2026.09.23 | GP | Pharma | Engimmune ENGI-003 Preclinical

Perspectives on ENGI-003, AI-Guided TCR Discovery, and T-Cell Engagers for HCC

Primary:

Engimmune Therapeutics AG

Viewpoint:

Academic KOL - Physician Scientist

Moderator: Sandeep Dukare (SD)

| Sep 23, 2026 | 29 Min Read

Paul Andrew Antony (PAA), Immunologist and Independent Consultant in Immunotherapy - GLG

SU MMARY

Overview

The discussion focuses on Engimmune's ENGI-003, a preclinical GPC3-targeted trispecific soluble TCR program aimed at treating hepatocellular carcinoma. The conversation explores the potential of GPC3 as a target, the unique approach of ENGI-003, and compares it with other therapeutic modalities targeting GPC3. The expert provides insights into the challenges and opportunities in developing GPC3-directed therapies and the potential impact of Engimmune's approach.

Key Insights

The expert highlights GPC3 as a highly attractive target due to its expression in cancer tissues and low presence in normal tissues, making it ideal for hepatocellular carcinoma therapies. Engimmune's approach of targeting the peptide processed on HLA-A*02:01 rather than the surface antigen is seen as innovative, though it requires further validation. The expert emphasizes the need for Engimmune to demonstrate the efficacy and safety of their trispecific soluble TCR in preclinical and clinical settings to overcome the limitations of previous GPC3-targeted therapies.

Competitive Landscape

Company/Product

Approach

Key Points

Engimmune (ENGI-003)

Trispecific soluble TCR

Innovative targeting of HLA peptide; needs validation in preclinical and clinical trials.

Immunocore

Soluble TCR (Kimmtrak)

Proven efficacy in uveal melanoma; serves as a benchmark for soluble TCRs.

EvolveImmune

CD2 Co-stimulation

Demonstrated potential of CD2 in enhancing T cell activity.

CAR-T Programs

CAR-T targeting GPC3

High response rates; challenges with solid tumor penetration and exhaustion.

ERY974

Bispecific GPC3-CD3

Faced therapeutic window issues; highlights challenges in bispecific approaches.

Quantitative Insights

Metric

Target Range/Expectation

Objective Response Rate (ORR)

20-30% for off-the-shelf therapies; competitive with CAR-T.

Duration of Response

Over 8 months, ideally 12 months for significant impact.

CRS Levels

Manageable, ideally below grade 3 for better therapeutic window.

The expert stresses the importance of demonstrating consistent and durable responses in clinical trials to establish ENGI-003 as a viable treatment option. The discussion also underscores the need for Engimmune to update their clinical data and website to reflect recent developments and validate their claims.

SD: Welcome to today's call. My name is Sandeep and I am an analyst at Guidepoint Insights. Today's discussion will be focusing on ENGI-003, which is the lead asset of Engimmune's preclinical GPC3-targeted trispecific soluble TCR program for hepatocellular carcinoma. We also discussed how ENGI-003 compares with other therapeutic modalities targeting GPC3 and the key considerations for its future clinical development. To help me understand more about this topic, I'm glad to have with us today Dr. Paul Antony. Thank you for joining today, Dr. Paul.

PAA: You're welcome. Thank you again.

SD: So, before we begin, could you briefly describe your background or your experience in hepatocellular carcinoma or GPC3-directed immunotherapies or any experience that you have with engineered T-cell therapies or soluble TCR platforms?

PAA: Well, I'm in the immunotherapy space. I've been in there since the 1990s. So immunotherapy involves, you know, using antibodies, cell therapies, or the like, vaccines to target cancer. Normally, you're trying to target some tumor-specific antigen. It could be something on the surface or it could be expressed by MHC. At the NCI, we studied T-cell therapies against gp100 and a lot of other different antigens. We also looked at different cancers; hepatocellular carcinoma was among them, but also melanoma. So we knew about MAGE, targeting MAGE and the problems with that. We also understood the problems with targeting T-cell receptors and why they didn't... we never really understood why they didn't work. And Engimmune, sorry, has published a paper in 2022 in Immunity showing that maybe we approached it the whole wrong way. We actually... there was always this problem with not understanding why a T cell receptor could bind so well, but it never would work clinically. And that was a huge question in the last 26 years. So I think Engimmune now has answered the questions we had when we were targeting antigens. We did not target GPC3 back then. We were looking at different antigens, but this antigen is definitely one of the top antigens now in hepatocellular carcinoma. It's been validated very clearly with different modalities.

SD: And in this ENGI-003, targeting GPC3 in hepatocellular carcinoma using a tri-specific soluble TCR architecture. So based on the current state of the field, do you view GPC3 as a target that remains fundamentally attractive or previous development efforts reveal some limitations that any future therapy will have issues to overcome?

PAA: Well, it actually is a really good target. I mean, it's a lineage-associated antigen, or it's a fetal antigen, so it's only expressed basically in cancer tissue. So it's a well-validated tumor antigen. It's already been clinically validated by different modalities, bispecific CAR T, antibody drug conjugates. So it's unusually high. It's highly expressed in hepatocellular carcinoma, but very low in normal adult liver and other tissues. So this is the classic bona fide antigen that you would want. This is exactly what you look for, that it's very unique, only expressed in cancer. It's definitely

been validated. I mean, a lot of different targets, different modalities in immunotherapy have targeted it. They all may not have all worked. Some bispecifics have not worked. Some CARs work, some work better than others. There's some recent data at ASCO this year with some CAR-T from China. Antibodies themselves have not worked very well, vaccines. So it doesn't mean if 1 modality fails, it's not going to work for another. So that's clearly true now. It's a great target just to sum up. I think the problem is heterogeneity in cancer. It can express and contain, and then what Engimmune is doing is they're actually not targeting the surface antigen GPC3; they're actually targeting the peptide that's processed on HLA-A*02:01, so that's very specific. That's a totally different approach than what others have done. That needs to be validated. They so far have not validated that.

SD: So given that GPC3 itself, you know, looks well validated as a target, what do you think explains why some of the previous GPC3 targeted approaches have worked while others haven't?

PAA: Yeah, that's a really good question. I think the history of it is it's not a bad target. That's not the reason. One is it could be, for instance, just what they used to target it. So the first thing they used was an antibody, I can never pronounce these, Codrituzumab, that's the one that's an antibody, but that's just an antibody that targets kind of like tocilizumab, so it depends on certain things for it to work like CD16. That may not be the best approach. Maybe in the liver, the CDC may not be available or there's too much heterogeneity.

SD: Thank you.

PAA: The vaccine one was the immunogenicity just didn't translate. You're vaccinating with a GPC3 peptide. But if you're vaccinating against a self-antigen, right? When you vaccinate against self-antigens, there's not enough T cells that have escaped thymic selection that will work.

SD: Thank you for joining us.

PAA: You really need to vaccinate against the mutated antigen. That's the only thing that will work well. But GPC3 was not mutated. That's just not going to work. We already know that from previous vaccines. That's why the neoantigen vaccine works so well, like Moderna, Merck, Moderna, and melanoma, for instance. But again, that's another story. Other things, you know, trafficking and persistence, exhaustion of CARs, it's very difficult for them to traffic into solid tumors. But the ORR experience from China shows very high response rates there, so that's promising, showing it can work. They have an armored CAR. They don't tell you what the armored part is, but that must be what improves over the regular CARs. There's also CT018 and other CARs that look like they're promising. Some modalities have not worked. I mean, ERY974, that was a bispecific, GPC3-CD3. It had a therapeutic window problem like a lot of bispecifics. So all of these have had some success, some more than others, some have not worked very well at all. So it comes down to really the modality. And I think Engimmune just needs to show that they can make a bispecific, which is now a trispecific with the CD2, and that works better and it's safer, but at the moment they don't have that.

SD: Mm-hmm.

PAA: So, given that you have seen both CAR-T and bispecific approaches, where do you think the soluble TCR format could overcome the limitations that you just mentioned, particularly the therapeutic window issue? Yeah, so one thing is the affinity. Well, one, it's a little bit different, right? They're not targeting GPC3 on the surface. They're targeting the HLA peptide MHC, which is presenting an antigen through an HLA molecule, and then that's binding the T cell receptor. So this is a little different. It's affinity matured. So that's a plus that's different than these other approaches. So it's like a T cell. Therefore, it can recognize the antigen very well. It is CD3, so it's a CD3 recruiting, so that part could be modified. They can modify the CD3 affinity, that's been shown in papers with other bispecifics. Possibly that can help open up the therapeutic window. And then lastly, they add a CD2 co-stimulation, which, again, a couple other companies are doing. This is not unique, but that co-stim can allow then the affinity on CD3 to be lower, and

that lowers the activation threshold, which helps dosing and also helps the therapeutic window. So all these can do that. They have some data in their patent showing they actually created this molecule, but against gp100, also against MAGE-A3, they also had against GPC3 as well, and they showed the differences in the trispecific and the bispecific, and they showed that the trispecific was much more better at activating T cells. This is an animal model, unfortunately, in vitro, so we don't have any, you know, Phase 1 data or anything, but the ideas here, they've improved on the bispecific, the GPC3-CD3 with the CD2, so that there shows that maybe then that will overcome a lot of the shortcomings of bispecifics in a human. They may be able to dose lower. They may overcome exhaustion with the CD2, for instance. The HLA part, the HLA-A02:01 part, that's very specific, so that actually is a negative actually, because now you have much less people you can treat. You can only treat HLA-A02:01 patients, and then lastly, cancer can lose HLA expression, so you have to monitor that; cancer is notorious for doing that. So that just adds another layer of complexity, but the engineering of the molecule may overcome some of the shortcomings of the current modalities.

SD: So I wanted to follow up on what you just said. Given that HLA-A*02:01 restriction, how much do you think that limits the addressable GPC3 positive HCC population?

PAA: I mean, it limits it. Obviously, HLA-A02:01 is very common in the United States, for instance. So there are patients you can treat, but not every HLA-A02:01 patient has hepatocellular carcinoma. In other countries, HLA- A*02:01 is less common, so it's not going to be very widespread. In China, for instance, they're basically very low, maybe it's like 10% or lower. Still, there is a population, but it just limits your ability to treat where a CAR, you're not limited by that or a bispecific, right? You're not limited by your choice. But again, then you're limited by other things with those modalities, right? You're limited by practicality, therapeutic window, CRS, et cetera, neurotoxicity. So there's a plus minus for all these modalities, right? There's always, but still, they haven't shown this in humans yet. We don't even know. And then in their patents, they never really targeted hepatocellular carcinoma and looked at exhausted cells with GPC3. They did use other targets, gp100 and others, but that doesn't mean it will work for GPC3. We still need to see that. And that's one thing that's lacking.

SD: So, and coming to the mechanistic differentiation part of this particular asset, so do you think ENGI-003's trispecific soluble TCR architecture would address the key biological barriers that limited prior GPC3-directed therapies?

PAA: Well, theoretically, I mean, that's why they made it because the third arm is a CD2. Again, if you look on the website, it's not there. But if you look in the patent, it's very clear it's CD2. Other people are looking at CD2, EvolveImmune, Evotec, other ones, you know, Novartis. This is nothing new. So there's no reason to hide it or anything. But CD2 costim is really important. Again, other people have looked at this, showing that it can enhance and overcome exhaustion. So the main problem with solid tumors is exhaustion of T cells. And if you can somehow overcome that, obviously PD-1 therapy was for that reason, but these are post PD-1 therapy patients, you know, second line, usually PD-1 isn't going to help. So you need something else. CD2 can possibly help overcome that. The other obstacle, hopefully, is the MHC part. You can target the MHC molecule with GPC3 because GPC3 likes to shed. And if you have shedding, the molecule sheds off the tumor. Now you can't target it. But with the MHC, you can still target it. So that gives you another sort of opportunity. But it also...

SD: Thank you.

PAA: Thank you. Introduces another problem is that the MHC can be lost and then you lose the GPC3 peptide expression. So again there's losses and minus all these and probably a lot of these will be combined. A lot of combinations can overcome resistance. There's also a TGF-beta problem. TGF-beta gets expressed. A lot of companies kind of overcome that with TGF-beta dominant negative CAR T cells. So, you know, it's not solving everything, but it's another method to possibly overcome resistance to this cancer.

SD: Right. And in terms of preclinical evidence, what kind of evidence do you think would convince you that ENGI-003 provides meaningful biological differentiation rather than just an incremental engineering strategy?

PAA: Yeah, so they obviously have some preclinical evidence. They show that the molecule enhances T cell activation, but this is not with hepatocellular carcinoma cell lines or anything like that. That's important. But regardless, they show with other antigens, gp100, MAGE-A3, they have an Immunity paper showing their TCR engine or whatever they call it, the modality that they use, works really well and they're able to match a T cell receptor to its function, which is really credible. That's probably 1 of the biggest findings in T cell receptor biology that I've seen in the last 30 years because no one could explain why a T cell receptor with such high affinity in vitro and it kills tumors and all that and then you send it into a patient it doesn't work that's always been a problem and I think they might have solved that but the way they approached it with a bispecific, you know, maybe they should have made a T-cell receptor and put it in a T-cell so that it works. But, you know, that's less practical. But the preclinical evidence, you know, what they need to show is, 1, they need to show that this molecule can treat endogenous HCC models like in mice, you know, xenografts, some type of patient-derived xenografts. They also need to show the natural peptide HLA densities on HCC, hepatocellular carcinoma. How much is this peptide expressed? Repeated challenges and looking at ways of does it overcome dysfunction of T cells? Does it improve tumor killing versus just expressing cytokines, for instance? What's the therapeutic window, at least in animal models? What's the EC50 and how does that translate then into humans? All those are really important, not just knowing gp100 or MAGE-A3, although those help. You want to show GPC3 bispecific with also a trispecific as a together in a preclinical model showing that the trispecific is doing what it's supposed to do, that it's better at treating, say, xenografts. And that, I think, would be a great preclinical package then to move into, you know, more rigorous testing like safety and then human.

SD: Got it. And given those experiments that you just mentioned, which one would be the real go-no-go experimental dataset for you? Would it be endogenous HCC killing, peptide HLA density, or the trispecific versus bispecific comparison?

PAA: To me, I would want to see a little bit of all of it. I don't... one or the other is less convincing. But when I see all of these contributing in some way, that makes me more confident. If you only see one but not the other, say, you get tumor killing, HCC in a xenographic model, for instance. But you get it with both the bispecific and the trispecific, right? Then it's like, well, what's the point? Why did you make the trispecific? So you want the trispecific to be better. That's the whole reason you designed it. I'm assuming that it is based on the patent data, the other antigens and their Immunity paper, et cetera, all these different. Again, when you combine it all together, that's what makes me confident about it. It's just the last part with hepatocellular carcinoma models and treating actual hepatocellular carcinoma, at least in a preclinical model, showing that it does what it's supposed to do and that the trispecific is better than the bispecific. That would be the key. Then I would want to go into humans.

SD: Since the whole rationale is that the trispecific should ideally outperform the bispecific, what magnitude of improvement in terms of tumor killing or therapeutic window do you think would be a convincing difference?

PAA: Yeah, so, I mean, in humans, you would want to see. When you look at all the other modalities out there so far with the CARs, the other bi-specifics, especially the one, there was the... I always forget the name of it... 971. Let me make sure I remember this one, but there was a bi-specific GPC3 that didn't do so well. It actually showed very good, and cytokines it showed. So the ERY-974, for instance, bi-specific... it was a GPC3, CD3 bi-specific. It had high CRS, hepatic inflammation, but the tumor killing was just not as good as you expected. So the therapeutic window there was not as good. You'd want an agent to show and Engimmune to show that they can improve on that therapeutic window that company had a problem with the ERY-974, and that this therapeutic window is something where it then generates durability, some type of response in hepatocellular carcinoma patients, that it's not generating toxicity and that patients have long durability of those responses. That would be the key: that this CD2 mechanism is allowing T cells to get activated better and cause more duration of responses, which you could look at ctDNA, circulating tumor

DNA... those responses are going down with time... and then it's repeatable. It's in multiple patients, not just 1 or 2, but many different patients. That's what I would look for; that's what I would want. And then ORR somewhere around greater than 25, 30% would be something because the space is getting more competitive. I mean, CARs are already in the upper 30 range, some are even in the 50% range. Again, this is all preliminary data but still they're getting high ORR so the competitive bar is moving so Engimmune is going to have to be up in the least 30% or that's just my opinion but.

SD: And in terms of, you know, Phase 1 data set, what do you think would be convincing the biological proof of concept for this particular asset?

PAA: Yeah, just 1. So a validating Phase 1 data set would have to show more than, say, just the tolerability or that it activates T cells, as I kind of already mentioned. You want to see reproducible pharmacology. You want to see, again, the ORRs, 30% range. You want to see durability of those responses, repeatability, also circulating tumor DNA reduction, not just some CRS signal or cytokines, you know, CXCL9 and 10, interferon gamma and all that. That doesn't always correlate. You want to see ctDNA going down and durable responses over time and that this is repeatable in many different patients, not just a few. So other than that, I think, yes, the main key evidence would be, you know, also a good therapeutic window. That's key to have that as well. And I think that's about it.

SD: Mm-hmm. And, I mean... Like you mentioned earlier as well, given that you're looking for reproducible pharmacology, ctDNA reduction or durable responses and not just T cell activation, what would you consider the minimum duration of response and the level of ctDNA reduction that would be clinically convincing?

PAA: Yeah, so I would say, if you look at all the other data out there, like ADP-A2M4, which is a different antigen, but they had 29% ORR for different antigens. And then ERY974 again had high CRS; that's not much to compare with. But the CT018 CAR had an ORR 28%. About the ADC conjugate MRG006A had an OR about 23. Again, I'm just quoting recent numbers that some of these may have changed, but then there's a car C-CAR031 with an OR 44%. So, that's the ballpark. So I would say you'd want something reproducible again in the 20% to 30% range. And you say, "Well, why not higher?" Well, remember, this is off the shelf. This is much easier to give and people are going to give this first over a CAR for sure, I think. So even if the OR is a little bit lower than a CAR, it's just easier to give, and you could always go to the CAR later as a backup because remember, patients will relapse. But so I would say a 20% to 30% range would be a strong OR as long as it's durable, safe. Anything below 15% probably would not be that interesting. Again, this is hepatocellular carcinoma. Others might disagree with me and say anything that works to try to in second line to help a patient, they might go down to 15% and say, well, we'll still use it. But if you have competing modalities with higher ORs, well above 50%, then you might not consider this. So, but durability, OR 20% to 30% durability over 8, 6 months. That would be my, and that is safe. You want safety, not a lot of CRS, grade 3 or higher should be very low, not common.

SD: So, given that off-the-shelf advantage for this particular asset and it can tolerate somewhat lower efficacy than CAR-T, what level of CRS or other treatment-related toxicity would still give ENGI-003 a meaningfully better therapeutic window than any other GPC3 approach?

PAA: CRS is manageable. It could be in the 3 range. People don't like it, but CRS can be manageable if it is, say, a little higher than normal. CRS can actually help with cancer therapy. It's been shown that higher CRS to get better responses. Again, it's not always true, but CRS is manageable. It's already in CAR T-cell therapies; other bispecifics have it. So if they were manageable... wasn't like over 3, not getting into the 4 range, very low, less than 2% in the 4 range, one would be better. But then, if you had very consistent responses, say 15% to 20%, and it was consistent over and over again, not 5 and 1, 6 and up, it's very consistent. Again, consistency is also very credible. If something is consistently in the 15% to 20% range, people might accept and say, well, I'll use this. My patient doesn't have any other options at the moment. I'll call my patients a HLA-A*02:01 patient. So this gives them that other option. But

other than that, if the CRS is too high or it's consistently lower than 50% in real-world practice, then I don't see this as a possible candidate.

SD: Got it. And given that you accept 15% to 20% ORR, if it's highly reproducible, how much in terms of durability or ctDNA response do you need to strengthen that signal for you to view it as a credible GPC3 specific effect?

PAA: Definitely, you're talking about duration of response. Is that what you mean?

SD: Yes.

PAA: Yeah, definitely over 8 months, even longer would really be exciting. And if it were consistent, I think, again, that would make people still use it knowing that there's risk, but knowing that the risk is manageable and you can improve a patient's lifestyle with over 12, maybe up to 12 months durability, duration, response. I guess another, and you have to think of it this way, it's another tool in the box. If you have another option, especially for an HLA-A*02:01 patient where you don't have to go to CAR-T right away, you don't have to go to cell therapy, you don't have to move to an antibody drug conjugate which has its own toxicity. That leaves those other modalities there for later when the patient relapses, then you can say now we have this other therapy. So I think it just allows the physician to have another tool and if it's, again, very manageable, consistent ORRs and a good duration of response over 8 months, even better if it's over 10, then that would make it more likely to be used, it's also off the shelf, much easier to give than a CAR T.

SD: Got it. Building on that sequencing point, if ENGI-003 is positioned as an off-the-shelf option before CAR T or ADC, would you initially select patients with high GPC3 expression and preserved HLA-A*02 expression or would you want to test a broader GPC3 positive population?

PAA: Well, you know, you have to test for one HLA-A*02:01 and then that they actually express the peptide. That the antigen itself, like by IHC, is not going to be enough; that's the whole difference. You're looking at this surface antigen, so you're going to want to look at HLA peptide presentation. I mean, generically, if they have GPC3, you can assume that they're expressing it, but that's not scientifically... that's the shortcut. You really want to know: are they expressing GPC3 peptides on the surface? That takes... that's a little bit extra work, but you can do it, and that would then clear them for the... so that would be a biomarker, right? You would test for that, for that expression. But GPC3 surface expression, that's not enough; you need to know if it's actually being presented on the HLA molecule. That's always been a problem with cancer therapies in the last 30 years is everyone just assumed that the cancer expresses the antigen, like if you take the cancer, digest it, and show all these antigens. I remember everyone saying, "Oh, well, it has the antigen. It has gp100." But that doesn't mean gp100 is on the surface of the cancer. That is a whole different... that's another ballgame. That's totally different. It could have... it could express it within the tumor. It can even be on the surface, say, you know, like GPC3, but that doesn't necessarily mean it's actually being expressed by the cancer. This has always been a mistake people have made. This is where you have to use something like peptidomics and HPLC and all these things looking at peptide expression, the immunopeptidome, what's actually being expressed. That's key actually, so we'll have to look at that. That's just another, you know, biomarker to look at.

SD: Got it. And in terms of, you know, comparison with other programs, which existing therapeutic program do you think is the most appropriate scientific benchmark for ENGI-003 and why do you think that is the reason?

PAA: Yeah, so there are a lot of different programs out there. Obviously, Immunocore or Adaptimmune are good examples. So how can I start here? So Immunocore has shown that the soluble TCR can work, right? They've shown with Kimmtrak, and you can make a soluble T cell receptor against gp100, the whole molecule I've been talking about. And that can work as a therapy approved for uveal melanoma. Now they're looking at melanoma. So they've shown, you know, again, as a benchmark that you can use a soluble TCR. And Engimmune adds the CD2 component. So that just adds another layer of complexity that we don't know about yet. We know, I think it's EvolveImmune with

the Evolve 104 has shown that CD2 can work. If you modify the CD3 molecule, it can get better activity. So the CD2 component has been shown by EvolveImmune. So it's been, a soluble TCR can work as a bispecific, again, different antigen, but again, showing that these concepts can work and are practical. The CAR-T programs show that targeting GPC3 can work. So we know GPC3 is a target, but that's on the surface. So that doesn't answer the question about the HLA peptide part. So I think what it comes down to, the only thing that's missing here is no one's targeted the HLA peptide yet. This is what's new, right? You have Kimmtrak with gp100, you have Adaptimmune with MAGE-A4 and A8, right? You have bispecific targeting the surface, CAR-T targeting the surface, but we don't have, and we have ADCs targeting the surface. But we don't have the MHC complex being targeted with its soluble TCR yet. That's the novelty here so far as I can tell. And so that's the part that's not been shown to work yet. I'm not saying it wouldn't work. I'm just saying it hasn't been shown clinically to give us responses. You know, again, preclinically there's some data there, anecdotal data. And it looks like it may work based on these other programs. You can target melanoma, you can target, you know, mostly melanoma, but other GPC3 targeting modalities have worked. When you put it all together, you can say, well, yeah, probably it will work, but not yet. We don't have that proof just yet.

SD: Sorry. And trying to understand about the platform, to what extent do you think Engimmune's platform increase the probability of clinical success for ENGI-003 versus conventional TCR engineering?

PAA: Yeah, so their platform, if anything, so their Immunity paper establishes that platform. And what was really interesting there is they didn't look at just GPC3, they looked at other antigens, gp100, MAGE-A3, and they were able to show. The problem that MAGE-A3 had with the Titan recognition, and they were able to overcome that, but also show that affinity isn't the number 1 quality of a T cell receptor that you need to, while you're affinity maturating a TCR, you need to know that it's functional, that it actually signals. And so they've incorporated that along with reducing cross-reactivity all in the development process.

SD: Thank you.

PAA: So that itself gives me hope, again, not proof, but hope that with the GPC3 antigen that they've affinity matured their T cell receptor to recognize a peptide that doesn't cross-react to anything else and also causes signaling. Well, that's if it were a T cell receptor. The problem is this is a bispecific. So the problem is here, I just figured this out here, their Immunity paper doesn't translate to the bispecific because it's not a T-cell receptor anymore. It's a bispecific with a T-cell receptor on it, but that doesn't have anything to do with T-cell receptor signaling. This is where a pure T-cell biological cell therapy with a T cell receptor that they designed then I would say yes, it translates. But the problem is if they're taking that T cell receptor they just defined that it signals really well in a T cell And then they put it on a trispecific, but that has nothing to do with downstream T cell signaling in a T cell that it eventually grabs onto. Because remember, it has a CD3 component, the antibody that then binds to any T cell that has CD3 that has nothing to do with TCR signaling that they just now defined in their Immunity paper. So there's a whole disconnect there. And I hope you understand that. If you don't, I can answer that again. But the problem is a bi- or tri-specific does not signal like a T-cell receptor signals. That's the problem. So they still need to prove this in humans. This is not, the Immunity paper gives some credence to it, but there's a disconnect because the Immunity paper is looking at T cell receptors in T cells, not as a tri-specific molecule. That's the issue.

SD: Got it. Before we finish our conversation, I just want to understand one last thing.

PAA: Okay.

SD: When you have seen all the data, or I know that there's not much available, but when you have seen this strategy of how they've developed the asset, is there any future data set or milestone that you think would reduce your current scientific uncertainty surrounding this particular asset?

PAA: Yeah. So, I think, honestly, you need Phase 1 data. You need, first of all, you need PK, PD, safety, even before you get all the efficacy, right? You want to show that you can give this in humans, that it's safe, that it gets to where it needs to go, the PK showing that you have a therapeutic window, there's no toxicity that's getting into the tumor sites with some type of paired biopsies, looking in blood but also looking at tumors, knowing it's getting into the tumor site and then eventually efficacy, is there efficacy, ctDNA going down, T-cell biology, T-cells getting activated, CD8 T-cell infiltration, that the CD2 is contributing somehow. Obviously, they're not going to run a bispecific, trispecific cohort. That would be great, but no one ever does that. So, you have to rely on preclinical data plus Phase 1. But eventually, if they show that, then showing the ctDNA going down on, again, over time, durable in multiple patients, not just a few, but multiple patients over time, that would be the main things I'd want to see. Thank you very much.

SD: Yeah, I think with this I don't have any further questions, Dr. Paul. Thank you once again for your time and thoughtful insights. I appreciate your participation today and hope you have a great rest of your day.

PAA: Okay, great. No, that's a wonderful conversation and I think if they can at least show a clinical package along, you know, backing up what they claim in the patent and on their website because if you look at the website, a lot of the data, there's some information there from 2 years ago, so it doesn't even look like it's been updated recently. So that's a concern there as well. They really need to update their website, show us some phase 1 something to guarantee that what they're saying is translatable. But I just want to make a clear point about the Immunity paper again. Remember, that's in a T cell receptor on a T cell. That's totally different when you have a bi or tri-specific. Signaling will not translate to a bi-specific. That's a misconception people make. That's a whole different ballgame, so I hope that was clear.

SD: Great. Again, I appreciate your perspective. Thank you once again.

PAA: Okay, you're welcome.

SD: Bye-bye.

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