | – reference: 14) Hobbs, R. F., Song, H., Huso, D. L., Sgouros, G., et al., A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry, Phys. Med. Biol., 57, 4403–4424 (2012) – reference: 20) Wilbur, D. S., Chyan, M. K., Hamlin, D. K., Vessella, R. L., et al., Reagents for astatination of biomolecules. 2. Conjugation of anionic boron cage pendant groups to a protein provides a method for direct labeling that is stable to in vivo deastatination, Bioconjug. Chem., 18, 1226–1240 (2007) – reference: 23) Bellamy, M. B., Veinot, K. G., Hiller, M. M., Manger, R., et al., Effective Dose Rate Coefficients for Immersions in Radioactive Air and Water, Radiat. Prot. Dosimetry, 174, 275–286 (2017) – reference: 6) Hosono, M., Ikebuchi, H., Nakamura, Y., Kinuya, S., et al., Introduction of the targeted alpha therapy (with Radium-223) into clinical practice in Japan: Learnings and implementation, Ann. Nucl. Med., 33, 211–221 (2019) – reference: 15) Goddu, S. M., Howell, R. W. and Rao, D. V., Cellular dosimetry: Absorbed fractions for monoenergetic electron and alpha particle sources and S-values for radionuclides uniformly distributed in different cell compartments, J. Nucl. Med., 35, 303–316 (1994) – reference: 7) Kratochwil, C., Bruchertseifer, F., Giesel, F. L., Morgenstern, A., et al., 225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer, J. Nucl. Med., 57, 1941–1944 (2016) – reference: 17) Sato, T., Masunaga, S., Kumada, H. and Hamada, N., Microdosimetric Modeling of Biological Effectiveness for Boron Neutron Capture Therapy Considering Intra- and Intercellular Heterogeneity in 10B Distribution, Sci. Rep., 8, 988 (2018) – reference: 5) Parker, C., Nilsson, S., Heinrich, D., O’Sullivan, J. M., et al., Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer, N. Engl. J. Med., 369, 213–223 (2013) – reference: 21) Poty, S., Carter, L. M., Mandleywala, K., Lewis, J., et al., Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma, Clin. Cancer Res., 25, 868–880 (2019) – reference: 2) Yano, T., Hasegawa, K., Sato, T., Hirabayashi, Y., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 2—, Pharma. Med. Device Regula. Sci., 50, 118–130 (2019) – reference: 12) Goddu, S. M., Howell, R. W., Bouchet, L. G., Bolch, W. E., et al., MIRD Cellular S values: Self-Absorbed Dose per Unit Cumulated Activity for Selected Radionuclides and Monoenergetic Electron and Alpha Particle Emitters Incorporated into Different Cell Compartments. Reston, VA: Society of Nuclear Medicine and Molecular Imaging, (1997) – reference: 1) Yano, T., Hasegawa, K., Hachisuka, A., Hirabayashi, Y., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 1—, Pharma. Med. Device Regula. Sci., 49, 676–684 (2018) – reference: 4) Yano, T., Hasegawa, K., Sato, T., Tatsumi, M., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 4—, —First-in-Human Clinical Requirements—, Pharma. Med. Device Regula. Sci., 51, 364–377 (2020) – reference: 8) Watabe, T., Kaneda-Nakashima, K., Liu, Y., Shirakami, Y., et al., Enhancement of 211At Uptake via the Sodium Iodide Symporter by the Addition of Ascorbic Acid in Targeted alpha-Therapy of Thyroid Cancer, J. Nucl. Med., 60, 1301–1307 (2019) – reference: 18) Sato, T., Iwamoto, Y., Hashimoto, S., Ogawa, T., et al., Features of Particle and Heavy Ion Transport Code System PHITS Version 3.02, J. Nucl. Sci. Technol., 55, 684–690 (2018) – reference: 11) Henderson Robertson, A. K., Ramogida, C. F., Schaffer, P. and Radchenko, V., Development of 225Ac Radiopharmaceuticals: TRIUMF Perspectives and Experiences, Curr. Radiopharm., 11, 156–172 (2018) – reference: 16) Akabani, G., Kennel, S. J. and Zalutsky, M. R., Microdosimetric analysis of alpha-particle-emitting targeted radiotherapeutics using histological images, J. Nucl. Med., 44, 792–805 (2003) – reference: 3) Yano, T., Hasegawa, K., Kadonaga, Y., Fukase, K., et al., Discussion on Translational Research of Drug Product for Targeted Alpha Therapy—Part 3—, Pharma. Med. Device Regula. Sci., 50, 750–764 (2019) – reference: 9) U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry-Pharmacology/Toxicology, August 2019, https://www.fda.gov/media/129547/download (accessed 2020-3-10) – reference: 10) European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), Draft Guideline on the non-clinical requirements for radiopharmaceuticals—First version, November 22, 2018, https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-non-clinical-requirements-radiopharmaceuticals-first-version_en.pdf (accessed 2020-3-10) – reference: 13) Hobbs, R. F., Song, H., Watchman, C. J., Sgouros, G., et al., A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy, Phys. Med. Biol., 57, 3207–3222 (2012) – reference: 19) Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., et al., Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98), J. Biol. Chem., 273, 23629–23632 (1998) – reference: 24) Todde, S., Kolenc, P., Elsinga, P. P., Koziorowski, J., et al., Guidance on validation and qualification of processes and operations involving radiopharmaceuticals, Eur. J. Nucl. Med. Mol. Imaging, Radiopharm. Chem, 2, 8 (2017) – reference: 22) Poty, S., Mandleywala, K., Carter, L. and Lewis, J., Leveraging 225Ac-pretargeted radioimmunotherapy for application in pancreatic ductal adenocarcinoma therapy, J. Nucl. Med., 59(supplement 1), 540 (2018) – ident: 2 – ident: 3 – ident: 7 doi: 10.2967/jnumed.116.178673 – ident: 6 doi: 10.1007/s12149-018-1317-1 – ident: 13 doi: 10.1088/0031-9155/57/10/3207 – ident: 4 – ident: 23 doi: 10.1093/rpd/ncw103 – ident: 1 – ident: 14 doi: 10.1088/0031-9155/57/13/4403 – ident: 12 – ident: 19 doi: 10.1074/jbc.273.37.23629 – ident: 11 doi: 10.2174/1874471011666180416161908 – ident: 10 – ident: 16 – ident: 24 doi: 10.1186/s41181-017-0025-9 – ident: 15 – ident: 21 doi: 10.1158/1078-0432.CCR-18-1650 – ident: 8 doi: 10.2967/jnumed.118.222638 – ident: 18 doi: 10.1080/00223131.2017.1419890 – ident: 20 doi: 10.1021/bc060345s – ident: 17 doi: 10.1038/s41598-017-18871-0 – ident: 9 – ident: 5 doi: 10.1056/NEJMoa1213755 – ident: 22 |
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| Title | Rationale for Translational Research on Targeted Alpha Therapy in Japan —Renaissance of Radiopharmaceuticals Utilizing Astatine-211 and Actinium-225 |
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