Hi, everyone, welcome to our first R&D update, which is coined Agenus Insights. There's never been a more important time in the history of cancer therapy. Technology, partnered with genomic and proteomic insights, have accelerated our pace of drug discovery to speeds that have never been seen before. Agenus is at the forefront of this, with more than 50 new discoveries advancing in the clinic in just the past four years. A few of those first agents are en route to BLA with filings already underway. Our anti-PD-1 is delivering differentiated activity compared to commercially available PD-1 antibodies. AGEN1181, our Fc engineered anti-CTLA-4, we presented a data update yesterday, and that molecule is producing very exciting results in difficult-to-treat tumors. Now TIGIT, the topic of our conversation today. It's shaping up as the next breakthrough target in IO. Only as recently as last year, anti-CTLA-4 and anti-PD-1 were the only validated immune therapy combinations for patients with cancer. Today, this third pathway and target, TIGIT, has emerged. TIGIT's upregulated with PD-1 therapy. With the growing number of patients treated with anti-PD-1s, addressing the biology of TIGIT and blocking these tumor escape mechanisms is critical to deliver durable anti-tumor benefit to patients. I believe we have the best TIGITs. Actually, when in a company's portfolio do we have some of the best-looking compounds? AGEN1181, it's really an elegant molecule. PD-1, showing great benefit in PD-L1 negative and positive tumors. TIGIT, which you're going to hear more about today, is demonstrating superior benefit as a monotherapy compared to competitor TIGITs in our preclinical models. Today, we're joined by Dr. Steven O'Day. This is Agenus' Chief Medical Officer and a veteran in successfully delivering immune therapies for patients with cancers for many, many years, leading to the approval of multiple compounds. Dr. Dhan Chand, a molecular biologist and Head of our Drug Discovery programs here at Agenus, is also with us. I'll open with you, Dr. O'Day. Can you share your interpretation of the evolution of the clinical data emerging to date with anti-TIGIT antibodies? You're on mute. Thank you, Jen. I'm delighted to be part of Agenus now as the Chief Medical Officer. As you said, I've had almost 30 years of experience in the clinic as a clinical oncologist and clinical researcher. Was involved with the initial human studies with ipilimumab that launched the immune revolution. As you know, CTLA-4 and PD-1 have really become standard validated checkpoints in T cell activation that has led to remarkable success in the clinic. We have been waiting for some time now, after plateau phase, for new validated markers. TIGIT appears to be an emerging marker both on T cells and NK cells, an important checkpoint that may further make an impact clinically. As you know, there's different formulations of TIGIT, both the competent antibody monoclonal, as well as silenced or an Fc-enhanced. Today, there was great hope that TIGITs would be able to overcome, as a primary mechanism of PD-1 resistance, overcome this in the clinic. To date, with the competent monoclonal TIGITs that have clinical data that is emerging, what appears to be the case is that these molecules have shown very little monotherapy signal and have been primarily targeting now combinations with PD-1, particularly in lung cancer in the first-line PD-1-naive setting in high PD-L1 expressing tumors. Obviously, this is an important discovery and will pursue further clinical data. There's tremendous opportunity here with TIGIT as a validated marker in randomized phase II trial, particularly in the PD-1 resistant category. What I'm particularly excited about, and really prompted my desire to come to Agenus, was both AGEN1181, but this TIGIT bispecific molecule that Dr. Chand's going to talk about has some features that have been engineered both with Fc enhancement and bispecific nature that we think may fill a gap in the existing signal area of the present TIGIT antibodies. I can't wait to have it in the clinic, which we hope to have by the end of the first half of this year and start developing this as a potential important impact in patients as an IO therapy. You've brought up a few very important mechanisms here. TIGITs alone have not delivered the kind of benefit we thought they might based on some of the biologic insights that we've had. It appears to be based on the data that's been generating to date, that combinations with PD-1s may be necessary to truly get the kind of improved performance or clinical benefit. As we think about TIGIT, and I mentioned earlier, I use the word pathways plural, right? It's a complex biology. Our scientists have been hard at work understanding this biology in deep and insightful ways, and looking at developing products that can achieve not just blocking TIGIT, but also some commensurate tumor escape mechanisms that we've discovered in different ways. Blocking TIGIT perhaps in a better way with Fc engineering, and then addressing biology with bispecific approaches or alternate approaches. Maybe I'll ask you, Dr. Chand, to speak with us about how was your thinking about how do we build, expand, and improve on what's currently available? Thank you, Jen. As you rightly pointed out, TIGIT has emerged as perhaps the next validated immune checkpoint after PD-1 and CTLA-4, and we have made several important discoveries on the TIGIT pathway, some of which we have published and presented at major conferences. These discoveries we have leveraged to build our bispecific TIGIT antibody, AGEN1777, that allows for superior activity than the current generation of TIGIT antibodies based on all preclinical modeling we have done thus far, including the opportunity for single-agent activity and improved responses in PD-1 relapse refractory models. Now, the first discovery we made was that Fc gamma receptor co-engagement by TIGIT antibodies, like that of CTLA-4, is absolutely critical for enhancing T cell activation and antitumor immunity. What I mean by that is that blockade alone is not enough. TIGIT antibodies that also engage activating Fc receptors promote better immune activation. More importantly, Jen, I think the big discovery we made was that enhancing the binding to the activating Fc receptor through Fc engineering allows for monotherapy activity in preclinical tumor models, as shown here on the slide, where you see the superiority of Agenus' Fc enhancement compared to that of competitor-like molecules. AGEN1777 is Fc-enhanced to capture this important mechanism of action. Now, you brought up bispecific. The next important discovery we made is that co-targeting another immune receptor with TIGIT, not yet disclosed, but also expressed on NK cells using our bispecific platform, addresses a potential escape mechanism to TIGIT therapy. Now, as you know, we have a platform called Vision, and I'm sure you'll hear more about Vision in future series, that validated the importance of this pathway, specifically in settings where tumors escape independent of PD-1 or PD-L1. That is where we see the opportunity for AGEN1777 to optimally modulate the TIGIT pathway, to make single-agent activity possible, but also improve responses in PD-1 relapse refractory models. In fact, if I can get the previous slide, you will notice in a model here where it's poorly responsive to PD-1, you see almost complete responses in all of the treated mice that was given AGEN1777. This is a remarkable finding. TIGIT therapy alone, particularly conventional approaches, do not have such compelling activity. Through Fc engineering and through co-blockade of potential escape mechanisms of TIGIT therapy, we were able to see monotherapy potential and activity in PD-1 relapse refractory models. Dhan, maybe I'll stop you there for just a moment. You've brought up the Vision platform, and just for those of you who may not be familiar, this is a platform that our scientists have designed that allows us to recapitulate the human tumor microenvironment, essentially the interaction and fitness of immune cells or cancer-fighting cells. What this system allows us to do is to actually monitor. As our immune cells are fighting tumors, there are points at which they may upregulate certain markers that illustrate that they may be exhausted, they start to lose their cancer-fighting potential. We can identify at what point in that cycle we could actually intervene, modulate, and change the fate, increasing the tumor-fighting capability of the immune cells and decreasing the chance of cancer survival. This has helped us not only to accelerate our drug discovery, but also it has allowed us to determine at what point in the development should we be including monospecific agents, the combination or the sequence of certain monospecific agents, or do we better address the biology with a bispecific? Maybe what I'll ask you to do, Dhan, is talk a little bit about how you came up with the bispecific approach here to optimally target TIGIT. Absolutely. When we discovered this pathway as being critical for enhancing both T and NK cell biology, we looked at whether or not co-blockade of TIGIT and this other receptor was possible with the combination of monospecific antibodies. What we determined was that the added benefit was not as impactful as we would have predicted. When we took those targets, the antibodies to those targets, and we reformatted them using our bispecific platform, we started to unlock biology that you could not get from the monospecific antibodies. That's a critical piece of our drug development here at Agenus. We are, as you know, platform agnostic. We want to pursue the best biology, but also format matters. Fc format matters, as well as the format at which you are going to co-block these receptors or co-target these receptors. Thanks, Dhan. Maybe just one more point. You mentioned Fc engineering. We have seen at Agenus, we have a first generation CTLA-4, zalifrelimab, very active, performing like a first generation CTLA-4 in IgG1. We've applied this Fc engineering technology to optimally target CTLA-4 biology. We're seeing that we're achieving that now in the clinic, improving the tumor-fighting capability, improving immunogenicity, expanding the population of patients who benefit from the agent. That includes patients over 40% of whom have a polymorphism in their CD16 allele. Maybe for those listeners on the line, Dhan, who don't really know. We're looking at TIGIT landscape. There are a number of TIGITs that are emerging. What does this Fc engineering mean or do? What is the landscape, the variation of this engineering that's available today? Absolutely. Apart from the finding that Fc gamma receptor co-engagement is important, we also identified the specific receptor that was needed, and that was the Fc gamma receptor IIIa or CD16. We have seen from not only our experience with CTLA-4, but others as well, that molecules that depend on this binding show activity in patients that express a high-affinity variant of this receptor. Patients, as you mentioned, up to 40%, can express the low-affinity variant. The reality today is that the conventional approaches to TIGIT, such as IgG1 approaches, or much less so Fc-silent approaches, do not adequately engage this receptor. We have done head-to-head comparisons of our Fc-enhanced approach to those of the IgG1 or Fc-silent, and what we see is improved binding to all polymorphic variants. We would expect better activity in patients that express the low-affinity variant of this Fc receptor, as well as the high affinity Fc receptor. Jen, this is playing out clinically as you see with 1181. That's right. Maybe importantly, Dr. O'Day, with AGEN1181, you've made specific comments about the Fc engineered CTLA-4 was designed to avoid complement mediated toxicities. If you could perhaps explain what that is, what those toxicities are, and what the experience has been with an Fc engineered CTLA-4, and then I'd like your prediction as to how this may play out with an Fc engineered TIGIT with related to toxicity? Well, as you know, Jen, with CTLA-4 as one of the pioneers in the clinic with this, there are a spectrum of toxicities with these activated relatively early adolescent T cells that are migratory, and that includes skin, GI, liver, and neuroendocrine, as well as other endocrine abnormalities. Complement mediated toxicities, particularly around neuroendocrine and hypophysitis is the pituitary gland is a central gland that controls endocrine function, is a very important gland. We know with ipilimumab and first generation CTLA-4s, this is in 10%-15% of patients, they may develop these toxicities, which are manageable but can be essentially lifelong replacements of drugs. The preclinical models with 1181 suggested that these complement mediated neuroendocrine toxicities would be abrogated. So far with over 40 patients treated in the clinic, we have not seen this toxicity, which we would have likely expected to see with the traditional CTLA-4 drug. That's very encouraging. Obviously, as we move this technology over to TIGIT, this will be an important issue. With AGEN1181, we've seen little to no liver toxicity, another major toxicity for a CTLA-4 and to a lesser extent, PD-1 drugs. Again, the profile of this Fc engineering in addition to improving efficacy, potentially priming and depleting regulatory T cells, the toxicity piece may be very important for patients and clinician management. We're excited about all these things. I think just for the listeners we have in the clinic now, there are Fc-silent molecules, and I'll ask Dhan for his opinion on Fc-silent molecules and where the complications or challenges may be, Fc-competent, and then the Fc-engineered TIGITs that you're seeing here. Yeah, absolutely. Maybe I'll start with the Fc-silent variant. These are molecules that are designed primarily to block the TIGIT pathway. They do not capture that important Fc mechanism, which includes binding to Fc gamma receptor IIIa, improved immune synapse formation, which we're seeing with our molecule, or perhaps myeloid activation, which others have reported. The premise there is that by just blocking TIGIT alone, you may spare depletion of effector cells, the tumor fighting cells, T cells. We, of course, have validated this extensively internally, and others have as well, and that is a piece of biology that we believe is critical to the activity is that Fc co-engagement for added T cell function. Blocking TIGIT alone is not enough. In fact, we've been down this road before with CTLA-4 molecules where we know that it's not all equal. You need to leverage additional mechanisms. The famous example I like to use is ipilimumab versus tremelimumab. Both good blockers of CTLA-4, but very different activity when you consider the Fc piece. TIGIT in preclinical models has played out the same as well. Now, with the Fc-competent TIGITs, that of course captures some of the biology, but not all of it. As you've seen in our preclinical models, the Fc-competent TIGITs still do not show good activity as a single agent in our tumor models or in T-cell activation assays. That is because while they still engage the Fc receptor, they're not binding optimally. They're not creating that strong immune synapse that you'd expect if you had an Fc-enhanced approach like what we have advanced here. That Fc-enhanced approach opens up biology for us that is not captured by the Fc-competent, and much less so by the Fc-silent. Biology that is leading to single-agent responses and biology that is leading to responses in PD-1 relapse refractory models. Thank you very much, Dhan. Consistent with our intent with these miniseries, we're doing a deep dive, but not too deep, right. We want to keep this to about 15 minutes, 15-20 minutes on content, and then open it up for questions, which we'll do now. Using your chat function, you can ask questions for our panelists here. We're happy to answer them. I think importantly, just for forward going, you're going to see topics here on new mechanisms, new insights, new molecules in our portfolio and beyond. Some of the most sought-after information in immuno-oncology, we'll be bringing to the table a series of experts who can speak with you in more detail. In addition to this format, we also very actively publish every two weeks a newsletter. That newsletter is a more detailed summary of some of the activity, clinical data, some of our talent, our science, and upcoming activities on our portfolio. That newsletter will continue. It's issued biweekly. It's also available on the Agenus website. While our listeners add questions into the chat room, perhaps, Dr. O'Day, what I'd like to know from your thinking is what are you going to do with this molecule? It's actually heading into IND-enabling studies actively. Our IND is just a matter of weeks, not months away. We're really enthusiastic about that. What's next? Where are you going to test it? It's pretty clear that the data we have in the field with the competent Fc and a monoclonal is that they're actively targeting high PD-L1 expressing advanced lung cancer in the first-line PD-1-naive setting. That's a niche that obviously is moving forward quickly to larger trials. Because of what Dhan has talked about and the Fc-silent monoclonal data, we hope to see sometime in this year from others. What we're really focused on is both the Fc enhancement component and the bispecific nature of this molecule. What I can tell you is we're very excited to have it in the clinic, and we will obviously look at initially in the phase I/II trial in solid tumors, obviously enriched for tumors that are more immunogenic as is our platform. As we clear doses of the single agent, obviously be very interested in combining it with PD-1. We will be looking for signals both for monotherapy and combination. This is really important because I think we shouldn't rush to any conclusions yet about monotherapy with TIGITs for the reasons Dhan discussed. Both the monotherapy and the PD-1 resistance and even low PD-L1 expressing cohorts of solid tumors, which is a huge population, is what we're going to be focusing on in addition to any niche drivers of high PD-L1 expression, which is certainly potentially low-hanging fruit in addition. Thank you very much. I think it's really important. We didn't go through the preponderance of data we've generated, but we have shown that 1777 does have that preclinical monotherapy potential as well as complementarity with PD-1 and other molecules within our portfolio. I'm going to turn it over for a couple of questions that we have from a grad student at Johns Hopkins, and I'll send this question over to Dhan Chand. The author writes, "Great experimental data on Fc-enhanced anti-TIGIT. Insufficient immune activation and cancer resistance is one of the main reasons for low response rates in similar checkpoint blocker therapies. So to say, does Fc engineering have the potential to overcome this? Do you think this will be a better treatment option, certainly than chemotherapy in cancers? Certainly. Thank you for that question. To address the first point of whether or not Fc engineering can overcome some of the resistance seen, the answer is yes. We've had this experience in the clinic as well with our next-gen CTLA-4. We have seen with improving the Fc gamma RIII engagement, we can improve immune activation on both T cells and NK cells, two important cell types for TIGIT therapy. We've seen the same with CTLA-4. Consider patients that only express the low affinity allele of Fc gamma receptor III. Those are patients that will not be receiving optimal T-cell activation from the conventional therapy. We would expect our Fc-enhanced approach to expand benefit to this patient population. Of course, you can bring resistance for many reasons. The Fc polymorphism is one of those we have seen played out for CTLA-4. We've also seen it played out for HER2 targeting therapies as well. Yeah. Can I just add from a clinical perspective? Obviously, we know that there's a broad activity level of the PD-1 across solid tumors, the low-hanging fruit, so to speak, and clearly CTLA-4, we've worked out doses and schedules now, lower dose at six-week intervals, that seem to recruit the important memory T cell early priming response that creates durability. With TIGIT now, we need to understand this further. Is this a drug that, as a class, and again, our drug maybe augment the monotherapy class in and of itself with bispecific, but are we just going to be driving deeper PD-1 responses at the outset with durability? A great option, particularly if there's less toxicity or combining with CTLA-4. Are we really going to open this field up to the resistant phenotype, which is huge. To the extent that we can do that with either our engineered monoclonal or more promising, based on pre-clinical, the bispecific, this could open the field up for real applicability well beyond the PD-1 sensitive tumor. I'm looking forward in the clinic to quickly trying to make that assessment. Where does it fit and how do we drive it? Excellent point. To this note, we have a couple of questions on what is TIGIT? Dhan, can you just say a few words about that? We've overlooked it. Absolutely. TIGIT is a very potent co-inhibitory receptor expressed on T and NK cells. It's been shown to be upregulated in response to PD-1 therapy and limits, particularly CD8 T cell responses, particularly memory responses, as well as NK cell activation. It is a very potent escape mechanism to immunotherapy and cancer immune escape. By blocking it with the antibodies, Dhan? By blocking the antibodies, we want to remove that signal. We want to remove that co-inhibitory signal. What's interesting about TIGIT, unlike that of, say, PD-1, is that TIGIT is also expressed on NK cells, so you can harness the innate immunity and enhance that response. It also allows, when you block TIGIT for co-stimulatory signaling through a paired receptor known as CD226. Quite analogous to the way CTLA-4 works, when you block CTLA-4, you get CD226 signal. It's a very powerful checkpoint molecule. Thank you, Dhan. Dr. O'Day, is there a scientific rationale why TIGIT may only work in tumors with high PD-L1 and were you surprised by the recent Roche data showing no correlation with TIGIT PVR expression and response? Thanks for the question, Matt. I'm going to let Dhan also pipe in here. Obviously it's a little surprising. Again, we have limited data. It's not a large database, but it is a randomized database, placebo-controlled trial that you're referring to where recently TIGIT IHC expression did not seem to correlate with response that outweighed PD-1. Right now, PD-L1 expression seems to be the enrichment predictive biomarker for TIGIT therapy. Again, based on mechanism, I'll let Dhan sort of address this a little bit in terms of why these findings might be a little bit surprising at this point or not particularly. Thank you, Steven. Just to add some color to that, when you consider high PD-L1 expressed in tumors, you're most likely in an immune privileged environment or an inflamed environment. No, it's not surprising that the current TIGIT therapies are showing activity in this population. We have addressed this as well with our bispecific molecule, where we are starting to unlock activity in models that are resistant or relapsed to PD-1 therapy. Part of that is because we have not only Fc-enhanced the molecule for better T cell activation, NK cell activation, but we're targeting a very important escape mechanism as well, and our preclinical models are showing that. Dhan, thank you all, and to our listeners, thank you so much for joining us on our first of a number of series. It's been great to have you. It's 1:30 P.M. As promised, we would discontinue this in 30 minutes. If there are any other questions that we didn't get to, please send us an email. We'd be happy to get back to you. Also on our website, we've summarized some of this information in our most recent newsletter on TIGIT. We'll be providing, of course, updates very soon on this program. Thank you very much. Thanks, Dr. O'Day. Thanks, Dhan. Thanks, everyone. Thank you.