Alpha is More Than Just Ac-225: Pb-212

This month's episode of the JNM Podcast takes the discussion of Pb-212 worldwide! Researchers from the UK, Australia, and North America discuss the logistics of using lead-212 as a radionuclide imaging agent. From availability to production to transportation, Pb-212 presents both great opportunities and great challenges. Moderator Ken Herrmann, MD, leads this intercontinental panel in a discussion about other radionuclides and their pros and cons. He's joined by David Bauer, PhD, from Memorial Sloan Kettering Cancer Center, Jane Sosabowski, BSc, MSc, PhD, from Queen Mary, University of London, and Nick Fletcher, PhD, from the University of Queensland, Australia.

Transcript

Ken (00:01.479)
Hello, everyone. My name is Ken Herrmann. I'm a nuclear medicine physician from Essen. And I welcome you to the third podcast of the JNN with a very exciting topic. The topic is allowing lead 212 as it's really happening. And the idea of this, I think, very interesting topic comes because of a very recent success in an editorial written by Richard Zimmerman in the Journal of Nuclear Medicine, which I just checked, had 4,000 downloads in the first two months published earlier this year. And I'm very happy and pleased that I

three outstanding guests from three different continents who are really lead experts who helped me and hopefully everyone else who's interested in the field of lead to understand what are the challenges and opportunities. And I'm very happy to welcome first Professor Jane Sobakovsky. She's a professor of ray-nuclide imaging and therapy at the Barthes-Kenns Institute in the Queen Mary University of London in the UK. Welcome, Jane. Then very early this morning, got up David Bauer, David Bauer.

Jane Sosabowski (00:54.621)
Thank you.

Ken (00:59.991)
is a research fellow at MSK at New York in the US and works in the very successful group of Jason Doers. Good morning, David. And last but not least, the one who is actually concluding the day already is Nick Fletcher. He's a postdoctoral research fellow in radiobiology, steam leader in the Australian Institute for Bioengineering and Nanotechnology. And he's also serving as a postdoc in the group big group of Professor Chris Turecht. Good evening, Nick.

David Bauer (01:08.462)
I think I can, good morning.

Nicholas Fletcher (01:28.294)
How you doing?

Ken (01:30.503)
So I want to start off with the opening question to all of you. Where do you see Lat-212 in five years from now? And I think ladies first, Jane.

Jane Sosabowski (01:41.037)
Thank you. Thank you, Ken. I think, first of all, for us in the UK, it's a very important issue, is radionuclide supply. We'd like to see several GMP generators on the market, both the thorium-228 and the radium-224 generators. For that, we need the supply of the parent radionuclides to increase and become more widely available. There's also issues around regulations that make it difficult to house sufficiently large thorium-228 generators on hospital sites.

hopefully these can be resolved and really I'd like to see clinical trials coming through that can lead to approvals of new radiopharmaceuticals in the next five years.

Ken (02:19.795)
Super, David.

David Bauer (02:22.038)
I would say in the next five years, the three big alphas, actinium, acetatein, and lead will have emerged into the clinic, and we'll still have to figure out when we want to use which nuclide, where the benefits and advantages, but we also will have figured out the distribution quite a bit, and then we are talking about upscaling lead in really different entities of cancers.

Ken (02:43.035)
Thank you. And the Australian perspective?

Nicholas Fletcher (02:46.834)
Yeah, so similarly, I see it led to on to be progressing into the clinic, probably not displacing the tissue, like I was saying, sort of talking about combinational approaches and probably moving out of just prostate cancer is a low hanging fruit where it is at the moment. And then hopefully looking to the next generation of approaches where once we have more mechanistic understanding, you can start pairing it up for combination therapies or harnessing the immune responses to some of these alpha therapeutics as well.

Ken (03:13.351)
Thank you. Now in the next part, I want to pick your brain on certain topics. I think, Jane, you started with a very important topic, the sourcing of the raw material. You mentioned OI-2, mother materials. Please comment. Where do you see the problem, and how can this be solved?

Jane Sosabowski (03:30.201)
Yeah, so I guess in the UK, we have a problem with radionuclide supply. In the US, it's a bit easier to get hold of the DOE generators for lead 212, the radium 224 generators. So in the UK, we have a really exciting program to reprocess uranium and to get thorium 228 from nuclear.

legacy materials. This has been initiated by the UK National Nuclear Laboratory and they really have some good supply of thorium-228 in their stocks and are working towards making it available for companies to build generators because obviously no matter what generators you have you need this source material in order to put it in the generators. So that's something a really exciting development in the UK at the moment.

Ken (04:27.067)
And this is only a UK approach or how is it worldwide? Is this sourcing of the raw materials a real problem?

Jane Sosabowski (04:35.061)
Well, I'd say, AranaMed, I believe they source it from natural stocks, natural uranium or thorium, and they purify out the thorium 228. And so they have obviously a big operation going, but they I don't see their generators coming on the market. They want to provide radium pharmaceuticals rather than generators. So that won't be available for, you know, researchers or for other, you know, commercial entities.

And then of course there's the DOE which has their own supplies. NRG is going to start, NRG Palace is going to start producing it and they're actually going to produce from stocks of radium 226 that they have. So that's an alternative route. So there are various routes that are going to hopefully come online.

Ken (05:22.345)
In the excellent editorial by Richard Zimmerman, he also talks about different production routes, liquid-based, solid-phase generators, duration. Maybe David, you want to comment and help a simple MD like me to understand what is important to know and what does it depend on?

David Bauer (05:36.53)
Absolutely, I would love to. First, I want to jump in that, as Jane explained, thorium-228 is currently the limiting factor. We are currently completely safe with thorium-228. We have enough supply for what we're doing preclinical and we'll have enough supply for the first clinical trials. Later on, when we ramp up the production, we need to think about where is more thorium-228 coming from and that could be, as Jane mentioned, from radium-226 production with neutron capture.

But I think the future of lead is pretty secure and more secure maybe than at the moment actinium, even though that's also changing a lot in the next five to ten years. So once we have the thorium 228, there's several methods to get lead out of there. One is a more tricky method that is like liquid extraction. You basically capture thorium 228 on a resin and have the radium 224 coming out of there. So you separate these two.

And the radium 2 to 4 will be then the mother nuclide for producing lead 2 to 12 with another resin. So it's a resin based production thorium to radium, radium to lead. There is a benefit and a disadvantage. The benefit is it is quite a robust method and you yield a lot of lead out of that. The disadvantage is it's resin based and resins are usually quite toxic.

which means if you think about FDA and GMP approval, you wanna make sure that no resin can escape from this production method, and you have no radiolysis going on, that nothing, no traces will be in your final product. That's very hard to prove, but it's a very good production method. The other one is basically based on a gas transfer, so you can actually have a thorium-2-8 source, and it will decay over radon gas.

So you can capture the radon gas and once it's captured, it will decay to lead to 12. So you basically have a very pure production method. We go over that gas transfer and have absolutely zero impurities. So that's something very interesting for GMP and would be something very easy to realize. There, I think the disadvantage is a little bit, first of all, radioactive gas. So you will have to have a very controlled environment, shielded fume. And the other one is that your yield might be slightly less.

David Bauer (07:51.486)
slightly at the moment than with the liquid-liquid extraction.

Ken (07:56.295)
Super. Nick, I mentioned that different sizes of generators, so some of them apparently are available for a week, some of them for months or years. First of all, how realistic is what I heard? And the second thing is, what is the reason that they are so significantly different?

Nicholas Fletcher (08:13.669)
Well, David's just been explaining the different methods of production and the different sources, I guess. In Australia, we don't really have access to the resin based systems or limited anyway. So where most of the gas exchange type approach through, we work closely with advanced cell as the Australian producer, but there's others around, just not here. So for them, and those sort of sources, they're similar to any other generator, they can be parked in a hot cell.

pot cell setup dedicated for it. We've got a GMP lab that's got one sitting in it now. Not ready to go for production yet, but it's feasibility sort of scale. And that's relatively straightforward in that you have your gas transfer, as you said, really, with a long lived source. So that sits there for months to years. For us, that's quite nice. And all the hospitals are used to having to swap out generators for gallium and things anyway. So it's not that different and approached in my mind anyway.

Ken (09:12.263)
So you both already mentioned GMP. For me as a clinician, it's super important to get a GMP certified generator, to perform clinical studies. David, you made comment quickly, what is a realistic timeframe to expect such a GMP certified generator to be available?

David Bauer (09:26.974)
I think that depends a lot on the clinical phase one, two phases that we have right now, because I think the translation to a GMP is relatively easy to achieve. It's very expensive, of course. So I think with the right motivation, that is a possibility within month to years. So it's not too complicated to hopefully realize that. And with, as Nick mentioned, thorium 228 gas transfer source, that is a 1.9 year half life, which means this generator.

would be also available for a very, very long time, talking to months to years that you can basically elude lead from this generator. So if that would be a GMP generator, I think that secures the future of lead quite.

Ken (10:09.083)
So we talk about lead and you mentioned before lead is not the only alpha ray nuclei. I want to ask all three of you, but I was going to start with you, Jane, explain a little bit the advantages and disadvantages of lead compared, for example, to actinium or to astatine.

Jane Sosabowski (10:17.181)
Thanks for watching!

Jane Sosabowski (10:24.925)
Yeah, so lead for me, I work on small peptides. So for me, the half-life of lead is much more favorable. It's got a 10-hour half-life, much more suitable for the short half-life of peptides. Acetene-211 we're also interested in, seven-hour half-life. The disadvantage of that is you need a high-energy cyclotron. You need at least like a 29 MeV alpha to make the acetene-211.

So there's only about 30 of those cyclotrons in the world. So it can be, you know, it's a much more kind of localized, you can't transport it either really, you know, from Europe to the UK, for instance. So we have to have our own cyclotron. We have one, but it's not really, it doesn't have any production facilities around it. So we need new infrastructure in the UK to do that. The generator system is really attractive. You know, as David was mentioning, I think that lead has the advantage.

better availability in future. It's only got one alpha. So you're just going to, when you look at the challenges around actinium, for instance, with the four alphas and the recall energy of the alphas, that's always going to be a problem with toxicity. And I think at the moment we're looking at, you know, end stage patients, et cetera. But when we reach looking at other patients with alphas, then this toxicity is going to become more of an issue. But you know, you're a clinician, Ken, you probably have more to say on that.

Ken (11:53.935)
David, Nick, please comment as well. Add some color.

David Bauer (11:59.086)
Shall I jump in? OK. So let's talk about the negative sides or the challenges that we have with lead. I think that's also fair that we stress them out a little bit. One big thing compared to actinium astatine is a shielding problem that we have with lead 212 that we need to think about. In the decay chain, we have thallium-2-08, and that has a 2.6.

Nicholas Fletcher (12:00.837)
Yeah.

David Bauer (12:25.822)
mega kV emission. That's a really, really energetic emission that is hard to shield. So compared to actinium, I would say the factor for our patient dose, if you compare them, is 400 times more radiation for the MD than you would have with actinium, for example. So the shielding will be an issue. We need a different kind of setup for lead than we have with actinium or lutetium. So then there is one more challenge.

that might be actually a good thing. Compared to Actinium, where you can ship the radiopharmaceutical label to the clinic, we don't really plan doing that. We can do that with LAD, but due to the shorter half-life, it is more suitable to ship the generator and to ship the precursor. So what we need basically is a clinical setup. We need radiopharmacists who can do the job of radiolabelling and can see control in-house, which basically means we need a real clinical setup for translating LAD into the clinic.

And that could also be disadvantage or advantage, however you want to see it. And then I think to say a few positive things as well, as Jane mentioned, I think the half-life is just perfect. We like the half-life of lead, it's a little bit longer than astatine, definitely shorter than actinium, which means a patient who got lead basically is decayed by let's say two days out, which is a really suitable half-life. And that brings one more point where lead really shines, that is the storage.

waste. If you think about actinium, especially about actinium-227, the biggest problem is not really the toxicity that we expect for the patient, but where will we store patient waste in a hospital? Actinium-227 has a half-life of over 22 years. With lead, basically, the waste is cleared after two, three, four days. That really helps the clinic a lot with high throughput of patients, and we do not have that with lutetium or actinium, even without the 227, because then we still store for several months.

Ken (14:25.955)
Nick, you want to add some color?

Nicholas Fletcher (14:26.65)
Yeah. I was gonna say they've covered most of the key points. I think I was saying the half-lives, to my mind, pretty spot on. So that means even in Australia, which is fairly spread out from a nuclear medicine point of view, we're capable of shipping copper-64 with a very similar half-life across the country, which is fine. So lead two on two fits within the networks we've already got established for these isotopes.

like David was saying, all of our hospitals already geared up for the T-sham storage. So if they have the capability for that, that two on two is not so bad. We are interested in other alphas, as you're saying, like there's a there's not just lead, not just actinium, even terbium, things like that are really interesting, but the requirement for accelerators and or cyclotrons depending if you're talking about astatine and things sort of limits application outside of your radio pharmaceutical hubs, I guess.

Load two on two is a nice mix between them, I think.

Ken (15:21.199)
I would like to follow up on the logistics, but David mentioned. So how central or how local does the production have to be? Because let's be honest, right? Academic sites, we love to produce locally. The moment you want to go into the periphery, it's a problem. It's a hassle. It's, it's, it's prohibitive. My question for you in the end, you mentioned it quickly, but maybe you elaborate a few more sentence on this, for example, in the U S we know how big the U S is.

How many production sites do we really need? I heard in literature, some of them want to do scent production, just one in Indianapolis, and fly everything out to FedEx. I always thought maybe four production sites is reasonable because then you can cover a little bit the coast and a little bit in the middle, but what do you think? And it's one thing, and the second thing is also for the UK, maybe Jane Newcomen, how likely is it really that the hospitals do a real pharmaceutical production locally with all the manufacturing? Because in the end, we talk about, yeah.

medical substances, it's really pharmaceuticals.

Jane Sosabowski (16:16.697)
Yeah. Okay, I can start off with the UK perspective. I mean, really, what we're trying to push for in the UK is a centralised radiopharmacy that can make these radi We think that if we make it somewhere in the middle of the UK, then we can ship to two sites all around the UK. And also one of the reasons that we think this might be a good solution for the UK is that we have some legislation that doesn't allow us to have a thorium generator of more than 700 megabit corals.

on site if it's a dispersible source. We don't know definitively if it's a dispersible source yet or not, but otherwise we have to go into a huge rigmarole for each hospital of looking into some radiation emergency preparedness regulations. So you can imagine how easy that's going to be in the middle of a city, for instance, like London. If there's a fire of more than a thousand degrees, we've got to show that it won't be dispersible. So for us, it may be to start off with a centralized radio pharmacy approach.

would be the fastest route. We want to resolve the repeal regulations in the UK and really talk about these with the nuclear regulators because we have a lower limit than other European centres. Although there are some other European countries that also come across this legislation that will make it difficult for them with thorium-228 generators.

Ken (17:35.416)
Any more comments?

David Bauer (17:38.026)
Maybe one. I can make it even a little bit more complicated, because one thing we have not mentioned yet is LED 203. And if you really want to have LED 203 as an image compatible component, and then it's getting a little bit more complicated because then a center needs to have access to both nuclides at relative this is the same time. Is it necessary to do imaging with LED 203? Not really. We have already seen quite successfully that spec emitting with LED 212 is possible. But there is a...

Jane Sosabowski (17:41.431)
I know.

David Bauer (18:07.254)
Well, it's for sure that lead imaging, 203 imaging, is way more feasible. You can apply a higher dose, so the imaging is more accurate. Both is possible, but I think if an institute needs access to both nuclides, then the challenge is a little bit higher. And then we would benefit from having more distribution centers, especially in the US.

Ken (18:28.775)
So I'm very opinionated on this topic. Don't overcomplicate our life. Gaium 68 and copper 64 do the trick, if you ask me. But one other question, money plays an important role. How do the cost of goods, because they play an important role when you talk about long-term production of our physicals, how do the cost of goods compare for lead compared to any other radionuclides? Who wants to answer this?

Nicholas Fletcher (18:37.601)
Ugh.

Jane Sosabowski (18:52.529)
Hmm. It's difficult to say that because we don't have generators on the market yet. You know, we have the DOE generators, which for us are really expensive and difficult to get hold of because we're not a US-based organization. So it's very difficult for us to get them outside of the US. Maybe David would like to comment on that for a US, you know, you can get them from the DOE. So.

Nicholas Fletcher (18:56.707)
Yeah.

David Bauer (19:18.23)
Yes, that's no question. The generators at the moment are ridiculously expensive, but that's because they're still in development. But the material costs, actually, the thorium costs to produce it, they are veritably small. If you compare to actinium or astatine, astatine is also relatively low in production cost. I think we will be in the cost below actinium radiopharmaceuticals or in the same price range at least. So I think...

Ken (19:39.719)
What about Hesium?

David Bauer (19:42.614)
Lutetium at the moment is already quite cheap and it's getting even cheaper because we ramp up the production with a neutron capture quite a bit. But I think with lead, give it 10 more years and I'm pretty sure we will be in a similar range as we are right now already with lutetium.

Nicholas Fletcher (19:43.653)
Thank you.

Nicholas Fletcher (19:58.661)
Yeah, the benefit with the lead as well is that once you've got a generator sitting there, it's constantly putting out, especially with the gas transfer. It's not like you're buying a new dose every day. It's producing it every day. So for us as a researcher, it's very accessible.

Jane Sosabowski (20:13.265)
I mean, clinically for us in the NHS, it's a real problem with the cost. I mean, Plovicto has not been approved in the UK simply because of the cost, because the cost benefit calculation that our regulators do, I mean, it's been approved as a drug, but it hasn't been approved for use in the NHS. So cost of the final radiopharmaceutical is a completely different question as to, you know, than the cost of the radionuclide.

Ken (20:39.655)
So I want to smart ass, but I think there's really difference between the cost of goods and the price, the value from single costs. And I was really purposely asking for the cost of goods because pricing is beyond my IQ. I cannot understand this. Thank you all very much. This was a fantastic podcast. We are really barely at 20 minutes, which is perfect. This is what our listeners requested for. I really, I'm sure that I will invite you again.

Jane Sosabowski (20:53.821)
Ha ha ha.

Ken (21:07.715)
in a few months or at least a few years because that is a topic which is here to stay. Thank you all very, very much. This was really fantastic. Thank you. And stay tuned for podcast number four, hopefully soon. Goodbye.

Jane Sosabowski (21:16.413)
Thank you so much for having me.

Nicholas Fletcher (21:17.286)
Thank you.

Jane Sosabowski (21:20.677)
Thanks again, bye.

Nicholas Fletcher (21:22.013)
See ya, bye.