NEW YORK – Researchers in Australia, Germany, and the US are exploring a new lead-212-based approach to radiopharmaceuticals that they believe could get around several limitations hindering widespread adoption of commercially available lutetium-based theranostics like Novartis' recently approved Pluvicto (177Lu-PSMA-617).
The research collaboration includes the Peter MacCallum Cancer Center in Melbourne, Australia; Uniklinik Essen in Germany; University of California Los Angeles; and University of California San Francisco. Together, the co-investigators are developing a radiopharmaceutical that selectively delivers the cell-killing alpha particle radioisotope, lead-212, to patients' cancer cells without harming surrounding tissue.
With the help of a $10 million three-year grant from the Prostate Cancer Foundation, the researchers are initially studying their lead-212 theranostic in prostate cancer. But according to principal investigator Michael Hofman, the director of the Peter MacCallum Cancer Center's Prostate Cancer Theranostics and Imaging Center of Excellence (ProsTIC), the treatment could be effective against other tumor types, too, especially if researchers decide to study new targets, such as ROR1 and DLL3, which have documented expression in different cancers.
At the moment, the researchers are identifying molecules that bind to these targets. "What we hope is that by the end of this [Prostate Cancer Foundation] award, we will have identified some small molecules targeting novel receptors labeled to the lead-212 that are ready to take into the next stage, the clinic," Hofman said.
Selecting targets, peptides
Within the project, researchers are hoping to improve on currently available prostate cancer theranostics using a multi-pronged strategy: by going after new targets, investigating biomarkers of resistance to available radiopharmaceuticals, and using an alpha particle, lead-212, that could theoretically be generated in-house to overcome supply chain challenges.
Hofman and co-investigators are using a new, messenger RNA-based technological platform to select the peptides they'll use to deliver the lead-212 payload to novel targets. With current commercially available and many late-stage investigational prostate cancer theranostics, a lutetium-177 payload is loaded onto a molecule targeting the prostate-specific membrane antigen (PSMA). But since the goal of this project is to develop a therapy that's improved versus available options, Hofman and collaborators are going a different route.
The researchers are using mRNA to create what Hofman called "massive libraries of peptides," which the researchers then put in a test tube and observe which ones bind the strongest to a preselected target. "It's almost like having a drug discovery company within a test tube," he said. "This can reduce the time frame of discovery work to weeks [rather than months]." The discovery phase involves additional steps after selecting the peptides, including modifying the peptides to minimize off-target effects and optimizing them for radiolabeling with lead-212.
"The targets we've chosen are the ones of interest that either other groups around the world aren't targeting at the moment or that we think might really benefit prostate cancer [patients] and be complementary to PSMA," Hofman said.
Whichever target and accompanying small molecule the researchers initially select to link with their lead-212 isotope and move into the clinic, Hofman said the plan is to screen patients with PET imaging first to ensure they express the target. This will involve developing a gallium-68-labeled version of the agent and using it to view full-body target expression before giving patients the new lead-212-linked therapy. This is the same approach involved in selecting patients for Novartis' Pluvicto. Before undergoing therapy with the lutetium-177-labeled PSMA-targeted therapy, doctors make sure patients' cancers express PSMA using gallium-68-labeled imaging with either Novartis' Locametz or, as of a recent supplementary US Food and Drug Administration approval, Telix's Illuccix.
"PET [imaging] is critical to selecting patients that are most likely to benefit," Hofman said, adding that from Pluvicto's trials, the field has "really strong evidence that the higher the uptake is on the PET scan, the higher the likelihood of response."
The researchers will develop an imaging version of their novel compounds before taking them into the therapeutic phase to ensure high uptake of the imaging isotope, which in turn will provide confidence that there will be high uptake of the lead-212 in the therapeutic setting. This imaging research, which Hofman called "Phase zero" trials, would precede Phase I therapeutic trials.
With the targets that Hofman and colleagues eventually select, the goal is to home in on tumor cells with treatment more precisely while avoiding exposure to healthy tissues. Even with the PSMA target, patients can sometimes express PSMA on cells of the salivary glands and small bowel and experience toxicity from PSMA-targeted radiopharmaceuticals.
With lutetium-labeled therapies like Pluvicto, the off-tumor toxicities have been relatively low and tolerable. But when it comes to delivering the much more potent type of radioisotope, an alpha particle, these off-tumor toxicities could be more severe. This underscores just how crucial it is for Hofman and colleagues to select the right target for their lead-212-based therapy.
Lead-212 potency, feasibility
Unlike the beta-emitting therapeutic radioisotope lutetium-177 used in Pluvicto, lead-212 is an alpha particle. "It's a different type of radioactive substance," Hofman said. "Alpha emitters travel a much shorter distance than beta emitters but have energies that are an order of magnitude greater. They cause a lot more damage."
To date, lead-212 has only been used in the preclinical setting and has yet to enter human theranostic trials. Hofman is hoping that will soon change. Though the toxicities are certainly a concern, the more potent cell-killing effect of the isotope could have an advantage in terms of anti-tumor activity, he explained.
Perhaps more top of mind, however, is the possibility that lead-212 may lack the manufacturing and supply chain issues that affect lutetium, which makes the lead-212 isotope more amenable to point-of-care production.
"There's a desktop-sized medical device where essentially you can push a button and it generates a dose of lead-212 that can be labeled to your target using an automatic synthesis device," Hofman said. "That can be done closer to the patient, as opposed to the Pluvicto production model where Novartis will manufacture lutetium in a large facility and then ship that dose around the world."
The idea of producing the radiopharmaceutical in-house is especially appealing in light of recent supply challenges that have hampered Pluvicto's availability. Earlier this month, Novartis paused all new patient starts for Pluvicto because it lacks regulatory approval for its US-based radiopharmaceutical manufacturing facilities. As of now, Novartis can only make commercial supplies of Pluvicto at a facility in Italy and has struggled to produce and ship sufficient quantities of the radioactive therapy to meet demand.
The in-house desktop generator approach that Hofman envisions for lead-212-based therapies would, of course, require centers to acquire these devices. This is what Hofman is currently in the process of doing for the Peter MacCallum Cancer Center. Hofman and collaborators are putting the first chunk of their $10 million grant toward acquiring some of these desktop lead-212 generators from AdvanCell. There's no set commercial cost yet, since the devices are still in a prototype phase, but Hofman thinks they might offer a more scalable solution for radiopharmaceuticals.
"It does have the potential to be cheaper than the existing lutetium-177 model, which requires a nuclear reactor to produce," he said. Meanwhile, the compound necessary for making the lead-212 generator is thorium, which is basically a waste product from the mining industry, Hofman said. "It is a compound that is widely available, [and] if you truly amortize the cost from the beginning to the end, this model ought to be cheaper … depending on how the commercialization pathway goes over time."
In other words, a cancer center would need to make the upfront investment in a desktop lead-212 generator, but acquiring the element that the generator uses to turn it into the therapeutic isotope would, in theory, be low-cost and scalable.
Commercialization discussions for a therapy that has not yet entered clinical trials may seem a bit premature. But given the challenges of trying to scale up Pluvicto, researchers in the radiopharmaceutical space, like Hofman, are increasingly thinking about manufacturing and production early in the development process, even during the earliest, target selection phases of drug discovery.
At the same time, Hofman pointed out that researchers are conducting tissue-based and circulating tumor DNA-based analyses of patients receiving Pluvicto to identify potential biomarkers of resistance. Hofman envisions a future in which this biomarker research could identify patients who could receive a new lead-212 theranostic after they stop responding to Pluvicto or new ways of sequencing or combining these treatments.