Abstract
Targeted alpha therapy (TAT) is gaining attention for its superior therapeutic efficacy compared to conventional radionuclide therapy using beta-emitters. Recently, astatine (211At) has been garnering attention as an alpha-emitting radionuclide, as it can be produced by irradiating natural bismuth targets with alpha beams using a 30-MeV cyclotron. We are conducting an investigator-initiated clinical trial using [211At] NaAt as an iodine analogue for patients with refractory thyroid cancer. Compared to beta-emitters such as 131I or 177Lu, the administration dose is small for alpha-emitters. Furthermore, 211At emits lower-energy gamma rays than beta-emitters, resulting in reduced radiation exposure to the surrounding individuals. We have already conducted investigations and demonstrated that radiation exposure remains far below the limits for the general public and caregivers, even if the patient leaves the radiation-controlled area immediately after the administration of [211At] NaAt (Watabe T, et al. Ann Nucl Med. 2021). Therefore, hospitalisation in an isolation ward within the RI-controlled area is not required for targeted alpha therapy using [211At] NaAt. Moreover, the imaging capability of 211At enables precise estimation of the absorbed doses in organs at risk. With the potential for labelling to peptides and antibodies, 211At is anticipated to be a versatile therapeutic agent for various cancers.
INTRODUCTION
Recently, theranostics, a technology combining diagnostic imaging and targeted isotope therapy, has been gaining attention. This approach involves using the same target compound with different labelled radionuclides for both diagnosis and therapy. The primary radionuclides in current radioligand therapy are beta-emitting nuclides, such as 131I and 177Lu. However, targeted alpha therapy (TAT) is emerging as a potentially more effective treatment. Alpha-rays, due to their high energy transfer in a short range, can produce larger therapeutic effects, particularly in patients who are refractory to conventional treatments using beta-emitting nuclides. In fact, in radioligand therapy targeting prostate-specific membrane antigen (PSMA), a membrane protein highly expressed in most prostate cancers, patients showing progression with beta-emitting therapy using lutetium (177Lu) can achieve complete remission after switching to treatments labelled with the alpha-emitter actinium (225Ac) (Kratochwil et al., 2016). Consequently, there is active worldwide development of therapeutic drugs using actinium (225Ac). In the case of prostate cancer, besides 225Ac-PSMA-617, various 225Ac-labelled peptides and antibodies are undergoing clinical trials. However, the global production yield of 225Ac remains limited due to the scarce availability of raw material radionuclide, radium (226Ra)— a rare radioisotope—resulting in a worldwide supply shortage. This limitation has recently spurred increased interest in exploring other alpha-emitters.
In this article, I would like to introduce the current state of clinical TAT and radiation protection in the clinical trial using [211At] NaAt.
Production and supply of astatine
Astatine (211At), an alpha-ray-emitting nuclide with a half-life of 7.2 h, can be produced by irradiating the natural isotope bismuth (209Bi) with alpha beams using a 30-MeV cyclotron (Fig. 1). In contrast to beta-emitters such as 131I and 177Lu, which require manufacturing in medical nuclear reactors, 211At can be produced domestically using accelerators. This is particularly relevant for Japan, where there are no medical reactors, necessitating the import of therapeutic isotopes. Currently, Japan has four supply bases that form a network for the domestic production and delivery of 211At. Furthermore, as the raw material, bismuth (209Bi), is abundant in nature, the establishment of new supply bases will enable large-scale supply for clinical use.
(Left) Decay scheme of astatine (211At). It is a simple decay without any toxic daughter radionuclides. (Right) AVF (azimuthally varying field) cyclotron (30 MeV) in the Research Center for Nuclear Physics at Osaka University.
Astatine exhibits chemical properties and pharmacokinetics similar to iodine. We have demonstrated that astatine (211At) is taken up by thyroid cancer cells, offering greater therapeutic effects than conventional radioiodine (131I) therapy (Watabe et al., 2019, 2022) (Fig. 2). While radioiodine is a standard therapy for differentiated thyroid cancer, treatment effects were sometimes insufficient for patients with recurrent or metastatic lesions. Furthermore, its gamma-ray emission necessitates isolated hospitalisation in specialised rooms to reduce radiation exposure to the general public and caregivers, which limits the availability of this treatment in many medical facilities in Japan. This isolation becomes particularly challenging for elderly patients with dementia. In contrast, 211At emits lower-energy gamma rays, significantly reducing radiation exposure to the surrounding individuals and allowing patients to leave the controlled area immediately after administration (Tables 1 and 2). Consequently, Osaka University is working to develop sodium astatide ([211At] NaAt) as a next-generation TAT drug, a highly effective outpatient treatment for thyroid cancer.
(Left) Whole-body planar image of astatine (211At) in a mouse xenograft model (K1-NIS) using a gamma-camera. The arrows indicate xenografted thyroid cancer. (Right) Comparison of tumour growth curves between 211At and 131I. The administration of [211At] NaAt (1MBq, arrow) demonstrated a sustained decrease in tumour size compared to radioiodine (131I).
Comparison between radioiodine (131I) and astatine (211At).
Physical properties of 211At.
Includes contribution from 211Po, which is in radioactive equilibrium [source: Radioisotope (12th Edition) published by the Japan Radioisotope Association, 2020].
At Osaka University Hospital, we have established a system for manufacturing investigational drugs and received approval from the Institutional Review Board. Since November 2021, we have been conducting an investigator-initiated clinical trial targeting refractory thyroid cancer (Principal Investigator: Tadashi Watabe; ClinicalTrials.gov ID: NCT05275946). This Phase I trial involves administering [211At] NaAt intravenously in a single dose to patients with refractory differentiated thyroid cancer. The study evaluates the safety, pharmacokinetics, absorbed dose, and efficacy of the drug in a dose-escalation setting. The goal is to determine the recommended dose for the Phase II study. The investigational drug is manufactured in accordance with GMP standards at the short-lived radiopharmaceutical manufacturing facility in the Department of Nuclear Medicine at Osaka University Hospital. Specifically, we receive irradiated Bi targets as raw material from the RIKEN Nishina Accelerator Science Research Center and use automatic separation and purification equipment to produce the [211At] NaAt injection solution (Fig. 3). As of December 2023, a total of eight patients have received the administration of [211At] NaAt.
(Left) Automatic separation and purification device of 211At. (Right) Labelling synthesiser for 211At-labelled compounds. These devices are installed in Osaka University Hospital and used for the manufacturing of clinical trial drugs.
The Scientific Research Group of the Ministry of Health, Labor, and Welfare, led by Prof. Makoto Hosono from Kindai University, Japan, has conducted investigations about the radiation exposure from patients to surrounding individuals. In the assumed scenario, caregivers and the general public are exposed to external radiation at a distance of 1 m for 12 h and 6 h per day, respectively, as well as potential internal exposure using the Yodo River water system model (Watabe et al., 2021). Even if the patient leaves the radiation-controlled area immediately after the administration of [211At] NaAt, effective doses are estimated as 0.072 mSv for caregivers and 0.017 mSv for the general public after the administration of [211At] NaAt (700 MBq/kg: 10 MBq/kg) to a patient. It is far below the limits in the safety standards of ICRP and IAEA recommendations (upper limit: 5 mSv for caregivers and 1 mSv for general public). Therefore, hospitalisation in an isolation ward within the RI-controlled area is not required for targeted alpha therapy using [211At] NaAt, and patients can be released immediately postadministration.
Absorbed dose calculation
Astatine (211At) emits x-rays from its daughter nuclide, 211Po. This emission allows for the acquisition of biodistribution images using conventional single-photon emission computed tomography/computed tomography (SPECT/CT) scanners. In this clinical trial, whole-body SPECT/CT images of the patient were obtained at 1, 3, and 24 h after the administration of [211At] NaAt. Volume of interest analysis was performed using PMOD software, and the residence time of each organ was calculated. Absorbed dose in each organ and effective dose are estimated using iDAC-dose 2.1 software (Andersson et al., 2017). The imaging capabilities of 211At are advantageous for estimating the absorbed dose in organs at risk.
FUTURE PERSPECTIVE
We have presented the current status of TAT and an investigator-initiated clinical trial using [211At] NaAt. In terms of safety management, we have confirmed that isolation in a specialised hospital room is not necessary after careful evaluation of the release criteria. Furthermore, the absorbed dose can be assessed from whole-body distribution images of a patient after administration of [211At] NaAt, aiding in the identification of organs at risk. A new production facility, equipped with a dedicated cyclotron for 211At, is currently under construction at Osaka University. These developments pave the way for future investigator-initiated clinical trials of 211At-labelled drugs, hereby enhancing the prospects for the further development of clinical applications of TAT using 211At.