Agenus Inc. (AGEN) Earnings Call Transcript & Summary

It's 2 minutes past the hour, so we will start as promptly as possible. Firstly, thank you very much for being here today. We appreciate your time. I know for investors, this is a precious time as the market will be opening soon. So we particularly appreciate your efforts to be here. Let me start by -- I guess I'm controlling things here -- with our disclosure of forward-looking statements. All I'll say is that there's a lot more detail on our website on this and in our SEC filings, so we invite you to do that. We have -- over the years, as you know, we have been in the cancer immunotherapy business for -- it'll be 26 years in April. The company was formed 26 years ago. And so it's been a long haul. And it's been a long haul with no regrets because the field of cancer immunotherapy has advanced to the point where now it is the most promising treatment modality for cancer patients going forward. Of course, I'm not suggesting that nothing else will be used, but cancer immunotherapy is front and center, stating the obvious, so to speak. And we've, over the years, had ambitions to cure cancer. And of course, that's a dicey word to cure cancer. And this is the best that we've come up with, inspired by some recent developments that came to my attention. So we strive to, or aim to, have cancer patients living longer and better. That's the objective. Better is also very important because living longer alone, which has been the regulatory standard for a long time, is not sufficient. For example, if a patient lives longer by a month or 2 months. In their case reporting forms, they showed that as a benefit, but the patient is not functional and not happy. That, of course, doesn't really accomplish much. So this is our new tagline. Now today, we invited you here to tell you about the latest developments with the company. Over the years, we have strived to have a very broad portfolio of cancer therapies. And we have also strived to be fully integrated as a company. Now fully integrated is a very important component because without being fully integrated, we couldn't have made the advances that we have. Treating cancer requires more than 1 or 2 agents. It is like a Military force battling the enemy. And having just 1 component of a military force doesn't really work well. That's one of the reasons we have strived to have many of the components that are necessary and can be called upon when they are necessary to battle this disease. And so today, we have a fantastic lineup, actually. To start from the left, Dr. Charles Drake is the Co-Director of the Cancer Immunology at Columbia. But more importantly, he has had a very long pedigree in cancer immunotherapy. He's one of the experts, among other things, in the field of CTLA-4, which is something that we will be talking about today. Next is one of the top experts in cervical cancer. And why cervical cancer? Because that is a target for our first set of product approvals, and we will be filing our BLAs this year for 2 compounds for cervical cancer, to be presumably followed with other cancers as well. But Dr. Brad Monk is one of the world's top people in cervical cancer, and we had the pleasure of meeting him a couple of years ago, and he has been a fantastic inspiration in directing our programs in this field. Next is Dr. Tyler Curiel from the University of Texas in San Antonio. Dr. Curiel, I believe, was the first one to publish on PD-1 -- sorry, PD-L1. So he is a Phase I experimentalist, physician and a scientist, and he will be telling us about the how of some of what we're doing. Then we've got the lineup from Agenus. Mostly, mostly homegrown, mostly individuals that have risen to the top in their fields over the years at our company. Dr. Jen Buell is now President and COO, has risen to the ranks over the last 15 years, entirely internally. Then Julie DeSander, also a professional. She's the Head of our Business Development. She will make some few comments about how we're going about our business model. And Julie has risen to the ranks as well through the Agenus tenure. Then, we have Dr. Dhan Chand. Dhan has been with us for 7 years now. He's the Head of Discovery, and he and his team have been responsible for making the innovations and filing as many INDs as they have in the last few years, and he'll be talking about our pipeline. Then we have Dr. Mark Exley, who is one of the world's top experts in the field of iNKT cells. We believe iNKT cells are going to be a key driver of our cell therapy strategy, and he will be talking to you about that. And Dr. Anna Wijatyk, who I cannot claim to be homegrown, but she is a consummate professional, a drug developer in the field, and she is the Head of our Clinical Department. So we will be having a very succinct presentation to you covering all areas. And with the exception of commercial development, which I promise you we will do at our next meeting, because we are feverishly working on our commercial development strategy, commercial launch strategy, building the department and that will be ready for discussion next time we convene. Last time I was here, I made a statement that we will have 6 clinical readouts in 2020, 6 clinical readouts. And 2 of those are readouts from our first-generation CTLA-4 and our PD-1 molecule, which is now being ready for filing for cervical cancer with 2 BLAs. Now people may say, why does the world need another PD-1, because there are so many of them. And here, I draw your attention to the fact that it isn't another PD-1 that matters, it is what we do with it. And the prospects for our PD-1 in combination with many other agents that will make that PD-1 potentially a very, very competitive agent. And so we don't claim to have a differentiated PD-1, but we do claim that what we can do with our PD-1, which is a very important building block for cancer immunotherapy, will be highly differentiated, highly differentiated. For example, if we look at our PD-1 in combination with our CTLA-4 molecule, the first generation CTLA-4 molecule, there are certain advantages, as you will see from Dr. Mark's presentation, that are going to be unique to us in getting to the market with a differentiated strategy first. But also very importantly, if you look at our PD-1 in combination with our highly innovative agents in the pipeline, including our second-generation CTLA-4, that could offer an advantage that no other PD-1 has today. And that will drive the market potential of our PD-1 in combination with the other agents in our portfolio. Next, we will discuss our clinical data from our 1181 molecule, which is not just the next-generation CTLA-4, but much more than that. And we'll provide you with some of the details of that, including a very important development in terms of a very exciting early response in one of our dose escalation patients. The other 3 molecules here, AGEN1223, 2373 and the Gilead 1423, which is a compound that we licensed to Gilead last year, that was a preclinical compound, now it's in the clinic. But when we licensed it to Gilead as a preclinical compound, that was a subject of a $150 million upfront payment from Gilead to us. And Gilead is progressing that molecule in the clinic very rapidly now, and there's a possibility that they will be disclosing data on that this year as well. In addition to that, as I mentioned, we expect additional IND filings. So more specifically, we expect at least 2 IND filings this year, and you'll hear about some of them in stealth mode. We're not going to disclose the targets for competitive reasons, but we will discuss the mechanisms of what they do. And then, of course, the 2 BLA filings. So with that, it is my pleasure to introduce Dr. Monk.

So thank you, Garo, and good morning. I appreciate you being with me today. My patients appreciate you being with me today. I've been working on cervical cancer for 30 years. As a medical student, I worked in the lab, where GARDASIL, the HPV preventative vaccine was developed. And we still have a lot of work to do, and I get it that vaccination is the cure, but it will not happen in our lifetimes. So we have to continue to develop effective and tolerable medicines for the patients who have not had that opportunity. So I chair the GOG. I also run the U.S. Oncology, GYN Committee, and I'm the international Chair for the group of groups, called the Gynecologic Cancer Intergroup. So I'm very passionate about this. You'll feel my enthusiasm. I come from Arizona, where we have a high cervical burden -- cervical cancer burden. In this country, there are about 3,000 deaths, about 12,000 cases. I get it, it's a global disease, but there's certainly more -- too many deaths here, and we have our work to do. So I want you to see, I don't know if I have a pointer here, I want you to see -- I mean you can see this, this lesion here. My residents call it a cauliflower lesion. You'll probably never look at cauliflower the same, right? You look at that and it's staring at you, HPV related, and that tumor has been resected, you don't need to be a radiologist -- I wish I had a pointer. If someone had a pointer, I'd appreciate it. You can see this lesion here on the left, where it's too big to resect, and she was treated with chemotherapy and radiation. So that's what we're here to fight. And I want you to understand it, the average age for these patients is 49. So these are young women, okay? So within our group, the Gynecologic Oncology Group, we did 7 studies over 3 decades and really didn't get much accomplished. We showed that platinum works. We showed that paclitaxel, which you know is Taxol, in combination with platinum works, and we didn't get really anything accomplished over 30 years, okay? So it was this cisplatin, it was paclitaxel, and patients were still only living about a year after the diagnosis of metastatic disease. And then we kind of broke through. We broke through, in the New England Journal, also published in Lancet. Krish Tewari was my medical student, resident and fellow and the last author here on both of these publications. And we really sort of had a breakthrough with the addition of bevacizumab or Avastin to this paclitaxel, cisplatin combination, a triplet. And it helped patients live 4 months longer to Garo's point, okay? It's not enough. So we've continued to push, but this was transformational. Genentech really needed -- really never needed to sell it because once the doctors heard it, they immediately pivoted to this becoming the standard of care. And so this is a great example where the need was really unmet. And even though it was an expensive medicine, it still was transformational. And we really didn't have much happen between 2014 and 2018 until we got pembrolizumab approved in second line. Approved for after failing platinum taxane bevacizumab. That's great, really, it's great with a response rate of 14%, okay? The need was so unmet that even -- and generally, as you know, accelerated approval, you need about 100 patients, okay? This was 77 patients. And this was in a biomarker-restricted population, okay? And then biomarker is positive PD-L1 expression in about 80% of patients. So I get it that this was sort of interesting, again, Merck never really had to sell this because doctors in a day, once they heard about it, began to use it. Because there's really no other option. So that's been now in June of 2018, and we've continued to labor. And I think all of you recognize that the way to make anti-PD-1 molecules work better is 3 things. Adding it to chemotherapy or radiation. You see that in lung cancer, in breast cancer and all sorts of things. Adding it in anti-VEGF. You see that in kidney cancer, all sorts of cancers, lung cancer. And then third, adding an anti-CTLA-4. And so those are the three ways. And that's where we're at. And we're working on all of them. I'm here to talk to you about adding anti-CTLA-4 to anti-PD-1 because 14% response rate isn't enough, all right? So there's this company, it's called Bristol-Myers Squibb, you probably heard of it, BMS, right? And they make these medications called nivolumab and ipilimumab. And why don't they do a cervical cancer study? Well, they did. And it was really -- it was an investigator-initiated trial, okay? Because BMS really had no intention of expanding their brand. But with my friends, Anna, presented this at ESMO. She's in Barcelona, Spain, and it was a study really of all sorts of different patients and doses. They really didn't have a strategy because Garo doesn't run BMS, at least not yet. And so these are patients with metastatic cervical cancer, and they study two different doses. This nivolumab 3 milligrams per kilogram and then sort of a slow, consistent ipilimumab dose or the higher ipilimumab dose of 3 milligrams per kilogram, okay, every 3 weeks. It was lots of different types of patients. It was patients that had PD-L1 or didn't. It was patients that had bevacizumab or hadn't, and it was patients that were either newly diagnosed or in the more traditional setting of second line. So it was a group of patients and really had no regulatory intent, but sort of an investigator-initiated trial. And again, there are lots of different groups of patients, biomarker positive, first-line or second line, all presented at ESMO and in the public domain, but they showed that even in the lower dose ipilimumab that there is an improvement in response rates sort of back in the napkin inappropriate cross-trial comparison, which we do anyways. The 23% in this patients -- prior systemic therapy for recurrent or metastatic disease, the 23% was a step in the right direction, okay? And maybe it was even a little better if you used a higher ipilimumab dose, but the higher ipilimumab dose, as you know, is more toxic. So we love this because we were already working with our commercial sponsor, Agenus, to do this exact same thing. So we were encouraged that there was, indeed, a proof of principle, a concept. And quite frankly, we were ahead of this even if they decided to develop this commercially. So my good friend, Wendel Naumann, who works at the Levine Cancer Center in Charlotte, North Carolina. And this is his patient. And you can see -- you don't need to be a radiologist. This is a heart, this is a CAT scan, you can see all this white, which is cancer. And just after 2 months, basically, it's gone with combination ipilimumab and nivolumab. And he biopsied this patient after 7 weeks, and you could see that there is an infiltration, these little dark brown spots, of immune cells that are trying to fight the cancer. So the addition of the CTLA-4 causes dramatic improvement in clinical, I think, in clinical response and was very innovative, and we're excited. And by the way, I'll go back a slide, this patient had failed radiation cisplatin and sort of the typical New England Journal FDA-approved 2014 regimen that we developed. I get it, it's all about tolerability, okay? So the treatment-related adverse events in this nivolumab ipilimumab proof-of-concept, relatively high. Grade 3, 4, 28.9%. That however, those leading to discontinuation, or the serious ones, is relatively low, particularly with the low dose ipilimumab. And you guys know this, you're familiar with nivolumab and ipilimumab in combinations in many different tumor types. And we were concerned because many of these patients that had radiation that we'd see higher intestinal toxicity because, as you know, we radiate the colon. It's in the pelvis. And we didn't really seem to see higher intestinal toxicities than what we had seen in other tumors, although they generally are between 5% and 10%, and you see that. So we strive as a group, you as an investment community, me as a clinician and investigator and as a company to be best-in-class and really to bring this to the clinic. And that's why I got on an airplane yesterday and flew all the way to New York, and that's why I have a 1 o'clock flight back, okay? Because I need PD-1, anti-PD-1, anti-CTLA-4 in the clinic. And again, if and when this becomes available, it will just be transformational. Doctors will use it. And what else are they going to use? Single agent anti-PD-1? Of course not, right? And there's nothing else approved, okay? And that's why single-agent pembrolizumab got FDA-approved with 77 patients and a 14.3% response rate, because duh, right? It's what patients need. So we're here today, and why am I presenting this here today? We -- I was asked by my friend, [ Han ], he says, "Why aren't you showing this in the AACR in San Diego, or ASCO?" It's an excellent question. This is so impactful for the company and for my patients, I can't wait. So it's a little unusual, but this -- we have to move forward quickly. And so we really don't have time to present it at a meeting because the BLA filing is soon. And we'll just present the entire data set. So we didn't really think that it was worth it to send half of the data to the meeting, but we thought it was important to disclose to you. And also, I think, to the scientific community, sort of in a more informal setting, that this is a big deal. And it's a big deal, not only for patients, but it's a big deal because it shows that these agents are effective and tolerable. So that's -- and that's why we're here today, and I think that's why the room is full. So again, trying to, here in green, to improve upon the -- in the lighter color, the anti-PD-1 or PD-L1 signal, an anti-CTLA-4 can make that deeper responses and more impactful across many tumor types, and we're here to talk about that cervical cancer opportunity. So these are our data sets. This is as of October. As you know, it takes 3 months or so to clean it, and I want to thank Anna and her team. She is supposed to be on vacation, and thank you for being here. That's how excited we are about this. So there's 42 patients. I told you, pembro has a 14%. This is 12%. I think that the duration of these responses, and these patients are still on treatment. That one, for example, I think, is encouraging. It's not enough, but it shows that this class of molecule, as manufactured by Agenus, works. I get it, it's 5 out of 42 patients, but there was some CR, and that's interesting. It's really not, at least, my goal to make a replacement for pembrolizumab, right, because we already have it. My goal is to bring the combination to the clinic because this isn't nearly enough, right? So in a smaller subset, now we're seeing more CRs. Now we're seeing about a doubling of the response rate, very similar to the nivolumab ipilimumab sort of investigator-initiated trial that I saw you -- showed you. This data set is a little -- was in July, not October. So -- and these are valuable patients. There are other patients on study, and I'll let Jen and the team talk to you about what the anticipation is. For the timing of the filing, I can pretty much assure you, in my opinion, that if the application is accepted, and it should be, it will be a priority review, and as you know, priority review is generally 6 months or less. So I'm really excited about this. And you can see these responses are still ongoing, okay? And some patients have long-term stable disease. So I think this is sort of an impactful opportunity, and that's why I'm here, and that's why I'm excited because now we're getting into durations of responses and the number of responses, I think, that me and my colleagues can get behind and will be exciting for our patients. And again, this is at the lower dose. The same dose that was studied by BMS in nivolumab and ipilimumab really for the tolerability opportunity. So I hate to do cross-trial comparisons. So I'm going to do them. It's just kind of what we do. And so you can go ahead, and you can compare either the combination that I showed you from BMS presented at ESMO, or this that I just presented today, and these numbers are in the same range. Again, our goal is to be better. And we have our scientists and our business development to talk about the next-generation CTLA-4. So yes, this is better than single agent anti-PD-1, but we really want it to be even better still than what the anti-CTLA-4 opportunities are. And then here's the single agent, same sort of thing, 11.9% versus 14.3%. So again, this is encouraging for the CMC and the manufacturing capability. It's encouraging. If you're interested in investments, I'm not. But what's most important, it's encouraging for patients, and that help is on the way, okay? So this is the adverse event profile that -- for this combination. Again, these on-treatment As are what they are. And -- but importantly, leading to discontinuation is relatively low, which is what we're interested in. So cervical cancer is still here, even though we have a vaccine. And it's not going away in any of our lifetimes. Hopefully, someday, it will be like polio and smallpox, but it's not today. Accelerated approval from small single-arm clinical trials is an established way to the clinic. We did it in cervical cancer with 77 patients last year. We did it in ovarian cancer with niraparib, and endometrial with pembrolizumab and lenvatinib. So we do this over and over again, it's established paradigm. Anti PD-L1 activity is in this 10% to 15% range, and now we have a balstilimab, which is an opportunity. And there's no question that the combination of CTLA-4 to PD-1 is an opportunity. So accelerated approval alone and maybe in the combination, in my opinion, is likely. So thank you for having me. Thank you.

Good morning. My name is Anna Wijatyk, and I'm the Head of Clinical Development at Agenus. Before I start, I wanted to thank Dr. Monk and the GOG Partners for their support to Agenus, not only in the execution of our clinical trials with cervical cancer, but also strategic support for the BLA path, and their continued commitment to cervical cancer patients, very much in line with what our mission is to help patients live longer and better. I joined Agenus 18 months ago after more than 20 years in various organizations, including Shire, BMS and Baxter, freshly off the successful BLA filing for ALL indication with Shire. At the time I joined Agenus, there were only a handful of people in the clinical organization. In the last year and a half, clinical development has grown exponentially, and added number of functions essential to not only deliver 2 BLAs in the 2020 year, but also, at the same time, to execute clinical studies in an accelerated manner, true to our commitment to help patients live longer and better lives. Data from our cervical cancer trials that Brad just shared, shows that we are on track to deliver data sets that will be needed for the BLA filing. This, coupled with the fact that we enrolled required number of patients with exceptional speed, confirmed that we are on target for the 2 BLA filings in 2020, both as a monotherapy with balstilimab and combination balstilimab and zalifrelimab. When we met last time, I shared with you cases of patients that were a complete responders in our cervical cancer studies. I wanted to just briefly review those cases again with you, just to remind you what we presented last time. First case is a 60-year-old patient from our monotherapy trial. She presented with recurrent metastatic squamous cell cancer of the cervix after being treated in 2016 with a platinum doublet. That patient presented to the target lesion in mediastinal lymph nodes. And as you can see from the data on the right side hand, this patient was a complete responder, already on week 6, and maintained that response, as you can see from the pictures on the left side from screening versus the cycle 36, the patient remained a complete responder for a very long period of time. Another case comes from our combination study with balstilimab and zalifrelimab. So that patient is also a complete responder. She presented with the recurrent metastatic cancer and her target lesion was in vaginal stump. So you can see the picture from the screening at the top, comparing it to the week 27 on treatment. So that patient started to respond already on week 6 and continue to be a responder at week 27. So durable complete response. As a clinical organization, we are set to deliver unprecedented outcomes. This slide shows you a glimpse how we executed in 2019, and how we are set to deliver even more in 2020. In 2019, we have been operating in 25 countries with 120 sites. We have enrolled more than 300 patients and carried out 8 clinical studies in different stage of development and different indications. We delivered data for 2 interim analyses, and we continue to analyze our data in an ongoing manner. And as Garo said, we are set to deliver unprecedented number of readouts in 2020. Our organization now counts 54 people, and I mean, clinical organization, remarkable growth from just 1.5 years ago when we only had a few people. We have and are continuing to deliver data on a number of programs with different molecules, different indications, including novel molecules, which would potentially address significant unmet medical need. We broke industry record for the time from the IND clearance to the first patient dose. It is 65 days versus industry standard of 168 days. Our operation team has performed exceptionally. We enrolled patients with unprecedented speed in a very complex setting. As you know, there is a big competition for patient and notably in cervical cancer space, where there are already some treatments registered. But there are also many clinical trials that are competing for the same patient population. So it's very challenging to enroll patients in this type of indication, and we did it. In 2019, we enrolled the required number of patients to deliver 2 BLAs in 2020. So we are off to a very good 2020 with 2 filings on target and multiple studies, either continuing or starting to deliver the readouts, for patients to live better and longer and better lives. Thank you.

That is very exciting to be able to share with you. Maybe just to take a moment to let you digest some of the key points that both Dr. Monk and Dr. Wijatyk presented to you. Now Anna did share some metrics, and I will just highlight another very important one. We will be filing -- we're on track to file our BLAs within about 3 years from our IND for second-line cervical cancer. That's another record-breaking time line. It's exceptional. Now I am so honored and proud to be a part of an organization who did spend the time that was required to actually interrogate tumor biology and understand the underlying mechanisms of tumor escape mechanisms of how to actually prime and educate the immune system, and then to really learn how the immune system -- how the tumors are fighting back to protect themselves from the immune system. And from those learnings, we had the knowledge, the intelligence and the foresight to develop not just one CTLA-4 because we knew the value of it, but a next-generation and enhanced molecule that you're going to hear more about today. Before we go into that, though, I'm standing in the precipice behind our speedy and very productive, exceptional clinical development team, led by Anna; our expert clinician, Brad, who's been guiding us along the way in identification of patients Who need these types of therapies. Patients with cervical cancer, these are predominantly virally-induced tumors, they exhibit some features that are phenotypically akin to those tumors that respond very well to PD-1, but respond much better to CTLA-4 and PD-1. These are tumors with high mutational burden. These are tumors with already some semblance of baseline immunogenicity. Some immune recognition is already existing de novo. When we add a CTLA-4 to patients who present with that phenotype, you see this doubling and sometimes tripling of response rates. And that's where we very much want to see our products advancing, where we could make meaningful differences to patients. And this is why we've been focusing on the durability and the response rates. And I think you can see a semblance of both. We have presented the data to you here today, not only because we want your undivided attention, we want to give you ours as well, we also certainly didn't want to wait any longer to midyear to present at ASCO or a little sooner at AACR. But we had these data in our hands last year, and we had wanted to share them with you. In our discussions with the FDA, they asked us to partner with them and to hold the data and not share them until we were closer to our filing -- our BLA filing. There were a few reasons for this. Number one, they did not want us to dilute or compromise the integrity of the patient population that we were accruing, so they didn't want the data to be in the public domain that might influence our ability to complete our accrual with patients that were homogeneous, which, by the way, our patient population is different than some of the populations that Brad has presented to you earlier. The patients from Merck as well as from Bristol, some of whom have -- were treatment-naive. Our patients are a homogeneous patient population that ideally represent how patients with refractory cervical cancer are treated today. These are patients who have failed the platinum doublet, and in some cases, have also been treated with bevacizumab based on the data that Dr. Monk and his team at the GOG has presented. The -- this allows us to actually understand where and how our products are working. So we've decided to present these data to you now because we've not only completed accrual, but we've surpassed what our accrual obligations were. So we have an even more robust data set to draw from. We also -- so we have -- there's no problem with us potentially compromising accrual. Our patients are in, they're on treatment. They're being followed. The FDA was also concerned that if our interim analysis did not represent our final analysis, there would be a conflict. However, we have enough data now with -- having completed accrual and gone beyond our requirements for our analyses, to feel very confident in the data that we're presenting in this interim analysis. And we're quite excited, and now we're just watching and monitoring the durability, which we anticipate, much like other tumors that present similarly to cervical cancer, CTLA-4 in combination with PD-1, will not only enhance response rates like we're seeing, but will also enhance the durability of response, which is so important. Now these patients, who have had complete responses or partial responses, when you take a look at the [ surplus ] that Brad presented to you, you see some durability peaking through. You see some complete responses, who have -- the patients with complete responses and with partial responses have durable responses. So those are continuing, which is very exciting. And of course, akin to our mission to enable patients to live longer and better lives. This is a semblance of our ability to do that. But now I'm going to talk to you about what's next. We've brought some experts to speak with you today. We have been interrogating the immune system for many, many years. We've designed CTLA-4 and PD-1 for all of the reasons that I've told you, and they're playing out in the ways that we want them to play out. We know that PD-1 and CTLA-4 represent a multibillion-dollar opportunity. As a matter of fact, the PD-1 market today is about $20 billion. Ipi and Nivo themselves are approaching $8 billion to $10 billion in revenue. We have the most clinically advanced CTLA-4. Bristol has an approval with YERVOY, and ours is the most clinically advanced CTLA-4, which we believe, if we remain on track, will be second to market, which is incredibly exciting. But we didn't stop there because we've been interrogating why do only 20% of patients respond to YERVOY as a monotherapy? How can we actually expand the response rates, the durability of response and broaden the population of patients who respond to a CTLA-4 inhibitor? So Dhan and his team, as he presented to you at our last meeting, went to work to figure out what's going on with these patients, these nonresponders. And there are a few things, and one that's very important. Patients with -- CTLA-4 in and of itself, it activates T-cells. Our first-generation CTLA-4 does the same, our next-generation CTLA-4 is designed to do the same. But there are some pieces that are missing. We need to prime the immune system. And to optimize priming, we need to better educate our immune cells. So we've designed our next-generation molecule, 1181, to actually increase the time that the antigen-presenting cell and the T-cell are together. And that education time improves the way that the immune system can recognize that antigen. The molecule is designed to, and preclinical data have demonstrated that it is doing so. And I'm going to hold my urge to tell you a little bit about the clinical data for just another moment. The other component that CTLA-4 antagonists were designed to do were intratumoral Treg depletion. And we don't see that with the first generation molecule, in as much as I'm aware and many of the experts have shared with us. However, the way that we've designed our next-generation CTLA-4, we have demonstrated preclinically that we may be able to achieve this. Now the only way we're going to know that today clinically, as the translational data are being analyzed, are clinical responses. So we've designed a molecule that can go beyond what the activation of T-cells with a first-generation CTLA-4 can do. And we've designed something that can also prime, and it can also deplete these PD suppressive Tregs. That's why we're calling it something beyond CTLA-4 antagonist. It's a multifunctional T-cell engager because of the features that it presents. But the most important feature that I see in this molecule is its ability to increase the exposure from the 20% of patients who respond to YERVOY to over 60% of patients and maybe even more. These are patients who we've seen, and others have reported on as well, who exhibit a genetic polymorphism that renders them unable to respond to a first-generation CTLA-4. These are patients with a mutation in their CD16 allele status. We're measuring that. We've brought in today, Dr. Chuck Drake, who is world-renowned in this space. And I asked him, if for as long as I have been in this field, I asked him how long he has been in immuno-oncology. And he said, "Since, I think, 1990." Maybe he might have said 1989, but [ we were 6 ]. So I thought this is just -- it's so exciting to be able to share the stage with him. And what Chuck will tell you about today, of course, are how important T-cells are. But what about -- the effectors are important, but what about some of these other cells? What about the T regulatory cells? How about the myeloid cells, the macrophages? And Tyler is going to speak with you a little bit about that as well. So today, we are going to present to you data on AGEN1181. A case example, what we have seen in the clinic right now with over 20 patients treated. We've seen disease stabilization in the majority of patients who have -- who are response evaluable. And we have a patient with a solid tumor, a patient with endometrial cancer, a patient who has had the poorest prognostic factors genomically, phenotypically, who has had a complete response on AGEN1181. In only the first few patients, the first 20 patients, we've seen this complete response, which is incredibly exciting for us. I'll tell you why it's so exciting. Beyond metastatic melanoma, there have only been 4 solid tumor complete responses to YERVOY to first-generation CTLA-4. Those are all in prostate cancer. And Chuck Drake [ knows ] those cases quite well. So we are in a position where we are seeing something. And those 4 patients were observed in more than 1,000 patients treated, as you can imagine. This is outside of melanoma. And we're seeing something quite exciting with just a limited sample size right now. Now AGEN1181 has -- is in the clinic. We launched it. We're dosing as a monotherapy as well as in combination with our own PD-1. And the molecules moving forward, it's one of the components that we'll be looking very forward to sharing additional data with you, ideally at major medical conferences, and specifically, this year, certainly, beginning of next year as well. These data are very dynamic, and are continuing to present. Tyler Curiel is here, and he's going to share with you a deeper look at what might be happening with this patient with the cell types, and he's going to introduce Dhan Chand. And Dhan, our Head of Drug Discovery, is going to share with you how we're now going beyond just effector T-cells. We have the most robust and productive research engine that exists in the industry today, I believe. We have outpaced big pharma in our ability to deliver novel agents to patients. And these molecules are moving forward in our own hands as well as, importantly, in the hands of our partners. And with the company of just about 320 employees, we've outpaced Bristol, Merck and AstraZeneca and Novartis and many others in delivering new discoveries in I-O to patients with cancer. As Brad just mentioned to you, he is -- it was palpable how urgently he is seeking new therapies that will work for his patients. And we know right now, it's a volume game, right? You need more discoveries, we need to continue to test them and interrogate them. We need to combine them optimally. And we need to be able to deliver them to patients in a way that is feasible. And we've designed a portfolio and a pipeline to do that with our monoclonal antibodies, our bispecific programs, with our allogeneic cell therapy approach that Mark is going to speak to you about and so -- and many more. Now in our hands, we have experts who now -- who not only have been able to discover and develop the molecules targeting CTLA-4 and PD-1, optimizing what is working to something that may be working much better and continue to discover to manipulate other components of the tumor microenvironment. And these are going beyond effector T-cells, as I mentioned earlier. We developed the ILT4 anti-ILT4 molecule for Merck. We're experts in this space. We've discovered and licensed to Gilead, as Garo mentioned, GS-1423. This is a first of its kind, CD73 TGF-beta-Trap molecule. Dhan is going to highlight a couple of features of that. And then we have some undisclosed targets as well that we will be looking forward to speaking to you more about. And of course, our programs with Incyte are also advancing in Phase II in multiple combination studies. We have our discoveries advancing in our own hands, in the hands of partners and generating a series of key catalysts throughout the course of the year, including cash milestones that we are quite excited to be reporting to you as these data continue to mature and these milestones come out. So without further ado, I am going to turn it over to the esteemed Dr. Chuck Drake, who's going to walk you through some important features Of CTLA-4 and AGEN1181.

Thanks. Well, thank you all for coming, and thanks for your introduction. I'm not so sure about all the esteemed parts, but I -- one part that is true is I've been working on cancer immunology a long time. I treated the first kidney cancer patient with anti-PD-1 with nivolumab in 2007. That person was lucky, they had a complete response, actually. And today, they're still alive in a complete response with no evidence of recurrence. So that's some of the things that we can see immunotherapy do when it works. Today, I'm going to talk to you about our regulatory T cells and CTLA-4. And what I'm going to first show you is some clinical and then a little bit of preclinical data to tell you why Tregs are so important. Then I'm going to talk to you about a new approach to address the problem of Tregs in patients. And then we'll talk about the generation of the molecule that you've heard about 1181, how it's worked. And then I've been privileged to share some of the early clinical data from the Phase I trial. So actually, there's a little bit of confusion in the field. So in the tumor micro environment, there's many cells. There are suppressive cells like macrophages and myeloid suppressive cells. But frankly, anti-PD-1 works mostly on the CD8 cells. So it blocks the interaction between PD-1 and PD-L1 or PD-L 2. If it works, CD8 T cells are activated, they proliferate, most importantly, they make interferon gamma. Interferon gamma reprograms when it works, the entire tumor microenvironment and actually, cure some of the many other problems, but within many tumors, there's a population of T cells called regulatory T cells. They express economical transcription factor called FoxP3 and they are designed to be bad. They are like our enemy in cancer immunotherapy. They secrete factors that make CD8 T cells not work. Not only that, they make natural killer cells not work. They basically make a tumor effectively cold even when it's infiltrated. And so tackling this problem has been a goal for cancer immunologists for a long time. And we knew this from Mouse Models, okay? So this is an old Mouse Model data, which we wanted to replicate in humans forever. So these are mice, well, this is B16. This is your cold tumor. It grows in mice, has like no T cells, it grows anti-PD-1 doesn't work, anti-CTLA-4 doesn't work, it doesn't work actually. I've done this Mouse Model hundreds, perhaps thousands of times. What happened was a group engineered a Mouse Model where you could deplete all the Tregs. So these had FoxP3 with a diphtheria toxin receptor. So basically, when you give the mice diphtheria toxin, all their Tregs disappear. And even in this cold tumor, getting rid of all the Tregs is amazing. It basically cures the mice. And so this is 2010, right? So we wanted to have a drug like this in humans for a long time, and I could tell you that we've been looking for such a drug actually. And frankly, we don't really have that yet. What I'm going to show you next is 3 pieces of data that tell you even more why we need something to address regulatory T cells. And the first one is from a cold tumor, which is prostate cancer. So before anti-PD-1 and anti-CTLA-4 and checkpoints were cool, what we did was vaccines. And this is a trial to try to make a cold tumor hot with the vaccine. This is old vaccine. Some of you may be invested and lost money in a company called Cell Genesys. So this was the Cell Genesys' GVAX vaccine and we had data from animal models that if you give hormonal therapy, which is the most common treatment for prostate cancer, you get a T cell influx. And the idea here was we're going to convert that to hot with a vaccine and see what happens. And this data showed us something very, very interesting. So on the top line, we have the primary outcome of the trial. That's how many T cells are in the tumor. That's 96 cells per millimeter square, that's a low. Melanoma is typically 400, 500. So that's baseline, that's the control. If you give hormonal therapy, it works. Hormonal therapy is a kind of immunotherapy. You double the T cells in the prostate gland the vaccine kind of worked a little bit. So you went from 200 to about 250. This was, in fact, not statistically significant. And we actually did see a small signal in terms of progression-free survival. But what's most important is the next line. So at the baseline, there's plenty of Tregs in the prostate gland. Most of the CD4s in the gland are, in fact, evil Tregs. When you double the CD8, you exactly, exactly, this is like not something you can make up. You exactly double the Tregs, double. If you get a little bit more CD8s from the vaccine, guess what, the Tregs go up another notch, actually. So this is a phenomenon that probably occurs in multiple tumor types when you have an immune response and we call it and other people have called it the same thing, Adaptive Treg Resistance. So this suggests that we should really do something about these regulatory T cells. And I'll show you in a little bit exactly how. This actually happens in mice, too. So we have a Mouse Model of prostate cancer. These mice develop cancer, it responds to hormonal therapy for a while, just like patients and then it grows out. If you look at those mice, the green bar up there, CD8 cells. So guess what, in the mice, the same exact thing happens. You castrate them and you double the CD8s in the tumor, but you also double the Tregs. So what can you do about it? What is a good target for regulatory T cells? Well, it turns out that the drug you've been hearing about many times this morning, YERVOY, ipilimumab and the new Agenus' molecule are really probably mostly focused on regulatory T cells. These are RNA-sequencing data from sort of Tregs from prostate cancer. We've done the same experiment from GBM, from bladder cancer and from several other tumor types. These are multiple patients. This is about 12 patients and this is RNA-sequencing profiling. So where is CTLA-4 in the tumor microenvironment? The answer is crystal clear. It's almost entirely on the regulatory T cells. That's the total Tregs. There's some methodology and some people present this in a confusing way. And I can tell you it's not true. There's very little CTLA-4 on the CD8 cells in the tumor. It's mostly a Treg marker. So anti-CTLA-4 like ipilimumab and the next generations probably target mostly regulatory T cells. And that's good. Right? Because that's why you can have like the effects we saw before, which are potentially even synergistic. Anti-PD-1 on the CD8s, anti-CTLA-4 and the Treg, it's actually not rocket science immunology, it's fairly straightforward, actually. So it turns out, though, that the antibody that's in the clinic and ipilimumab anti-CTLA-4 is not a good drug for depleting regulatory T cells. It blocks them, but it doesn't deplete them. These are experiments in these mice trying to treat them. This is a really, really challenging model, just like patients, it doesn't respond to anti-PD-1. So on the bottom, you see androgen deprivation therapy drug called degarelix was anti-PD1, none of the mice were cured and it doesn't even slow down the cancer. Importantly, on the top right is a version of anti-CTLA-4, the mouse version that's like YERVOY. It's like ipilimumab. It's a nondepleting. It doesn't deplete Tregs and it doesn't work. However, if you use an antibody, this is a mouse IgG2a that binds the mouse Fc gamma RIV, if you do this, actually, you can reliably cure between 15% and 25% of the mice forever, their cure, actually. So the idea is that if you really could deplete Tregs in humans, you might have a different effect than just blocking CTLA-4 like the top panel. This is not only with the hormonal therapy, it probably happens with any time you push the immune system within a tumor, the tumor probably adapts with adaptive Treg resistance, okay? And so radiation therapy, there are many trials that show that radiation therapy increases the CD8s in the tumor. This is looking at the Tregs in the tumor. These are 3 different kinds of tumors: melanoma; a kidney cancer; and a colorectal cancer. And you can see on the top, it is controlled, and the bottom is after radiation. When you increase the CD8 cells, you increase the regulatory T cells, reliably actually. So radiation therapy also increases the regulatory T cells in the tumor. And we've performed similar experiments in these models. On the top is untreated mice, treated with radiation. Radiation doesn't cure advanced tumors in mice, if you want the tumors become more advanced. We were the first -- our group with Michael Lim, we were one of the first to publish that anti-PD-1 combines with radiation therapy and you can see on your -- in the middle row on your far right, it does. Actually, with anti-PD-1 plus radiation, you can cure some of the mice actually. Anti-CTLA-4 has some activity in this model, this is the colorectal model. But the depleting anti-CTLA-4, is amazing, actually. So basically that, plus radiation, cures the majority of the mice. But the question you should always ask me, see mouse data like, okay, how reliable is this? How relevant is this? And also, like, are they really cured? So these experiments were done by a radiation oncology resident who was in the lab, and somehow he left, okay? And he went down to the NIH to do a rotation and he was there for like 3 months. And then he came back and he came back and he said, "I still have a lot of these cured mice, what should I do with them." And so first of all, he wasted a lot of money, but second of all, we should try to see if they really are cured. And this was a surprising finding, which was repeatable. That is if we challenge the mice that were cured with radiation plus anti-PD-1, they weren't all cured. They were not all cured, 50% would still take a tumor. But the mice that were cured with the depleting CTLA-4, the enhanced CTLA-4, they were all permanently protected, actually. So the idea -- and Jim Allison says this all the time, and I didn't believe him, quite frankly, that anti-CTLA-4, given in the proper context, promotes T cell memory, and that's a good example of this. These mice had sat for about 60 to 80 days. And so I think this is enough time to show that we really do have memory. So that's what we want. We want this kind of drug actually. What do we have this kind of got a little space. So we have ipilimumab, it's an IgG1. It almost certainly does not deplete Tregs in humans. In fact, in some experiments after ipilimumab, you see what I just showed you, Adoptive Treg Resistance, in fact, they are sometimes more Tregs. There is about 25% grade 3, 4 immune-related adverse events. Tremelimumab is an IgG2. This is a nondepleting antibody. So tremelimumab doesn't deplete Tregs. You just heard about the first generation molecule from Agenus, BMS has a version in the clinic, it's an afucosylated. It is an enhanced CTLA-4. It hasn't been reported yet. Merck has a trial, a drug that's actually reported nothing, their CTLA-4. They affectionally call this Merck, IPI or MIPI, actually. And we know nothing about this actually. So there is some enthusiasm in the clinic for anti-CTLA-4. And there's other molecules. These are just a couple of selected ones. But if you had -- if you could -- and the reason I'm here is because I'm just excited about this molecule. So if you can have an ideal anti-CTLA-4, what do you want? So first of all, you want a high affinity for anti-CTLA-4. That goes without saying that comes with most modern antibody selection techniques. What you'd really want, though, is the Fc optimized enhanced depletion of regulatory cells. You really want to get rid of them. If that occurs, then you would see enhanced T cell activation. And as I showed you, which you would really hope for in the long run is those long-term responses with T cell memory and also reasonable tolerability, but we know that drugs like this are likely to cause some related -- immune-related adverse events. So how can you do this? So this is a lovely paper. And if you really want to like read into the heart, I think, actually, of Agenus, you should read this paper in Cancer Cell, okay? It's a great paper. You got to read it slowly. It has a lot of abbreviations and things. It took me a long time. I read it once and I read it again yesterday to be sure I had it right. So what they did was they enhanced CTLA-4 molecule, so that it would bind more strongly to the Fc receptor, particularly in humans, the version is Fc gamma RIIIa. This would -- so here I'll go over here and show it to you. So here's an antibody, right? So it's an IgG it has 2 arms, right? And this is the standard IgG1. It blocks the interaction of CTLA-4 with CD80 and 86 on antigen-presenting cells. So that's the blocking function, right? What you'd really want, though, is not just that. You'd want to bind more strongly to Fc gamma RIIIa. And how can you do that? It turns out that there have been mutations in the Fc portion of antibodies described that would more strongly bind to Fc gamma RIIIa. And one of these is called DLE, actually. So it's a scaffold of IgG1 that binds more strongly. So that's what 1181 is, okay? It's an Fc engineered, enhanced CTLA-4 antibody that's intended to bind very strongly to Fc gamma RIIIa so that the mutations or the variance don't make any difference. And that should lead to enhanced depletion and to enhance T cell activation. That's the molecule that we're going to talk about a little bit next. So I'll show you 3 pieces of preclinical data. And you might say to yourself, why aren't you showing any like mouse data. The reason actually is this is enhanced to buy the human Fc gamma RIIIa. Mice do not have human Fc gamma RIIIa. So it's hard to show those kinds of things. So this is -- I think the job 1 of an enhanced CTLA-4 molecule would be to deplete Tregs. This shows a parental IgG1. Again, similar to ipilimumab showing perhaps in vitro some depletion, but the enhanced molecule is showing a gorgeous depletion of regulatory T cells. So these are important in vitro data. More importantly, I like this figure the best. This is from the paper, which I encourage you to read once again. So this is a wild-type IgG1 and this is T-cell activation measured by IL-2. Here's the wild type. This is what you'd expect from ipilimumab or potentially other IgG1 antibodies. This is pretty good, right? It basically leads to T cell activation. These molecules really do have to bind to the Fc receptor for this to work. So this is a mutant antibody that doesn't bind to the Fc receptor and it quite simply doesn't work, actually, only moderately leads to T cell activation. This is the one that's in the clinic. This 1181, the DLE engineered, and it really increases our T-cell activation through that enhanced finding. We heard from Dr. Monk that anti-CTLA-4 by itself was a monotherapy, is FDA-approved in melanoma and we don't do it that way. Nobody does that anymore. It's always used in combination with anti-PD-1. So if there's really going to be a good clinical candidate, then it should work with anti-PD-1, right? And these data are, frankly, even more impressive. So here's the parental antibody plus anti-PD-1 down here, these black bars. And here's the next-generation with anti-PD-1. And you can see this doesn't look like additive. It looks like it might even potentially be synergistic. So again, the idea is this is enhanced molecule, potentially with more activity. We have a little bit of data, and I've been tasked with presenting some of the early clinical data. This is a first look, take it for what it's worth. But it's -- I think it's interesting. I'm actually involved in Phase I. This afternoon, at 5:00 or 4:30, I'll go to our Phase I meeting. And we'll review Phase I. Phase I is like not what it used to be, right? So Phase I patients have a lot of options and to see activity in Phase I has become much less common than it used to be. We're actually very, very happy when we see stable disease in our Phase I trial because there's so many other treatments that the patients can have, including off-label anti-PD-1 by compassionate use or other molecules. So this is a dose I suppose, I'm going to go back. I don't know if I can go back. Okay, good. It is. So this trial was initiated. The combination was initiated in 2019. So far, 20 patients have been treated either alone or a combination with balstilimab, the anti-PD-1 that you just heard about, which I think amazing or surprising is there's been a complete response in this small group of patients, actually. This is the patient. This is a patient with endometrial cancer. They had, as is typical, a long treatment course, initially with surgery, adjuvant radiation, anti-PD-1 pembrolizumab, almost every patient in our Phase I group has had prior anti-PD-1. So this is not atypical, they progressed, they were treated with the PI3-kinase inhibitor, palliative radiation and then went on to trial. This is a monotherapy response to the enhanced molecule. This is one of the target lesions, large lymph node lesion. They had -- this patient is a woman who had severe abdominal symptoms. After 2 doses, she had her symptoms resolved. And after 4 doses, she had a complete response. And we heard recently that this has been confirmed yet another time. So this is unusual. It's unusual to have a complete response to a monotherapy in Phase I in a patient like this with multiple prior treatments, including, again, pointing out anti-PD-1. To compare it to the literature, like as Dr. Buell talked about in the entire literature of anti-CTLA-4 in clinical trials is all with ipilimumab, there are really not a lot of complete responses as a monotherapy. We ran 2 large Phase III randomized trials that was the global PIN1. In prostate cancer, there were a handful of complete responses, but again, that's well over 1,000 patients and very, very few complete responses. So seeing a complete response at this stage is actually quite rare. And to be honest, really surprising. I said surprising. There are also multiple patients on this trial who have the long-term stable disease. But I think this is important because this shows an early signal for this drug as a monotherapy. It's now in a combination with the anti-PD-1. And I think that's where we're going to see enhanced activity. And we're excited for this to move forward, actually not only in the Phase I, but in multiple tumor types. So this is my summary. And actually, even though I'm not an investor guy, I made this say forward looking, right, so forward looking. So this is an interesting molecule. This is a really, really unique enhanced Fc Enhanced CTLA-4. If you look at the paper, you'll see there's beautiful data of in vitro activity in multiple models with multiple controls and multiple. It's really -- it's a cancer cell paper, it's a very strong paper. We already have some data for monotherapy activity, but the real future of a molecule like there are slides in combination with anti-PD-1 or as I showed you, potentially with radiation therapy or potentially with any anticancer therapy that induces this adaptive Treg resistance because I personally believe that our data and other data really point to this as a mechanism by which multiple tumor immunotherapies or other therapies fail. In bladder cancer, we actually showed that the response to chemotherapy depends on Tregs. So if you look at initial response to chemotherapy, patients who have a lot of Tregs, it doesn't work. The patients who have fewer Tregs, it works. And so I think Tregs hold back the response to multiple cancer therapies, making this an attractive candidate going forward. That's it. I'd like to thank you for your attention for coming up. Thanks.

Thank you very much. Thank you very much, Dr. Drake. That is thrilling for us to hear and to see how the molecule preclinically was designed is now playing out in the clinic. And I'm going to have Dr. Curiel walk you through what might be happening just at the cellular level as well based on our findings in the clinic. Tyler?

Thanks. Can I get a mic up or do I have to stand in front of this? All right. I like to move around. So well, good morning, everyone, and thanks for giving us a few minutes of your time. So I just want to clarify on the -- your program, my credentials, I actually am also a medical doctor, board-certified medical oncologist, and I specialize in -- thank you, in cancer immunotherapy Phase I trials. And I used to run the Phase I program for immunotherapy and all Phase I cancer drugs at UT Health. And I initially trained in infectious disease and actually switched to cancer immunotherapy back in 1995. So I've been doing this a very long time as well. And our group was involved. Thank you. With work that led to the drug that's now durvalumab and I was the local investigator for the registration trial for that. And we were also the group that showed the relevance of Tregs to cancer immunotherapy in humans for the first time. So what I want to do now is just I'm going to go back to that patient that Dr. Drake just presented that had the remarkable response to 1141. And -- try moving this, so how do I advance? Okay. Take a look at that patient's response and just talk a little bit about what might be going on there. What it might mean. And then where the future holds going from there. So if this patient had came to -- had come to see me in the Phase I clinic, this is -- I would have looked at her and I would've thought, okay, her tumor's BRCA1 type. She's MSI stable, meaning not likely to have a lot of mutations that are actionable for immunotherapy. Tumor's PD-L1 negative. And you heard a little bit about the Fc isotypes or Fc gamma III, which is also CD16, she's the FF phenotype. That's the low prevalence, low-affinity phenotype that's associated with poor outcomes with many types of immunotherapy, particularly with first-generation anti-CTLA-4 and now that I heard the presentation, I'll also add that she failed another immune checkpoint agent, anti-PD-1. So these are all terrible risk factors for response to immunotherapy. And I would not have predicted that she would respond to another immune checkpoint agent or for immunotherapy in general. And yet she didn't just respond, she had a complete response that's confirmed and durable. I think that's really remarkable in this one single patient. So when I'm thinking about immunotherapy for cancer, what's going to happen next. First, I think about these things here and as poor risk factors and yet she had a response and there's 2 big areas that I think about. So Garo led off by talking about cancer as being a battle. And so you think about in the battle, you had the troops, which are the killer cells and then you have the battlefield itself, which is the tumor microenvironment. And if you're going to have effective immunotherapy, you either have to improve the numbers or function of your troops or you have to soften up the battlefield. And what I'm going to show you is 1181 can potentially do both of those things. And then we'll also talk about how that plays into thinking about other treatments as we go forward. So what's becoming pretty clear is, you've heard a lot about the fact that in cancer immunotherapy, the prime driver, CD8+ T cells. Well, they're really important, but we're now understanding that there are many other immune cells participating in that immune response that are also very important and we're just starting to pay more attention to those cells. So how do you do the laser point around, is it the red thing? Let's try it. Does it? No. Okay. So I'm mic'd up, so. Okay. So this is an analysis of blood cells. And this is an in vitro analysis of the 1181. This is the second-generation anti-CTLA-4, you've heard about. Okay. And 1884 analog, this is essentially first-generation anti-CTLA-4. So you can do an in vitro analysis, take peripheral blood cells from humans, treat them with the control with first generation, which is 1884, our second generation, which 1181, then you do an analysis called RNA SEQ. When you look at the gene expression of the cells and then you do bioinformatics and you say, put the cells in different groups and let me see what's going on. And you get maps that look like this that will show you different populations of immune cells. And I want to call your attention to this population of memory cells here in these patients that are treated with 1181, which is here. So if you -- here's your isotype control and you see this population of memory cells looks like this in control, the first-generation anti-CTLA-4 can increase that population a little bit, but 1181 increases it a lot more. And now what you can do is go back and say, who are these cells and they're these cells here. So this is a specific population of memory cells. And Dr. Drake just got done telling you about the importance of immune memory and how first-generation anti-CTLA-4 can induce memory. And memory is critical to immunotherapy. Without memory, your responses are not likely to be durable. And so here's an important memory population that is largely improved by the second-generation anti-CTLA-4 1181. And that's a pretty good candidate mechanism for why this patient could have responded as well as she did despite all those negative factors. So the next thing is looking at other kinds of killer cells. Next -- this is data that's mined from a publicly available source, which is in the reference that I can't -- it's up there somewhere, I don't see it highlighted. So this is publicly available data. These are patients in a trial of metastatic melanoma receiving ipilimumab plus nivolumab, anti-PD-1 plus anti-CTLA-4, you do the same kind of analysis that I just showed you. And if you remine the data with bioinformatics, you can see that in the patients, there's a population of gamma delta T cells, and these gamma delta T cells are different than conventional CD8+ T cells. Conventional T cells that everybody is talking about are antigen-specific, they're tumor-specific. These gamma delta T cells are prevalent, they're in most tumors that have been looked at. They are not as antigen-specific as conventional cells, but they're clearly important to anti-tumor immunity. And now we're starting to see they're relevant to immune therapy outcomes. So if you take this publicly available data and you mine it and do the same type of analysis that I just showed you from our in vitro data, you can see that these gamma delta T cells are highly activated by this combination therapy, whereas other cell clusters, looking at these same genes were not so activated. So this is fairly gamma delta T cell specific. And then if you look at patients that were defined as responders versus nonresponders. In the nonresponder patients, their gamma delta T cells did not go up on therapy, whereas the responders, the gamma delta T cells went up quite a bit. So this is correlative data. It doesn't prove anything, but it says that maybe gamma delta T cells are important in this treatment outcome as they've been seen in other kinds of outcomes. So we go back to our in vitro analysis. So now we're back to Agenus data, again, looking in vitro, taking peripheral blood T cells, activating them with the agents as I showed you before and now we're going to take that data that we generated with 1181, the second-gen anti-CTLA-4 and compare it to that data we mined from the public data set in that clinical trial and here's what you see. So this is the data in the publicly available data set from the clinical trial and this is the data from our in vitro experiments using 1181. And what we can see is this is a heat map of activation of gamma delta T cells, and 1181 is also activating the gamma delta T cells, also activating the same genes, but also looking like it's doing a better job. You're not seeing so much in other kinds of T cells. Further, consistent with the data that's in the public data set, you can see that the second-gen 1181, anti-CTLA-4 is increasing the number of gamma delta T cells much more so than the first-generation anti-CTLA-4 analog that we're comparing it to here in vitro. And then when we look at specific genes that everybody cares about, this is the interferon-gamma gene. That's also strongly activated by the second-generation anti-CTLA-4, but not the first. So this suggests that activation of gamma delta T cells can be contributing to the immune response and it requires more work to understand that better, but the preliminary data suggests that, that could be a player. And then I'm not showing you the data here because Dr. Drake already presented it, in vitro, you've got the ability of 1181 to activate T cells that have that low affinity, poorly responsive FF allele of their Fc gamma receptors. And so you now see that because of that ability of 1181 that's another reason why it can activate the soldiers. So that's improving the killers in the army here, activating gamma delta T cells, bringing in a new kind of solder, inducing the memory is improving the soldiers that are already there. The conventional T cells, there are lots of reasons to think why 1181 could be better than anti-CTLA-4 and a first generation, and I'll say a little bit more about that again. So to summarize this, we've seen that 1181, the second-generation anti-CTLA-4, could be a superior approach over first generation because it's improving immune cell memory, it's activating another killer cell, the gamma delta T cell, it's effective in a patient that has the FF, low affinity, low responsive allele and I'll say more about there's other experiments ongoing to improve on these observations, which can be summarized here. But the next steps are, we want to make better killers and we want to make better battleground softening agent. So when you look at most biotech companies, look at big pharma companies, they tend to have 1 approach. They're either going to have drugs that are going to improve the killers or they're going to have drugs that soften the battlefield. It's unusual to see a company that has agents that can do both. And Agenus has products that Dhan is going to talk about in a minute and you're going to hear from Mark also that are in these other categories of agents that can either improve the killers, improve the battle softening, all in one company, and these agents are rationally designed to work with each other. So that within the company, you have the improved killers and the improved battleground softeners as well. And in that regard, don't ask me to operate the microwave. Okay. So let me see if I can finally do this. So 1181 in terms of making better killers, I've talked about that CAR iNKT cells here are better killers. In silico algorithms that can predict immunogenic epitopes for which you can direct immune therapy and other approaches that you may hear about today. And then on the softening the battlefield area, 1181 reduces regulatory T cells. So regulatory T cells are keeping the killers from doing their job even though they're there. And there are other agents, bispecific agents, you hear about that are reducing soluble immune suppressive factors, TGF-beta, you heard about, CD73, adenosine you heard about can improve myeloid cell function, which is a major reason that the killer cells don't work. And all of this is in the pipeline moving into the clinic. And I'll let Dhan give you the details.

Thank you very much, Tyler. Maybe I'll just give you a well-deserved pause, a thinking pause, and I'll have you take off your science hat for a moment. And just walk with me on the business side of things and think about, you're the one company who has a CTLA-4 and a PD-1, that's Bristol. And they knew that they needed something more besides the first generation. So they launched the 2 molecules that Dr. Drake told you about which are moving not at the pace of ours. To the best of our knowledge, we have exceeded the pace to getting our 1181 into combination with PD-1. And to our knowledge, they have not yet. But what's more important, imagine yourself now all of the other companies with the PD-1, who need to compete in this space and need to differentiate themselves to actually take advantage of the opportunity that is out there, the business opportunity, the opportunity for patients. And that comes to the likes of Merck and Pfizer and AstraZeneca. And these companies who have a PD-1 or a PD-L1 and need a molecule to differentiate. 1181 really jumps ahead in years to accelerate the opportunity for some of these PD-1 molecules as our own to be differentiated and to start to actually take advantage of a very significant revenue opportunity out there. So I'd like to just -- you've seen the science. You've seen the data on our first-generation CTLA-4 on our next-generation CTLA-4. And I just want you to spend a minute thinking about what this molecule, 1181 could mean for our PD-1. And then I'll ask you to think about what it could mean now in combination given the features with some of our other therapies that only we can do, such as our allogeneic cell therapy combinations as well. So I'm going to turn it now over to Dhan who is going to share with you how we're thinking about the rest of the tumor microenvironment and some novel and exciting targets and then we'll close with Mark Exley and Julie DeSander. Thank you.

Thank you, Jen, and thank you to the experts for providing their insight into how Agenus innovations are already creating better outcomes for patients today. And to all of you on this journey, welcome. Thank you for being with us. My name is Dhan Chand, and I'm the Head of Drug Discovery at Agenus. And when we last met almost 3 months ago, we spoke about the innovations that went into the design of our next-generation anti-CTLA-4 agent. And you heard from the experts today, the promise that this molecule holds for patients, including a case report of a complete responder who, by all means, would not have been eligible for therapy with the first-gen CTLA-4 or anti-PD-1. But this represents a fraction of the innovation that's occurring at Agenus. And today, I will provide you with an overview on our next wave of innovation. Molecules that are designed to go beyond the T cell. Address mechanisms of resistance and relapse the current therapies and condition the tumor microenvironment for a better response. In fact, 2 of these molecules are already in the clinic and 2 more are expected to have -- to see INDs filed later this year. This speed to innovation, this ability to go from an idea to an IND in less than 2 years is inherent to us. It is reflective of our capabilities to identify relevant targets and mechanisms and design optimal solutions in real-time to address the biology. And I'll provide you with 4 mature examples today. The first is addressing 2 very potent immune-suppressive factors in the tumor microenvironment. You heard from Dr. Curiel the need to soften the battlefield. Well, here is a case where in the tumor microenvironment, you see high expression of adenosine and TGF-beta. And in the presence of adenosine and TGF-beta, you cause broad immune suppression as well as contributing to relapse in resistance to current therapies. Now adenosine is generated by an ectoenzyme, known as CD73 that is expressed on tumor cells and tumor stroma as well as certain immune-suppressing cells. This target is well-known to you. TGF-beta, on the other hand, is a pleiotropic factor that enhances tumor progression, promotes angiogenesis and fibrosis but also drives myeloid-deprived -- or myeloid-derived immune suppression. What we observed in our studies is that TGF-beta also drives the expression of CD73. And, in fact, in PD-L1 low patients, you see a high expression of CD73. So our solution to this problem was to design a bifunctional molecule that potently blocks CD73 and prevents the degeneration of adenosine in the tumor microenvironment and neutralize all forms of TGF beta. This design of the molecule demonstrated superior activity compared to either therapy on its own or the combination of either therapy on its own. So this molecule, GS-1423, binds the CD73, blocks the adenosine production and neutralizes TGF-beta, essentially conditioning the tumor microenvironment for a better immune response. And as you heard from Garo earlier today, this molecule was one of the features of the Gilead transaction and is currently advancing in the clinic. And just to give you an example of the activity of this molecule. Here, we used a system that mimics the suppressive nature of the tumor microenvironment. A system that you heard 3 months ago, here is it in action, you see GS-1423 or CD73 TGF-beta-Trap molecule, enhancing the ability of antigen-specific T cells to kill tumor cells. More importantly, it enhances that in combination with anti-PD-1. So this molecule is currently advancing in the clinic and we look forward to further updates. Now the second barrier, as Dr. Drake so eloquently described, are regulatory T cells. Now these are cells that, by nature, protect you and I from over activation of our immune system and autoimmune-like symptoms or diseases, but cancer coops these regulatory T cells to protect themselves. So the challenge here is addressing that Treg barrier. That barrier that Dr. Drake mentioned was promoting resistance to current therapies, relapse the current therapies with multiple -- through multiple mechanisms, suppress it to a microenvironment. Even including secreting TGF beta sopping up IL-2 and directly inhibiting effector T cells. But the problem with Treg or directive -- therapies that have been directed to complete or get rid of regulatory T cells is that they're not specific to intratumoral Tregs. That is why you see autoimmune or systemic toxicities with some of these therapies that are designed to just go after Tregs. Our solution to this was based on an observation that we made that on intratumoral Tregs, the coexpress 2 targets and that the engagement of these 2 targets can lead to selective binding to intratumoral Treg. So we designed a bispecific molecule, AGEN1223 that binds the -- to these 2 targets and we're not disclosing the targets there. So we'll just refer them to -- as X&Y that are only expressed in intratumoral Tregs. They're not expressed on peripheral Tregs. But more importantly, we engineered this bispecific molecule to engage activating Fc receptors by introducing mutations into the Fc portion of this bispecific molecule. So not only are you getting selective targeting of intratumoral Tregs, we are also enhancing its ability to deplete these Tregs. And this is reflective of the innovation and discoveries that we have at Agenus. This molecule is already in the clinic, as of December 2019 and we look forward to providing you with updates. But to give you an example of the power of this molecule, its ability to deplete regulatory T cells, here is an example of AGEN1223, compared to that of monospecific approaches to the same targets. Now the targets are well known. In fact, there are drugs in the clinic already going after either one of the targets, but none of them are designed to deplete regulatory T cells. So in this particular example, we cocultured regulatory T cells that are reflective of intratumoral Tregs with depleting cells, such as NK cells. And we demonstrated that when you treat these cells with AGEN1223, you significantly deplete or enhance depletion through selective binding and through enhanced Fc gamma R interaction. Now when you compare that to monotherapy approaches to either all of those targets using competitor antibodies, you do not see that depletion because they're not designed to do that. The only way you can get this selective depletion is using Agenus' bispecific platform and combination with Fc engineering to extract this unique activity. And this highlights why you'd need to design it this way. Designing the bispecific is important to us because it gives us activity that you otherwise cannot extract from the monospecific antibodies. More importantly, if you use the monospecific antibodies in combination, you still do not see that same level of activity. So this is unique to AGEN1223. The third example, as you heard from Tyler and Jen, is addressing myeloid cells, tumor-suppressing -- tumor-promoting or immune-suppressing myeloid cells. Now when you think of the activity of PD-1 and CTLA-4, they're generally driving T cells or cytotoxic T cell activity or addressing the Treg bar in the case of 1181 and 1223. Now macrophages or myeloid cells by nature, protect you and I from infection, they clean up cellular debris. So they act on -- they act on our behalf. But when they infiltrate the tumor microenvironment, they get converted into immune-suppressing macrophages. Now unlike the previous example where we wanted to deplete regulatory T cells, here, we want to turn those macrophages back into tumor-fighting macrophages. We don't want to deplete them. Because not only are they important for phagocytosis of target cells, but they're also antigen-presenting cells. So we need those cells to further the immune response and deepen immune response. It's similar to what we did for Merck. We built Merck's ILT4 antibody, a very difficult target where only Agenus was able to deliver an antibody and that molecule is also advancing the clinic. Here, we discovered another receptor expressed on tumor-associated macrophages that binds to a ligand expressed on tumor cells and that engagement results in a suppression of macrophages, converting them from tumor-fighting macrophages to tumor-promoting our immune-suppressing macrophages. Moreover, the engagement of this receptor suppressed Fc gamma are signaling when done in combination with targeted therapies, like cetuximab or other targeted therapies that depend on Fc Gamma R interactions. Our solution to this problem was to design an antibody that potently blocks the interaction between this target and the engagement of its ligand on tumor cells. And unlike the first 2, it's just a more specific antibody. That's because that's -- that was the best solution to this target. So we're not designing bispecific, just because this is fashionable, we design it because it is necessary. In this case, a monospecific antibody is absolutely necessary to block this interaction. And we observed a blockade of this interaction, turned those tumor-promoting immune-suppressing macrophages, otherwise on its M2 macrophages, back into tumor-fighting macrophages. So now they work on your behalf. And then they can -- in addition to that, work in combination with other therapies that depend on antigen presentation. This molecule is projected to C&I to have their IND filed by the end of this year. And just to give you an example of the activity of this molecule, AGEN1531, you will see on the left a coculture assay of macrophages, but in this case, M2 macrophages treated with AGEN1531. So the tumor-promoting immune-suppressing macrophages treated with 1531, you will see that when you block this interaction with its ligand, you convert those macrophages into tumor-fighting macrophages, as shown by the pink graph. This conversion was analogous to just adding the M1 or tumor-fighting macrophages to your culture. So rather than taking like cell therapy approach to give you these macrophages, this molecule can convert those macrophages for you. The next example was the ability to enhance Fc gamma R signaling when done in combination with targeted therapy. And as I mentioned earlier, one of the other features of this molecule -- of this target, sorry, where it engages ligated, it suppresses Fc gamma R signaling. When we block the molecule at AGN1531, we are able to enhance Fc gamma R signaling in combination with a targeted therapy. Now the last molecule I'd like to speak to you about, which is in line with our goal of bringing therapies to patients that do not respond or relapse to current therapies like anti PD-1, is based on patient progression due to the upregulation of secondary immune checkpoints upon treatment with anti PD-1. Now there are multiple immune checkpoints out there, several of them. But identifying the right ones is important. And we used several different approaches to identify and guide us to what are the right mechanisms and right targets to go after. You heard about the Treg depletion, addressing adenosine. Those are all relevant mechanisms that can enhance an immune response. In this particular example, we observed that patients treated with anti PD-1, upregulate a network of interactions that contributes to relapse. In addition to that, nonresponding patients showed high expression of this particular network. When we investigated this network that was promoting immune evasion outside of anti PD-1 we discovered that blocking these targets not only promoted responsiveness and settings where PD-1 no longer matters, but also enhanced both innate and adaptive immune arms of the immune system, enhancing both T-cells and NK cells. The ligand for this target is overexpressed on tumor cells. It's driven by interferon gamma, the same signal that drives PD-L1 expression. And if you take away the PD-L1, the system becomes heavily dependent on this ligand. So blocking these targets became critically important. But when we approached them, we observed that the best way to block these targets was in a bispecific format. A bispecific format that cold blocks the 2 inhibitory targets move the ligand over to a co-stimulatory target on T and NK cells. So not only are you reducing inhibition, but you're also promoting the activation at the same time of both T and NK cells. We also used our bispecific platform in this case, and engineered the Fc to further promote and further enhance the activity using a unique combination of mutations that were specific for this particular drug. This molecule is also expected to have an IND filed later this year. And just to give you an example, a small -- an example of the activity of this molecule. Here we used a PD-1 refractory -- a model that responds very poorly to anti-PD-1. This is a mouse model, using CD26 colon carcinoma cells. So PD-1 in this model does not work very well. When you treat this model with AGEN1777, our bispecific molecule that targets -- that cold blocks these 2 targets, what you observe is almost a mere complete response in almost all of the mice treated with this bi -- with this unique bispecific molecule. 13 out of 50 mice showed a complete response. When you rechallenge those mice with tumors, you see no growth. Consistent with the method of action of enhancing both innate and adapted immune arms of the immune system. And we look forward to having the IND filed later this year. Now not only will novel therapies allow us to expand the therapeutic reach of I-O but novel combinations. And no one is better equipped than Agenus to advance and explore these novel combinations. We are the only ones with a next-generation CTLA-4 like AGEN1181 cell therapy approach as well as tumor microenvironment conditioning agents that we can use to broaden the therapeutic reach of immunotherapy. And promote durable responses and enable curative combinations. And I'm pleased to announce that later this year at AACR, we will be presenting data on these combinations, particularly around our next-gen CTLA-4 AGEN1181 with other novel agents in our pipeline, including cell therapy. So I look forward to presenting that at AACR. Now what I'd like to end with, and I hope you've seen this exemplified throughout our journey together is that Agenus is biology focused. We're not a one-trick pony. We're not married to 1 specific platform. We're committed to the biology. We're committed to what patients need next. And we're going to build the therapies that best address the biology. Our bifunctional CD73 TGF-beta, we licensed to Gilead is representative of this. These are capabilities that prior to discovering these targets, we did not have, but we knew -- we saw the need to build a molecule that does that. So we did it. Treg depleting agents that target a novel peer or a novel finding that Tregs only coexpress two targets, required us to build a bispecific molecule that was Fc optimized to selectively [ be tearing ]. We did that. We're not trying to force one particular platform onto a whole biology, we're looking at the biology and building solutions for patients. And this is a type of innovation that allows us to go from an idea to an IND in less than 2 years. And why? As Garo and Jen mentioned, we've been able to outpace big pharma. We're bringing new solutions and new therapies to patients. Thank you.

Well, it's a privilege to be here presenting AgenTus. For my colleagues, AgenTus is a cell therapy subsidiary of Agenus. And it's also a privilege to be presenting it with this audience and the world's top immuno-oncologists here and Dr. Hidalgo and others who are working with Agenus on our clinical trials. My background is that I was working in academia for many years. For last 5 years, I've been with Agenus and then AgenTus. Before that, I was in Boston in Harvard Med School, as a professor of a lab working on a population of cells called Invariant NKT cells, and I'll briefly just summarize them and their capabilities. And that work was to understand them, but also to exploit them and to develop reagents and tools to manipulate them in people and in the clinic. And that's where we are now with AgenTus. And during that process, we founded as an academic NKT therapeutics, which develops some reagents, which we are now using and as we acquired them into AgenTus. So what is AgenTus? What do we have? We have several attributes, which are unique in the cell therapy industry in which you're obviously synergistic with everything you've heard about so far with the checkpoint antibodies. And those are -- we have novel targets as well as validated targets that we've worked with Agenus and my colleagues on to identify for tumor targeting. We have a mammalian display platform for developing CARs and TCRs, which we have shown is very effective at producing highly specific TCRs in particular. And this has actually benefited and was derived from the mammalian display platform. It was used for developing all the antibodies you've just been hearing about. So a very powerful tool and platform for developing and weaponizing the cell platform. And finally, we have the sole platform itself, and this is the thing that I've been working on for many, many years and taking now into the clinic, in the AgenTus context. So what are NKT cells. So there are a type of T cell, which has some of the benefits of NK cells, but none of the disadvantages of either T cells or NK cells. So it ticks the box for many attributes for our desirable cell therapy, which are not so present or are only partially present in the other types of immune cells and other types of approaches are being -- are exploiting. They are able to kill tumor cells directly, as shown here. And this is important for their activity, certainly, clearly, and they are very potent killers of tumor cells with the right targets, expressing the right targets. But you can also either modify and effect, repolarize the myeloid cells, the antigen presenting cells that Dhan was just talking about in the tumor microenvironment, or if necessary, if you like, kill them. So this gives them a second way in which they can have an antitumor activity. And the third way is, indirectly, they are able to activate NK cells, other T cells in the immune system. They have an adjuvant like activity in the tumor microenvironment. They can repolarize the antigen presenting cells, which helps to generate the right T cell responses that you want in an antitumor setting. So this is how they can function in a very synergistic way of other approaches as well as independently have clinical activity. And this has been shown in some early clinical trials in various different ways, including a clinical trial that I did with my colleagues in Harvard on autologous NKT cell therapy on which we're now moving into allogeneic NKT cell therapy. So one of the features of NKT, which make them attractive. Some of these are that they actually not only don't cause GvHD, unlike classical allogeneic T cells would. Well, they suppress GvHD. And you don't need gene editing to use them in an allogeneic context. So that makes it a lot simpler to use them. They have the capability to home to tumor cell -- tumor sites, makes them very attractive for low solid tumors as well as some hemological malignancies. They are feasible to use in this context. That's critical because they're very rare cells. And one of the reasons, obviously, that they're not fully functional in patients is that there are limited numbers and they're functionally defective in patients who actually progress, although they have an antitumor activity and probably as any surveillance role in healthy people. And so consequently, because we can expand them dramatically. And this just shows a typical example of what we are doing routinely now in our clinical manufacturing process, as we go from few million cells of NKT cells, purified with this monoclonal antibody I mentioned that we developed a while back, and then we used to purify them and then we expand them in a proprietary process and we're in a [ month ]. And given this is allogeneic, that's very convenient, but it doesn't even need to be as short as that for allogeneic use, of course, because you're stockpiling it. We get a very reproducible massive exponential expansion. This is a log scale locked to its base 10 scale expansion, you can see. So we go from a few million cells to tens of billions of cells, enough for treating a whole clinical trial Phase I in our current process, and we know that they can expand well beyond this to the 1,000 dose or more patient scale. So this is a really practical, feasible and powerful cell platform to exploit. And in terms of its targeting, we know that we can target a variety of different tumors, and particularly -- we're particularly excited about those where CD1d is expressed and CD1d is the target for this NKT cell population and its only inherent receptor. So we can target those even without genetic modification or addition of a CAR or TCR because these are TCR expressing -- CD1d expressing tumor targets. We can add to that, their ability to target the similar microenvironment beyond the tumor cells themselves. And then to augment other immune cells and to work in synergy with checkpoint antibodies then you have a really powerful sole platform. So of course, if you add CARs, TCRs to that, you can then widen this to include all tumors, essentially. So that's the summary of our AgenTus portfolio and its capability and how it fits in nicely with the Agenus checkpoint antibody approaches.

Thanks, Mark. Hi, I'm Julie DeSander, and I head up Business Development and Alliance Management at Agenus. In the short 4 years that I've been here, we have generated over $525 million in cash from partnership transactions, and we have an additional $2.5 billion in potential future milestones and royalties. These transactions are born out of the highly innovative programs, the incredibly efficient research, clinical and manufacturing operations and the unique suite of technology platforms that you've heard about today. And these transactions enable us to rapidly advance novel therapies to the clinic, where they offer transformative promise to patients, not benefiting from available therapies today. As you know, we have a number of notable strategic partners today. Last year, we brought in $172 million from Gilead through our upfront payments as well as achieved milestones with an additional $1.7 billion pending in future milestones and royalties. As you heard about today, Gilead licensed our CD73 TGF-beta bispecific and received options on 2 additional programs. We also closed a transaction, a $210 million transaction with UroGen late last year. UroGen licensed the rights to use zalifrelimab in combination with UGN-201 for local delivery of urinary tract cancers. Insight continues to advance 4 checkpoint antibodies in the clinic and 1 preclinical antibody, all discovered by Agenus. And Merck is advancing our first-in-class ILT4 antibody discovered by Agenus, which is expected to enter Phase II studies next year. And GSK continues to develop vaccines with our QS-21 adjuvant, including Shingrix. But that's not all. In 2020, we will continue to pursue new partnerships to grow and advance our portfolio. We intend to retain U.S. rights to the majority of our pipeline to build our future commercial business, but we're in active discussions with a number of large pharma and strong regional players for several assets in our portfolio, including AGEN1181, our next-generation CTLA-4. We've also received interest in platform collaborations from companies that want to access our technology platforms to enable their own portfolio. So like the iNKT platform, you just heard about from Mark, we've had quite a few parties express interest in accessing that platform, so that they can take their autologous or individualized cell therapies and transform them into allogeneic or off-the-shelf format. We've also been approached by a number of companies interested in clinical collaborations to access the PD-1 and CTLA-4 antibodies that you heard about today. These companies believe that Agenus is a faster, more flexible and collaborative partner than working with big pharma. And finally, we're exploring research collaborations and in-licensing opportunities to continue to expand our pipeline with complementary technologies. These transactions deliver value to Agenus in multiple ways. They deliver financial value in the form of upfront milestones and royalties. They accelerate the clinical development of our programs by expanding the geographies and indications under evaluation. They enable us to expand the benefit of immunotherapy to more patients through novel combinations within and outside of our portfolio. And they support the expansion and future growth of our pipeline. As you've heard today, we have an incredibly productive research engine for generating first-in-class and best-in-class immunotherapies. But the pace at which we're developing new discoveries is such that we cannot internally develop all of these programs on our own. Our business strategy is to out-license a portion of our portfolio to generate upfront and long-term financial value and bring these discoveries to patients as efficiently as possible. But we will continue to retain a significant portion of our portfolio to build our commercial business, including U.S. rights to AGEN1181 and a number of the programs you heard about today. Thank you, and I look forward to updating you on our partnerships as the year progresses.

Thank you very much, Julie. I'm alive and live here. I just wanted to close with putting things into perspective. We started with Dr. Monk, and he gave us the reality of cervical cancer. It is a young woman's disease, by and large, and the best treatment today, that's approved, provides 14% response rates in a select population. These are not old comers. It's a select population, whereas in our trials, we have taken truly relapsed patients and with monotherapy with our PD-1, shown 12% response rates. Now if you adjust the Merck response rates to that overall population, it's somewhere between 11% and 12%. So we have to make sure that we put those numbers into perspective. When we treat patients with our combination agents, our CTLA-4 and PD-1. That's the first-generation CTLA-4, by the way. Then in the same relapse population that we're showing 12% response rates, and Merck is somewhere between 11% and 12%. We're showing 20% plus response rates. And as Jen and Anna alluded to, we wanted to wait to disclose the interim analysis, which was available to us last year until we were more certain that the continuation of the trial was going to confirm that. And those data will be available in the next few months. Now Dr. Drake showed about -- told us about the importance of CTLA-4. CTLA-4 and the uniqueness of 1181, our next-generation CTLA-4, in comparison to other CTLA-4s that are out there. One thing that, I think, is very important to put into perspective here, as Jen talked about, 20 patients having been treated with 1181. I just want to make sure that you understand how we've gotten to those 20 patients. So we've treated 4 patients at the lowest dose, which is 0.1 milligrams per kilogram. 3 more patients at the next highest dose, which is 0.3 milligrams per kilogram. And then patients beyond that with 1 milligram per kilogram, both in single therapy and in combination. When we talk about 20 patients, the data on those 20 patients have not matured yet, meaning, we're not suggesting that 1 patient out of that 20 has seen a complete response. The data as it matures may, fingers crossed, may see more complete responses, even in that 20, even in that 20. So I just want you to understand the perspective of Dr. Drake that while it's unusual to see anything really meaningful in a dose escalation study. What we're seeing here is the dose escalation study where 1 of 3 patients at that dose that has been treated with more than 2 doses basically showed that complete response. So that's what gets us excited about it. Then Dr. Curiel talked about the mechanism of all of this. It's all deep science, it's high science. What he talked about and what Dhan Chand talked about are how we interrogate the biology, the tumor, the patient responses. So that we can learn from that process. And please be cognizant of the fact that while the world likes to simplify things, meaning let's simplify and let's have a single agent or a simple combination that does all the trick in cancer immunotherapy because of the complexity of this disease, that's not possible. And that's why Dr. Chand talked about how we are advancing our understanding of the biology, so that we can continue to innovate in order to battle this nasty disease. So that's the overall perspective on the reality of what we do. Now what we talked about, also, is in the context of our business model. Julie mentioned that we intend on increasingly keeping North American rights to our products for ourselves. And on that note, when we have started talking about 1181 with prospective partners, which is currently in active discussions, we have qualified it and said we're only interested in licensing out ex-U.S. rights. And normally, large companies don't like that, but none of the companies have so far have left the table because of this restriction. So that's in a nutshell, along with the fact that what Julie presented, we have raised $525 million through corporate collaborations and innovative financing mechanisms in the last 4 years, which has not -- which has basically allowed us not to come to the public markets with a marketed offering during that period of time. It will be in the next 1.5 months, 5 years since we have done a publicly marketed offering, 5 years. And so during this year, our expectation is that we will continue to finance our operations with existing cash plus milestones that are -- we're certainly to receive, which amounts to about $70 million. These are milestones that have already been achieved in some format, and we're going to be receiving cash in the next 3 months. And expected new transactions. So that's basically the story in a nutshell. Now I know that you may be anxious to ask questions, and we invite you to do that. Thank you very much for your attention.

Please, Matt.

Matt Phipps, William Blair. Thanks for all of that data and presentation and academic context. So one question on the data presented for cervical cancer. I'm sorry, if I missed it, but did you disclose the percentage of patients who are PD-L1 positive? Obviously, Merck's data was 100%. Bristol's, I think, was 60% to 70%. And I guess, for Dr. Monk, what would you expect across second-line cervical cancer patients?

So thank you for that. I should have emphasized. Those are on unselected patients. So we would suspect that if we would biomarker restricted, the activity would even be higher. That just takes time. And so the initial data cut did not have that information. But the tissue have been collected and that will be a key component moving forward. Thank you for recognizing that because that actually makes the activity look better because it's unrestricted patients. The number of patients that are PD-L1 positive of 1% is 80% and it's virtually all squamous tumors. And about 20% to 30% are at no carcinomas, and that's where the fraction of patients are generally PD-L1 negative. Thank you for that.

Great. And the safety profile of the combination, it's small numbers, but actually, it's almost like better than monotherapy. I mean, is that -- it's rare to fluctuation. But regardless, you're not really seeing added toxicity...

That's the point. And it's really based on the dose and schedule of the anti-CTLA-4 product. That's right. Thank you for that.

And then moving on to 1181. I mean, great to see HCR so early. But you've got a lot of different data thrown out at us with kind of the different ways that this antibody could work better than ipi or other first generation CTLA-4s. How do you really parse out, I mean, Treg depletion, Fc gamma receptor, activation of antigenic presenting cells leading to more memory, T-cells. These -- Treg depletion has been tossed around a lot and been tough to really show. You had the CCR4 antibody, really not show anything when used in PD-1 combos, which to me, made it tough to really try to validate the Treg depletion strategy. So my question really being on, going forward, you brought up interesting ways to, maybe, deplete more Tregs, specifically with a bispecific antibody, is that really going to be enough by itself? Or is it really you have to have this whole thing going on where you're getting better priming of naive T-cells through antigen- cells. You're kind of making the tumor microenvironment more susceptible...

Cellular therapy?

Yes, cellular therapy. Yes. It's a long question there.

It's a great point. But I mean, to be fair, no agent has really documented clear Treg depletion in human tumors yet. The CD4 -- CCR4 antibody -- actually, when we did these experiments with sort of human Tregs. CCR4 doesn't even come up actually until Tregs. It comes up in peripheral but not until Tregs. So there's a number of markers that are more specific for Tregs. And while CTLA-4 is a great one. It's a good start, actually. There's other ones as well, actually. So I think the proof of the pudding that you're asking for is going to come from on treatment biopsies where Treg depletion is clearly demonstrated, and that should correlate with antitumor activity. The other added features of antigen-presenting cells and T-cell activation will come from those studies. When we do these studies at Columbia, what we do is, we do single cell RNA sequencing of on treatment biopsies. And those are really the only kind of data, I think, that will demonstrate that carefully. The other drugs that are in the clinic have not shown that yet, but there's not been a lot of data on any of those drugs yet. But that's what you want to look for, right? If you want to look for a drug that really shows that it alters the TME, depletes the Tregs and shows more CD4 and CDL activity.

I want to add to that. So the mogamulizumab data anti-CCR4, that the complete Phase I data is going to come out in clinical cancer research in the not-too-distant future. But a couple of key points there. One is that there wasn't really good data on depletion of Tregs in that trial in the tumor. It was mostly in blood and the tumor data didn't show a lot of Treg depletion. And point number two is, most of those patients had pancreatic ductal adenocarcinoma, which is a really tough tumor in any regard. So all the animal modeling and all the correlative human data suggest that Tregs are really important. They're multifactorial in how they impede antitumor immunity. I think they're great targets but, like Chuck said, we need -- we'll see in the trials. We have the technology to see that. But it won't be put up by anti-CCR4 because of these issues.

But just in ovarian cancer, right? So checkpoint inhibitors don't work in ovarian cancer. And we'll show you that at the SGO here in a month in Toronto. So you guys got to figure this out and once you figure that out, then we're going to be here. I'm already your best friend. But I'm going to be your old best friend.

It's happening. It's happening. But to answer your deeper question, Matt. I want to ask Dhan Chand to address it. It is, of course, there are so many components that we're addressing with the 1181 version of CTLA-4, but it's very important to know that we're also dissecting every element in the context of the clinical outcomes and looking at, for example, this particular patient, I don't think we're ready to talk about it because it will be publishable. But we're looking at specific traits of this patient that would corroborate our expectations of the molecule to work in such a patient.

So Matt, thank you for the question. And you're right. Treg depletion alone is not going to be enough. We see this in our models. And 1181 is designed to not just be a Treg depleting age, but also to enhance T-cell priming. And that is a very key factor here because when you think of what CTLA-4 does, it's really a molecule that prevents T-cell priming. And because 1181 is designed to enhance T-cell priming, you're going to get better T-cell priming, better T-cell activation in combination with Treg depletion. So you need to have more than 1 biological activity occurring to get a meaningful outcome. On top of that, as you saw from Tyler's presentation, 1181 is best designed by virtue of in-housing T-cell priming, it also generate better memory cells. And that's where you see the durability of responses, generating those memory cells. So 1181 is not just a Treg depleter. It's a T-cell activator, promotes T-cell priming and also promotes better memory formation. And to your question about the Fc requirement. Ipilimumab does not bind well to the low affinity CD16 allele. This is 40% of your population. And because of that poor binding, as Dr. Drake showed, the activity of that molecule in promoting T-cell activation is very poor. 1181, on the other hand, can bind well to both polymorphic variants. And you see consistently, including in the patient report, the activity in a patient that, by all means, should not have responded. To your second question about the other molecule in the clinic, the one we haven't disclosed the targets, the bispecific, while it is designed to specifically deplete regulatory T-cells, the other feature that I didn't mention was that it also directly co-stimulates effector cells. So you're getting both the depletion of Tregs and the stimulation of effector cells together. So you are correct. Treg depletion all alone is not going to be enough. You need to have other modalities. And we've accounted for that in 1181, and we've accounted for that in our bispecific molecule.

And just one quick follow-up, Dhan. You showed a ability to deplete Treg like cells with that bispecific 1223. Have you compared that ability to 1181? And in similar assays, just kind of how they compare?

So we haven't directly compared it, but I will say that not all Tregs are CTLA-4 expressing. So it's going to be very difficult to say, Tregs are all the same. They're not all the same. They are driven by the same stimulation conditions as effector cells, but we've observed that they are CTLA-4 expressing Tregs, which make up a significant proportion of Tregs in the tumor. But there's also highly suppressive Tregs that don't express CTLA-4, but expressed this unique combination of targets that we discovered.

So these molecules could potentially be used in combination as well. Other question, please.

Sahil Kazmi from B. Riley FBR. Congratulations on the progress. Can you discuss a little bit about the disparity that we see in the discontinuation rate in the CheckMate trial in both the ipi low dose and high-dose ipi compared to what we're seeing in the combination data today? I believe it's around 18% and 33% in the ipi/nivo trial and quite low here. And how does that really translate in the clinic? And maybe as a follow-up to that as well. Is there any sort of optionality to go up on the 1884 dose?

Well. I mean, to start, if I may, you can't really compare those, it's a bit of an apples and oranges because, for example, in the other trials, you had a mix of first line patients, patients that were untreated even if they were second line, they were untreated with previous treatments. So we don't really know what the tolerability differences would be in those populations. So it's too early to really compare because they were not randomized trials and patient populations were heterogeneous. But Anna, if you...

I completely agree with your statement, Garo. I think right now, this is difficult to make that comparison. This is not a randomized study. So populations might be different but also moreover, our data, it's a small number of patients so far. We continue to observe the required number of patients, so the data is maturing. And the reasons for discontinuations might be different. They might be due to the disease progression or they might be due to the adverse events. So there are different combination factors that translate into discontinuation right.

So I would actually just slightly caution you as looking at discontinuation rate as an indication of safety. So for example, in CheckMate 650, which is ipi/nivo and prostate, the discontinuation rate is really, really high, right? And so do -- you say, just it's like 50% may be in higher. And you say, well, this is just not tolerable in prostate cancer. But that is actually a feature in the way the trial was written. So the trial is written that if patients have a grade 3, 4, they just completely stop forever, which is not what we do in the clinic. So it's really hard to compare discontinuation rates as a function of grade 3, 4E. And in fact, the other thing you have to remember is when you stop, for example, kidney cancer, a patient has an [ REE ] to ipi/nivo. Those are patients who tend to do fairly well actually. So I think it's one way to look at safety, but I think that there's -- you got to be a little bit cautious in terms of the context of trial design.

Great. And then, maybe, just thinking more broadly in terms of capital allocation, could you just provide some color on how you think about investing in future trials with 1181 in terms of other tumor types versus how that might compare to commercial regulatory preparations for the combination?