Comparing Lead-212 and Actinium-225 Alpha Emitters for Prostate Cancer Treatment "Presentation" - Alfred Morgenstern
April 30, 2025
At the 2025 UCSF-UCLA PSMA Conference, Alfred Morgenstern compares two alpha emitters: actinium-225 and lead-212. He explains each requires different strategies for capturing daughter nuclides - internalizing ligands for actinium-225 and appropriate chelates for lead-212. While actinium-225 lacks a theranostic pair, lead-212 offers better imaging capabilities.
Biography:
Alfred Morgenstern, European Commission, JRC Karlsruhe, Unit G.I.5 Nuclear Science & Innovation for Energy & Health
Biography:
Alfred Morgenstern, European Commission, JRC Karlsruhe, Unit G.I.5 Nuclear Science & Innovation for Energy & Health
Read the Full Video Transcript
Alfred Morgenstern: So hello again. I guess being the alpha guy, I was asked to speak about lead 212 and actinium 225 in comparison. And actually, I think both are very promising alpha emitters. As you know, the actinium 225 has a relatively long half-life of nearly 10 days, generating 4 alphas in its decay chain, while lead 212 is a bit shorter-lived, with a 10-hour half-life, generating 1 alpha in its decay.
So for both nuclides, it's going to be important to capture the daughter nuclides at the target site, to make sure they contribute to the therapeutic effect, instead of inducing toxicity. For the actinium 225, it's very helpful to work with an internalizing ligand, while for the lead 212, the general strategy is to have an appropriate chelate that's capturing the bismuth 212 upon beta decay of the lead 212.
The typical dose for actinium PSMA is 8 MBq. For the lead 212 PSMA, this is still under evaluation. At the moment, it's between 60 and 200 MBq, which is being looked at. Imaging with actinium 225 is challenging. It's doable, and technologies are improving, but it's challenging, with lead 212 much more useful.
There's no theranostic pair for the actinium 225. But for the lead 212, you can work with lead 203 for imaging. Radiation exposure of staff is very low, with 8 MBq of actinium. With the lead 212, it's a bit more challenging, and we need to manage because of the high-energy gamma emission of the thallium 208, with 2.6 MeV.
If you look at waste in the clinical setting, typically, the actinium waste needs to be stored for about three months to have a good decay. For the lead 212, this is really a matter of days.
Looking at supply, for basically 30 years, the supply of actinium all came from extraction from thorium 229. Sources were initially at JSC and Oak Ridge. Later on, the Russian source came online. And more recently, Canadian Nuclear Laboratories and TerraPower started supplying.
Then, of course, you have the possibility to get actinium 225 from spallation of thorium 232, which was pioneered by the DOE in the Tri-Lab effort. But that product contains actinium 227, which is a bit problematic for handling and waste issues in the hospital.
And then, there's other processes like γ,n and p,2n reactions on radium 226, which now have come online. And that will really strongly improve the supply situation in the future.
For the lead 212, I think the supply is much better. You can extract thorium 228 from natural ores containing thorium 232 or uranium 232. And another possibility is multiple neutron capture on radium 226 targets during irradiation at a high-flux reactor. However, we have to keep in mind that radium 226 has become a very expensive and rare starting material nowadays, because it's also used for production of actinium 225.
So there's a number of approaches to have lead 212 generators. For the sake of time, I'm going to skip this. But maybe the message is, with a 10.6-hour half-life of lead 212, it's still possible to have centralized manufacturing of lead 212-labeled radiopharmaceuticals in distribution.
We've already heard much more about radiobiology than I can cover here. We all know alpha emitters induce a very strong immune response. There's so much more than just DNA double-strand breaks. The lead 212 has a half-life which is 22 times shorter than the actinium. So that is a possibility to match it with ligands with different pharmacokinetics. FAPI might be a good candidate there for lead 212, for example, in contrast to actinium.
Of course, with the lead 212, you have a more rapid deposition of dose and production of radicals and immune responses. So there might be a difference between lead and actinium. But that still has to be investigated.
This is a slide that has been shown by Thomas Kryza from AdvanCell at EANM last year in Hamburg, and I'm very grateful to him for sharing this. He looked at the molecular mechanisms triggered in prostate cancer cells after irradiation with lead 212 AdvanCell-001 targeting PSMA. And he saw a number of pathways that were modulated after lead 212 treatment in DNA damage repair, cell cycle, immune-response regulation, and so on.
And he was actually also able to look at this in prostate cancer xenografts, comparing lutetium PSMA I&T and lead 212 AdvanCell-001. And actually, there are a number of pathways that were overlapping. They were dysregulated by lutetium and actinium.
But there were quite a number of pathways that were unaffected by the lutetium but that were modulated due to the alpha radiation, in particular, with respect to cell-cycle regulation. So I think this will be really an important approach in the future to utilize these mechanisms and to design appropriate combination therapies.
On the clinical side, the number of clinical studies ongoing with lead 212 in prostate cancer is still few. There is the Phase 0 study that was just recently published by ARTBIO, then, much more advanced, the Phase I/Phase II study by AdvanCell, and a study by ORANO on a different target.
The Phase 0 study was just published two weeks ago by the Oslo colleagues. The primary objective of this study was basically to investigate the feasibility of gamma-camera imaging of lead 212, to assess biodistribution and lesion uptake. They injected a very low dose of only 9 MBq of lead 212 AB001.
They found this was safe. The compound was stable in vivo, which is really good. Imaging was feasible but still needs optimization. And they are now in the process of designing Phase I studies utilizing higher lead doses. And these were some of the images that were published by the Oslo colleagues. And you can see that imaging of 9 MBq lead 212 is quite challenging.
Much more advanced, obviously, is the Phase I/Phase II study done by AdvanCell. And thank you very much to Anna Karmann for sharing these slides with me. This is a study that currently enrolls at 60, 120 and 200 MBq of lead 212. Intermediate results are very promising. There are no signs of myelosuppression, no Grade 3 serious adverse events.
And, very interesting, there's very low salivary-gland uptake of this compound—so far, only Grade 1 xerostomia with no treatment discontinuation. I understand the intermediate results of this study will be presented at ESMO later this year.
And last year, there was an image published out of this study. The patient receiving 60 MBq of lead 212, which is showing a very nice biodistribution, with low salivary-gland uptake and rapid kidney clearance. And another very recent image, and again, thank you to Anna for sharing. This is an image of a lead 212 AdvanCell-001 patient, treated with 160 MBq. Again, you see a very nice biodistribution—nice images, low salivary-gland uptake.
So to conclude, I think both actinium PSMA and lead PSMA are very promising compounds for therapy of prostate cancer. The therapeutic efficacy of the lead 212 PSMA ligands is still under investigation, still needs to be demonstrated. But we have two alpha emitters here with different half-lives that we can combine with ligands of different pharmacokinetics, like FAPI, for example, for the lead 212, might be an interesting combination. But of course, securing the supply of both alpha emitters will be crucial for rapid further development. Thank you.
Alfred Morgenstern: So hello again. I guess being the alpha guy, I was asked to speak about lead 212 and actinium 225 in comparison. And actually, I think both are very promising alpha emitters. As you know, the actinium 225 has a relatively long half-life of nearly 10 days, generating 4 alphas in its decay chain, while lead 212 is a bit shorter-lived, with a 10-hour half-life, generating 1 alpha in its decay.
So for both nuclides, it's going to be important to capture the daughter nuclides at the target site, to make sure they contribute to the therapeutic effect, instead of inducing toxicity. For the actinium 225, it's very helpful to work with an internalizing ligand, while for the lead 212, the general strategy is to have an appropriate chelate that's capturing the bismuth 212 upon beta decay of the lead 212.
The typical dose for actinium PSMA is 8 MBq. For the lead 212 PSMA, this is still under evaluation. At the moment, it's between 60 and 200 MBq, which is being looked at. Imaging with actinium 225 is challenging. It's doable, and technologies are improving, but it's challenging, with lead 212 much more useful.
There's no theranostic pair for the actinium 225. But for the lead 212, you can work with lead 203 for imaging. Radiation exposure of staff is very low, with 8 MBq of actinium. With the lead 212, it's a bit more challenging, and we need to manage because of the high-energy gamma emission of the thallium 208, with 2.6 MeV.
If you look at waste in the clinical setting, typically, the actinium waste needs to be stored for about three months to have a good decay. For the lead 212, this is really a matter of days.
Looking at supply, for basically 30 years, the supply of actinium all came from extraction from thorium 229. Sources were initially at JSC and Oak Ridge. Later on, the Russian source came online. And more recently, Canadian Nuclear Laboratories and TerraPower started supplying.
Then, of course, you have the possibility to get actinium 225 from spallation of thorium 232, which was pioneered by the DOE in the Tri-Lab effort. But that product contains actinium 227, which is a bit problematic for handling and waste issues in the hospital.
And then, there's other processes like γ,n and p,2n reactions on radium 226, which now have come online. And that will really strongly improve the supply situation in the future.
For the lead 212, I think the supply is much better. You can extract thorium 228 from natural ores containing thorium 232 or uranium 232. And another possibility is multiple neutron capture on radium 226 targets during irradiation at a high-flux reactor. However, we have to keep in mind that radium 226 has become a very expensive and rare starting material nowadays, because it's also used for production of actinium 225.
So there's a number of approaches to have lead 212 generators. For the sake of time, I'm going to skip this. But maybe the message is, with a 10.6-hour half-life of lead 212, it's still possible to have centralized manufacturing of lead 212-labeled radiopharmaceuticals in distribution.
We've already heard much more about radiobiology than I can cover here. We all know alpha emitters induce a very strong immune response. There's so much more than just DNA double-strand breaks. The lead 212 has a half-life which is 22 times shorter than the actinium. So that is a possibility to match it with ligands with different pharmacokinetics. FAPI might be a good candidate there for lead 212, for example, in contrast to actinium.
Of course, with the lead 212, you have a more rapid deposition of dose and production of radicals and immune responses. So there might be a difference between lead and actinium. But that still has to be investigated.
This is a slide that has been shown by Thomas Kryza from AdvanCell at EANM last year in Hamburg, and I'm very grateful to him for sharing this. He looked at the molecular mechanisms triggered in prostate cancer cells after irradiation with lead 212 AdvanCell-001 targeting PSMA. And he saw a number of pathways that were modulated after lead 212 treatment in DNA damage repair, cell cycle, immune-response regulation, and so on.
And he was actually also able to look at this in prostate cancer xenografts, comparing lutetium PSMA I&T and lead 212 AdvanCell-001. And actually, there are a number of pathways that were overlapping. They were dysregulated by lutetium and actinium.
But there were quite a number of pathways that were unaffected by the lutetium but that were modulated due to the alpha radiation, in particular, with respect to cell-cycle regulation. So I think this will be really an important approach in the future to utilize these mechanisms and to design appropriate combination therapies.
On the clinical side, the number of clinical studies ongoing with lead 212 in prostate cancer is still few. There is the Phase 0 study that was just recently published by ARTBIO, then, much more advanced, the Phase I/Phase II study by AdvanCell, and a study by ORANO on a different target.
The Phase 0 study was just published two weeks ago by the Oslo colleagues. The primary objective of this study was basically to investigate the feasibility of gamma-camera imaging of lead 212, to assess biodistribution and lesion uptake. They injected a very low dose of only 9 MBq of lead 212 AB001.
They found this was safe. The compound was stable in vivo, which is really good. Imaging was feasible but still needs optimization. And they are now in the process of designing Phase I studies utilizing higher lead doses. And these were some of the images that were published by the Oslo colleagues. And you can see that imaging of 9 MBq lead 212 is quite challenging.
Much more advanced, obviously, is the Phase I/Phase II study done by AdvanCell. And thank you very much to Anna Karmann for sharing these slides with me. This is a study that currently enrolls at 60, 120 and 200 MBq of lead 212. Intermediate results are very promising. There are no signs of myelosuppression, no Grade 3 serious adverse events.
And, very interesting, there's very low salivary-gland uptake of this compound—so far, only Grade 1 xerostomia with no treatment discontinuation. I understand the intermediate results of this study will be presented at ESMO later this year.
And last year, there was an image published out of this study. The patient receiving 60 MBq of lead 212, which is showing a very nice biodistribution, with low salivary-gland uptake and rapid kidney clearance. And another very recent image, and again, thank you to Anna for sharing. This is an image of a lead 212 AdvanCell-001 patient, treated with 160 MBq. Again, you see a very nice biodistribution—nice images, low salivary-gland uptake.
So to conclude, I think both actinium PSMA and lead PSMA are very promising compounds for therapy of prostate cancer. The therapeutic efficacy of the lead 212 PSMA ligands is still under investigation, still needs to be demonstrated. But we have two alpha emitters here with different half-lives that we can combine with ligands of different pharmacokinetics, like FAPI, for example, for the lead 212, might be an interesting combination. But of course, securing the supply of both alpha emitters will be crucial for rapid further development. Thank you.