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Oliver Sartor: Hi, I'm Doctor Oliver Sartor and I'm with UroToday as part of our leadership series in radionuclide therapies. Really a pleasure for me to be able to welcome Philippe Legenne and from Molecular Partners, he's the chief medical officer there. Welcome, Philippe.

Philippe Legenne: Thank you very much, Oliver. And I'm very happy and glad to be with you today. And I'm happy to share some thoughts from Molecular Partners with you.

Oliver Sartor: Good. The first question is a very basic one. Right now, we have CAR-T cells. We have bispecific T-cell engagers. We have ADCs, small molecules, and radioligand therapies. Now, you're working in radioligand therapies. Why? Why do you think that radioligand therapy is going to be a key for treating cancer?

Philippe Legenne: Yeah, thanks for this opening question. Maybe I can try to address it in two different ways. One is why, as a company, did we also join the radioligand, the radiopharmacy as Molecular Partners. And the second is why we think that our protein platform, DARPins can play a role there. So as a company, this company is 20 years old and is a protein engineering company initially.

And in fact, early on, the company there was development of a HER2 theranostics 15 years ago plus. But in fact, that preclinical work was stopped fairly early on because I think the infrastructure environment was not very mature at the same time. And the founders were working at the time with a PSI in Switzerland and I think on an iodine. But basically it was very difficult. The field was not mature at the time.

Anecdotally, I come from GSK a long time ago. I was close to the Bexar product, and we had a great product that was really helping patients. But in fact, the patient was not-- the Bexar was not very much used at the time because it was not the right time. And I think in the past three or four years, we at the time we had focused mainly on immunotherapy, which is what we have been doing the most.

But we were working in collaboration with Novartis. And Novartis suggested to us to use our DARPin They thought that they would be amenable to become vectors for radiopharma. So that was the idea.

Oliver Sartor: If you don't mind, you mentioned two things that your readers may not be familiar with. PSI, Paul Scherrer Institute. Just explain what PSI is. And DARPins, now that's a code word for something that you know, but many people don't. So what's PSI and what's a DARPin?

Philippe Legenne: Yeah, so PSI is a very Paul Scherrer Institute in Switzerland, next to Zurich. Close to University of Zurich is a National Institute for radiopharmacy in Switzerland. And basically, it has been a long time developer of different types of isotope and basically is a leader in Switzerland and internationally in the development of radioisotope. So it has capability to develop. So that's PSI is a natural partner for specialist Swiss based biotech as ours.

So that's one. And then the other part, which is I mentioned DARPin. And yes, I should have explained that because this is basically, this company was based around the development of designed, ankyrin repeat proteins, small protein vectors, which are-- small proteins which basically are in silico developed and can more or less be developed fairly quickly to address or to engage with quasi any type of receptors.

They are in the size and it's sorry to be technical. It's a 15 kilodalton. So which is made between an antibody obviously and a mini protein or and obviously it sits in the middle of that, that's a type class of vectors. And historically those DARPin designed ankyrin repeat proteins. So those proteins are present naturally in the natural cells. But basically the company has mastered the way to develop them, design them, and develop them, especially in Escherichia coli.

So they're quick to develop. That's what I'd like to say. And we develop them at Molecular Partners we have two big areas for development. One is immunal we link them together to make multi specifics like bigger sophisticated proteins. Or we do-- we try to keep them small. And we keep them small, we link them to radioisotope. And here's how we started to create the radiopharmacy group at MP.

And again, as I said initially it was stimulated by Novartis where they asked us to develop some targets. In the back end of that, we have developed our pipeline. And today, again, we are now very close to initiation, our first clinical program, which develops around DLL3, a target which is fairly well known in the neuroendocrine space and in combination with lead 212 which is an alpha isotope. But maybe we can expand on that later.

Oliver Sartor: Yeah, no. Very, very good. And, one of the questions that people are always interested in and I appreciate you mentioning that DLL3. I do not want you to disclose anything that is not appropriate, but are there other targets that you are using in your pipeline to be able to target using radioligand therapy, because this is a huge amount of discussion around what targets are amenable. But I don't want to get into confidential information, so.

Philippe Legenne: No. And thanks I will mention another one, which we have released and which is public now. So our first one is DLL3. And to arrive in the clinic immediately. In fact, for imaging and treatment, that's one aspect. Then, on following this one, we have also developed a program which is a little behind but not very much behind, targeting mesothelin, which is another well-known receptor expressing a tumor expressing target, which is validated.

And I think it's important to say that but which is not so easy to develop because the specificity of mesothelin is there is a lot of shedding. So it has, in fact, impaired some development from other. And we believe that because DARPins are small, they can link to the unshared parts of the mesothelin receptor. And we think that we may be able to-- we know that we are able to engage in fact, there and stay on the receptor long enough. So we think that we have a program in the making for that.

Oliver Sartor: Very nice. Now, you mentioned imaging, and I believe and I suspect you believe that imaging is very critical and that theranostic field, because we want to be able to treat what we image and image what we treat. If you're developing a lead 212, may be using a chelator that would be ideal for something like lead 203, but that SPECT imaging, not PET imaging. So I'm a little bit curious how you're managing the imaging for these molecules that are coming along. Are you going to use SPECT? Are you modifying to PET?

Philippe Legenne: So, very good question. Obviously, imaging can be used for two very different purposes in the development of a therapeutic or theranostic. One is, during the course of the development as the companion to the treatment. We think that 203 is the ideal one, because lead 203 is the ideal companion to initiate dosimetry, to calculate dosimetry, because it translates nicely into what you will get from 212.

So this is the ideal partner. However, we all also know that and it's the same chelator. OK. As we also do them. But it's difficult. It's not a very used let's say a isotope and not so easy to produce in a way that it could enable large scale diagnostic. So we believe that for the sake of the development, we want to work with 203 and we are currently working with it, I have to say.

But potentially we are considering if we need, and we believe that we will need this down the road of a broader available diagnostic that we may have to look for another imaging agent. Could be copper, could be indium, those types of--

Oliver Sartor: Yeah. No. And copper is quite good with a nice half life, indium of course, puts you back into specs. Zirconium is a little bit longer. There have been a variety of things to look at. Now, when you mention lead 212, there are a couple of interesting issues that arise. I'd like to get your take. Issue number one is the 10.6-hour half life means that the DARPin is going to be binding very quickly, because when you are using something like an antibody with a longer circulation time, obviously lead 212 would be a bad choice.

So do your DARPins get on the target quickly and then are they renally excreted. And if so, tell us about renal excretion. So a couple of things about lead 212 on target effects and renal excretion all mixed up there.

Philippe Legenne: Yes. So as you said, the DARPin or basically the vector profile needs to match with the isotope, basically. And why we think and our colleagues at Orano Med, I should have mentioned that earlier on, we develop and co-develop, in fact, this first program with our colleagues from Orano Med. Who are the one of the world leader in delivering and supplying lead 212. So as we do that, we need to have the right PK uptake profile in the targets.

And also obviously, I'm making sure that we don't go where we are not supposed to go in the healthy tissues. And we need to find that window and it needs to be in the window, which is compatible with a 10-hour half life radioisotope. So our preclinical work has enabled to think that we should match that window, and that's why we are moving with it. We were discussing very recently, obviously sharing some of our initial results with some experts.

And basically, it's an interesting DARPin is in the middle between the short, the small molecule, very small, very quick uptake, not staying very long, and the longer antibodies which stay, which are natural, I would say to actinium, for example, or to longer half life versus the others would be ideal for potentially for short term like lead. So we are there in the middle, but we believe that from what we have seen, what we have seen encourages us to move with our colleagues from Orano.

Oliver Sartor: Yeah. No, I mean Orano is, of course, the nuclear waste company that happens to have lead as a byproduct. It's an interesting story. I talked to Orano Med a little bit earlier, but yeah, it's an interesting story there. So that's terrific. You've got them as a supplier now. One of the other things whenever I'm talking about lead 212 and I happen to like lead 212. That people say, well, goodness gracious, how are you going to distribute it? How are you going to have a distributed model? So do you want to touch on that. Certainly you've thought about it.

Philippe Legenne: Well, yeah, absolutely. So I also want to say we also want to follow the science, and a DARPin yes, can be a good partner for a lead isotope. But if we were to see that the profile were not optimal, we could also combine with another type of radioisotope. So we want to follow the science. That's what is important and that's what patients need. So Orano Med, so we have been now partnering for a while on this and in fact, it's an interesting distribution model that they have.

It's pretty well centralized for the moment. I knew that other lead 212 providers have more decentralized models in terms of how they anticipate to supply. And, but Orano is partnering with us on this early program. But Orano also has been successful with alphametics or other programs. And they are going to start their phase III. So we're confident that they will be able that they already have shown to us that they can distribute a supply of the drug in many places, around the US first and that they are, I think, very close also to be able to distribute around Europe and then they will progress.

So we think we are comfortable to work with this central supply model like Orano. Yes, and for us it was also important-- I know there is a lot of attraction to actinium, which has come out as the first alpha for a little longer. But also Orano is a very strong supplier in terms of capacity to supply.

And so actinium has been a little more tricky. Although I think long term, it will be fine. But yeah.

Oliver Sartor: I want to ask a complex question, but I'm going to need a relatively succinct answer, if you don't mind. Because we could talk about this next question for at least an hour. What about combination therapy? This is getting more and more play. You saw the ENZA-P with its image showing synergy between the enzalutamide, and the lutetium. Are you thinking about combination in a way that is something we could discuss here? And if so, what type of combinations might you be interested in particular?

Philippe Legenne: Yes. So combination I would say, so there are different types of combination. But the most obvious that comes to mind, especially perhaps for an alpha, especially for short lived alpha could be combination with immunotherapy. So this is something which is in our clinical development for DLL3 and we want to get there.

And I just want to develop one second on an alpha likely seems to be because of the new antigen that we think it releases. And also because it's a short acting and short half life. We think that it could quickly preserve or let the immune environment reconstitute. This is the theory, by the way. No one has yet confirmed it clinically. But the theory is attractive.

So first, obviously, combining with immune checkpoint. And, we are talking DLL3, we are talking where in fact your immune checkpoints are part of standard of care is on the radar. That being said, I think we need to see first that we have-- we are doing something as a monomodality, as a monotherapy modality, but branch fairly quickly to that. So this is an obvious one.

Then obviously there are other combinations that could come up, PARP inhibitors or are also I think on the radar. And if I think of mesothelin, which one of the major initial indications where we could think of going first is ovarian cancer. This is also on the radar, for example. So those would be synergy between mechanism of action. Then I think it's more complex. I just touched on it and then I don't go too far is if I think of DLL3 again, I can also think of prostate cancer or neuroendocrine prostate cancer.

And I think there is also it's not truly synergy, but it's more complement this time between a PSMA engagement and potentially during the neuroendocrine differentiation, adding at that moment another agent, which would be a DLL3, for example. So it's more of a complement than a pure synergy in that case. But we need to think of those early on in our clinical development plans.

Oliver Sartor: Terrific well listen, Philippe, we've had our brief discussion where we're going to go ahead and cap it off. Very, very much appreciate your joining CMO from Molecular Partners. Looking at DARPins, DLL3, lead 212. Fabulous little discussion. Thank you so much for joining today.

Philippe Legenne: Many, many thanks, Oliver, for the privilege to be there.

Oliver Sartor: Great Thank you.