Current Radiopharmaceuticals - Volume 11, Issue 3, 2018

Background: The development of radiopharmaceuticals containing 225Ac for targeted alpha therapy is an active area of academic and commercial research worldwide. Objectives: Despite promising results from recent clinical trials, 225Ac-radiopharmaceutical development still faces significant challenges that must be overcome to realize the widespread clinical use of 225Ac. Some of these challenges include the limited availability of the isotope, the challenging chemistry required to isolate 225Ac from any co-produced isotopes, and the need for stable targeting systems with high radiolabeling yields. Results: Here we provide a review of available literature pertaining to these challenges in the 225Acradiopharmaceutical field and also provide insight into how performed and planned efforts at TRIUMF - Canada's particle accelerator centre - aim to address these issues.

Background: The radionuclide 225Ac and its daughter 213Bi are among the most interesting alpha emitters being evaluated for incorporation into targeted therapeutic vectors. Global supply of 225Ac is presently insufficient to meet anticipated clinical demand, but the deficiency has been targeted by many research and development efforts, privately and publicly funded. From more than a decade of these endeavors, no single production technology has emerged as a complete solution. In the foreseeable future, global supply of 225Ac will continue to be sourced from a patchwork of production methods and laboratories with a range of radioisotopic purities and achievable yields. Objective and Conclusion: This manuscript attempts to present an overview of availability sources of 225Ac and production methods by which additional supplies might be made available to the community of clinical researchers seeking their application in the treatment of human disease.

Objective: Actinium-225, and its daughter Bismuth-213, have great promise in Alpha Immuno Therapy (AIT) for treatment of various disease modalities. Unfortunately, current production levels of actinium-225 do not support broad use of either actinium-225 or bismuth-213 in development or use for disease treatment. Further, the current cost per millicurie is much too high to be sustainable long term. Resolution of both supply and cost issues allows clinical research to proceed through clinical trials and potentially produce one or more effective therapies for cancer or infectious diseases that could benefit the public. Methods: NorthStar Medical Technologies, LLC, has investigated several routes that could lead to commercial scale production of actinium-225. Results: This article will discuss those efforts and results to date. Conclusion: The outlook for future supplies of actinium-225 from multiple sources to support clinical needs is encouraging.

Objectives: Due to the shorter range and higher linear energy transfer of α-particles compared to β-particles, targeted α-particle therapy may produce more efficient tumor killing while sparing neighboring healthy cells. We will review the clinical studies using α-particle therapy for Acute Myeloid Leukemia (AML). Methods: A series of clinical trials were conducted to assess the safety, feasibility, and anti-leukemic effects of lintuzumab, an anti-CD33 humanized monoclonal antibody, labeled with the α-emitters bismuth- 213 (213Bi) and actinium-225 (225Ac). Results: An initial phase I study conducted in 18 patients with relapsed or refractory AML demonstrated the safety and antitumor effects of 213Bi-lintuzumab. Subsequently, 213Bi-lintuzumab produced remissions in AML patients after partial cytoreduction with cytarabine in phase I/II trial. The 46- minute half-life of 213Bi and need for an onsite generator has limited its utility. Therefore, a secondgeneration construct was developed using 225Ac, a radiometal that yields four α-particle emissions. A phase I trial demonstrated that a single infusion of 225Ac-lintuzumab could be given safely at doses up to 111 kBq/kg with anti-leukemic activity across all dose levels studied. In a second phase I study, 28% of older patients with untreated AML had objective responses after receiving fractionated-dose 225Aclintuzumab and low-dose cytarabine. Conclusion: Based upon the encouraging results seen in phase I trials of 225Ac-lintuzumab, a phase II study of 225Ac-lintuzumab monotherapy for older patients with untreated AML is now in progress and is also being studied in a subset of patients with CD33-positive multiple myeloma.

Background: Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy. Objective and Conclusion: This review describes methods for the production of 225Ac and its daughter nuclide 213Bi and summarizes the current clinical experience with both alpha emitters with particular focus on recent studies of targeted alpha therapy of bladder cancer, brain tumors, neuroendocrine tumors and prostate cancer.

Background: Radiopharmaceutical therapy is a cancer treatment modality by which radiation is delivered directly to targeted tumor cells or to their microenvironment. This makes it possible to deliver highly potent alpha-particle radiation. The short-range and highly potent nature of alpha-particles require a dosimetry methodology that considers microscale distributions of the alpha-emitting agent. The high energy deposition density along an alpha-particle track causes a spectrum of DNA lesions. The majority of these are irreparable DNA double-stranded breaks. Accordingly the biologic effects of alpha- particles are largely impervious to the adaptive and resistance mechanism that renders other therapeutics ineffectual. Objectives: In this review, the radiobiology and dosimetry of alpha-particle emitting radionuclides as related to their use in radiopharmaceutical therapy, are presented. Conclusion: Alpha-particle emitter radiopharmaceutical therapy is distinguished from other treatment modalities. Its safe clinical use requires an understanding of its unique dosimetry and radiobiology.

Background and Objective: The demand for the alpha-emitting radionuclide Actinium-225 (225Ac) for use in radionuclide therapy is growing. Producing 225Ac using high energy linear accelerators, cyclotrons or photoinduction could increase its supply. One potential problem with accelerator produced 225Ac using Thorium-232 targets is the presence in final product of 0.1-0.3% by activity of the long-lived 227Ac impurity at the end of irradiation. It is important to comprehensively evaluate the behavior of accelerator-produced 225Ac in vivo before using it in pre-clinical and clinical applications. Methods: Biodistribution of accelerator-produced 225Ac in acetate (free) and DOTA complex forms was performed in male and female CD-1 mice. The biodistribution data was used for radiation dosimetry calculations. The toxicity studies of free 225Ac were conducted in CD-1 mice at 1.036 and 2.035 kBq/g body weight. Blood counts, body weight and post-mortem histology were evaluated. Results: In both genders, there was a pronounced uptake of free 225Ac in the liver when compared to 225Ac-DOTA which resulted in 200 and 50 times higher liver radiation dose for free 225Ac in male and female mice, respectively. 227Ac contribution to radiation dose delivered by 225Ac was calculated to be negligible. Mice given free 225Ac did not lose weight, had only transient effect on their blood counts and showed no histological damage to the liver and bone marrow. Conclusion: Our biodistribution/dosimetry/toxicity study of accelerator-produced 225Ac demonstrated the patterns very similar to 229Th-derived 225Ac. We conclude that accelerator-produced 225Ac is suitable for the developmental work of targeted radionuclide therapy.

Background: Conjugates of bisphosphonates with macrocyclic chelators possess high potential in bone targeted radionuclide imaging and therapy. DOTAZOL, zoledronic acid conjugated to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), demonstrated promising results in vivo in small animals as well as in first patient applications using 68Ga for diagnosis via PET and the lowenergy β-emitter 177Lu for therapy of painful bone metastases. In consideration of the fact that targeted α-therapy probably offers various advantages over the use of β--emitters, the 225Ac-labelled derivative [225Ac]Ac-DOTAZOL was synthesized and evaluated in vivo. Here, we report on radiolabelling and biodistribution of [225Ac]Ac-DOTAZOL in healthy Wistar rats. Methods: DOTAZOL was labelled with 225Ac and injected without further purification into the tail vein with activities of 404 ± 47 kBq per animal. Ex vivo biodistribution studies were performed in healthy Wistar rats at 1 hour, 24 hours, 5 days and 10 days post injection. The accumulation of [225Ac]Ac- DOTAZOL on healthy bone and soft tissue organs was determined in terms of SUV. The results were compared to those of other radiolabelled bisphosphonates such as [68Ga]Ga-DOTAZOL and [177Lu]Lu- DOTAZOL. A group of 7 animals was observed over a period of 3 month after application of 394 kBq ± 10 kBq of [225Ac]Ac-DOTAZOL for signs of toxicity. After 3 months, kidneys were microscopically analysed for signs of chronic kidney damage. Results: Radiolabelling of DOTAZOL with 225Ac at 98 °C provided radiochemical yields ≥98 % within 30 minutes. [225Ac]Ac-DOTAZOL showed high femur uptake (SUVfemur = 4.99 ± 0.97, 10 d p.i.), which was comparable to that of other Me(III)-DOTAZOL derivatives. Ratios between bone uptake and blood pool activity reached levels of 5, 940, 2181 and 2409 at 1 hour, 24 hours, 5 days and 10 days post injection. During the observation period of the first two month no toxicity was observed clinically. Histopathology of kidneys after 3 month revealed significant tubular damage in most of the animals. Conclusion: [225Ac]Ac-DOTAZOL repeats the well-known pharmacology of DOTAZOL derivatives in preclinical evaluations. It thus may be considered for translational application together with strategies to reduce renal toxicity.