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Oliver Sartor: Hi, I'm Dr. Oliver Sartor with UroToday, and we really have a special guest today, Michael Schultz. And it's a pleasure to welcome Mike. Mike is a long-term academic from the University of Iowa Department of Radiology, and then, with tremendous help from his university and many others, spun out a company originally called Viewpoint. And currently, that has merged into Prospective Therapeutics, where Mike is the CSO. And I'll simply say that Mike is really a well-recognized expert in the field of radiopharmaceuticals. And welcome, Mike. Anything else you'd like to add to the introduction?

Michael Schultz: No, that's a great introduction, Oliver, and a lot of people to thank. Probably not enough time to do that, but I really appreciate this opportunity. Thank you.

Oliver Sartor: Well, one of the things that is really interesting, I think, for this audience is the reason for why radiopharmaceuticals, and we all know there are antibody-drug conjugates, we know there are bispecifics, we know there are CAR T cells. There are lots of ways to target cancer cells today. Why radiopharmaceuticals from your perspective? And it's your passion, and it's your profession. Tell us a little bit more about that choice and how you feel that this particular approach is the right approach.

Michael Schultz: Wow, that's a great question, Oliver. There's a whole long history to unpack there to answer that, but I think the short answer is that what we learned over a couple of decades really was that if we could deliver radiation specifically to the tumor microenvironment, the mechanisms of action for the interaction of radioactive particles with cancer cells were different than the mechanisms for ADCs, delivery of chemotherapies, and things like that. So, in a sense, what we learned is that if we could deliver especially alpha-particle radionuclide therapy specifically to cancer cells, we could have a higher rate of lethality that would result from the interaction of the alpha particles. And there are not the same kind of mechanisms by which cancer cells can circumvent those types of inhibitory-type pathway, inhibition-type therapies that are the basis for ADCs, for example.

Oliver Sartor: And I enjoy that answer because when you put an alpha particle in the right spot, you're going to cause a lethal change, double-strand DNA breaks and more. Mike, you have particularly focused on an isotope that a couple of years ago would've been thought of as unusual, lead-212. Now, help us understand a little bit about your passion for lead-212 and why that takes the lead in your research efforts.

Michael Schultz: Well, there's a long history behind that, Oliver, and I started my career at the National Institute of Standards and Technology, and that's where we really started looking at alpha particles for radionuclide therapy. And I looked at all the isotopes that were practical for that purpose, for this image-guided, receptor-targeted radionuclide therapy for cancer, and started with astatine-211. We looked at actinium-225, and then later we started looking at lead-212. And there were really key fundamental metrics that helped us to make this decision.

We learned over that period of time that peptides and peptide-like small molecules were going to be the ideal delivery vehicles for delivering the radioactive payload to cancer cells with the right kind of pharmacokinetic properties so that the residual radiation would clear the body fast. And as we learned that, we started thinking about what are going to be the right isotopes with these new peptides and peptide-like small molecules that have these really fast PK properties. And lead-212 really rose to the top, considering that it has a half-life that allows us to deliver high-dose radiation over a short period of time rather than a low-level radiation over a long period of time. And to me, that reduced the uncertainty about where the alpha particles were going to be delivered in the body.

The second really fundamental reason is we've got this elementally identical isotope in lead-203 that can be used for imaging. That is such a powerful tool for early drug development, or early clinical development, where we're making that transition from what is the biodistribution and PK properties of the new radiopharmaceutical in animal models to humans. And so, we can make very, very precise and accurate predictions about where the lead-212 is going to be delivering those alpha particles in the body in advance.

And then later we learned that we can actually, post-therapy, do very conventional SPECT scans of the lead-212 itself so that the physician can have a chance to be able to confirm that the dose was delivered to the tumor microenvironment and that the residual dose was washed out of the body quickly. So those are some key properties for lead-212. The radiobiology of alpha-particle radionuclide therapy was becoming clear. We needed to pick an isotope that was going to give us this kind of delivery of high-dose radiation over a short period of time. And lead-212 really rose to the top because of those things.

Oliver Sartor: Now you've got a short half-life, so distribution is going to be a challenge. Now, I hear some of the naysayers for lead-212 say, "How the hell are you going to take something that's a 10-hour half-life and deliver it to everybody who needs it in the United States?" So, I don't want to belabor the point, but tell me quickly how you would envision this distribution problem, which is very real with something that has a short half-life.

Michael Schultz: So I think that the reality is that the infrastructure and the logistical scenario for this has already been done. Think about today, how many doses of fluorine-18 deoxyglucose are going to be delivered around the country, and that has a two-hour half-life. So from the pure perspective of how are these logistics going to work, we've got the people, space, and equipment to be able to do that. And right now, we're manufacturing and delivering our lead-212-labeled radiopharmaceuticals for two clinical trials around the country from our production facility. And we're expanding that, and there are other companies now that are showing us that this can be done from one, two, three, or maybe more facilities around the country. So it's clear to me that the logistics are not going to be the thing that's going to make this difficult. I honestly think that lead-212 has a better chance of being commercializable because the supply chain for the thorium-228 that's necessary for it is much more robust than for isotopes where you need to have an accelerator facility to be able to manufacture on-demand.

Oliver Sartor: Thank you, Mike. Appreciate that. Now, realizing, of course, that Prospective has a lot of activity, and just generally speaking, what are you most enthusiastic about within the Prospective pipeline? We're not trying to get any confidential information, but just your perspective on where you see Prospective going in the next couple of years that you're excited about.

Michael Schultz: Yeah, absolutely, and I appreciate that question. We're absolutely enthusiastic about the peptides and peptide-like small molecules that are in the pipeline and the potential for some pan-cancer. We recently announced clinical use of our PSV-359 targeting fibroblast activation protein alpha. This is a really exciting target and a really exciting peptide with terrific PK properties and tumor delivery.

But I have to say that we're also extremely excited about this new pre-targeted approach to radiopharmaceuticals. I really believe that this is the next generation of radiopharmaceuticals. What we're basically doing here is taking advantage of the terrific specificity that we can make for a particular antigen that's expressed on tumor cells and not on normal cells. And we take that the antibodies can provide for us, but by allowing the antibody to accumulate with a basic catcher's mitt we can target, we're loading up the tumors with a target that we can make a molecule that binds very specifically and engineer to clear the body very, very quickly, and maybe even more rapidly than the peptides that we're using. This just expands the repertoire of cancer targets that we can explore for cancer therapy, and that's just a really exciting new phase of development for radiopharmaceuticals that I think has the potential to be transformative for our industry.

Oliver Sartor: Mike, not everybody is familiar with pre-targeting, and I'd like to go back just for a second, and if you could explain how this works. How are you going to take an antibody and then put a piece of lead on it? Because most people say, "Hey, if you put lead on an antibody, it's not going to work right." So explain pre-targeting to our audience, if you will, kind of from the beginning so they can appreciate your thoughts.

Michael Schultz: So that's a great question and happy to do that. And that really goes back to the history of radiopharmaceuticals. Antibodies have been used for a long time for targeting tumor cells, for delivering drugs as antibody-drug conjugates. The first radiopharmaceuticals employed antibodies that targeted CD20 for lymphoma. That was Zevalin and Bexxar. And the reality is that we found that we could deliver the antibody payload to the tumor microenvironment very effectively. The problem with antibodies for that application is that their circulating half-lives are too long. So you're delivering radiation for several days while the antibody is accumulating in the tumor target. So we know that we can take antibodies and we know that we can make them so that they're very specific for the tumor microenvironment.

So here what we're doing is a two-step process. So in the pre-targeting approach, we modify the antibody in such a way that we can send in a radioligand after the antibody has accumulated in the tumor tissue. So we allow it to circulate in the body for days. It accumulates in the tumor microenvironment, the rest of the antibody washes out through the body's mechanisms for that, and then we send in a radioligand that is specific for the antibody. So now we're pre-targeting the tumor, we're loading up the tumor with a target in a way that allows us to engineer a molecule that binds only to that, but has very fast PK properties. And in this way, we are just expanding the repertoire of potential tumor targets that we can go after for treating cancer patients.

Oliver Sartor: Interesting. And just from my perspective, there are a lot of targets that may not be amenable to the small molecules. So this really vastly expands the number of targets that you might consider in your strategy. So I really like pre-targeting and really look forward to seeing if it's going to actually work in the human being. So congratulations on that concept, and I think you're absolutely one of the leaders in that field.

One of the other things that a lot of people have been talking about, and I've heard you speak about it as well, is combinations. So radiopharmaceuticals and monotherapies are going to take advantage of the alpha, the double-strand breaks, et cetera. But what about combinations in this field, and are there any that you have a particular enthusiasm for?

Michael Schultz: Well, I can tell you that we're very interested in this, and we find that combination therapies are the rule in oncology as opposed to monotherapies in general. It's generally that way, and that's because cancer cells are able to circumvent pathway inhibition in general. And so, I think the most interesting thing right now is the combination of alpha-particle radionuclide therapy with checkpoint inhibitors and other immunotherapy-type cancer therapies. And there's a real biological rationale for why alpha-particle radionuclide therapy, and our published papers are showing that, and checkpoint inhibitors can really truly synergize, right?

So the idea here is that the alpha particle interaction with the cancer cell causes damage to the cell membrane that allows for the spillage of neoantigens. And so this just expands the repertoire of neoantigens that can be presented to the immune system in a way that can be synergistic with checkpoint inhibitors. And so we're finding from our research that low-dose alpha-particle radiation in the tumor microenvironment combined with checkpoint inhibitors can produce durable and complete remissions in the models that we have tested it in so far. And we're in clinical trials with our alpha particle therapy for melanoma right now, and we've got the potential to be able to expand that to include checkpoint inhibitor therapy in combination with alpha therapy. The results that we have presented so far in preclinical models are telling us that this could truly be a transformative combination therapy. There are certainly other combination therapies that we're exploring as well. The obvious ones would be things like double-stranded DNA repair mechanisms that there are inhibitors for and other combination therapies that are like that.

Oliver Sartor: Gosh, thank you, Mike. That's a really nice explanation and helps us understand your vision a little bit. Now, I'm going to ask you to bring out your crystal ball for a second. Maybe it's a little cloudy, but maybe it's pretty clear. I don't know. So envision yourself sort of five years into the future and explain how you believe the field will have evolved relative to today in five years. How are we going to be viewing this in five years that might be a little bit distinct from today, if you can, if that crystal ball is clear enough to see?

Michael Schultz: So I think that what I can say along those lines is that we've been seeing a transformation in oncology for several years now, and I think that the data is driving the industry, or I should say the community, to begin to work together in different ways than maybe was the case 20 years ago when the first radiopharmaceuticals were the first targeted antibody radiopharmaceuticals were introduced. And I think it's just a recognition by physicians that these radiopharmaceuticals can deliver a lethal payload with excellent safety profiles and recognizing that that has great potential for treating cancer patients.

So I see, particularly with the prostate cancer drugs, radiopharmaceuticals that have been introduced, an expansion of understanding by physicians outside of radiology and nuclear medicine of the potential for these radiopharmaceuticals. And so, as that's recognized, it will be integrated and become more mainstream as a therapy paradigm. Much the same way as external beam radiation became a significant contribution to cancer patient care, radiopharmaceuticals will be the next pillar in cancer care. Particularly due to the large number of prostate cancer patients that are being treated, the care centers are expanding their facilities in ways that are going to enable a more widespread use of radiopharmaceuticals around the United States and around the world.

Oliver Sartor: Thank you, Mike. And we're going to be wrapping up here in a second. Is there anything you might like to add before we wrap up here in the next minute or so?

Michael Schultz: No. You know something? I just really appreciate this opportunity, Oliver, truly, and it's been a terrific experience for me over the last several years to see the expansion of radiopharmaceuticals, something that I believed in for quite some time. And so, there's so many people to thank, and I just want to thank you for the opportunity to talk a little bit about this.

Oliver Sartor: Well, thank you, Mike. Mike Schultz, chief scientific officer from Prospective Therapeutics. Thank you for being here today, and thank you for sharing your vision.

Michael Schultz: You bet. Thanks, Oliver.