I think we're going to get started. Hi, everyone. My name is Daina Graybosch. I'm a senior analyst here at Leerink Partners. I cover mostly immuno-oncology companies and have had the pleasure of covering and following what Innate Pharma has done for several years now. I'm pleased to be hosting Jonathan and Yannis, their CEO and COO. Maybe we'll start, just give a quick introduction to both of you. Jonathan, you're relatively new, I think that will be helpful as well. Yeah, Jonathan Dickinson, I joined Innate Pharma on the 1st of November last year, I'm a little over 100 days into the role now. It's been a great initiation into the company. We've already updated our strategy and made a few changes, which we're quite excited about. We're focusing in really on our ANKET platform and also our ADCs and looking to partner our lead preparatory asset, lacutamab. I think we've put a good, solid, robust strategy in place for the future, which is exciting. Yannis? I'm Yannis, I'm the Chief Operating Officer of Innate. I've been with the company almost since the beginning, so a bit more than 20 years plus. I'm a scientist by training, I joined as a research scientist and had several different positions in the early research development of the company. I transitioned to the business development and portfolio strategy. Maybe I should say a little bit about my background because I missed that piece. I joined Innate Pharma from Incyte, where I was the head of Region Europe for Incyte. I have been there for eight and a half years. Before that, I was with Ariad, and I started the European operations for Ariad as their first employee and built a commercial organization across 16 countries. We were acquired by Incyte. Before that, I was at BMS and I had P&L responsibility for the European region for the immunotherapy portfolio. We launched Ipilimumab and the early days of Nivo. Before that, I was at Roche for nearly 14 years. I was the global brand lead for Herceptin and for Rituximab, as well as then working in life cycle leader roles where I had responsibility for everything from basic research all through to the commercialization of the molecules. Before that, Novartis business unit director for oncology in the U.K. Maybe you can get that from my accent. Before that, I'm a molecular biologist with an MBA. Awesome. Thank you. You have multiple clinical programs, and we're going to start with one of the priority ones, your ADC. It is IPH4502. It is a Nectin-4 directed antibody drug conjugate, and you've just begun your phase one dose escalation trial. It is wholly owned. I'll just start with the money question. Why should investors have confidence in Innate in this program when there's real serious competition in Nectin-4 on the ADC front? Yeah, maybe I'll start off and take this one. I think if you look at the molecule IPH4502, it's a very highly differentiated Nectin-4 targeted ADC. It's all about the epitope that we're hitting and the monoclonal antibody. What we've been able to engineer here is an antibody that will basically target also low expressing Nectin-4 tumors. I think that's one of the absolute key differentiators. That opens up a number of other tumor types where we can go where the competition is potentially a little less intense. That's one aspect from a differentiation perspective. The other is the payload that we have for our ADC. It's an exatecan payload, a topoisomerase inhibitor. That comes basically with a different resistance profile to Padcev that's out there and improves most of the other ADCs that are going into the Nectin-4 space. They're MMAE based. There are a couple of other topos, but we're one of the most advanced. If you combine that with our linker technology as well, we have a very hydrophilic linker, very tightly bound, only cleaved when the antibody is internalized. We think there are some advantages from a toxicity perspective there as well. I think the final piece is I think we've demonstrated already something that's really important to me is speed of execution. If you look at what we've done recently, the IND for 4502 cleared at the end of September last year. We actually dosed the first patients towards the end of January, and we actually completed the first dosing cohort by the end of January. We're going to the places where we can get this study done quickly and we can execute in a really, really expeditious manner. That is something that's really near and dear to my heart, making sure that we execute quickly and rapidly. It is certainly something we have a very significant focus on from a company perspective. We believe with the differentiation and the speed aspect that we really can compete very effectively here. There is ASCO GU. There was a company out of China, Jiangsu. They have a Nectin-4 ADC. It's also topo one. It also has an active Fc backbone, which you didn't mention, but I'll add that in there. I wonder what we can learn about the clinical data they presented, which was pretty substantial. Yannis is going to. Yeah, I think that the data presented at ASCO GU by Hengrui with their Nectin-4 exatecan, which is a slightly modified exatecan payload, are very encouraging for us. It was a data set on a quite significant number of bladder cancer patients, and they are actually transitioning the drug in phase three in China. I think that together with the data that we have presented at ESMO also in lung cancer, it's very encouraging because, I mean, so far this drug is not available for clinical development in the U.S. and Europe. It's solely developed in China. It showed that with this topo payload, they can dose patients up to 8 mg per kg. Really the therapeutic index compared to the Padcev that is dosed at 1.25 mg per kg is really increased by this exatecan analog. It shows also that there is no, I would say, no unexpected toxicity. It's mostly hematopoietic. Again, it's very reassuring for our own program. Maybe the last takeaway is that in this cohort of patients, a significant number of patients in China were pre-exposed to another ADC with an MMAE payload, a HER2 MMAE that is not available in the U.S., but that is developed in China. They are showing responses, very good responses. I mean, in the overall population between 6 and 8 mg per kg, they are between the 40-50% of response. I think they are in the 30 plus in the pre-exposed. That really showed that we can have this approach of sequential payloads with first an MMAE and then come back with a topo one. The patient should respond. Another piece of data that was also interesting at ASCO GU was the one from Corbus, if you did not ask, but it was also presented at this conference. The data were a bit degraded compared to what they have initially published in China. This is really a US trial. The data do not replicate exactly their previous Chinese trial disclosure. What is also interesting is that it is a very, maybe it is anecdotal, but it was two patients who were pre-treated with Padcev. Both of them progressed upon the Corbus treatment, which is actually using the same payload as Padcev. It is not really reassuring for companies using the MMAE as payload to come after a Padcev treatment. The interesting piece for us is that it's published in the literature, and as we have also demonstrated in preclinical model, is that the expression level of Nectin-4 seems to be maintained because this patient, there is in the waterfall, there is the H-score that is mentioned, and this patient pre-exposed to Padcev still do express Nectin-4, making them really a potential candidate for another Nectin-4 targeting agent, but with another payload. Altogether, these two data sets are encouraging for our strategy of development, which encompasses both the post-Padcev in bladder, but also in other tumor types like lung or prostate or colorectal. Was Corbus enriching for Nectin-4 expression, or was it only? No, not to my knowledge, no. Why are you skeptic with an Fc competent backbone where a lot in the field are going to Fc incompetent? Yeah, so it's a good question. It's actually a complicated one. I don't think there is a one-size-fits-all answer to that. I think it also depends on the target. Actually, when you look at, for example, this recent review with an interesting title, Living in Lalaland, I don't know if you will read that, because Lalaland, it's a mutation that can silence the Fc portion of the antibody. Reality is that out of the 19 antibody ADC that are approved or under regulatory revision, most of them are Fc potent. There is only even one which has an Fc enhanced, the BCMA MMAF from GSK, which has an increased ADCC potential. There is only one which is Polatuzumab from Roche, which has an Fc attenuated. All the other, they have potent Fc. When you look at the 70 ADC with a DCI name, an INN name, there is a minority of maybe two IgG2 and maybe one which is mutated to silence the FC. The field today is still very much into the regular FC backbone. I mean, one thing that is also granted is that when you silence the FC, you decrease the off-target binding to the FC receptor, which are expressed on many hematopoietic cells. That is translated obviously in preclinical models, and it is something that we have shown in our publication like 10 years ago already. It will increase the biodistribution to the tumor in mouse model. I don't know if it's really relevant for what's happening in humans because you may decrease this off-target binding and potentially off-target depletion of hematopoietic cells, but you don't know how much this contributes to the efficacy of the drug because you may also deplete myeloid suppressor cells. When you do that, you may increase the efficacy of your ADC. It's really difficult to determine the contribution of the better tumor bioavailability and less hematopoietic depletions. If you do that, you can imagine also that you will have an increase on-target binding, but that means that you can also increase on-target binding on LC tissues. You may know that Nectin-4, for example, is expressed in the skin. You may not want to have an increased binding of your ADC on the skin. Altogether, it's very difficult to, as of today, as a field, to understand whether it's preferential to go towards an Fc potent or Fc silent. Our own analysis for the Nectin-4 case, especially for this skin expression, was to go rather with an Fc potent antibody that can also mediate immune mechanisms like ADCC or CDC or ADCP. There's one other hypothesis I've heard, and you'll allow me to get down this rabbit hole. One more thing is that the topo one could actually act as a STING agonist if it's internalized into macrophages. Have you done any work showing that? We didn't do that yet, but it's an interesting hypothesis. Throw another hypothesis into the mix. Got it. Let's talk about what we could see in the phase one trial. Let's assume it has pretty promising activity, 4502, but you're sort of enrolling this pretty rapidly in a heterogeneous population. Just to set our expectations, assuming it's good, what do you think is the worst and best case for what the outcomes could look like in this particular trial? Yeah, obviously we'll continue to try and move this as quickly as we can as we move through the dose finding stage and we go to MTD and then the dose expansion phase. I think the best case is that you could see, we will see data sometime in the second half of this year, probably more towards the end. In the worst case, it will come in the first half of next year, to keep it simple. Just in terms of, I guess, on FISHing-4, are you taking on risk by doing a lot of different tumor types, by not enriching for Nectin-4 expression to any extent? Should we have our expectation a little bit lower because of that? I don't think so. I think the design of the study allows us to really follow the signals. We're going in, it's a basket of tumor types. That gives us the ability when we see a signal to backfill those cohorts. We'll be looking for Nectin-4 expression levels retrospectively, we'll be able to correlate that with responses. I think based on that information, it will allow us to really follow those signals, follow the science, and basically hopefully go into some new tumor types where we've not seen Nectin-4 targeted antibodies pursuing those indications, which comes back to your intensity of competition perspective. If we're able to do that, we can go down a tumor type where the competition intensity is less, and I think that increases the chances to win. I think we're very happy with the way the study has been designed and the results which we will be able to get from it. Watch this space. Yeah. Actually, one more on this asset and competition. This Hengrui molecule in China, why hasn't it come to the U.S.? Seems like any interesting molecule has been acquired or licensed in the ADC world. Yeah, I have no idea. No idea, no. Got it. Okay, let's talk about Lacutamab. That's your another wholly owned asset, which potentially you could file soon for registration accelerated approval in a rare disease, Sezary syndrome. You just received breakthrough designation. You already had FDA Fast Track and EMA PRIME. Just can you help us on the regulatory path? What can we read into the Fast Track, and when might we expect potential accelerated approval or even start of a confirmation study? Yeah, we're working, I would say working very hard in the background at this moment in time on the design of the confirmatory study. We had an excellent meeting with FDA in the latter half of last year where we basically aligned on the high-level elements that would be required for an accelerated approval. That included agreeing on the dose to be carried forward into the phase three, which I think is a big deal today in terms of Project Optimus to actually have clear direction on what that dose can be. We also agreed that we could basically do a cutaneous T-cell lymphoma study that was powered for not only for Sezary's, which would be the accelerated approval opportunity, but also for MF, for mycosis fungoides. We could also go into an earlier line of therapy. After one line of treatment rather than after two lines, which we studied in our phase two studies. We know from our phase two that we're treating patients for a lot longer. This creates a very nice business opportunity. I think having the breakthrough designation is quite reassuring in the context of FDA today and some of the uncertainty in terms of FDA and review timelines, et cetera. Having that BTD designation ensures that you're prioritized and you get faster meetings so that when we basically with the phase three design that we have now, we'll get a quicker meeting to be able to finalize that and then be able to take that into patients. We are hoping to have a finalized phase three study before the middle of the year, which we can then basically start out the rollout of that phase three program and in the best case, recruit patients towards the end of this year, early next year into that study. Irrespective of whether we have a partner or whether we do it on our own, we are really pushing to move that forward as quickly as we can. You will push forward on your own if you don't have a partner? We are keeping our options open and we're basically working on a backup plan in the absence of a partner to take it forward. In the absence, I think we want, our preferred strategy is to move forward with a partner. If we're not able to do what I would consider to be a good deal, then we're not going to give away the value of this asset because it's a differentiated asset. It's a de-risked phase three ready program with the relevant health authority designations. I think we owe it to our shareholders and to patients to find a way to take this forward. You had really interesting biomarker analysis at ASH this year. The target of Lacutamab is KIR3DL2, Lacutamab's an antibody. You can look at expression in the skin and then you looked at expression in circulating tumor cells as well as looking at macrophages and NK cell density. I wonder whether any of those biomarkers that you've done post-hoc, you could see prospectively helping you expand to broader population to make this more commercially attractive, let's say in PTCL or even earlier CTCL lines. Yeah, does she want to take this one? Yeah, maybe just to remind everybody the finding that we have published at ASH, we have looked at the efficacy data of Lacutamab, which is our phase two in Sezary syndrome and mycosis fungoides. In Sezary, there are multiple compartments that are having tumor cells, like there are circulating tumor cells, the Sezary cells in the blood, but there is also a skin involvement. What we have shown is that in the blood, the circulating tumor cells, patients who had circulating tumor cells with a higher level of expression of the KIR3DL2 had a better objective response. Whereas in the skin, it is pretty much independent of the level and density of the antigen. What correlates best with the skin responses is the density of macrophages that outnumber actually the number of NK cells in the skin. Yeah, it's an interesting finding. We don't know yet because this is an antibody that can mediate two mechanisms, ADCC through NK cells and ADCP through macrophages. We don't know yet which one is dominant in which compartment. It looks like NK cells may be dominant in the blood and macrophages in the skin, but it's a hypothesis. It indeed could help us to better delineate patients that could benefit from the treatment. We see, for example, that in PTCL, there is roughly across, even there are some differences between the different subtypes of PTCL, roughly half of the PTCL patients do express high level of KIR3DL2, 40-50% do express high level of KIR3DL2 in the skin. It would be also interesting to map the infiltration of macrophages in these patients. Let's talk about your phase three asset, Monolizumab, that's licensed to AstraZeneca. We haven't talked about that much because it's been in this trial for a long time now. The phase three, I think, could come as early as next year in early stage non-small cell lung cancer. Just give us your most updated on when we could see that data readout and remind us why you're confident in Monolizumab, which is in a combination of Durva post-CRT and lung cancer. Yeah, so as you stated, this is in partnership with AZ, and AZ are taking this forward. If you look on clinicaltrial.gov, they put May 2026 as the expected timeline for this outcome. In the original PAC9 Pacific study, it was basically a three-year timeline to the outcome. The first patients were recruited in the PAC9 in May 2022. Three years would take us to May 2025. I think there's a window there in terms of when you could expect a result, but I think it most likely will be sometime in early 2026. It's an exciting one for us. It will be obviously our first phase three study to deliver. Obviously, there are some very significant upsides associated with a positive study. I think we have over $800 million of potential milestones to come from AstraZeneca in case of a positive study. We have a double-digit royalty on sales. We have a profit share for Europe. That will be obviously a very exciting study if and when it's positive. Are all $800 million in milestones possible here, or do you need to get to other indications to reach that? No, I think it's we did not disclose the breakdown. I mean, it's $1.2 billion in total milestone. We already cashed in $450 million, and there is still $825 million in development, regulatory, and commercial milestones. Got it. Why are you confident sort of mechanistically? People might not even know what Monolizumab is besides the nice name. Yeah, thank you for the name. It's actually a pure internal teamwork at Innate to find this name. Yeah, we are confident because the mechanism actually and the biological hypothesis that is supporting the PAC9 trial is very strong because NKG2A, it's a checkpoint inhibitor, which is a negative receptor expressed on NK cells, but also on CD8 T cells. It's not expressed on all CD8 T- cells. It's expressed on tumor infiltrating CD8 T cells, and it's mostly co-expressed with PD-1. That's why the simultaneous blockade of the PD-1, PD-L1 pathway together with NKG2A is really required to see the full potential of the NKG2A. That's what we have shown in various preclinical models, and we have shown also that both the NK and the CD8 are contributing to the efficacy. It's also a very interesting setting because in the PACIFIC line, it's post-radiochemo, and it's been described that radiochemo is increasing the ligand for NKG2A, which is HLA-E because there is a local production of gamma interferon, and HLA-E is a bit like PD-L1. It's upregulated by gamma interferon. This is really for the biological rationale. When we look at the clinical data, also you need to keep in mind that we are having three different proof points in three different controlled phase two showing the added value of Monalizumab over Durvalumab in lung cancer. There were the two trials in a slightly different setting in a neoadjuvant setting called NeoCOAST and NeoCOAST-2, where Monalizumab was given on top of Durvalumab either alone in NeoCOAST or with Durvalumab plus chemo in NeoCOAST-2, showing that we can improve the pathological complete responses in these patients. This is for the new adjuvant part, but most importantly for Pacific line, we had the COST data, which is basically the very same design as Pacific line, but as a phase two with 60 patients per arm, where it has been shown that the addition of Monalizumab can really increase the prolong the PFS of the patients in this consolidation setting. Great, okay. Let's talk about the last clinical, sorry, it's one of your priorities, and I left it till the end, but the ANKET platform. You have multiple ANKATs in the clinic, and I wonder if you could describe what ANKET is and where the three programs currently are and when we might see more data. Yeah, I'll start off and then I think Yannis can maybe add something. Our ANKETs are our NK cell engagers, and basically this is a platform where we target CD16, NKp46 on natural killer cells, and we attach a tumor tag to that antibody. It is a tri-specific antibody. The lead ANKET, IPH6101, is licensed to Sanofi. It's being developed. The tumor tag is CD123, and it's being developed in AML. Sanofi completed a phase one study in treatment refractory patients in the one milligram per kilogram dose. In 15 patients, they saw five complete responses. Three of those complete responses were long-term responses greater than 10 months. One was with MRD negativity. Off the back of that study, Sanofi initiated a phase two study in treatment refractory AML patients, and they also initiated a phase one study in combination with venetoclax and azacitidine, and those studies are ongoing today. The second ANKET, which we have licensed to Sanofi, is targeting BCMA, and this is being developed in multiple myeloma, and this is in a phase one study with data yet to be reported. It probably brings us to the most interesting ANKET from our perspective, which is our lead proprietary ANKET. This basically is an ANKET, but with an addition to it. We have basically engineered a cytokine into the NCAT as well. It is a tetra-specific antibody. It is targeting the same NKp46 CD16. It has a CD20 tumor tag, and we have engineered a non-alpha IL-2 variant into the antibody to basically activate and stimulate NK cells. This particular product is in phase one, which was initiated last year, and we're working through the dose cohorts, hopefully to get into an effective dose reasonably quickly. We expect to have the first data probably around the end of the year for IPH6501. What are you looking for there, both for the potential in NHL, it's very competitive, but also to validate the tetra-specific cytokine addition? Exactly. I mean, it's exactly what we're trying to do. We're trying to validate the potential in NHL. Preclinically, what we've demonstrated with IPH6501 is basically B cell depletion that is CAR T cell-like. We're seeing fantastic B cell depletion without the liability of the pro-inflammatory cytokine markers. We're not basically generating the CRS, levels of CRS that you see with a CAR T or with T cell engagers. That's what we're trying to validate in this particular study. We're trying to validate the safety in particular, and it gives us a very interesting opportunity also then to pivot the product into inflammation and autoimmunity. You can imagine a proposition of having CAR T cell-like B cell depletion without the liability of the cytokine release syndrome would give you a very nice positioning in an inflammation and autoimmunity perspective where the safety is super important. Yannis, if you want to add anything. Yeah, I think it's, and that is also supported by a very strong preclinical data package where we have shown the efficacy of this drug in different models and also using cells from patients. Across different BNHL patients, we see the fitness of the NK cells that they can be activated by the IPH6501, and in non-human primate models, we also see a deep depletion of B cells in secondary lymphoid organs, which is sometimes a challenge to obtain. That is why we are having here very strong B cell depletions that could potentially fit into the BNHL landscape, maybe starting with the late lines of treatment, but like Jonathan said, with the opportunity to transition to inflammation at some point. Do you see any increase in Tregs with this? I mean, in autoimmune, that could be positive. No, because the cytokine that we have is a non-alpha one. How about regulatory NK cells, if those exist? Yeah, maybe. Okay, I know we're two minutes over, thank you very much. It's always nice talking with both of you. Thank you all for your attention. Yeah, thank you.