Theranostics. I am very, very excited tonight to be able to have this first of our two series webinars. Today's webinar is around prostate cancer, treatment environment, and unmet medical needs, with a special focus around a new target, B7-H3, which is a new checkpoint inhibitor that is highly expressed in prostate cancer, among other things. I'm absolutely thrilled that we have two outstanding experts here with us tonight. I'm saying tonight because we're all based in the U.S., Australia, morning. Our evening. I'm excited to have everybody with us here. Also, Oliver and Dave are two experts here. We'll start with Dr. Oliver Sartor as our first speaker. Dr. Sartor is a renowned oncologist and research scientist who has now for many, many years specialized in prostate cancer. He received his medical degree from Tulane University and has held numerous positions throughout his career, including at the National Cancer Institute, the Louisiana State University Health Science Center, and Tulane University. He was most recently the Director of Radiopharmaceutical Trials at the Mayo Clinic in Rochester, Minnesota, and has now moved to East Jefferson General Hospital, where he is the Director of the Transformational Prostate Cancer Research Center. Dr. Sartor is internationally recognized for his many, many years of work in advancing prostate cancer research and treatment, in particular in the field of radiopharmaceutical therapies. He has authored hundreds of peer-reviewed articles and has led, or call it, multiple clinical trials that have resulted in publications and FDA drug approvals. With that short intro, I would like to start with the presentation. We will have two presentations. First, Dr. Sartor, followed by Dr. Piwnica-Worms. At the end, we will have a Q&A session that I will moderate. Without further ado, I will start with the presentation. Just give me one second. Matt, can you see my screen? Yeah, it's got a full screen. Yep. A little bit small second slide, but that's OK. We'll get it to the first slide. Yep. Give me one second. Good. Yep. Go to Oliver, and take it from here. Right. Thank you, Dimitris. Appreciate the introduction. I'll dive right into it. We're going to be covering a little bit of kind of a broad scope of prostate cancer for those who may not be familiar. I'm going to run through it in a little under 15 minutes, give a little time for question and answer at the end. I'm going to say that the old school of surgery, radiation, hormonal therapy, and chemotherapy is just that. It's old school. If you want to manage prostate cancer today, you have to understand about genetics, both germline and somatic, molecular imaging, artificial intelligence is playing a role, targeted therapy, immunotherapy, and molecularly targeted radiation, which is radiopharmaceuticals. We're going to be talking much more about that tonight. Next slide. This is a very simple slide that has a lot of information. We typically divide the prostate cancer into castrate sensitive, and those are people that have not seen hormones or have started on hormones and responding, and the castrate resistant. The castrate resistant is the patient who is resistant to the hormonal therapies initially applied. As it turns out that there is a—got to lower that hand there. As it turns out that there are a lot of changes in the way that we managed hormonal therapy from 1941, when Dr. Huggins did his Nobel Prize when he worked at today, where we're using these androgen receptor pathway inhibitors like abiraterone and enzalutamide to be able to augment the traditional hormonal therapies. We also have an important division between those who are metastatic and non-metastatic. If you want to just keep it simple, we have the castrate sensitive or hormone sensitive. We've got the castrate resistant. We have the metastatic, non-metastatic, and that's our framework. We have a bunch of choices that physicians can choose upon today, and they're good choices. Next slide. One of the things that is complicating is the fact that there's a heterogeneity within the genetic findings. There's some pretty common findings. There's androgen receptor. There's p53. There's PTEN loss. There are some interesting changes that can occur in the ETV and chromosomal intrachromosomal alterations. There are a lot of different types of prostate cancer. There's some that are a little more prominent than others, like DNA repair. The bottom line is it's a heterogeneous group of diseases. That means that all the precision therapies are only going to affect a minority. One of the reasons I like something like B7-H3 is it's expressed on a lot of cells. With a radiopharmaceutical warhead, an isotope warhead, you can kill cells with a variety of underlying genetic heterogeneity. Next slide. Don't have to go through this. These are all the phase III trials that show a survival benefit. I've been a little disappointed in the magnitude of the benefit. If you looked on the right-hand slide, we can see that there is 2.9 months, 4.1 months. We finally got up to 7.3 months and 8.8 months. Most of the time, we're not having as much benefit as we would like. Unfortunately, the terrible truth is that everybody with metastatic castration-resistant prostate cancer is going to progress and die from their disease unless they die earlier from something else. It is a fatal disease. We have a need for more therapies and more effective therapies. Next slide. I'm going to briefly cover some of the relevant points to the NCCN guidelines. NCCN is the National Comprehensive Cancer Network. It's a coalition of cancer centers in the United States. Basically, they put together guidelines that are quite good and which guide therapy in the United States to a significant degree. I want to bring to your attention that the sequence matters. We're going to be talking about novel hormones, no novel hormones. The novel hormones that I'm going to be talking about are ARPIs, abiraterone, enzalutamide, darolutamide, and apalutamide. Next slide. For patients who've had no prior novel hormones, no prior docetaxel, we have a set of options that might include things like docetaxel, olaparib or rucaparib if you have a BRCA mutation, and potentially Pluvicto. Interestingly, Pluvicto is not level 1 or radium. We have a variety of choices, but dictated in part by the fact that these patients did not receive prior novel hormones and no docetaxel. Next slide. If you have had novel hormones and docetaxel, it's a little bit different. Cabazitaxel, now things like Pluvicto, PSMA-617, Lutetium-177, are Category 1. Next slide. Don't want to drill down into the molecular biomarkers too much. We have two broad categories for genetic testing that drives therapy: the homologous recombination repair genes, BRCA1, BRCA2, PALB2, RAD54L, CHEK2, et cetera. We have PARP inhibitors for those in various iterations. The mismatch repair genes associated with Lynch syndrome, MSH2, MSH6, MLH1, PMS2. We can use immunotherapy like an anti-PD-1, pembrolizumab. Next slide. We have a biomarker for the use of radium. That's osteoblastic metastatic disease with the hydroxyapatite. We see it on a bone scan. Next slide. Radium has some new data. Enzalutamide plus or minus radium trials showing the combination of enzalutamide and radium led to an improvement in overall survival. Actually, this is a pretty good magnitude. If we look at this, we're going to be looking at about 7.3 months at median. That's good. A new weapon in our armamentarium. Next slide. Briefly talking about Theranostics. Simple concept, very simple. We're going to be talking more about it tonight. Cancer cells have targets on their cell surface. We can devise a ligand that binds to those targets. That ligand can be an antibody. It can be a minibody. It can be a small molecule. To that ligand, via a linker, we can put on a radionuclide. With that radionuclide, we can either diagnose using a PET scan or treat using an alpha-beta particle. PSMA PET has radically changed the way we look at the disease. PSMA Lutetium is changing the way we treat it. That's an example. Next slide. Here's the PSMA target. It's a transmembrane protein. It's a binding pocket on the top. We can put small molecules or antibodies on this and bind the PSMA. Next slide. We published. I had the honor of being the lead author on this New England Journal manuscript. Led to the FDA approval of Pluvicto. Lutetium-177, the beta-emitter, PSMA-617, the PSMA binder. It's got a little anchor in between. Bottom line is an important study brought Theranostics really into the realm of prostate cancer. Next slide. Overall survival improved. Radiographic progression-free survival improved. Hazard ratios 0.62. Hazard ratio for the RPFS is 0.4. Unequivocal benefit approved not only in the United States, but around the world. The United States led the way. Australia has got some unique problems I am very aware and won't talk about it. Not generally available in Australia because of the limitation that is in the reimbursement. Next slide. We have another Pluvicto study for patients without so much pretreatment. These patients had never seen any chemotherapy. Next slide. Got an FDA approval March 28th of this year. Radiographic progression-free survival being the primary endpoint. Turns out that you had a good effect on the radiographic progression-free survival. Hazard ratio about 0.43. Median survival was about two years. This shows you the underlying need. We need better therapies. Next slide. What about PSMA Lutetium and castrate sensitive disease? Brand new stuff. Next slide. A June 2nd press release from Novartis indicated that there was a statistically significant and meaningful benefit for PSMA positive disease when treated with Pluvicto upfront hormone sensitive, castrate sensitive disease, whatever you call it. Important new study. It's showing the power of the radiopharmaceuticals, and particularly this one. Everybody's still going to die. Next slide. What are the unmet needs? I've emphasized the fact that metastatic prostate cancer is a fatal disease. Even where you look at it, where it's reasonable prognosis, the median survival for patients treated with Pluvicto after failing an ADT and an ARPI is about two years. I mentioned chemotherapy like dose of Taxol. Patients hate chemotherapy. They want to avoid it. Patients don't want to be castrated. We don't have any choices now. We castrate all these men. We really don't want to do it, but that's our best therapy. We'd love to come up with something better than castration or tolerable than castration. Pluvicto is a good drug, but it's not a great drug. Post-Pluvicto, there are no drugs approved. We need to do better, and there are many opportunities that exist. One of the things that requires a lot of attention is the control group in future trials that are randomized. That's a whole other story. Next slide. I believe that's it. I've been covering about 15 minutes. I did that. Broad overview of prostate cancer. Of course, we'll have questions at the end. Thank you so much, Oliver. Thank you for this really fast ride through the prostate cancer landscape, which has really changed so dramatically over the past, I don't know, 15, 20 years. It started with radium back then when we worked on Xofigo. We have now so many different options for the patients, including, of course, with the new targeted radiotherapeutics. We will discuss much more at the end of this. I have now the pleasure to introduce our next speaker, Dr. David Piwnica-Worms. He is joining us from also the U.S. He's usually based at MD Anderson. Today, where are you again, David? I forgot where you said you were. Yeah, calling in from Minnetonka, Minnesota. There you go. David is a board-certified radiologist and biochemist who is the Chair and Professor of the Department of Cancer Systems Imaging at MD Anderson Cancer Center in Houston, Texas. He is also the Deputy Head of the Division of Diagnostic Imaging there. He has received both his MD and PhD from Duke University. His research involves developing and using non-invasive imaging technologies such as PET, fluorescence, and bioluminescence to understand biological processes in living systems. Dave and his group are working and have worked with us very closely on the preclinical development of our amazing B7-H3 targeting asset that David will introduce now and discuss a little bit in general, and also with regards to the applicability around the prostate cancer landscape. Very good. Great. Thank you very much. Are we launched OK? Yeah, looks great. Excellent. Great. Building on our previous dialogue with Dr. Sartor, we're going to dive into a novel therapeutic strategy targeting B7-H3, which is a known immune checkpoint protein, but we're going to be using it in a different way. I'd like to introduce the Lutetium-177 BetaBart, which is a product under development with Radiopharm Ventures. This would be targeting the 4Ig form of B7-H3 with a humanized monoclonal antibody for beta radio immunotherapy. Just by brief background, B7-H3 is highly attractive as a pan-tumor target and is known in the oncology world. It's a member of the B7 family of immune checkpoint proteins, which has a very complex biology. Even though it's in the same family where all the famous immune checkpoint inhibitors have been developed that have had significant impact on a variety of tumors, B7-H3 is an odd member of that family. With its complex biology, it has not been able to be targeted with standard cold antibodies. Independent of its role in immune modulation, it has a very, very interesting and curious set of properties in that it's highly expressed in a wide variety of medium and advanced tumors, but not in normal tissues. Independent of its biology, it's got characteristics that make it a great target for radio immunotherapy. You can see here on some published literature with immunohistochemistry, up at the top left, prostate cancer, breast cancer, colon cancer, lung cancer, gastric cancers all express B7-H3 compared to normal tissues below, which show none of the brown staining. Interestingly, and this is a point that goes beyond our discussion today per se, there's high expression of B7-H3 in a wide variety of solid tumors. Our opportunity is not just in prostate cancer, but head and neck, kidney, glioblastoma, thyroid, mesothelioma, melanoma, prostate cancer, pancreatic cancer, bladder, lung, breast, ovarian, et cetera, and a few other subtypes not even shown here. The point of the expression graph on the right is just to show very high expression of this target in all these tumors, 100% to 80%, 70%, et cetera, et cetera. Clearly, in prostate cancer, as our focus today, B7-H3 is relevant. Specifically, looking at some special opportunities in prostate cancer, B7-H3 is among the most highly expressed immunomodulatory genes in castration-resistant prostate cancer. In fact, 93% of them express B7-H3. Interestingly, expression of B7-H3 in metastatic castration-resistant prostate cancer is independent of PSMA by standard analysis. Also, expression of B7-H3 exhibits robust expression even in tumors that are PSMA low. Therefore, many companies, when you look at radiotheranostics, are developing me-too PSMA products. In fact, it's very crowded. Approximately 2/3 of agents under development are variations of looking at PSMA with variations of ligands and isotopes in a very crowded advanced prostate cancer arena. B7-H3 provides a very robust alternative we proposed to target as an alternative to PSMA, especially when we're thinking about post-Pluvicto treatment failures or PSMA low cases where B7-H3 expression is known to be high. There are special subsets. B7-H3 is highly expressed from the time of primary prostate cancer diagnosis in most patients with castration-resistant prostate cancer. Like PSMA, it's an early gene that's expressed in more advanced cancer. There's no difference in B7-H3 expression between primary and metastatic sites, which opens up the body. There's no difference in B7-H3 expression when comparing castration sensitive to castration resistant tissue. B7-H3 is there. Interestingly, there are subsets in today's molecularly targeted world. B7-H3 is expressed in prostate cancer with defective DNA repair genes, ATM and BRCA2 and BRCA, which can be interesting. Also, B7-H3 is negatively correlated with mismatch repair genes, which might highlight B7-H3 as a potential novel target in future treatments where other treatments have success in mismatch repair. Those that don't have mismatch repair, there are no alternatives. B7-H3 is highly expressed in those that don't have it. These then provide many additional applications in prostate cancer beyond PSMA by targeting B7-H3. Also, bear in mind, it provides a pan-tumor broad market opportunity. In other words, many shots on goal, not just prostate cancer. B7-H3 has been out there for a while. There's a variety of companies that have already tried trials with cold antibody, I want to emphasize, antibodies that were developed 10 years ago against this target and tried as sort of immune checkpoint cold antibody approaches or tried as the targeting reagents for CAR-Ts or other types of early bispecifics. However, amongst all these ongoing or completed trials, these all with prostate cancer, none are active with molecularly targeted radiation, you know, radioimmunotherapy. There's a unique opportunity that we have here. One little detail about that may provide a mechanism for prior failures. B7-H3 is expressed in multiple isoforms. There's a 4Ig, as demonstrated over on the left, in a 4 immunoglobulin B7-H3 isoform. It's the form of the protein that has four extracellular immunoglobulin domains. There's also a 2Ig isoform that's expressed in humans. Interestingly, mice only express the two. This two form actually presents a problem because it can be shed and circulate in the blood and therefore provides a pseudo-target decoy or a sink for therapeutic targeting agents, in particular antibodies that would bind to this circulating sink and not get to the target if you have a generalizable antibody that binds to both 4Ig and 2Ig, which most of the prior antibodies did. That's particularly important in low-mass regimes like r adioi mmunotherapy where small masses are injected and you could be bound up by the two forms circulating in the blood and not get to the four form. Our goal from the get-go is to develop a high affinity 4Ig selective isoform of an anti-B7-H3 antibody for tumor targeting, particularly in mind of radiotherapeutics. The comparative antibodies that are out there, again, most of these cold antibodies used in other ways, MacroGenics, the [ATC, AKO, ABB], MacroGenics, they're out there. They have nanomolar affinity, which was thought to be sufficient 5, 10 years ago, and tenfold or less, and in fact, even inverse selectivity for 4Ig over 2 Ig forms of B7-H3. That's a particular note then with that. However, BetaBart is the first humanized IgG1 monoclonal antibody designed for radiopharmaceutical therapy as best in class. It has the highest affinity of all known available antibodies. It's picomolar compared to nanomolar. It has the highest selectivity ratio for 4Ig over 2Ig B7-H3. BetaBart ratio is greater than 300. The best is close to 10 of the other ones. We're orders of magnitude better in both affinity and selectivity that we feel will provide a competitive advantage for the properties of this new and unique antibody. Our first product for development will be Lutetium-177 labeled BetaBart. As my colleague Oliver explained, the target here is B7-H3 4Ig isoform. We have a targeting molecule that is the BetaBart full-length antibody with a linker and a chelator that will now hold the radioactive isotope with very, very high affinity into there. That first out will be Lutetium-177. We will be going after prostate cancer amongst others. Multi-indication potential for B7-H3 solid tumors is emphasized. Prostate, pancreatic, hepatobiliary, colorectal, head, neck, triple negative breast cancer, ovarian, et cetera, et cetera. We have U.S. FDA approved IND just as of a couple of weeks ago, and phase I is planned in the second half of 2025. In particular, this antibody will now provide us with an advantage for isoform selective targeting of the 4Ig form of B7-H3 for PET and SPECT imaging and beta radioi mmunotherapy, long-term even alpha radio immunotherapy. This will traverse the soluble 2Ig, the decoy isoform that's circulating in the blood. Also, we've reduced the affinity by designing mutations into the Fc domain of the antibody, which is the back end. Our antibody will also be accelerated in its blood clearance and decrease its marrow binding where these receptors are present. That's also unique to our antibody in this class. In particular, some data here for blood clearance with what we've modeled in mice. The chart shows all the little bits of data, but the important point is highlighted over on the right box that we estimate the human half-life of our antibody to be a little over a day. That compares to 7 to 12 days for standard antibodies. The standard axiom for antibodies in radio immunotherapy is they circulate too long. They're too long in the blood residence. Antibodies aren't cleared quickly enough. We need to go to small molecules and peptides. It's just not true now with second-generation antibodies. We can engineer antibodies now that have much more rapid blood clearance that will predict lower off-target whole body radiation and predict lower bone marrow radiotoxicity. All of our preclinical data indicates that this antibody, BetaBart, with our design mutations, has that property. Proof of principle of targeting in vivo. Here's Zirconium-89, which is a PET imaging isotope that we could put into a precursor antibody known as MIL33B. It's the mirroring precursor to the humanized antibody. That's the product that we want to move forward. Here you can see in a mouse model of colorectal carcinoma, in this case, it's a flank tumor model, and PET imaging, 72 hours post-injection of the radiolabeled antibody and coronal images. Here you can see the tumor lighting up as we'd expect and clearance from the, you know, in major ways from the rest of the body. If we now take a tumor that's been genetically engineered through knockout to not contain the target, there's no target visualized. If we take the positive target but pre-inject cold antibody, that's called the in vivo blocking experiment to show specificity. Indeed, we massively reduce on-target binding. If we take an isoform of the target antibody, so it doesn't contain the CDR, the targeting warhead on the front end, again, no visualization. All that data is quantified on the right-hand side. These are the expectations we would see by imaging in these mice. We would hope to see that in a human. Now, here's the actual Lutetium-177 DOTA BetaBart. It's got properties with Lutetium-177 with the beta emissions, which are the therapeutic component to it. It also emits some single photons, which allows SPECT imaging, not PET, but SPECT imaging, which is common in nuclear medicine. Here, using the 4Ig B7-H3 tumor in a mouse model, again, injected with our product, the DOTA BetaBart Lutetium-177, we can see the tumor lighting up. It's a little grainier because of the imaging technique of SPECT compared to PET. That's as expected. We see the liver clearance. Note, there's no kidney, which is important in terms of where the clearance goes. We're not going to run into kidney toxicity because we're not clearing through the kidney. We're going to the liver, which is a radioresistant organ. Another test is the humanized FcRn transgenic mice. This is purely for biodistribution. These mice contain the human FcRNs. It's a test of the biodistribution. We don't see great levels of background binding of our antibody in this humanized FcRn transgenic mice, which was very encouraging. Yes, we see the liver because we've designed the antibody to now, once it's cleared, to go to the liver. This animal doesn't contain a tumor, obviously. It's just about the clearance to the liver. Tumor targeting is demonstrated with the Lutetium DOTA BetaBart. In terms of pharmacokinetics, the liver clearance predominates. The kidney is null as designed. We traverse renal toxicity as a cap. Testes are known to contain B7-H3, but behind the testes blood barrier. In these animals, we don't see it. It's below levels of detection. Similarly, subsets of cells in the spleen might, when activated, express it. Again, it's below the level of detection in these models. We're very encouraged by that. OK, proof of principle of therapeutic efficacy in vivo. Here was Yttrium-90, another beta emitter, Yttrium-90 DOTA MIL33B. Here, animals with the CT26 tumor in an immunocompetent, and I emphasize immunocompetent, model, we can see that a single dose of 100 µCi, which scales to what human doses would be, but 100 µCi of DOTA Yttrium-90 MIL33B produced greater than 50% cures just from a single dose. The other curves all represent when the tumor doesn't contain the target or non-treatment with the tumor. It kills the mice. Treatment of these established, interestingly, external beam radiation resistant CT26 colorectal tumors with a single IV dose of Yttrium-90 DOTA MIL33B produced 56% survival after 100 days. In terms of the tumors themselves, this just shows at midpoint, yes, we can see shrinkage. That shrinkage of the tumor compared to not treated leads to significant survival advantage. In terms of mechanism of action, we believe that in addition, there's secondary engagement of the immune system. That is shown here. We took long-term survivors, as shown on the right. These are animals that were treated with the Yttrium-90 DOTA MIL33B and survived. They're 100 days out, no evidence of tumor, and they've survived. We re-challenged them with the same CT26 tumor cells. That's known as immune re-challenge to look for memory. We compared that, as you see on the right, to animals that were age-matched but had never been pretreated. They were treatment naive. Indeed, the set of tumor cells, CT26 tumor cells, killed the naive animals as expected within 40 days. Interestingly, the ones that had been pretreated with our radioimmunotherapy, most of them survived. This is a direct example of immune memory. Clearly, there are secondary adaptive changes of the immune system that these re-challenge experiments show that the tumor cells are rejected in the animals. This demonstrates immunological memory. In effect, our approach here to beta radio ligand therapy is providing evidence of secondary in situ tumor vaccination, if you will. That may imply durable responses. In summary, we're introducing BetaBart as a beta radioimmunotherapy. It's a best-in-class antibody just based on the antibody itself. It has super high affinity, less than 30 picomolar as a humanized IgG1 antibody. It's best in class, greater than 300 times more selective for the 4Ig versus the 2Ig isoform, which we believe is very important for in vivo efficacy and success. It is already pre-engineered with Fc mutations to increase blood clearance, increase liver extraction, which is a radioresistant organ, and away from kidneys, a radiosensitive organ, as well as reduce bone marrow affinity, a radiosensitive organ. BetaBart has excellent 4Ig tumor-specific targeting and PET and SPECT imaging properties in vivo. The Yttrium-90 MIL33B shows greater than 50% efficacy in a long-term survival model with a challenging model, an external beam radioresistant colorectal carcinoma model. It confers immunogenic cell death and immune memory, foreshadowing durable responses in humans, of which our trials will be set out to examine. I would close the discussion and open it up to questions. Thank you. Thank you. Thank you, David. Thank you to both of you. Wow. What an exciting time to be in oncology research, right? It's pretty amazing. Thank you for this really run through the prostate cancer landscape and explaining the new target, B7-H3, and all the scientific background. Let's start with the Q&A. We have a few questions from the audience. Please feel free to keep it coming. The first question is for David. Is there any B7-H3 expression in normal tissues and immune cells? What's your perspective on target of tumor killing by radioligand therapies and normal tissues and immune cells? Great. Thank you. Yes. As well documented in the literature and implied at the beginning, B7-H3 is overexpressed in a wide variety of cancers and has no or low expression in the vast majority of normal tissues. There is B7-H3 expression in subsets of cells in the testes, but they're behind the blood-testes barrier. There is a subset of alveolar type II cells in the lung that can normally express B7-H3, but they're not readily available from the blood side. They're actually on the air side, if you will, of the alveoli of the lung. As you saw from our imaging, these sites are below the level of detection. In the context of chronic inflammation, the immune cells can begin to express B7-H3 in subsets. That has two consequences. One, in tumors that are chronic inflammation, actually, the target is not only on the tumors but also on the tumor immune microenvironment. That provides even more targets for us to hit with radioi mmunotherapy. The beta radiation has a zone of influence. Whether the target's on a tumor cell or the adjacent immune cell, both will cause tumor cell death. One thing that we're aware of is that if there are sites of chronic inflammation, such as chronic lung fibrosis, there could be B7-H3 expression there. We're going to look for that and traverse it in our early trials and then learn to manage that later on if that shows up. Thank you. Thanks, David. Oliver, maybe a question for you, you know, a little more general, I guess, around the B7-H3 landscape as a whole, particularly, of course, then now right now in regards to prostate cancer. Where would you see the competition right now in the B7-H3 fields? You already mentioned ADCs, but maybe give us a little bit of a background to gestalt, what other modalities, ADCs, and are there any other modalities out there against the target B7-H3? Yeah. Let me speak generally first. Then I'll speak a little bit about B7-H3. There There is some competition, but I don't think it's been announced. There is a company pursuing B7-H3 with the radiopharmaceutical, but I don't think it's been announced, so I'm not able to get details on that. When I think about the cell surface targets, there are a variety of ways to approach it. The radiopharmaceuticals I like, and I'll come back and I'll tell you why briefly. We could also use CAR-Ts, which I don't like for solid tumors because they have a terrible track record and they're horribly expensive. In addition, you have bispecifics. Here, we can use the T cell engager model, where we have a CD3 in combination with a cell surface target. The cell surface target could be something like B7-H3 and CD3, and you might be able to engage the T cells through that bispecific mechanism. Of course, ADCs have come on strong. You could make an ADC with this particular molecule, and you might be thinking about that as well. I don't want to go into the validity of B7-H3, but the fact is that other people have targeted unsuccessfully is not, to me, a detrimental finding. David pointed out the fact that the cold antibody approach doesn't work. I would agree. This approach should work. It's a great tumor target. There is some competition. I'll simply say I like what David is doing. He's engineered the molecule beautifully to get that rapid clearance, which is really key. He has fabulous affinity, and he has the right isoform. David, I didn't understand this bit about the tumor reach challenging and the immunity that might be triggered by the prior treatment with the antibody in combination with the isotope. That is super, super cool. I didn't realize that. Congratulations. Thank you. Thank you, Oliver. Another question for Dave, maybe just to explain a little bit more. Where do you see the potential competitive advantage of our compound, our B7-H3, the BetaBart? What makes it special from your perspective? I mean, you're the guy who basically invented it as a molecule with your team. Where do you think that our B7-H3 molecule could be different, maybe even better? I mean, you started talking about this. Give us a go. We have a number of questions around that. Sure. Thank you very much. There are, as mentioned, several other antibodies that have been developed, but without the mindfulness about this isoform selectivity of 4Ig over 2Ig. In the cold antibody arena where you're injecting literally up to gram quantities of antibody, it had largely been ignored that you've got this circulating 2Ig isoform of the B7-H3 circulating in the blood. If you've got a large amount of mass of antibody, you could bind all that up and still have leftover antibody, if you will, to target the 4Ig isoform and some of the 2Ig isoform that's on the surface of your tumor cell to have its effect. However, once you bind up, you now have an antibody antigen complex. Now that needs to be deposited somewhere. That ends up being, in the immunology world, deposited in the skin, deposited in the liver, deposited in the reticular endothelial system, even filtered in the kidney, which leads to a variety of immunologic off-target toxicities. That probably hasn't been really carefully thought about in terms of the standard mass effect used with cold antibodies. On the other hand, because we were dealing with low-mass regimes, meaning when we actually inject our antibody, even in the humans, we're projecting to inject only maybe 1 mg or 2 mg. That's a pinch of salt of actual mass of antibody. Of course, it'll be radiolabeled with therapeutic levels of radioisotope, but it's still a very low mass. If 2Ig is circulating and you're injecting a low mass of the antibody, the circulating 2Ig could bind up all the antibody, and then you won't be able to deliver your antibody to your target. It'll just be all bound up and again maybe perform immune complexes, et cetera, et cetera. Even more importantly, none of the radioactivity would be delivered. We were aware of that going in. As we looked at this very early on, we realized we needed to design our antibody to be 4Ig specific and traverse 2Ig by having a very low affinity to 2Ig and design that into our screening and development program. That's the biggest difference of our antibody compared to all the others, this design characteristic that we were especially aware of. Now, in terms of ADCs and other cold uses, I'm sure it'll be useful, but it's critical for radio immunotherapy. As mentioned by my colleague Dimitris, we also were aware of half-lives of antibodies, which became very critical for radiotherapeutic applications. We designed in Fc mutations that, again, would traverse some of the binding characteristics to Fc receptors that are known to be in the liver and in the bone marrow to drive our antibody that's radiolabeled away from the kidney, away from the bone marrow, and out of the blood, and then collect into the liver, if you will. Those are the two main design characteristics that we rationally designed into this molecule that none of the other competing antibodies have. Thank you. Thank you so much. Dimitris, can I make a very brief statement about why I like this approach? I think it's important. Absolutely, yes, please. Yeah. You know, I mentioned the ADCs, the CAR-Ts, the bispecifics in addition to the radio labeled antibodies. The radio labeled antibodies are going to deposit that isotope right on the cell surface. That cell surface is going to be within a complex microenvironment that actually helps to support the tumor. The stromal elements are critical for the tumor to be able to grow. When you're using an isotope, you're, number one, overcoming the heterogeneity of cells that may or may not express the target. That's an advantage you don't get with the others. You're also altering the microenvironment itself. You know, Dimitris, you know the ability of a stromal targeted agent to change the natural history of the disease. I believe that this is possible. The bottom line is this is an important concept. The isotopes, I think, are going to be superior to the ADCs and bispecifics for that reason. Thank you, Oliver. Thank you. One follow-up question maybe for both of you. How do you compare the B7-H3 to other checkpoint inhibitors in terms of immune suppression, how they're being expressed, and the role in various tumors, specifically in prostate cancer? Maybe starting with Oliver and then Dave. You know, I just regard this as a little bit of a different mechanism. The warhead here is capable of DNA damage, and that DNA damage is a reliable killer. We talk about external beam radiation. By the way, we love external beam. God knows how many patients, thousands, hundreds of thousands of patients are treated every year. There are huge limitations because you can't reach the small nuggets of tumors that are spread in the metastatic disease. This seeks out that metastatic disease, and it does so in a beautiful way. It doesn't depend on the microenvironment. It doesn't depend on the immunotherapy. As David showed, the immunotherapy can augment through that re-challenge experiment, which I commented. Very cool stuff, David. I don't know. I don't mean to talk so much. How about you, David? Yeah. I think exactly. Those are all good points that treating both the microenvironment and the cell and because of the properties that we've tuned into it, I mean, in the end, the human experiment will address it. The ADCs can only target the tumor cells or immune cells that contain your affinity target of interest, and tumor heterogeneity is always a problem. You know that you've got heterogeneity, and that's one general advantage of radio immunotherapy is that not every cell in the tumor needs to express your target to be within the field of radiation and have an effect. The details of how much is enough in humans, I think, is still under evaluation. Clearly, in many animal models, you don't, you know, 40%, 50%, 60%, whatever, you don't need every cell to express your target. In precision medicine in general, since you only affect that cell, tumor heterogeneity is your enemy. In radiotheranostics in particular, and we hope to prove with this one, tumor heterogeneity may not be as much of a challenge. Importantly, as mentioned, it's systemic. It's systemic therapy, so micrometastases that are in the bone marrow or even in circulation, as long as they express the target, the radiation will affect them. Versus external beam, you have to point it somewhere, usually only to the primary tumor or oligometastatic disease, whereas we can treat systemically, ultimately. Often, there are patients that you think are earlier stage, but they have hidden metastatic disease. We have the potential to treat that earlier. I did, in that context, want to follow up with John, who mentioned the difficulties that were faced with Omburtamab, which was an early B7-H3 targeting antibody, also known as 8H9, and progressed by Y-mAbs. That antibody, in particular, interestingly, actually has the inverse affinity for 4Ig versus 2Ig, which is why they've never done systemic therapy. It binds with higher affinity, only nanomolar, I might add, not picomolar. We've studied that. The Omburtamab antibody only binds to the 2Ig isoform and very poorly to the 4Ig. When it's injected systemically, it just has poor clearance properties. It clears too much. It doesn't bind with very high affinity to the tumor. That's why they went to intrathecal injection with some successes intrathecally because now you don't have a compartment with the soluble 2Ig isoform within the spinal fluid matter of the brain and the spinal cord. The biochemistry matches the failure of Omburtamab as systemic therapy, even though they were one of the first to get a radiolabel onto it for intrathecal injection. Once we show some success, we could compete in that domain too. Thank you. Thank you, David. Another question, which, of course, is on everybody's mind. I have a number of people asking about this. When you look at the prostate, and this is a question for both of you and maybe starting with Oliver again. When you look at the prostate cancer landscape, right, PSMA targeting agents, especially Pluvicto, of course, have changed, as you showed very nicely, the landscape in a pretty dramatic way. Still, patients relapse. No patients to this date, at least, are cured through Pluvicto. What's your perspective on new targets? There are, I don't know, more than 40 companies that are pursuing prostate cancer radiotherapeutics after Pluvicto. The vast majority, as you said, targeting PSMA, whether it's big pharma like AZ, Bayer, BMS, or smaller companies, including, of course, the Australian companies Helix and Clarity. They're all looking at PSMA. What's your perspective on how a new target is different or what should be done in patients after Pluvicto failure? Yeah, it's a really good question. Yes, there's a lot of effort in the space because of the Pluvicto success. I think right now, Pluvicto is sort of charting out about a $2 billion annual revenue. I did hear that the growth rate is about a 40% per year after the initial approval in the pre-chemotherapy space. Everybody likes the $2 billion number. It's growing very, very rapidly. People are targeting PSMA, but it's not the whole story. We know that so far, everybody is failing the PSMA-targeted therapies. There are probably some better ones coming. You probably can take an alpha like actinium or [Lead-212] and have a superior outcome over the Lutetium. That's yet to be proven, and the toxicity may be problematic as well. I believe there is a role for alternative targets. I think B7-H3 is an exceptionally good one because it turns out, and I'm going to go into a little bit of biology here, I'm going to categorize prostate cancer into four different groups. One group, which is the predominant one, is driven by androgen receptor. These are the androgen-dependent cells. There are also the neuroendocrine cells, and there are also the cells that we call amphicrine cells that are a combination of both the neuroendocrine and the AR. Then there are the double negatives. It turns out that B7-H3 is well expressed in a number of the cells that do not express the PSMA. We talked a little bit about the ability for isotopes to overcome cellular heterogeneity. David made the point nicely, and I alluded to it earlier. B7-H3 can complement the PSMA. I believe it'll take out cells that the PSMA doesn't touch. I believe this could be a therapy that could work where the PSMA is failing. That's a huge market right now, and it's only going to get a bit bigger tomorrow. As David said, the actual expression is across the entire spectrum of prostate cancer. I think it'll deserve to be looked at in a multiplicity of settings, and not only, of course, prostate cancer, but the colon and the bladder and everything else. This is a multi-tumor target, and there are many opportunities, many shots on goal. Thank you. Thanks, Oliver. Dave, your perspective on what to do after Pluvicto? New targets, old targets, how to go about those folks who progress after PSMA, Lutetium? Yeah. Kind of just building on that, the literature already shows that B7-H3 is overexpressed in PSMA low or null tissues, in particular also in prostate cancer. We clearly have an opportunity there to salvage patients that failed. I think there's some more biology that we need to learn about what the immune landscape and expression profile looks like after Pluvicto. We need a lot more biology and assessment in these patients to better understand some of these next steps. That's, again, where some of the me-too approaches, if I might say, are saying, let's come in with a different isotope or a different variant of the PSMA. We're thinking much more orthogonal. Get into a totally new regime, in this case, B7-H3. With or without, we could certainly, with our same platform, go to alpha particles. We could go to other betas on that. We've also got a biological target that's orthogonal. The other part of it too is the presumed window of opportunity that relates to the toxicity profile. I mean, with on-target off-tumor toxicity profiles, those can be pretty significant for some patients with the current agents, renal toxicities and managing that in particular. Some of the other known organ toxicities, marrow and otherwise. This is a completely different target. We know where some of the toxicities might be. We've engineered the antibody to try to traverse those. The point is, we'd have an orthogonal set instead of an overlapping set of toxicities to manage. In particular, we hope that patients that have been treated with Pluvicto and then are reaching radiation caps in their kidneys, for instance, that doesn't matter. This agent doesn't go to the kidneys. We'd be able to exploit the expanded radiation clearance of the liver, for instance. All these details matter in terms of how we could salvage patients post Pluvicto because of the orthogonal nature of the target and the reagent itself. Thank you so much. Thank you both. I think we are at the end. We have a lot of questions that I don't think we can all answer, which are some of them a little, you know, different from the discussion points. You know, we can try and come back to the people who asked those questions, or you can contact us. I did try to really answer the questions that are most pertinent to the discussion that we had tonight, the target and the prostate cancer landscape and how our compound or this compound would look like in terms of the competition. I can only say that we are all here, very excited. I'm personally super excited to get this into the clinic. For patients, we at Radiopharm Theranostics will run a study with this compound. We're planning to dose the first patient by the end of the year. The B7-H3 study is going to be a U.S.-based study where we will study a number of different indications. It's an umbrella study, obviously, castration-resistant prostate cancer (CRPC). We will also have colorectal, lung cancer, GYN tumors, and so on. The study is going to be about 33 patients in the dose escalation phase I, and then we'll have a dose expansion. We hope that we'll be able to have the first two cohorts of data completed then in the first half. The most important thing is that we have received the IND clearance from the FDA, and we're going to go into this in the clinic in the U.S. by the end of the year. This is all I had to say. I would like to, again, take the opportunity to thank both of our speakers for your tremendous insight into prostate cancer and B7-H3 as a new target, for taking the time for engaging in this discussion, which took us 10 minutes over. I really didn't want to cut this short. This was a great conversation to have with all of you. From my end, thank you very much again. We'll keep in touch, of course. Thank you, everything. Do we have any other closing remarks, Matt, or? No, we'll leave it at that. Thank you. Thank you again, everybody. For the folks in Australia, I wish you a wonderful rest of the day. For everybody else here in the U.S., a really nice rest of your evening. Thank you again.