Tri-Lab effort makes strides toward increasing supply of Ac-225

In experiment after experiment, the synthetic radioisotope actinium-225 has shown promise for targeting and attacking certain types of cancer cells.

Although researchers have studied this radioisotope’s cancer-fighting potential for more than two decades, there’s not a Food and Drug Administration-approved treatment using Ac-225 — yet. But with more Ac-225 available from the DOE Isotope program and multiple clinical trials now underway, it’s likely that both an approved treatment and increased demand for the radioisotope are in the near future — and the U.S. Department of Energy wants to be ready.

Since 2014, the DOE Isotope Program has sponsored the Tri-Lab research effort to provide accelerator-produced Ac-225 for radiotherapy. Thorium-232 targets are irradiated in proton accelerators at Los Alamos and Brookhaven national laboratories.

The purpose for all this collaboration is to produce large batches more quickly and more frequently. And in June, from the Tri-Lab effort, ORNL processed the largest batch of Ac-225 ever put into inventory.

The limited supply of Ac-225, a radioisotope that doesn’t occur in nature, is a major barrier to harnessing its promise for targeted alpha therapy cancer treatment. Researchers have found the high energy the radioisotope emits can attack cancer cells, destroying their ability to replicate and sometimes killing them altogether. To keep them from destroying healthy tissue as well, researchers attach alpha emitters — such as Ac-225 — to an antibody or protein with a receptor that can lock onto cancer cells. Alpha particles emit radiation for very short distances, so the treatment can be designed to leave surrounding cells unharmed. Ac-225 is ideal because of its 10-day half-life, the time it takes to decay to 50% of its original amount, which both gives it adequate time to reach the right cells and prevents it from accumulating in large amounts in the body.

ORNL presently produces the majority of the world’s Ac-225 by harvesting it from a supply of thorium-229 that slowly decays to Ac-225. But the amount of Ac-225 currently “milked” from the thorium-229 “cow”— about 1 curie annually — is not enough even for large-scale clinical trials, let alone widespread use for treating cancers. Increasing the amount of Ac-225 derived from the thorium cow is so difficult that it’s not a viable option for scaling up production.

That’s why so much is riding on the Tri-Lab effort, which can produce large batches more frequently. June’s record-setting demonstration batch was processed from targets irradiated at Brookhaven, which produces Ac-225 using a high-energy proton beam.

“We demonstrated that the accelerator route can generate about 60% of the current annual supply of Ac-225 in just 12 days,” said Dmitri Medvedev, a scientist in Brookhaven’s Collider Accelerator Department.

Last year, the FDA acknowledged receipt of a drug master file for the Tri-Lab accelerator-produced Ac-225, which outlines details about the facilities and processes used in manufacturing, processing, packaging and storing the radioisotope to ensure the product meets specifications. Accelerator-produced Ac-225 differs slightly from the Ac-225 harvested from the thorium cow, so it requires a unique DMF and, likely, separate clinical trials.

“The drug master file is one step forward toward this ultimately being used in an FDA-approved product,” said chemist Roy Copping, who leads the Tri-Lab production program from the ORNL side.

Now, researchers are looking at two ways to further increase output: processing batches more frequently and processing larger targets.

“We are able to recover the actinium and purify it from the irradiated thorium with high efficiency,” said ORNL project manager Dan Stracener.

As part of the Tri-Lab effort, a research and development team consisting of Copping, Ashleigh Kimberlin, Mikayla Molnar and Linda Lewis developed in-cell technology to manage gas produced during production. The team began developing the technology in November 2020, spent several months testing it outside the hot cell, then implemented it in the hot cell in April 2021 — working through the challenges of a global pandemic.

“It worked even better than we expected,” Copping said.

The technology benefits production of Ac-225 at ORNL, but it can be broadly applied to future target processing at Brookhaven and Los Alamos national laboratories as well.

ORNL is planning to increase Ac-225 batch processing frequency. It’s a challenge, since there are limits on the quantity of certain types of hazardous materials that can be contained in a facility at any one time. Also, time in the hot cell for processing must be scheduled around other priority projects.

Despite obstacles, staff have maintained a steady pace.

“Our production team worked side by side with masks on in warm, enclosed spaces throughout the pandemic,” Copping said. “We never stopped.”

Tri-Lab collaborators from both Brookhaven and Los Alamos have come to ORNL to observe processing, because those two national labs eventually will process Ac-225 at their facilities. Brookhaven will commission a hot cell for Ac-225 production in early 2022. Los Alamos has a longer-range plan for building a hot cell facility for processing alpha emitters. On-site processing would increase efficiency in part because it eliminates the need to transport the targets between Tri-Lab sites, which would decrease the amount of time the short half-life radioisotope spends in limbo.

“We are looking forward to addressing the challenges that come with scaled-up efforts in order to make this critical isotope more widely available to the research and clinical communities,” said Kevin John, acting site manager for LANL isotope operations.

Stracener said ORNL is sharing best practices.

“During the past two campaigns, we’ve had observers from other national labs who are developing their own chemistry processing capability,” he said. “They’re also observing the logistic aspects of production, the specialized tools and training needed to get the target from delivery into the hot cell.”

The DOE Isotope Program is also funding research at national labs to investigate additional production methods to increase the supply of Ac-225.

“There are several alternative methods, but the Tri-Lab effort using high-energy proton accelerators is the most advanced,” Stracener said. “It has the potential for putting large amounts of Ac-225 in single batches into inventory and supplying it to customers.”

UT-Battelle manages ORNL for the DOE’s Office of Science, the single largest supporter of basic research in the physical sciences in the United States. The Office of Science is working to address some of the most pressing challenges of our time. For more information, please visit energy.gov/science.