Good morning. Good afternoon. I'm Eugenia Litz, investor relations at ADC Therapeutics. It is my pleasure to welcome you to our webcast today, highlighting our ADC platform and solid tumor pipeline. I would like to remind you that this presentation may contain forward-looking statements which are subject to certain risks and uncertainties. Please refer to our SEC filings for more information. On our call today is Chris Martin, our CEO, Patrick van Berkel, our Head of R&D, and Joseph Camardo, our Chief Medical Officer. With that, it is my pleasure to turn the call over to Chris. Thank you, Eugenia, and welcome to the ADCT Pipeline - Solid Tumor Pipeline call. It was almost exactly 20 years ago that I sat down and met John Hartley in University College London to look at some pyrrolobenzodiazepine data in a couple of solid tumor models in cisplatin-resistant ovarian and glioma. These PBDs had been designed specifically to be active in hard-to-treat tumors which were resistant and refractory. The data was truly startling. That was the genesis of the formation of a company called Spirogen. 10 years later, we spun ADC Therapeutics out of Spirogen to develop a PBD ADC pipeline. Now, 10 years on from that, we have one drug approved, ZYNLONTA, which has been marketed in the U.S. A second program, Cami, which is well on its way to a BLA filing. Behind that, an exciting pipeline of five solid tumor programs. It's those that we're gonna focus on today. This last decade has been extremely productive. As you can see here, we have these seven programs, five in the clinic, two in IND-enabling studies, and behind that, multiple programs in research. As I said, today, we're going to focus on these solid tumor programs. For the first time, we'll be talking about ADCT-212, targeting PSMA, a highly optimized and differentiated program that Patrick will be able to describe to you in some detail. This pipeline has been produced by a world-class R&D organization with all of the capabilities you need to go from target right through to approved drug and beyond, as demonstrated with ZYNLONTA. It's a very capable program, a team based in London for research. They've recently moved to this state-of-the-art facility that you can see in these pictures, at I-HUB in West London. The clinical team that's based in New Jersey and Lausanne that takes these clinical candidates and turns them into oncology drugs. It's my pleasure today to introduce you to Patrick van Berkel. He was employee number 1 at ADC Therapeutics. He's the architect of the full pipeline, and he will be taking you through the solid tumor pipelines, asset by asset. Also to Joseph Camardo, our Chief Medical Officer, who's been responsible for the development of these drugs and is taking the solid tumor programs forward. Patrick, it's a great pleasure to introduce you. Patrick. Thanks, Chris. Thanks very much for this introduction. Thank you all for listening in. I'm really pleased to update you on our research and development activities as well as our solid tumor pipeline. First, let us take a step back. What really is an antibody drug conjugate as we develop it? An antibody drug conjugate is an antibody that targets to a tumor-specific antigen conjugated to a toxin. Now, we all know toxins. They're known as chemotherapy, and they've been very useful for the treatment of cancer patients. We all know that this typically is a mixture of different chemos and provide good efficacy, but the efficacy is very close to the toxicity profile of this chemo, which means that the therapeutic index of such a treatment is quite small, quite narrow. The idea of combining an antibody with chemo or a toxin is very smart, and that happened decades ago. Indeed, we've seen over the last 10 years or so that about 12 ADCs have been approved in different indications, and indeed give a real good benefit to cancer patients because they have a better therapeutic index. Of course, we're not there yet. We try to improve on the therapeutic index of our ADCs all the time, and we try to achieve that by improving the efficacy or reducing the off-target toxicity of our antibody drug conjugates. The way we approach that at ADC Therapeutics is basically in three different buckets. Of course, the toxin, so the chemo, as you call it, or the toxin, is really important. Chris already mentioned the PBD, and we're proud that we have PBD chemistry in the toolbox. Later I will explain what makes a PBD so unique. Going forward, we also think that it's important to have other toxins in our toolbox to develop antibody-drug conjugates. I'll explain in a minute also why we think that's critical. In order to do so, we have in-licensed a very important technology for us that's called the silent technology, and I will explain today what that technology brings to ADC Therapeutics. You can also think about a different concept. Instead of targeting a toxin to the tumor, you can also target, for instance, immunostimulant payloads. These are not toxins on its own, but they really activate locally the immune system such that the immune system will attack the tumor more efficiently. Even you can think about combinations of things. You can think about combinations of different chemos, different toxins, or a toxin with an immunostimulant payload. That will in the future be quite important. But of course, in order to do so, you have to be able to conjugate all these different things to the antibody, so the tumor-specific antibody. Therefore, we have a strong focus on our conjugation chemistry such that it's site-specific, but also that will allow us to conjugate different toxins, different payloads to the same molecule. Cancer treatment has been treatment based on different modalities quite often, and therefore it would be quite neat if you can combine different mode of actions in one product. That's really where we think the future will go. Having this optionality in the toolbox is quite important for us. Finally, of course, antibody and protein engineering. I mean, the antibody has to be tumor specific. How do you make it tumor specific? Of course, it will depend on the antigen, but also you can make the antibody maybe more tumor specific. We approach that by different techniques, such as masking or conditional binding techniques, such that the antibody will have a higher preferential binding to the antigen in the tumor versus the antigen on healthy tissue. Within ADC Therapeutics, we also have what we call xDC. We're not going into too much detail today, but we also have quite a few licenses for the PBD chemistry for what we call xDCs. This means that it's not an antibody that you use to target, but you can think of a peptide or another protein scaffold that you make specific for a tumor antigen, and you use that to conjugate the toxin, too. The advantage typically is that these molecules are smaller and may be able to penetrate the tumor more efficiently. Of course, there's one thing missing on this previous slide, which is the tumor target. The tumor target is quite important and maybe the most important thing when you select and gonna develop an ADC for a certain indication. The tumor target may be expressed on liquid tumors, it may be expressed on solid tumors, or maybe on both, or even targets that are expressed indeed both on liquid and solid tumors. The expression of the target on the tumor may be heterogeneous, may be homogeneous, can be high or low. There are different parameters that you have to look into. Typically, a target is not really tumor specific. There is healthy tissue expression, which can be high, it can be low, it can be on a critical organ, or it can be on a less critical organ. This is really an important component of the design of an ADC, because this ties into how you select your toxin. Depending on all these parameters, you may wanna go for a PBD, you may wanna go for a PBD which is lower potency, or you may wanna go for a PBD with high potency because you think there's no risk for healthy tissue toxicity. You may also decide that based on the tox profile or maybe based on the healthy tissue expression profile of the target, you think a PBD may not be the right toxin of choice, and you have to go for a toxin with another mode of action. All these things come into play. Then, of course, the real hard work starts, and that is finding the right candidate for this particular target of interest. That's a lot of work, I can tell, where you have to look into different parameters. The linker is important, the toxin is important. You have different flavors of both. Of course, the same is true for the antibody. You have many moving parts that finally have to give you the best candidate for your target of interest. Let's take a deep dive into PBDs. Chris already alluded to the PBD chemistry and how it was invented in the old days in London. We're really proud that we have succeeded as a young company to bring the first PBD-based ADC to market, which is ZYNLONTA. That was quite an achievement of our team and credits for the entire team who made that happen. Let us explain how a PBD works. The antibody drug conjugate is targeted to the tumor by the antibody, is processed, and that processing delivers the toxin to the nucleus, in our case, a pyrrolobenzodiazepine. The way the PBDs are developed is that they are able to cross-link DNA in the minor groove very, very efficiently. You see the cartoon in the middle where the cross-link is shown. Basically, once the PBD dimer has entered the nucleus, it will go into the minor groove and cross-link the DNA on any GATC sequence. It's a GG cross-link. These cross-links can be pretty persistent. That was of course one of the reasons behind developing the platform. They had to be active in patients that were relapsed or refractory to standard treatments. These PBD cross-links are very, very persistent. What does that mean? They sit and wait until the cell wants to divide, and basically the cell can't divide because the cross-links will keep the two DNA strands together, and this will drive the tumor cell into apoptosis by causing a stalled replication fork, as you can see in the cartoon there in the middle. The two strands of DNA are kept together and it can't separate, no translation will happen. These cross-links fit very nicely in the minor groove of DNA, which means nothing hardly sticks out, there's no distortion of the helix structure, and therefore the DNA repair mechanisms really have a hard time detecting these cross-links, and that explains why they're so persistent. PBDs are very potent, so you can tell from the graph on the bottom right that if you compare the potency of a PBD dimer to toxins that are more often used in ADC development, such as auristatins, calicheamicins, or maytansinoids, it's an order of magnitude higher than those toxins, and a couple of orders of magnitude higher than classical chemo. The beauty about PBDs is also that we can tweak the potency of the PBD dimer. Now we're working also with PBD dimers that have a potency which approaches that of the old-fashioned toxins, and I will explain later why this is important for product development. Just to summarize the benefits of PBDs. They were rationally designed to maintain activity in relapsed patients or patients that were refractory to treatment. They cause DNA cross-linking in such a way that the DNA helix is not distorted, not disrupted, and therefore the DNA repair mechanisms will have a hard time detecting these cross-links, and they are therefore pretty persistent. They're very potent. We're allowed to work with what we call drug-to-antibody ratios of 2, which is quite technical, but basically it means that we don't need a lot of toxin to add to each antibody, and that has some advantages in our drug development. Also, there is bystander activity of the PBD. This means that not all the cells express the target of interest in a tumor. Sometimes the expression is heterogeneous. Now, if a cell doesn't express the target, it can still be killed by a PBD that's released from a neighboring cell that has processed the ADC because it expressed the target. That toxin then is released from the cell that's dying and is able to penetrate the neighboring cell and kill that cell. In case of solid tumors, having bystander activity, we believe, is quite an important feature. PBDs also cause immunogenic cell death, which means that once the cell is going into apoptosis because of a PBD cross-link, it will cause a more immunogenic response against that cell, which is of course an advantage if you think about antitumor treatment. We have to think, of course, about a couple of things with PBDs related to its mode of action. We must pick targets that are relatively clean, that are not expressed on healthy tissue to a high extent, or at least not in critical organs. Of course, we also have to take into care when we do clinical development that this persistent cross-link may show up in patients. When you look into dose escalation or dose finding, you have to take care of that delayed cross-linking. Let's take a step... Let's take a closer look at the PBD chemistry itself. This slide shows you a structure of a PBD payload, as we call it, which means all the components that contribute to the PBD toxin linker and how we're optimizing it to make, to come forward with PBD-based ADCs that have an improved therapeutic index because we think we reduce off-target toxicity, and therefore, we should be able to increase the dose levels of these PBD-based ADCs in patients. On the left, you see conjugation. Now, why is conjugation important? Because that determines how you conjugate the payload to the antibody. Of course, you want a stable chemistry to do that. We use classical maleimide on the right spots in the antibody, or we use things like bioorthogonal click chemistry to make it very stable. Another important component is the spacer, as indicated here. We have shown that, for instance, if you change the PEG spacer to something called HydraSpace, you improve the off-target toxicity of the ADC, at least preclinically, quite significantly. In a few of our candidates, we have chosen to work with HydraSpace as the spacer in the entire payload. The linker, of course, is important, whether it's cleavable or non-cleavable. We believe that for solid tumors, a peptide-based cleavable linker is quite important because that will give you the bystander kill, as I just explained. A non-cleavable linker will not give you that. Typically, for solid tumor programs, we will focus on cleavable linkers. Last but not least, of course, we play and tweak the potency of the PBD dimer. This example here is between a very highly potent PBD dimer called SG3199 and a less potent PBD dimer called SG2000. Later on, I will explain how that will impact the tolerability of the PBD. You can see by playing with these different structures and different modalities of the PBD payload, we come forward with novel PBD payloads that will offset toxicity and hopefully will allow us to dose higher in patients. This work has led us to a portfolio of 11 products or 11 product candidates. We have 11 target exclusive licenses for the PBD chemistry, and these, the projects are shown here. There are some undisclosed, but you can see how they are divided between solid tumors, hematological tumors, and we also make a division between clinically validated targets as well as novel ADC targets. As you all know, we've been strongly focusing so far on our Heme portfolio in the bottom left with CD19, CD25, and CD22. We're moving up now to the solid tumors, that's where we are talking about today, in fact. Some metrics with this portfolio. In order to get to this portfolio, we've looked at more than 170 different targets, whether we believe they were suitable as PBD-ADC conjugates. We prototyped more than 35 of them in our facilities in London, and that has led to this matrix of products between the four quadrants that you see there. We filed eight INDs to date. Our fastest timeline to IND was 13 months, so it shows that we as a company can deliver quite quickly a product to the clinic to be tested in the clinic. Once we are in the clinic, we have a very strong objective to go for rapid clinical proof of concept, just to see and to figure out whether we believe there's a way forward for the PBD-based product or not. We do that by performing quite robust, large phase I clinical trials, as we've done with Cami and Zynlonta. I think all of this shows and the success we had with the hematological programs that this is a very, very solid and robust approach, and we're therefore confident that this will also apply to our solid tumor pipeline, which we're gonna talk about in a second. Finally, before we go there, I want to explain in a little bit more detail about our selenol linker technology and why we think this is important. Well, as I mentioned, there are a lot of targets out there, and some of these targets, they may be better off with another toxin versus a PBD. Therefore, to have a toolbox that allows us to work with different toxins is very important to be able to target any target we like. We have in-licensed this new linker technology, which will allow us to basically work with every toxin that is out there. We've given here the examples of exatecan and MMAF, but these are just examples. We can stick basically every toxin to this particular linker system. Another important feature is the novelty of the selenol linker system. This is a linker system that is designed such that you can tweak the sensitivity to different pHs. We believe that may be a very important, nice attribute of the linker system. For instance, the tumor is more acidic than healthy tissue, so we can design the linker such that the warhead is preferentially released at the tumor and other healthy tissue, which is a higher pH. Finally, there is a nice feature of this system, of this linker system, which is called the adaptor. The adaptor will allow us to branch off from this one payload. We can design payloads that have 2, 3, 4 toxins, for instance, per payload. You can also think about combinations of toxins that you can make in one particular payload. I explained in the beginning that combinations can become very important, and this linker system will allow us to combine two different toxins or, for instance, combine a toxin with an immunostimulant quite efficiently. Going on into deeper detail in our solid tumor pipeline. Chris already mentioned that we're gonna talk about five different programs today. Three are in the clinic, and two are in the IND-enabling stage with ADCT-701 and ADCT-212. The first time you're gonna hear about this very exciting program targeting PSMA. To start with Cami. Cami, as you all know, is very advanced in hematological, in the hematological setting. We just have completed the phase II pivotal trial for Cami in relapsed refractory Hodgkin lymphoma. We also see a future for Cami in solid tumors. I will explain in a minute what the mode of action or the mechanism is behind this thinking. It's a completely novel immuno-oncology approach, and we're gonna show later that we have really encouraging data in patient biopsies that we took from the monotherapy dose escalation study. We think that Cami has a future in tumors that have been infiltrated with CD25 positive Tregs. There's a long list of tumors that has been shown to be infiltrated with T-cells, and the long list is over there, you can read it. It's quite a big list of tumors that, where we believe that Cami may have a future. Where we are right now is we are currently in a dose escalation phase of Cami with pembro, and Joe will later tell you about the next steps for this program. First, let me explain why we believe Cami works in solid tumors, because typically, solid tumors do not express CD25. In fact, they never express CD25. It's all about tumor infiltrating T-cells. This cartoon here shows you that there are basically two types of infiltrating T-cells. You have Tregs on the one hand, and you have the effector T cells on the other hand. Now what you really need is a high level of proliferating effector T cells because these are the cytolytic T cells that will attack the tumor. The Tregs, on the other hand, are the immunosuppressive cells. They dampen basically the immune response against the tumor. What you want to do is change this balance and favor the effector T cells over the Tregs. Now, the Tregs are CD25 positive, and that's where we come in with Cami. The idea is that we deplete the CD25 positive Tregs in such a way that we increase the proliferation of the T effector cells, which will then kill the tumor. Indeed, in our preclinical work, this turned out to be the case. Here we have pretty nice preclinical data that indeed demonstrates this mode of action. What we have done before we could go there is to make a surrogate for Cami, because Cami doesn't cross-react with mouse CD25. Of course, these are all mouse preclinical models. What we had to do is make a surrogate, which we call SURF-301, which basically is pretty similar to Cami. It targets CD25. It has the same payload, the same drug-to-antibody ratio as Cami. It's a very nice surrogate for our Cami molecule. We had to do that in order to be able to run these syngeneic models. Syngeneic models mean that these mice are fully immunocompetent. That's what you need because, of course, you're looking into the immune system of the mice. What it does, and what we show here is that indeed, in these syngeneic mouse models, SURF-301 is very active in a CD25 negative MC38 model. On the left, you see that a single dose of Cami basically eradicates all the tumor. Those are the curves at the bottom. A single dose of 0.5 or 1 mg/kg was sufficient to get rid of all the tumor cells. You can compare that to PD-1 there. That's the blue, dark blue curve. That doesn't do a lot, but there's some activity. At least you see that Cami by itself is much more powerful than the PD-1 control here. If we combine Cami with PD-1, as shown on the right, you get very nice synergy. In this case, we didn't take the high dose of SURF-301. We took a suboptimal dose of 0.1 mg per kg, which on its own is hardly doing anything. Combine it with PD-1, which on its own is hardly doing anything, and you get the light blue curves that are shown on the right. Very nice synergy if you combine SURF-301 with PD-1. We also showed that these animals build up immunological memory. In the middle you see that if we took the survivors of these studies and we grafted these mice in the other flank with the same tumor cell line, the tumor won't grow anymore. This is just because the immune system has built up immunological memory, recognizes the tumor, and gets rid of it quite efficiently. This happens after treatment with both SURF-301 on its own or the combination of SURF-301 and PD-1. Now, of course, the big question is indeed, is it explained by the knockdown of Tregs? This is a busy slide, but I will take you through it just so that you understand what we're showing here. Here we are showing immunoprofiling of these mice during the course of the study from day 2 to day 11. At the top row, you see the Treg. We counted the Treg in the tumors, and where the arrow is pointing, you see that already at day 2, there's a very strong depletion of Treg counts in mice treated with SURF-301 or PD-1 and the combination with PD-1. In the middle row, you see that this is accompanied by an increase in CD8 effector cells. Where the arrow is pointing at day 11, it takes a bit longer for the effector cells to come up, but there you see a very strong increase in the CD8 effector cells, again in both groups, the SURF-01 alone or the combination with SURF-01 with PD-1. Of course, as a result, at the bottom, the ratio of T effector cells to Treg has changed dramatically. If you see from day two to day eight, you see an increase in this ratio again in both groups. This shows that preclinically, indeed, the efficacy of SURF-01 is explained by depletion of CD25 positive Treg and an increase in CD8. We're happy to tell you also that this is also what's happening in the clinic. In our phase I monotherapy dose escalation trial, we were able to acquire biopsies from patients that were dosed with Cami. This slide shows you that in those patients where we do see T-cell infiltration in the tumor, there is indeed a change in the ratio between effector cells and Treg in those paired biopsies if you compare pre-dose with the biopsy taken after cycle 1. This happens both in the tumor as well as in the surrounding tissue. Basically, this confirms our preclinical observation that if you dose Cami in solid tumor patients, you're able to change the dynamics of the T-cell infiltrate in the tumor environment. We also looked at the blood. This slide shows you data from ASCO 2021, where we looked at the Treg and the T effector cells in the blood itself. On the left, you see all the data that we obtained from patients that were dosed with 125 micro per kilogram. Over the course of time, you see that there's an increase in the ratio in that patient population, in that patient group. You also see by the graphs on the right, that indeed there is a correlation between the effector cells, the ratio between T effector cells, Treg and Treg itself. In the middle, it's a correlation plot of all the data we obtained from all these patients in that particular study. We looked at the correlation between the change in ratio, T effectors to Treg over Treg itself in the middle or CD8 cells on the right. You see that in the middle, this ratio is accompanied by a decrease in Treg. On the right, you see that at the same time, there's an increase of the CD8 cells, which is what you were hoping. Again, both the paired biopsy data as well as this immunoprofiling data and blood support the fact that we're playing with the important T effector to Treg ratio in patients dosed with CAMI. Now finally, before I hand over to Joe, I want to tell you about some other potentials for CAMI. We already talked about the nice opportunity we see with PD-1, with pembro, or other PD-1s, but we also have nice preclinical data to show that we see more potential for CAMI with radiotherapy and with IL-2 therapy. On the right, you see combination with IL-2 therapy, and basically it's the same model as I just explained for the PD-1 combination. We dosed mice with IL-2 alone, with SURF-301 alone, or with the combination of the two, and you see that either drug on its own doesn't do a lot. There's some mild activity. If you combine the two, you get the curve in blue. Again, it shows there's a very nice additive to synergistic effect of combining IL-2 with SURF-301. On the left, you see the combination of Cami with radiotherapy or, sorry, SURF-301 with radiotherapy. Here we combined radiotherapy with a single dose of SURF-301. You can tell from the bottom right that this combination is highly effective. In the combination, 8 out of 10 mice were tumor-free, while only 1 out of 10 with SURF-301 alone, or 0 out of 10 with radiotherapy alone. It shows that combining these two treatments is very, very efficient in the tumor eradication. For the future, after the PD-1 combinations, we see a lot of potential for Cami in solid tumors. I'm happy now to hand over to Joe, who will give you some updates about our clinical progress with Cami. Thank you, Patrick. You know, it's really inspiring to listen to you present the data from the lab, and not just for me. You're welcome. It's a motivation for the clinical team to get these ADCs and make them into cancer medicine. Thank you. Sure. Thank you. You know, with Cami development program, we started out with a strong foundation, a biologic rationale backed by data, not just in the lab, but as you see, data in patients from their biopsies. I wanna tell you three things here, what we did, what we're doing, and where we're gonna go. On the slide, you see phase IA and phase IB. Looking on the left from phase IA, we completed dose escalation in 44 patients. We have a dose range now, and we understand the safety and tolerability. There's two things about the safety. One is we see and understand the PBD side effects, and we're not seeing any surprises. Secondly, we don't see any Guillain-Barré syndrome in these patients, and that's important. We are able to move with this dose range into phase IB. That's what we're doing now. Using that dose range that we've established as a single agent, which is standard for cancer treatment, we're moving up into dose range with a standard dose of pembrolizumab. We have safe, acceptable safety and tolerability now, and we have dose expansion proceeding according to the protocol. Which means that we are allowed to have small expansions if we see activity or we want some additional safety data, or we see a tumor that looks promising for our future development. We've already initiated a dose expansion at 60 micrograms per kilogram, but we're continuing to do the dose escalation, which is currently at 80 micrograms per kilogram. Dose range and safety from phase I A is a single agent. Ongoing dose escalation in combination with pembrolizumab. What's next? What we wanna do is enrich the population for patients who are likely to respond to Cami and pembrolizumab together based on the mechanism of Cami. We also wanna fill a gap because there are patients who either relapse or fail to respond to pembrolizumab, and it's a totally different mechanism. I want you to look on the left side where we will stratify patients based on T-reg infiltration levels. Now, why is this important? It's important because the CTLs, the cytotoxic lymphocytes that kill the tumor and the T regulatory cells tend to track together, and that's what that line shows you. If you're measuring CTLs, you can be sure that there's also T-regs. We want to eliminate the T-regs, so that correlation is very important. What we're gonna be able to do is take a look at our data when we have responses and see how they correlate with the infiltration of cytotoxic lymphocytes and Tregs in the tumor biopsies. We're using basic important data to guide the treatment and make sure that we're treating the patients who are likely to respond to this mechanism of action. On the right side, when we move forward into our dose expansion, we're gonna be using another measurable characteristic of patients' tumors, which is microsatellite instability related to DNA mismatch repair, which is dysfunctional, which seems to be a reason why patients relapse after PD-1, PD-L1 therapy. That reason is tied to the likelihood that the Treg infiltration is what's changing that balance from the patient. What you see in the graph is that the elevation of cytotoxic lymphocytes occurs with MSI microsatellite instability. If we measure microsatellite instability, we can be pretty sure that along with the cytotoxic lymphocytes infiltrating the patient's tumor, there are T-regs infiltrating the patient's tumor, and that's the reason why PD-L1 is not as effective anymore. Summary, we have a strong biologic rationale for camidanlumab combined with pembrolizumab. We have good phase I data in a dose range with safety. We're ongoing dose escalation with, again, good safety and tolerability. We have what I would call a modern way of designating and identifying patients who are likely to respond to the combination and really fill a gap where pembrolizumab turns out to be ineffective. With that, I wanna turn it back to you, Patrick. Yeah. Thank you, Joe. The next program we're gonna talk about is ADCT-601. I'm not gonna pronounce the INN name because I can't, to be honest. ADCT-601 targets AXL, and AXL is a pretty well-known cancer antigen, associated with poor prognosis, resistance to chemo, and tumor immune escape. I will explain in a minute what that means for us. We have very strong in vitro data, and it's very strong, preclinical in vivo data in various models. Again, I will give you some examples. AXL, of course, is known to be overexpressed in quite a wide range of tumors, including sarcoma, lung, breast, prostate, pancreatic, glioma, and esophageal cancer. Where we are now is that we're about to start our phase I/B combination study, and Joe will later tell you all about that design. First, let's talk about AXL itself. AXL is quite unique because it is expressed on two different compartments in the tumor, so there's a lot of data showing that AXL is also expressed on certain immune cells. We spoke about CD25 expression on Tregs. AXL is somewhat similar, but now AXL expression happens on what we call the M2 macrophages, and these macrophages have a similar role. They're immunosuppressive, which means that if you have a high infiltration of M2 macrophages into the tumor, it dampens the immune response to the tumor itself. Of course, if you're able to deplete those M2 macrophages, that of course would be great because then you would hopefully strengthen the immune response against the tumor. AXL, in this case, is also expressed on the tumor itself. In fact, it's expressed on a lot of mechanisms that are involved in tumor escape and tumor resistance. AXL, for instance, is expressed quite highly in metastases, and also it's known that AXL is starting to overexpress upon resistance to standard chemo or other targeted therapies like EGFR-targeted therapy. Here we have a protein that is expressed on immunosuppressive cells. It's overexpressed in tumor escape, and as you can tell from the immunohistochemistry analysis at the bottom, quite often you see tumors where there's AXL in both compartments. It would be great if you can target AXL quite efficiently and deplete both the tumor as well as the immunosuppressive cells. We've come forward with ADCT-601, which is our ADC targeting AXL, and here we've incorporated the HydraSpace technology. I already mentioned in the beginning that this is an important component of the PBD payload. For this particular molecule, we've shown that inclusion of HydraSpace offsets the off-target toxicity quite significantly. In our preclinical models, it was about three-fold better compared to a payload that didn't have HydraSpace in its structure. This data was recently published by Francesca Zammarchi in Molecular Cancer Therapeutics. It shows that by playing with the structures of the PBD payload, you can come forward with PBD payloads that have a better therapeutic index. Of course, they're still very active. This data shows you that ADCT-601 is highly active in the pancreatic PDX model. In this particular experiment, we compared the activity of 601 to an auristatin-based ADC. You have the two curves where the two boxes are. At the bottom, you see the efficacy of ADCT-601 at a single dose of 0.3 mg/kg, quite active. If you would apply that same dose of the ADC with an auristatin, as shown in the other box, you don't see a lot of activity. Basically, it's inactive. Only if you increase the dose of that auristatin-based ADC tenfold, you get similar activity compared to our single dose at 0.3 mg/kg with ADCT-601. It shows it's a very active ADC in this preclinical setting. We also are doing a lot of work on finding combinations for our PBD-based ADCs, and gemcitabine is one of those combination partners that typically works quite well with a PBD-based ADC. That also turns out the case for 601. This slide here shows you some in vitro data where we looked at additive or synergistic effects of gemcitabine with 601, and you see that it's always additive or synergistic. Also in vivo, we see a very nice combination treatment effect. In the middle, you see the tumor volumes for the monotherapy treatments in green and red. On gray, you see the combination of the two, gemcitabine and 601 in this particular model. You can tell from the right that the impact on the survival, if you combine the two, is huge. We go from all animals that are surviving at the end of the study, if you combine the two, to about 1 animal only surviving in the groups where only one of the two drugs was given. It shows that combining the two seems like a smart idea. Of course, we're also looking a lot into indications where AXL is expressed, and this slide shows you some data of AXL expression in sarcoma. We spend a lot of time finding the right assay to detect AXL consistently in tumor samples, and especially to detect AXL in the membrane of these tumor samples. We now have a very nice assay that allows us to measure AXL in patient biopsies very robustly. We're quite pleased to see sarcoma as one of our top indications where AXL expression is always typically quite high and on the membrane of the tumor, which is quite important if you think about the mode of action of our antibody drug conjugate. I'm happy now to let Joe update you on our clinical progress. Okay. Thanks, Patrick. In this case, we're beginning our clinical program with a couple of really important pieces of information from Patrick's laboratory. One is that you can identify tumors that express AXL, that's really important, and that have genetic activity that's related to AXL expression. That's very important, so it will help us identify the tumors. Second, we have an indication here, sarcoma, which is very, very difficult and very resistant to current treatment. That's an area of really compelling medical need. The third thing is, Patrick showed you a slide where, in this case, the potency of the PBD, highly potent, is very important. We have three pieces of information to start our clinical program. I'm gonna tell you two things here, what we've done and what we plan to do later in the year. What have we done? phase I-A dose-escalation study, not a surprise, very typical for cancer programs. We had 18 patients dosed. We established a dose range, which if you know anything about ZYNLONTA, you'll see is pretty much like the dose range we studied in ZYNLONTA. We're seeing again, we know about the PBD side effects. We're not seeing any surprises. That's important. We have a dose range to work with. 15 patients had at least one post-treatment evaluation. Some patients had stable disease, and we had one patient with sarcoma who received several doses and actually had a partial response, which is consistent with what Patrick showed you about the expression of AXL in sarcoma. Not a surprise that we will be pursuing this in the future. Okay, we reached the maximum dose, which is good, and we have an acceptable safety profile, the two things that you really need to identify in phase Ia. Later in the year, we'll be moving on to the phase Ib combination, and this reminds me to tell you the next thing that we learned from Patrick's lab, which is the combination with gemcitabine is synergistic. In addition to the potency of the PBD, when we add the gemcitabine, we actually get additional effective response on the tumors, which is really important. Here's where we are now in our stage for starting phase Ib. On the left side, what you see is the dose escalation. Very standard, except for the fact that we're using flat dosing, which means we're not adjusting by body weight. We will go in an ascending order. If you look at the top part of that left slide, what you'll see is the ascending doses of 601 combined with pretty much standard dose of gemcitabine. Again, we're gonna be looking at safety and tolerability. Down at the bottom, you see Arm B. That's dose escalation with 601 on its own without gemcitabine. The reason we're doing these two separate dose escalations is because we have two separate cohorts that we wanna test. One in, showing you on the top right, is patients with sarcoma. As I said, sarcoma is highly resistant to cancer treatment, highly resistant. This is an area of compelling medical need. We'll study around 18 patients with a dose that we believe will be effective based on preclinical data and tolerability, and we'll be combining that with gemcitabine based on the preclinical data. That will proceed once we get the recommended dose. On the bottom, we're taking advantage of what we know about AXL expression and AXL amplification to study tumors in which AXL is shown to be highly expressed and where the genetic activity supports that expression. Those are tumors that are more likely to respond to the AXL-based antibody and the PBD. In summary, safety and tolerability is very good from phase I single agent. We have a good plan for phase I-B, which is a dose escalation, taking advantage of the known expression of AXL in sarcoma and taking advantage of the known synergy between the PBD and gemcitabine, and we'll be starting this off later in this year. Patrick. Yeah, Joe, thanks. Okay. Now we're gonna talk about ADCT-901 targeting KAAG1. KAAG1 is a truly novel cancer antigen. I will explain in a second, some more information about KAAG1. It gives you some more information about KAAG1. We really see this as a very nice first in class opportunity for our company. KAAG1 expressed in what we believe expressed in platinum-resistant ovarian cancer, fallopian tube cancer, prostate, cholangiocarcinoma, renal cell carcinoma, and triple-negative breast. We just started a dose escalation of KAAG1 at the end of last year, and Joe will update you on our next plans. More about KAAG1. We think KAAG1 has a very attractive expression profile if you compare healthy tissue or normal tissue versus cancer. On the right, you can see a tumor TMA showing a lot of ovarian tumors as well as a lot of triple negative breast. You can see from the brown staining if you detect it with a KAAG1-specific antibody, that there are a lot of patients that are positive for KAAG1 in their tumor. In the middle, you see the healthy tissue expression. Although there is some expression in cervix and fallopian tube and a little bit in kidney, it's quite good if you look at all the other tissues, if not negative. It's also important to mention that KAAG1 is by definition an intracellular target. In healthy tissue, it's intracellular, and somehow it's exposed on the membrane of tumor tissue. That's another important discriminator between expression of KAAG1 in healthy tissue and tumor tissue. Now, this protein was initially identified in a cDNA library of renal cell carcinoma cell line as an antigenic peptide recognized by cytotoxic T cells. This was already back in 1999. Alethia is a Canadian company and did its subtraction cloning analysis between healthy tissue and ovarian cancer tissue. They identified KAAG1 as one of the most abundantly overexpressed proteins in ovarian cancer. They moved on and confirmed that messenger RNA for KAAG1 was indeed expressed in a high percentage of ovarian cancer patients as well as triple-negative breast cancer patients, and they confirmed this by immunohistochemistry analysis of these samples. This was further evidence that KAAG1 is highly overexpressed in these tumors. There is some functional analysis which I won't explain today, but finally, we acquired the portfolio, the IP portfolio around KAAG1 from Alethia, including the antibody that binds to KAAG1, 3A4, which we used in the development of our clinical candidate ADCT-901. That candidate is shown here. We have the antibody 3A4 that binds to KAAG1, and you see that the payload we're using here is tesirine. The clinically validated molecule that we also use for ZYNLONTA and Cami. No surprises with this particular PBD dimer. In the preclinical models, KAAG1 is overexpressed quite often, and we picked four ovarian cancer models, as shown here, with different levels of KAAG1 expression. We dosed the mice with a single dose of 901, and we also dosed the mice with a non-binding control ADC called B12. This is a control we typically do. What you wanna see is that the non-binding control is basically inactive, and of course, our ADC 901 should be active. Again, this slide tells you that indeed, in all four ovarian PDX models, we see very nice efficacy with 901 after a single dose of treatment, especially if you compare that to the purple curves, which is the non-binding control, which is basically inactive in most of the models. A very highly efficient ADC in ovarian cancer, and I'm looking forward to hear from Joe what the next steps are. Okay, thanks, Patrick. Well, you shouldn't be surprised to hear that we're going into clinical development with a strong foundation from laboratory research, identifying KAAG1 as a surface protein that appears to distinguish normal tissue from cancer cells because of the expression. The second thing helps to identify the various cancer cells that are actually expressing KAAG1. Probably the most exciting thing about this is it's totally novel, and it's like a frontier for us that remains undiscovered. We have a lot of opportunity here for something that's totally new. This is really a great motivation for everybody in clinical. We're starting out with a standard dose escalation, not a surprise, 40 patients. However, we do have the ability to identify tumors that are likely to express KAAG1 based on the preclinical data. That includes cholangiocarcinoma, ovarian tumors, prostate cancer, renal cell cancer, and triple negative breast cancer. Some of these continue to be resistant to current treatments. Again, a medical need that's very important. There's a long list of key selection criteria, but just two. ECOG status is important in early clinical studies, and these are patients who are refractory or intolerant of existing therapies, which, you know, just a reminder that our clinical development programs depend on patients who are willing to be in clinical trials, and who are in a state where there's really no other treatments. That's another motivation for us to do what we do. In this case, we're just starting. We started at a dose of 15 micrograms per kilogram. We moved on to 30 micrograms per kilogram. That's where we are now. We'll continue this dose escalation to establish a dose range. Like to get to a maximum tolerated dose. Again, we're using a PBD, so we understand the side effects already. When we see where we are with the dose, we'll be expanding using the dose that we choose from phase I into a monotherapy program, looking at these various types of tumors that are expressing KAAG1. Down the road, we'll be able to probably measure KAAG1 expression and try to identify patients who are more likely to respond. Back to you, Patrick. Thank you, Joe. Okay. We spoke about CD25 Cami, we spoke about 601 targeting AXL, and we spoke about 901 targeting KAAG1. The last two projects are our IND-enabling programs, and the first one is ADCT-701 targeting DLK1. Again, DLK1 is a novel cancer antigen expressed in many tumors. I will give you more insight into that later. We are going after rare neuroendocrine malignancies, such as small cell lung cancer, adrenocortical carcinoma, pheochromocytoma, paraganglioma, and neuroblastoma. As I mentioned, we are currently finishing the IND-enabling work, and the next step would be to work with NCI together on the phase I A study in solid tumors. DLK1 and the expression profile of the DLK1 is shown in this slide. Here we compare the expression of DLK1 in healthy tissue versus cancer. Now DLK1 is highly expressed in the embryonic stage, and also in cells that have sort of stem cell-like properties. During the progression to the adult stage, that DLK1 expression is winding down. There are some cells that do show some expression of DLK1, but typically it's quite limited, if not absent. From that perspective, it's a very attractive target for ADC development. If you look at cancers, there's quite a long list of cancers that are reported to express DLK1. We have verified that in-house, and we think that the real robust expression of DLK1 is in certain neuroendocrine tumors, and therefore, we think that that's the best way forward for this project, at least to start in clinical development. Of course, we can always go into other indications when we see fit. 701, like 601, incorporates GlycoConnect technology and the HydraSpace. Basically this payload here called PL1601 is the exact same payload as we used in the ADCT-601 program because we believe that offsets the off-target toxicity significantly, if you use this PBD payload for this antibody. I forgot to mention, by the way, that we licensed the HydraSpace and GlycoConnect technology from Synaffix in the Netherlands. In terms of preclinical data, we are working with John Maris from CHOP in Philadelphia, and they have a lot of preclinical models regarding neuroblastoma. This slide here shows you seven different neuroblastoma PDX models with different levels of DLK1 expression. In fact, one is negative. That's the one in the middle, bottom, at the bottom in the middle. Indeed, you see that in this particular model, ADCT-701 doesn't give any antitumor activity, which is explained by the lack of DLK1 expression. In all the other models, all the other six models, you see that DLK1 is present, at least for most of them, you can see there's one immunohistochemistry picture missing. In the majority, there is DLK1 expression at a high level, and this is accompanied by a very strong antitumor response of ADCT-701, the red curve. Again, you can compare it to the non-binding control ADC in green. Again, it shows that ADCT-701 is a very active molecule in this particular setting in neuroblastoma. This data has led us to go into a collaboration with NCI. Why NCI? Well, we're going into a rare disease area, neuroendocrine tumors. NCI brings together all the leading experts in this space, will help us to identify the patients and to get the patients into a study, and also provide financial sponsorship for this particular study with ADCT-701, while we can maintain governance flexibility if we see that, if we want so. The next step here is to continue to IND and then start the dose escalation in this NCI-sponsored phase I study, enrolling adult patients with all the indications I just mentioned in the beginning, all neuroendocrine tumors. If we see a signal, we'll expand in a given indication where we do see efficacy. Secondly, we will expand in a basket with more indications, at that dose, at that particular dose. Finally, I'm happy to talk about ADCT-212. ADCT-212 targets PSMA, and this is really a very nicely optimized second-generation PBD-based ADC targeting PSMA. Those of you who are following us for quite a while, we had a PSMA-based ADC with AstraZeneca in the clinic, and I will tell you later how we've changed from that particular molecule to ADCT-212. PSMA is a well-validated cancer target in prostate cancer, but there also may be other applications of this ADC. PSMA is also known to be expressed quite highly in the neovasculature of a lot of solid tumors. You could potentially also target these solid tumors, target the neovasculature, cause disruption of the vasculature, and create antitumor activity. We are currently completing the IND-enabling work for ADCT-212, and of course, hope to plan to submit the IND and start the clinical study later. I mentioned that we had another PSMA-based ADC in the clinic together with AstraZeneca MedImmune, and that one was called MEDI3726. The good news was that in the dose escalation study, we saw clinical activity. However, patients couldn't really tolerate a lot of cycles, especially not at the high dose levels. We found that the PK of this ADC was quite rapid. Of course, if the PK is rapid, the exposure in the patient will be quite low. On top of that very fast PK, there was an instability. Basically, the ADC was unstable, and that further didn't help with finding or getting the right exposure in the patient. We worked around all of these issues and come forward with ADCT-212. First of all, we looked into changing the antibody in such a way that the new ADC has a much better PK profile than the old ADC. This was done by changing the antibody to a fully human antibody. Secondly, we changed the PBD payload. We used SG3249 in the previous candidate, and we're changing to PL1801, which is based on the lower potency PBD dimer, SG2000. We think by doing so, we can increase the dose in these patients because the tolerability of this ADC will be much better. I will show you some data later that supports that. Finally, we changed the conjugation. We went from a site-specific conjugation approach on cysteine 220 to GlycoConnect, which we're using in 601 and 701 as well. This mitigates the heavy light chain instability that we saw with MEDI3726. Altogether, we believe that we basically changed every component of the ADC in such a way that we think we have a very strong candidate for PSMA targeting right now. Before we go there, this is the ADCT-212 structure. On the left, you see the antibody with the GlycoConnect remodeling, and on the right, you see the new payload PL1801. Here we've made the change from the highly potent PBD dimer, SG3199, to the lower potency PBD SG2000. You can also see that we still incorporate here the HydraSpace structure to mitigate or to offset the off-target toxicity. Compared to the first PBD payloads that we were using, we now made these two important changes around the spacer and the PBD dimer itself. This slide shows you that indeed, they still work very nicely. On the left, you see a xenograft model, prostate cancer xenograft model, and you see that a single dose of 5 or 10 mg per kg is still very active. Of course, the dose is slightly higher than what you're used to see with our PBD-based ADCs because the PBD dimer itself, as we're using it right now, is slightly less potent, so you have to give a little bit more. Still, 5 or 10 mg per kg is a very reasonable dose. Single dose activity, very good tumor regression in this model compared to the non-binding control ADC in purple. Also, the toxicity profile has changed considerably. Now we can dose up to MTD, which is around 20 mg/kg of this ADC in the rat, and you can compare that to 2 mg/kg for the previous candidate in the rat. We can dose about tenfold higher of this ADC in rats, and that is accompanied by a very nice PK profile, as shown in the graph on the right. Very high and nice PK, stability very good, all looking very nice. And this, in the end, means that the therapeutic index for the new candidate has gone up from 4 to 10. Quite significant improvement, preclinically at least, in therapeutic index if you compare it to the previous candidate, MEDI3726. I think this nicely shows how we are continuing to improve on our PBD chemistry and how that results in even better candidates for the future. As you may know, we still have quite a few targets to go in our PBD portfolio, and of course, we will do the same going forward with those candidates. That brings me to the end of my slide. I'm happy to go back to Chris and- Thank you very much, Patrick. It's a real privilege to work with two such innovative, productive, and dedicated scientists and clinicians as the two of you. It's a real privilege every day. Thank you very much for the dive you've given us into the ADCT solid tumor pipeline today. It strikes me that they're really innovative drugs. Each one is highly differentiated. If you look at the different mechanism of action of Cami, for example, operating on the regulatory T cells, or you look at KAAG1 as a really unique first-in-class target. Also, you're addressing areas of very substantial unmet need. We're looking at lung cancer, ovarian cancer, prostate cancer, head and neck, sarcoma. Areas where patients have few effective options. There are many patients which relapse and have very poor prognosis. They're very large patient populations as well. These are important opportunities that we're looking at. It's also been absolutely fascinating for you to show us how you optimize the therapeutic index of these molecules, how you can tune each individual component of an ADC and the ADC as a whole to optimize that therapeutic index, and increasingly provide these targeted therapies which are well-tolerated by patients and effective in hard to treat relapse refractory tumors. This next generation of ADCs is really looking very promising. Behind that, you've continued to create the toolbox of technologies which we can use for our research pipeline in the future, which I very much look forward to. With that, I look forward to updating you all with these data as they become available over the next 12 or 18 months. It's very exciting for us. I'd now like to open the line for questions and hand over to the operator. Thank you. Operator, can we have the first question, please? Yes, sir. Our first question or comment comes from the line of Tazeen Ahmad from Bank of America. Your line is open. Hi, good morning, and thank you for hosting this. It's been super helpful. A few questions from me. Can I start maybe with Cami? So, you guys are enriching pembrolizumab, your pembrolizumab and Cami study, and I just wanted to get a little bit more color from a comment that was made in your prepared remarks about, you know, that this combination could fill in the gaps where pembrolizumab is ineffective. I'm just wondering, can you give us a little bit more color on what that gap is? And potentially, I know it's difficult, give us a sense of how big that market opportunity could be and when would be the next time we would see data from this study. Thank you, Tazeen. Joe, can I ask you to? Yeah. Fill in the gaps, a term I use because I know that there's patients who relapse after PD-L1 and, you know, the gap is that PD-L1 doesn't have any effect on the Treg. It's that other mechanism that comes into play. I mean, you know, the immune system has lots of ways of, you know, responding and adapting. It's the way that we get around the fact that, in these relapsed patients, there's this new mechanism might be available. I think it's, you know, it's sort of a rule I use for. Well, there's a couple. I don't estimate the market size because I'm the medical person. However, one of the things that happens with cancer treatments is the more patients that get a new therapy, unfortunately, you know, the more you learn about relapse. You know, what we like about this is this combination makes really good biologic sense. We can test it really well with biopsies, we can enrich the population, and we can really add to the response rates from a very good drug that's widely used. That all adds up to, you know, very positive medical impact. Thanks, Joe. Any idea about how big the market opportunity is? Just so that we have a sense. When is the data due? Yeah, Chris, I'm gonna have to pass on the market opportunity because I just, you know, I just don't. That's not medical for me. Sorry. I mean, I look at it as a large population of patients who are on PD-L1 therapy. I mean, you know what that market opportunity is. You know that's broad-based. You know that this is gonna be a broad-based therapy because it's not, you know, it's not tumor specific, it's mechanism specific. Okay, having settled all that, we're getting close to the end of the dose escalation. We're allowed to do some expansions, but I can't tell you when we're gonna have data next because it depends really on when we see responses, how many patients we want to enroll before we feel comfortable. You know, I don't wanna speculate on a date until I know that we, you know, we can make a date. We're still in the area where there's a bit of uncertainty about what may happen next in terms of how many patients we need and what we see. When we know something, we will make sure it is disseminated appropriately. Thank you, Joe. Okay. Next question, please, operator. Thank you. Our next question or comment comes from the line of Matthew Harrison from Morgan Stanley. Your line is open. Hi. Hi, can you hear me? Hello, Matthew. Yeah. This is Trent speaking for Matthew Harrison. I wanna ask about the Cami combo program as well. What's your view on what kind of responses you need to see to move the combo ahead? Sorry, to move? The responses to move pembrolizumab ahead. To move pembrolizumab ahead? I wasn't sure. Yes. Combo. To move Cami pembrolizumab ahead. This is unexplored for us. I can't really tell you a number. You know, it depends on the patients. It depends on the tumors that we choose to expand. It depends on the refractory status. You know, there really isn't a number yet. As you probably know, just to give an example, the response rates for pembrolizumab in ovarian cancer, just pick one of the cancers that we were looking at, are in the range of 8%-10%. You can think about a number above that for this combination that would be really significant. That's just one example. You know, we have to adapt as we see data, and we have to adapt as we choose tumors before I say, "Here's our decision. Thanks, Joe. Okay. Next question, please. Got you. Yeah. Oh, sorry. Next question, please, operator. Thank you. Our next question or comment comes from the line of Brian Cheng from Cantor Fitzgerald. Your line is open. Hey, guys. Thanks for taking my questions, and thanks for putting this event together. I have a question on your AXL-targeted ADCT-601 program. So, you know, we get a lot of questions on the amplification selection from the investors. It's great to see the visibility that you have in the program today, you know, with the TMA and sarcoma and TMAs, the AXL-amplified tumors. Can you give us some guidance on how you're selecting the AXL-amplified patients? Any color on where you differentiate in terms of the screening assay that you'll be using compared to others? And I have one more follow-up. Thank you. Thank you, Brian. Patrick, maybe you'd like to talk to the assay first, and then Joe, perhaps you- Well, the assay, it's a clinical thing, so I'm not entirely sure which assay they finally decided to pick, but it's one of the standard foundational, Foundation Medicine. Yeah. There's actually a li- The question could- Yeah. There's a library of patient data that we can choose from, but I can't give you really the specifics of the assay at this point in time. Because you were referring to the assay to measure the gene amplification, right? And also, how are you thinking about the cutoff? You know, since the threshold to be seen as AXL-amplified is still a little bit hand-waving. I don't know if you have any- Yeah. Insights on how we should think about what should be classified as AXL-amplified tumor? That is a really good question. I'm sure we can do better than hand-waving, but we have to do some learning and validation here. We have to see what happens with, you know, how that, you know, you know this as well as I do. You have to look at what happens with this level of amplification and that level of amplification. Actually, the kineticists here can actually do that kind of modeling for us once we have some patients. Ultimately, once we have some data, we'll be able to choose a kind of a cutoff. As you also know, the regulatory agencies often have some input into, you know, how you're deciding on which patient may or may not qualify. It's at this point in time. We still have to look at some data before we can give you an answer like, you know, to that question. Okay. Thanks, Joe. One more question on your manufacturing front. I recall that you were looking at a new lyophilized formulation for the AXL program. I'm just wondering if you can give us an update on where you are, and how that, you know, overlaps with the, you know, your expansion cohort. Correct. I mean, we have reformulated ADCT-601 into a lyophilized product. The phase I-A was done with a liquid. We now reformulated into a lyo, and that's ready for the start of the phase I-B. In fact, it's ready. Mm. From now onwards, we will use the lyophilized product in the clinical development, and that can also be the commercial product if we make it to market. Great. Thank you, Pat. Next question please, operator. Thank you. Yes, sir. Next question or comment comes from the line of Boris Peaker from Cowen. Your line is open. Great. My first question is on Cami. Can you maybe discuss what is the mechanism of the Guillain-Barré syndrome? Why do you think the mechanism may be active in liquid tumors but not solid tumors? Patrick, I think you could do that. Well, to start with, of course, we don't know exactly yet what the mode of action is for the existence of Guillain-Barré in Hodgkin. It's clear that we only see it in Hodgkin lymphoma patients and not in any other indications. We haven't seen it in non-Hodgkin lymphoma, in AML or in any of the solid tumor patients that we've been dosing so far with Cami. The hypothesis we're working on is that, of course, we deplete Tregs with Cami in the Hodgkin lymphoma patient as well. There is a fair theory that some patients may have pre-existing autoantibodies against the myelin sheath. There may be various reasons why they have them, but at least the idea is that if you would then deplete Tregs and these patients then become activated and start to produce more of these autoantibodies against the myelin sheath, that will finally cause the Guillain-Barré. This is a hypothesis. We're currently trying to bottom it out whether this is indeed the case. Of course, it's likely that it's somehow linked to the depletion of Tregs in the Hodgkin population specifically. The mechanism behind that in the end and what then gives this the Guillain-Barré is still an area of research for us. Got it. My second question is on the ADCT-212. There's a lot of competition in PSMA targeting and various approaches are being used. Just curious, where do you anticipate to develop this? How do you think this will fit into the treatment paradigm, and how do you think it'll differentiate from other approaches? You wanna take that? Well, I can respond to that. First of all, we're still in the early stages here, so I wanna, you know, get it into the clinic, get through phase I, et cetera. I mean, my sort of view of prostate cancer is that in the metastatic realm, I don't think that there's, you know, anything that's, you know, that is not gonna allow for a new competitive product. That's what I think this is gonna be. You know, it's yeah, and as you know, one of the ways cancer treatments progress is that new drugs become available. Then instead of patients going, you know, onto, you know, a place where there's no new drugs, they get these new drugs. I mean, I look at the landscape for prostate cancer, the aging population, the detection and all of that, and just say there's definitely gonna be room for a new drug like this. You know, we already showed you that we improved the antibody, we improved the payload. We've got all these things that are very positive here. I just, you know, I don't think about too much that there's not gonna be room. That, you know. But like I said, I'd like to get into clinic, I'd like to get through phase I, and then I'd like to find out, okay, where exactly could this make an impact? But I just don't think there's gonna be a problem finding a spot for this. Great. Thank you very much for taking my questions. You're welcome. Next question, operator. Thank you. Thank you. Our next question or comment comes from the line of Tazeen Ahmad from Bank of America. Your line is open. Hey, guys. Thanks for taking my follow-up. I did need to ask you one question. Is it primarily the case that your, you know, your HydraSpace, you know, which eliminates a lot of the off-target expression is your view of how you mainly differentiate from other AXLs that are in the market or trying to be developed? I was just wondering what your thoughts were about the Genmab molecule that was discontinued and if there were any learnings from that. Thanks. Oh, well, of course. I mean, having less off-target toxicity is quite key, but of course, in the end, it's all about efficacy as well. I think our PBD molecule really differentiates from, for instance, the Genmab molecule that you just mentioned, which was auristatin-based. We really think the true differentiator in the end is the PBD chemistry and the mode of action of the PBD. The fact that we're using this linker, which has less off-target tox, of course, is a very important step. In the end, the ADC has to work in patients, otherwise you don't have a drug. I think that will be driven by our PBD warhead. That's really our differentiating factor in this case. Regarding Genmab, I really can't comment. I don't know why they stopped the studies. It's their study, so not much to comment from my end on that. Okay, thank you. Next question, operator. Thank you. Our next question or comment comes from the line of Kennen MacKay from RBC Capital Markets. Your line is open. Hey, thanks for taking the question. This is Kennen MacKay with RBC Capital Markets. I had a candidate-specific question and then more of a technology question. On 601, it seems like the synergy with GEM is very exciting. Wondering if you expect to see single-agent activity there, sufficient to advance that as a monotherapy, or will synergy need to be an inherent part of that mechanism? Then more broadly, on the platform, Amgen is giving their business review this morning as well. They just talked about a lot of the low-hanging fruit, so to speak, regarding biologic targets having sort of been picked so far. They've used that statement to pitch multi-specific medicines like bispecific antibodies. I'd love to get your perspective on how your payload and conjugation platform solves some of the therapeutic index problems associated with some of the remaining targets that are out there, as well as whether bispecific targeting could become a part of your strategy in the future. Thank you. Patrick, do you want to start with the gemcitabine combination? It was more a clinical question. Yeah. Okay. I'm happy to do that one. Just, I'll remind you what we're doing in our dose escalation is combination in sarcoma because that synergy is really impressive. The single agent activity of 601, we saw some stable disease, we saw partial response, but that's a perfect place where you wanna have you know, add a synergistic molecule. It's a setup for sarcoma for us to use gemcitabine combination. That's the one thing. However, what we couldn't do in our phase I A is AXL amplification. In the study that we will start later this year, we're gonna be looking at AXL amplification. In that case, the single agent may have more activity. You know, keep in mind, I mean, there's a theme I've been sort of reciting throughout the clinical part of this presentation, which is you want to identify patients whose tumors will respond to your mechanism. In this case, the mechanism would have to include, you know, sufficient AXL expression for the PBD to be able to get into the cell. We're really testing, I think, both sides of your question, which is gemcitabine a good combination? Yes, it is. We already know that. Might it work in monotherapy? Yes, it might, but it has to be AXL amplified. This is a really, a very, I think, very sophisticated, clever protocol, which the clinical team designed. I, you know, I think it covers your question actually pretty well. The bispecific question was the other one. Yeah, I'm trying to. Not, not- For the low-hanging fruit. ... not necessarily bispecific. Just wondering, again, with a lot of the targets that are usually druggable with standard monoclonal antibodies or small molecules having been targeted and a lot of the remaining targets have to have very hard therapeutic indexes, or in some cases being undruggable, either with a small molecule or monoclonal, really wondering like how your platform sort of addresses some of the remaining targets, or again whether using multivalent approaches is something that the team's thinking about. Thank you. Kennen, I'll start off with that, and then I'll hand over to Patrick. I think it's something that I've been hearing about ever since we started working with antibody-drug conjugates. You know, there was. I think famously originally only 30 tractable targets. If you look at a program like KAAG1, you see there, you know, a very novel target, very clean in terms of its tumor expression and healthy tissue expression. You know, you could describe that as a low-hanging fruit in terms of being an ADC target with those kind of characteristics that you're looking for. But it was a hidden fruit, which, you know, thankfully others and working with Patrick have discovered and elucidated. Yeah, I'm sure there will be more targets like that. You're absolutely right. There are targets where, you know, the healthy tissue expression is higher. The expression on some sensitive tissues is high. I think that's where the toolbox that Patrick has been developing over the past years really comes into its own. The ability to add another layer of specificity with the tumor microenvironment, you know, for example, the pH of the environment, as Patrick alluded to, in the selenol linker system, and other approaches in terms of, you know, modifying the CDR region so that it only binds in the tumor microenvironment or capping it. I think there are a whole raft of tools that we have available that we are working on in research, which allow us to add a layer of tumor microenvironment specificity on top of the fundamental ADC delivery approach. Going beyond that, there's a multimodal cytotoxic approaches. Maybe, Patrick, you'd like to elucidate on those a little bit. Yeah. Although, I mean, it's basically all similar to what Chris already explained about how we can improve the antibody and make it more specific for the tumor. You can do the same, basically. I mean, we're building up now our knowledge about how you can make the release of the toxins more tumor specific, or you can make or design the toxins in such a way that they won't be active in healthy tissue. Again, playing with the pH properties of these payloads. There are a lot of things emerging in our R&D toolbox that in the end will allow us to make them really more tumor-specific, and less toxic for healthy tissue. Well, of course, that in the end may provide a technology or a couple of technologies that will allow you to target those low-hanging fruit targets. That will certainly happen. Yeah. Got it. Thank you very much. Thank you. Our next question or comment comes from the line of Kelly Shi from Jefferies. Your line is open. Thank you for offering a very comprehensive presentation. My first question is about ADCT-601 program targeting AXL. I'm wondering, besides selecting patients based on AXL expression level, do you also prioritize the subtypes of sarcoma? Because there are more than 100 subtypes and there are probably a variety of AXL expression level across subtypes. That's a very good protocol question. We're certainly not gonna have 100 subtypes. No. We're trying to be somewhat permissive here. Unfortunately, I can't recite the ones that I know are going to be included. We know based on literature that some are more likely to express AXL, so that's what we're going to do, is try to include those ones. I just can't recite it for you 'cause I don't have it in my head. That's a key to the program for us to try to maximize AXL expression. You're 100% right on that. Great. Thanks. I also have a follow-up question on Cami. Does CD25 also express a cytotoxic T-cells beyond the regulatory T-cells? Do you consider this might compromise Cami's efficacy? Yeah, that's a very good point, and that's something we hear quite often, that people are worried about the CD25 expression on T effector cells. But the data, as I showed you and some more data we have and others have shown as well, is that that doesn't really seem to be the case. So, doesn't seem to really be the case. Cami or any other CD25 targeting antibody doesn't really seem to impact the T effector cells. So you can tell from the data that I showed you that you really see nice depletion of Tregs, but you don't see that the T effector cells go down, whether preclinically or in the clinic. We believe it's due to the fact that CD25 expression on T effector cells is there, but it's quite low compared to the high level of CD25 on the Tregs. You get a sort of preferential binding of Cami to the Tregs versus T effector cells. You're absolutely right, it is expressed in T effector cells, but so far the data doesn't seem to suggest that you also impact T effector cells or deplete T effector cells. Okay, super helpful. Lastly, FDA released a guideline for ADC development this week. Is there any impact to ADC's early phase pipeline candidates? Do you have any plans to expand the PK/PD studies based on the guidelines? Thank you. We actually had a chance to look at the guidelines that they released, and our view is that they pretty much codified what they've already been telling us, and we've adapted our dose finding and our kinetics and clinical pharmacology to incorporate most of this guidance. We're prepared to be able to follow it. As I said, it codifies what we already knew. We feel we're confident that we can, you know, proceed as planned. Great. Thanks again. You're welcome. Well, thank you very much, everyone. It's been a pleasure to be able to present our solid tumor pipeline and our platform to you today. We very much look forward to updating you as data becomes available. Particular thanks to Joe and to Patrick for your contributions. It's been fantastic. Really interesting. Thank you, everyone, and good night.