Hi everyone and welcome to our first R and 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 15 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-one is delivering differentiated activity compared to commercially available PD-one antibodies. In November, our Fc engineered anti CTLA-four, we presented 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. And only as recently as last year, anti CTLA-four and anti PD-one were the only validated immune therapy combinations for patients with cancer. Today this third pathway in target TIGIT has emerged.
TIGIT's upregulated with PD-one therapy with the growing number of patients treated with anti 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 digits and actually when in a company's portfolio do we have some of the best looking compounds. Eleven eighty one is really an elegant molecule. PD-one showing great benefit in PD L1 negative and positive tumors and 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. So today we're joined by Doctor.
Steven O'Dea. This is a Genesis 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. Doctor. Dan Chan, a molecular biologist and head of our drug discovery programs here at Agenus is also with us. I'll open with you Doctor.
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, and I'm delighted to be part of a Jen established the chief medical officer. As you said, I've had almost thirty years of experience in the clinic as a clinical oncologist and clinical researcher and was involved with the initial human studies with ipilimumab that launched the immune revolution. As you know, CTLA-four and PD-one 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, and TIGIT appears to be an emerging marker both on T cells and NK cells, an important checkpoint that may further make an impact clinically. And as you know, there's different formulations of TIGIT, both the confident antibody monoclonal as well as silenced or an Fc enhanced.
So today, there there was great hope that, TIGITs would be able to overcome as a primary mechanism of p d one resistance, overcome this in the clinic. To date, with the confident monoclonal TIGITs that have clinical data that is emerging, what appears to be the case is that these molecules have shown very little mono monotherapy signal and have been primarily targeting now combinations with PD-one, particularly in lung cancer in the first line PD-one naive setting in high PLM expressing tumors. And obviously, this is an important discovery and will pursue further clinical data. But there's tremendous opportunity here with TIGIT at the validated marker in randomized Phase II trial, particularly in the P1 resistant category. And so what I'm particularly excited about and really prompted my desire to come to Agenus was both November, but but this TIGIT bispecific molecule that that doctor Chen's gonna 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.
And 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. Right? TIGITS alone have not delivered the kind of benefit we thought they might based on some of the biologic insights that we've had, right? You know, 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. And I'd like as we think about TIGIT and I mentioned earlier I used the word pathways plural, right?
It's a complex biology and 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. So blocking tumors blocking TIGIT perhaps in a better way with Fc engineering and then addressing biology with bispecific approaches or alternate approaches. So maybe I'll ask you, Doctor. Chan, 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-one and CTLA-four. We have made several important discoveries on the TIGIT pathway, some of which we have published and presented at major conferences. And 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 one relapsedrefractory models. Now the first discovery we made was that Fc gamma receptor coengagement by TIGIT antibodies, like that of CTLA four, is absolutely critical for enhancing T cell activation and antitumor immunity.
And what I mean by that is that blockade alone is not enough. TIGIT antibodies that also engage activating Fc receptors promote better immune activation. But 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 Agen's Fc enhancement compared to that of competitor like molecules. And AGEN seventeen seventy seven 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 T and 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 validates the importance of this pathway, specifically in settings where tumors escape independent of PD-one or PD L1. And that is where we see the opportunity for AGEN1777, to optimally modulate the TIGIT pathway, to bring single agent to make single agent activity possible, but also improve responses in PD-one relapsedrefractory models. In fact, if you look at if I can get the the previous slide, you will notice in a model here where it's poorly responsive to PD one, you see almost complete responses in all of the treated mice that was given agent seventeen seventy seven.
This is a remarkable finding. TIGIT therapy alone, particularly conventional approaches, do not have such compelling activity. But through Fc engineering and through co blockade of potential escape mechanisms to TIGIT therapy, we were able to see monotherapy potential and activity in PD-one relapsedrefractory models.
And Ken, maybe I'll stop you there for just a moment. You 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 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. And 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? And maybe what I'll ask you to do, Dan, 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 a combination of monospecific antibodies. And what we determined was that the added benefit was not as impactful as we would have predicted. But 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. And 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, Dan. And maybe just one more point. You mentioned Fc engineering. Now we have seen with at Agenus, we have a first generation CTLA-four, zalifrelimab, very active, performing like a first generation CTLA-four in IgG1. We've applied this Fc engineering technology to optimally target CTLA-four biology and 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 And that includes patients over forty percent of whom have a polymorphism in their CD16 allele. But maybe for those listeners on the line, Dan, who don't really know what you know, we're looking at TIGIT landscape, there are a number of TIGITs that are emerging. What does this Fc engineering mean or do? And what is the landscape, the variation of this engineering that's available today?
Absolutely. So apart from the finding that Fc gamma receptor coengate is important, we also identified the specific receptor that was needed. And that was the Fc gamma receptor three or CD16. Now we have seen from not only our experience with CTLA-four but others as well, that molecules that depend on this binding show activity in patients that express a high affinity variant of this receptor. Now patients, as you mentioned, up to forty percent can express the low affinity variant.
The reality today is that the conventional approaches two TIGIT, such as IgG1 approaches are much less so Fc silenced 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 silane. And what we see is improved binding to all polymorphic variants. So 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. And Jen, this is playing out clinically as you see with eleven eighty one.
That's right. And maybe importantly, Doctor. O'Dea, with eleven eighty one you've made specific comments about the Fc engineered CTLA-four 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-four. And then I'd like your prediction as to how this may play out with an Fc engineered TIGIT with related to toxicity.
Oh, as you know, Jen, with CTLA-four, it's one of the pioneers in in the clinic with this. You know, 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. So complement mediated toxicities, particularly around neuroendocrine, and hypophosphatous is a is the pituitary gland is a central gland that controls endocrine function. It's a very important gland. We know with ipilimumab and first generation CTLA-four, this is in ten percent to fifteen percent of patients they may develop these toxicities, which are manageable but can be like are essentially lifelong replacements of drugs.
So the preclinical models with eleven eighty one suggested that these complement mediated neuroendocrine toxicities would be abrogated. And so far, with over forty patients treated in the clinic, we have not seen this toxicity, which we would have likely expected to see with the traditional C2A4 drug. So that's very, very encouraging. Obviously, as we move this technology over to TIGIT, this will be an important issue. Also, with eleven eighty one, we've seen little to no liver toxicity, another major toxicity for CTLA-four and, to a lesser extent, PD-one drugs.
So 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. So we're excited about all these things.
Excellent. Thank you very much. And I think just for the listeners, we have in the clinic now there are Fc silent molecules, and I'll ask Dan 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. So maybe I'll start with the Fc silent variant. So these are molecules that are designed primarily to block the TIGIT pathway. They do not capture that important Fc mechanism, includes binding to Fc gamma Fc receptor 3A, improved immune synapse formation, which we're seeing with our molecule, or perhaps myeloid activation, which others have reported.
And the premise there is that by just blocking TIGIT alone, you may spear 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 for the activity, is that FC28 and four added T cell function. Blocking TIGIT alone is not enough. In fact, we've been down this road before with CTLA-four molecules where we know that, you know, it's not all equal.
You need to leverage additional mechanisms. You know, the famous example I like to use is italizumab versus trimilizumab. You know, both good blockers of CTLA-four, but very different activity when you consider the FCPs. You know, TIGIT and preclinical models have 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 of a single agent in our tumor models or in T cell activation assays. And 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. And 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's leading to responses in PD-one relapsedrefractory models.
Thank you very much, Dan. And 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 fifteen minutes, fifteen to twenty minutes on content and then open it up for questions which we'll do now. So 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 and 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 and 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. So that newsletter will continue. It's issued biweekly and it's also available on the Agenus website. And while our panelists while our listeners add questions into the chat room then perhaps Doctor.
O'Dea what I'd like to know from your thinking what are you gonna do with this molecule? It's actually heading into IND enabling studies actively, and our IND is just a matter of weeks, not months away, and so we're really enthusiastic about that. What what's next? Where are you gonna test it?
Well, it's pretty clear that the the data we have in the field with the competent SC monoclonal is that that they're actively targeting high p d o one expressing advanced lung cancer in the first line PD-one naive setting. So that's a niche that obviously is moving forward quickly to larger trials. Because of what Dan 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. But 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 III trial in solid tumors, obviously, enriched for tumors that are more immunogenic as is our platform.
And then as we clear doses of the single agent, obviously, be very interested in combining it with PD-one. But we will be looking for signals both for monotherapy and combination. And this is really important because because I think we shouldn't rush to any conclusions yet about monotherapy with TIGITS for the reasons Dan discussed. So both the monotherapy and the PD-one 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. And I think it's really important we didn't go through the preponderance of data we've generated, but we have shown that seventeen seventy seven does have that preclinical monotherapy potential as well as complementarity with PD-one 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 ask this I'll send this question over to Dan Chan, 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? And do you think this will be a better treatment option certainly than chemotherapy in in cancers?
Certainly. Thank you for that question. So to address the first point of whether or not Fc engineering can overcome some of the resistance seen, the answer is yes. And we've had this experience in the clinic as well with our next gen CTLA-four. Now we have seen with improving Fc gamma R co engagement, we can improve immune activation on both T cells and NK cells, a
very
important two important cell types for TIGIT therapy. We've seen the same with CTLA-four. Now consider patients that only express the low affinity allele of Fc gamma receptor three a. Those are patients that will not be receiving optimal T cell activation from the conventional therapy. So we would expect our Fc enhanced approach to expand benefit to this patient population.
Of course, you can do resistance for many reasons, but the Fc polymorphism is one of those we have seen played out for CTLA-four. We've also seen it played out for HER-two targeting therapies as well.
Can I just add from a clinical perspective, obviously, we know that there's a broad activity level to PD-one across solid tumors, the low hanging fruit, so to speak? Clearly, CTLA-four, 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. And so with with TIGIT now, we we need to understand this further. Is this a drug that, as a class and, again, our drug maybe augment the the monotherapy class in and of itself with bispecific. But are we just gonna be driving deeper p d one responses at the outset with durability, a great option, particularly if there's less toxicity or combining with c two a four?
Or are we really gonna open this field up to the resistant phenotype, which is huge?
And to the extent that we
can do that with either our engineered monoclonal or more promising based on preclinical, the the bispecific, this could open the field up for real applicability well beyond the p d one sensitive tumor. So I'm looking forward in the clinic to quickly trying to make that assessment. Is it where does it fit, and how do we drive it?
Excellent point. And and to this note, we have a couple of questions on what is TIGIT. Dan, 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-one therapy and limits particularly CD8 T cell responses, particularly memory responses, as well as NK cell activation. So it is a very potent escape mechanism to immunotherapy and cancer immune escape.
And so by blocking it with the antibodies, Dan?
So by blocking the antibodies, you want to remove that signal. We want to remove that co inhibitory signal. But what's interesting about TIGIT, unlike that of, say, PD-one, is that TIGIT is also expressed on NK cells, so you can harness the innate immunity and enhance that response. But it also allows, when you block TIGIT, for co stimulatory signaling through a paired receptor known as CD two twenty six, quite analogous to the way CTLA four works when you block CTLA four and get CD 28 signaling. So it's a very powerful checkpoint molecule.
Thank you, Dan. And doctor 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 in response? Thanks for the question, Matt.
So I'm going to let Dan also pipe in here. So obviously, it's a little supply. Again, we have limited data. You know? It's it's not a large database, but it is a a randomized database placebo controlled trial that you're referring to where recently TIGIT IC expression did not seem to correlate with response, that outweighed PD one.
So right now, p one PD L1 expression seems to be the enrichment predictive biomarker for TIGIT therapy. So, again, based on mechanism, I'll let Dan 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.
So thank you, Steven. So just to add some color to that, when you consider high PD L expressing tumors, you're most likely in an immune privileged environment or an inflamed environment. So no, it's not surprising that the current TIGIT therapies are showing activity in this population. But 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-one therapy. And part of that is because we have not only Fc enhanced the molecule for better T cell activation, in NK cell activation, but we're targeting a very important escape mechanism as well, and and our preclinical models are showing that.
Dan, 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 01:30 as promised. We would discontinue this in thirty minutes and 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, and we'll be providing, of course, updates very soon on this program. Thank you very much. Thanks, doctor O'Day. Thanks, Jen.
Thanks, everyone. Thank you.