Supply and Clinical Application of Actinium-225 and Bismuth-213

Abstract

The recent development of ²²⁵Ac-PSMA617 for therapy of prostate cancer has strikingly demonstrated the clinical potential of targeted alpha therapy. Further promising applications of the alpha emitters ²²⁵Actinium and its daughter nuclide ²¹³Bismuth include the therapy of brain tumors, bladder cancer, neuroendocrine tumors, and leukemia. This paper will provide a brief overview on the current status of the clinical development of compounds labelled with ²²⁵Ac or ²¹³Bi and describe the various production routes that are in place or are under development to meet the increasing demand for these radionuclides.

Introduction

The concept of applying ²²⁵Actinium and its daughter nuclide ²¹³Bismuth for targeted alpha therapy (TAT) of cancer was described by Geerlings et al in 1993.¹ Although the nuclides were hardly accessible at that time, the authors recognized their potential for medical application, given their favorable decay characteristics and chemical properties combined with the inherent advantages of alpha radiation of high energy and short-range in human tissue. For two decades thereafter, extensive research was performed, including the development of methods for production of ²²⁵Ac and ²¹³Bi, numerous preclinical studies and several clinical investigations. Early pioneering clinical work focused on treatment of leukemia,^2,3 non-Hodgkins lymphoma (NHL),⁴ malignant melanoma,^{5, 6, 7} brain tumors,^{8, 9, 10, 11} neuroendocrine tumors,^12,13 and bladder cancer.¹⁴ In 2013, 20 years after the initial work of Geerlings et al, the compound ²²⁵Ac-PSMA617 was first synthesized and investigated at Joint Research Centre (JRC) Karlsruhe. The remarkable efficacy of this novel compound manifested already in early patient studies conducted in collaboration of JRC and University Hospital Heidelberg and was first reported by Kratochwil et al in 2016.¹⁵ While the clinical application of ²²⁵Ac-PSMA617 was further developed in collaboration of JRC with hospitals in Heidelberg,^16,17 Pretoria,^{18, 19, 20} and Munich,²¹ the remarkable benefit observed clinically in an increasing number of patients stimulated worldwide interest in applying ²²⁵Ac in TAT. Consequently, an increasing number of novel ²²⁵Ac-labeled compounds are currently under development, and production facilities to meet the increasing demand for the nuclide have been set up or are under construction. This paper will summarize important clinical investigations with ²²⁵Ac- and ²¹³Bi-labelled compounds just briefly, as they will be described in much detail in other contributions in this issue. Furthermore, the current status of production of ²²⁵Ac will be reviewed.

Clinical Experience With ²²⁵Ac and ²¹³Bi

The current state of clinical investigation of ²²⁵Ac- and ²¹³Bi-labelled compounds is summarized in Table 1. The early studies on TAT of leukemia, NHL, malignant melanoma, and the more recent pilot trial on bladder cancer investigated ²¹³Bi- or ²²⁵Ac-labeled antibodies. While the combination of short-lived ²¹³Bi (T_1/2) = 46 minutes and full antibodies holds promise for the targeting of rapidly accessible, blood-associated cancers such as leukemia^2,3 or NHL,⁴ the ²¹³Bi-labelled anti-MCSP-antibody investigated for the treatment of malignant melanoma^{5, 6, 7} probably failed to deliver sufficient tumor dose due to the slower pharmacokinetics of the construct. In contrast, the intravesical application of ²¹³Bi-anti-EGFR-mAb for therapy of carcinoma in situ¹⁴ is an excellent approach that facilitates rapid and very selective targeting and minimizes toxicity to other organs.

Table 1.

Overview of Current Clinical Experience With ²²⁵Ac- and ²¹³Bi-Labeled Compounds

Cancer Type	Radioconjugate	Patients	Reference
Leukemia	213Bi-anti-CD33-mAb	49	2,3
	225Ac-anti-CD33-mAb	76	22
Lymphoma	213Bi-anti-CD20-mAb	12	4
Melanoma	213Bi-anti-MCSP-mAb	54	5, 6, 7
Bladder cancer	213Bi-anti-EGFR-mAb	12	14
Glioma	213Bi-Substance P	68	8, 9, 10, 11
	225Ac-Substance P	20	23
Neuroendocrine tumors	213Bi-DOTATOC	25	12
	225Ac-DOTATOC	39	13
Prostate cancer	225Ac-PSMA617	>400	15, 16, 17, 18, 19, 20, 21

The combination of short-lived ²¹³Bi and low molecular weight, rapidly diffusing peptides, such as DOTATOC and Substance P analogues, showed promising results for the treatment of neuroendocrine tumors^12,13 and gliomas,^{8, 9, 10, 11} in particular after locoregional administration for improved tumor uptake. In collaboration of JRC Karlsruhe and University Hospital Heidelberg 25 patients with multiresistant neuroendocrine tumors refractory to therapy with beta emitter labeled ⁹⁰Y-/¹⁷⁷Lu-DOTATOC were treated with ²¹³Bi-DOTATOC. Although patients presented in clinically challenging situations and had developed resistance against therapy with beta emitters, TAT with ²¹³Bi-DOTATOC resulted in a high number of long-lasting antitumor responses, including one complete remission. Hematotoxicity was dose-limiting, and potential long-term renal toxicity has to be considered and closely monitored.

Locoregional application of ²¹³Bi-[Thi⁸,Met(O₂)¹¹]-substance P for treatment of gliomas has been found safe after injection of doses of 2 GBq in 2-month interval up to cumulative doses of 11.2 GBq with only mild and transient adverse reactions. The median overall survival after recurrence of 10.9 months observed in a cohort of 20 patients with recurrent glioblastoma (GBM) compares favorably to available alternative treatments.¹¹ Also in a small cohort of nine patients suffering from secondary GBM, treatment with ²¹³Bi-[Thi⁸,Met(O₂)¹¹]-substance P was well tolerated and resulted in median overall survival of 18.6 months after conversion of the primary low grade glioma to grade IV GBM.¹⁰ Two out of nine patients with secondary GBM were still alive 39 and 51 months after initiation of locoregional alpha therapy.

While the combination of low molecular weight, rapidly diffusing peptides with local modes of administration holds promise for therapeutic application of short-lived ²¹³Bi, the high cost and currently still limited supply of high activity ²²⁵Ac/²¹³Bi generators required for preparation of patient doses in the multiple GBq range still poses considerable limitations for clinical application of these treatment approaches. These limitations can be overcome to some extent through application of ²²⁵Ac with its longer half-live of 9.9 days and its higher cytotoxicity associated with the multiple alpha particles generated in its decay chain.

The first in human clinical investigation of a ²²⁵Ac-labeled small molecule was started in 2011 in collaboration of JRC Karlsruhe and University Hospital Heidelberg for therapy of patients with neuroendocrine tumors using ²²⁵Ac-DOTATOC.¹³ In a group of 39 patients, the treatment was found to be safe with activities of 18.5 MBq given in 2-month interval up to a cumulative dose of 75 MBq. The MTD of a single dose was determined as 40 MBq. Although several of patient responses were observed, further investigations are needed to improve patient selection and fractionation regimes.

The development of ²²⁵Ac-PSMA617 for therapy of prostate cancer can be considered a milestone in the evolution of TAT. The pharmacokinetics of PSMA617, in particular its rapid tumor uptake within a few hours, its extended tumor retention as well as its rapid renal clearance of unbound compound provide an excellent match to the decay characteristics of long-lived ²²⁵Ac. In particular the high degree of internalization of PSMA617 allows intracellular capture of the decay daughters of ²²⁵Ac and utilizing their cytotoxicity for tumor cell kill, while minimizing toxicity of errant daughters. Following the development and in vitro characterization of ²²⁵Ac-PSMA617 at JRC Karlsruhe in 2013/2014, clinical testing was started initially in collaboration of JRC Karlsruhe with University Hospital Heidelberg, and subsequently extended to Steve Biko Academic Hospital Pretoria and Technical University Munich.

For initial clinical application of ²²⁵Ac-PSMA617, a standardized protocol was developed based on a dosimetry estimate and retrospective evaluation of the efficacy and tolerability of salvage therapies performed in 14 advanced stage metastatic castration-resistant prostate cancer patients, consisting of a treatment activity of 100 kBq/kg of ²²⁵Ac-PSMA617 per cycle repeated twice every 8 weeks.¹⁶ In a cohort of 40 advanced stage patients the protocol demonstrated remarkable antitumor efficacy, while xerostomia (dry mouth syndrome) was observed as main adverse effect leading to discontinuation of treatment in 10% of patients.¹⁷ In subsequent clinical investigations, ²²⁵Ac-PSMA617 was administered in fixed activities of 8 MBq for the first cycle (corresponding to 100 kBq/kg body weight in a typical patient of 80 kg) for reasons of standardization and simplification of procedures. In addition, to minimize damage to salivary glands, administered activities in subsequent cycles were de-escalated to 7-4 MBq as function of patient response.¹⁸ An analysis of 73 patients treated with ²²⁵Ac-PSMA617 at Steve Biko Academic Hospital in Pretoria demonstrated excellent therapeutic efficacy and increased tolerability of this de-escalation approach, showing a Prostate specific antigen (PSA) decline of ≥50% in 70% of patients, while 83% of patients had any PSA decline and 0% of patients discontinued treatment.¹⁹ Another promising approach for maintaining high therapeutic efficacy while minimizing toxicity to salivary glands is the combination of alpha- and beta emitter labelled PSMA617. An interim analysis of a first group of 17 patients with advanced metastatic castration-resistant prostate cancer treated with a combination of 4 MBq ²²⁵Ac-PSMA617 and 4 GBq ¹⁷⁷Lu-PSMA617 demonstrated improved tolerability with a response rate of 76% (PSA decline >50%).²⁴ Notably, therapy with ²²⁵Ac-PSMA617 was also found to be effective for brain metastases in advanced prostate cancer patients.²⁰

Production of ²²⁵Ac and ²¹³Bi

Radiochemical Extraction of ²²⁵Ac From ²²⁹Th

The radiochemical extraction of ²²⁵Ac from ²²⁹Th (T_1/2 = 7917 years) sources has been the workhorse for production of ²²⁵Ac and ²¹³Bi since the early 1990s. All clinical investigations and virtually all preclinical research with ²²⁵Ac and ²¹³Bi-labelled compounds to date have been conducted with radionuclides obtained from ²²⁹Th decay. Worldwide three sources of ²²⁹Th are available that allow the production of clinically relevant activities of ²²⁵Ac/²¹³Bi, located at the Directorate for Nuclear Safety and Security of the JRC of the European Commission in Karlsruhe, Germany (formerly known as Institute for Transuranium Elements),²⁵ Oak Ridge National Laboratory (ORNL), USA²⁶ and at the Institute of Physics and Power Engineering (IPPE) in Obninsk, Russia.²⁷ The ²²⁹Th sources have been obtained by separation from aged, fissile ²³³U originally produced for weapons applications by neutron irradiation of natural ²³²Th. More recently the preparation of a small scale ²²⁹Th source has been also reported from Canadian Nuclear Laboratories.²⁸ Notably, it has been reported that from 2019 onward a very significant increase in availability of ²²⁹Th will be generated through extraction of ²²⁹Th from legacy wastes stored within the US Department of Energy. The total amount of accessible ²²⁹Th has been estimated to up to 45 g, corresponding to a potential increase in ²²⁵Ac supply of up to 40 fold compared to current levels.²⁹

The production of ²²⁵Ac from ²²⁹Th at JRC Karlsruhe is based on a combination of anion exchange and extraction chromatography,^25,30 while the process in place at ORNL is utilizing anion and cation exchange.²⁶ JRC has been the first laboratory to prepare ²²⁵Ac/²¹³Bi for clinical use in the mid 1990s and has since then produced approximately 13 GBq ²²⁵Ac annually for preclinical research and clinical testing performed at JRC Karlsruhe or in collaboration with a wide network of clinical partners. The maximum annual production of ²²⁵Ac at ORNL is approximately 33 GBq, while IPPE has reported a production of 22 GBq per year.²⁷ While ²²⁵Ac produced at JRC Karlsruhe and ORNL has been extensively applied for patient treatment and found safe for administration to humans, direct clinical application of ²²⁵Ac produced at IPPE to our knowledge has not been reported to date.

²²⁵Ac can be used directly as therapeutic nuclide or can be loaded on ²²⁵Ac/²¹³Bi generators to provide short-lived ²¹³Bi on site. In general ²²⁵Ac/²¹³Bi generators based on AG MP-50 cation exchange resin are most established and have been used for all patient studies with ²¹³Bi to date.³¹ The high activity generator system developed at JRC Karlsruhe allows reliable operation of the generator when loaded with activities up to 4 GBq ²²⁵Ac with yields of ²¹³Bi elution exceeding 80% and a low breakthrough of ²²⁵Ac parent nuclide of less than 0.2 ppm (activity).³² A key feature during preparation of this generator is the process of loading the parent nuclide, resulting in the distribution of ²²⁵Ac activity over approximately two thirds of the generator resin in order to minimize radiolytic degradation of the organic resin and to assure reliable operation over several weeks. The generator has been successfully used clinically for preparation of therapeutic doses of ²¹³Bi-labelled peptides with activities up to 2.3 GBq at time of injection.

Accelerator-Based Routes

Currently the global supply of ²²⁵Ac from ²²⁹Th is still insufficient for widespread routine application of ²²⁵Ac and ²¹³Bi-labelled compounds in hospitals worldwide. Consequently, a variety of alternative methods for large scale production of ²²⁵Ac have been investigated, including the spallation of ²³²Th or ^natU targets with highly energetic protons and the irradiation of ²²⁶Ra targets using protons, deuterons or gamma-rays.³³

Among these routes, the production of ²²⁵Ac by spallation of ²³²Th is currently the most advanced. The feasibility of the process has been demonstrated at the Institute for Nuclear Research, Russian Academy of Sciences, in Troitsk, Russia^34,35 and at Los Alamos National Laboratory in the US.^36,37 In the last years the routine production of ²²⁵Ac via spallation of ²³²Th has been successfully established within the US DoE Tri-Lab (ORNL, BNL, LANL) effort. Irradiations can be performed at Brookhaven National Laboratory (200 MeV at 165 μA) and Los Alamos National Laboratory (100 MeV at 275 μA), while targets are processed and the final product is distributed from ORNL.³⁸ The main limitation of the process is the coproduction of long-lived ²²⁷Ac (T_1/2 = 21.8 years) at levels of 0.1%-0.2% activity (at EOB). Since ²²⁵Ac and ²²⁷Ac isotopes cannot be chemically separated, the implications of the ²²⁷Ac impurity for the clinical application of the ²²⁵Ac product have to be considered. Initial studies indicate that the impact of the ²²⁷Ac impurity on patient dosimetry will be negligible.³⁹ However, issues related to licensing, safe handling, and disposal of long lived ²²⁷Ac in hospital settings still have to be resolved.

The production of ²²⁵Ac by proton irradiation of ²²⁶Ra targets in a cyclotron through the reaction ²²⁶Ra(p,2n)²²⁵Ac offers a number of advantages over the ²³²Th spallation reaction. The process can be performed with high yields in a cost-effective manner in medium-sized cyclotrons at proton energies below 20 MeV.⁴⁰ A 24 hour irradiation of 50 mg ²²⁶Ra at the maximum of the excitation function at 15-16 MeV with a current of 100 µA protons is expected to yield approximately 5 GBq ²²⁵Ac, equivalent to 500 patient doses of 10 MBq ²²⁵Ac. Chemical purification of the irradiated targets yields ²²⁵Ac of high isotopic purity as no other long-lived actinium isotopes such as ²²⁷Ac (T_1/2 = 21.8 years) are co-produced. Co-production of impurities of short-lived ²²⁶Ac (T_1/2 = 29 hours) and ²²⁴Ac (T_1/2 = 2.9 hours) formed according to the reactions ²²⁶Ra(p,n)²²⁶Ac and ²²⁶Ra(p,3n)²²⁴Ac can be minimized through selection of appropriate proton energies. In addition, their activity will further decay to low levels during the time required for target cooling and reprocessing. The main challenges of the process are related to the preparation and handling of targets containing milligram amounts of radioactive ²²⁶Ra (T_1/2 = 1600 years) and management of its gaseous decay product ²²²Rn (T_1/2 = 3.8 days). Currently research on implementation of this production route is ongoing in facilities in North and South America, Europe, and Asia.

The irradiation of ²²⁶Ra with deuterons according to the reaction ²²⁶Ra(d,3n)²²⁵Ac has been suggested as an improved method for production of ²²⁵Ac.³³ Cross-sections for the reaction have not been measured experimentally yet, however, model calculations are predicting a maximum cross-section of 864 mb at 18.5 MeV and slightly increased production yields compared to the ²²⁶Ra(p,2n)²²⁵Ac reaction. However, deuteron irradiation would lead to an enhanced co-production of ²²⁶Ac (T_1/2 = 29 hours) via the reaction ²²⁶Ra(d,2n)²²⁶Ac, making an extended cooling time necessary to allow for ²²⁶Ac decay. In addition, only few accelerators are available that can provide deuteron beams of sufficient energy.

Another route for production of ²²⁵Ac via irradiation of ²²⁶Ra is based on the photonuclear reaction ²²⁶Ra(γ,n)²²⁵Ra and subsequent beta decay of ²²⁵Ra to ²²⁵Ac. The reaction has a photon energy threshold of 6.4 MeV, experimentally measured cross-section data are not available to date. However, as modeling data predict moderate reaction yields,⁴¹ modern accelerators providing high-intensity electron beams are required for commercially viable production. Proof of principle of the process has been demonstrated on laboratory scale at JRC Karlsruhe.⁴² Betatron irradiation of a zircaloy capsule containing 1 mg ²²⁶Ra embedded in 800 mg BaCl₂ matrix for 3.5 hours at 52 MeV led to production of 0.24 µCi of ²²⁵Ac. Feasibility of the process has also been successfully demonstrated at Joint Institute for Nuclear Research, Dubna, Russia⁴³ and at the Illawarra Cancer Centre, in Wollongong, Australia.⁴⁴ Maslov et al reported a radiation yield of 550 Bq/(µAh mg ²²⁶Ra) at 24 MeV maximal photon energy. The detailed measurement of cross-section data for this reaction is highly desirable for more accurate prediction of production yields. Nevertheless, implementation of the process for large scale production of ²²⁵Ac is already underway at several facilities.⁴⁵

Conclusions

Reports on the remarkable therapeutic efficacy of ²²⁵Ac-PSMA617 for therapy of prostate cancer have stimulated significant global interest in applying ²²⁵Ac as therapeutic nuclide in TAT of cancer. It is expected that in order to meet the rising future demand for supply of the alpha emitter a variety of production routes will be utilized, including the extraction of additional ²²⁹Th stocks from US legacy wastes and the implementation of various accelerator based routes. In this respect common criteria for quality of the ²²⁵Ac product need to be established in order to facilitate safe clinical use of the radionuclide independent of its production pathway.