Sutro Biopharma, Inc. (STRO) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Sutro Biopharma Virtual Deep Dive Research Forum, Next-Gen Innovations in ADCs. [Operator Instructions] Please be advised that the call is being recorded at the company's request and will be available on the company's website for at least 30 days. I would now like to turn the call over to Bill Newell, Chief Executive Officer at Sutro Biopharma. Sir, please go ahead.

Thank you all, operator. Good afternoon, everyone, and thank you for joining us. With me on the call today are Dr. Trevor Hallam, our President of Research and Chief Scientific Officer; Dr. Kristin Bedard, our Vice President, Discovery; Dr. Shabbir Anik, our Chief Technical Operations Officer; and Dr. Venkatesh Srinivasan, our Senior Vice President, Process and Analytical Development. Before we start, I would like to remind you that today's call will include forward-looking statements. These forward-looking statements are based on Sutro's expectations and assumptions as of the date of this call, and Sutro's clinical development programs, future results or performance could differ significantly from those expressed or implied. Please refer to Sutro's filings with the SEC, including our most recent 10-Q for information concerning factors that could cause Sutro's actual results to differ from those expressed or implied on this call. As a company, we've been looking forward to this opportunity to share with you our most recent pipeline and platform advances which include what we believe could be truly transformational next-generation therapies for patients with the most challenging-to-treat cancers. Our team has been hard at work developing additional novel therapeutic candidates and even new therapeutic categories, which Trevor will share with you in greater detail momentarily. On the agenda today, we will share an overview of STRO-003, our newest wholly-owned product candidate, a novel antibody drug conjugate designed to target ROR1, which is broadly expressed across a wide range of tumor types. A deep dive discussion of platform and our differentiated approach to generating impactful therapies, including immunostimulatory ADCs or iADCs. Our process development platform, which enables all of our innovation, and for which we are constantly innovating, and our manufacturing strategy, which includes an in-house fast to clinic supply and a robust path to commercialization. Following the presentation, we will open the call to questions at which time Trevor and I will be joined by our research and CMC leaders, Doctors Anik, Srinivasan and Bedard, who have been instrumental in supporting the efforts that have led to today's forum. To kick off the discussion, I'd like to provide a brief overview of our pipeline. As this slide indicates, Sutro now is responsible for 6 product candidates in clinical development, and STRO-003 will be our seventh. We have assembled a diversified portfolio for product candidates for hematologic malignancies, including CC-99712, our BCMA targeting antibody drug conjugate, partnered with BMS, and STRO-001, which is targeting B-cell malignancies. We've also assembled product candidates for solid tumors, such as STRO-002, which is in dose expansion phase of Phase I clinical development, and we're excited to be moving that molecule forward into a registration-directed study. More will be spoken about that later in the year. We also have M1231, partnered with EMD Serono, and most recently, MK-1484 partnered with Merck. In addition, our platform has enabled VAX-24, a 24-valent pneumococcal conjugate vaccine by our spinout Vaxcyte, which is in Phase I/II development as we speak. As a little bit of history, I want to remind you that beginning in 2018 and through today, Sutro's averaged more than 1 IND filing per year from products emerging from our platform technologies, and we look forward to adding to that with a STRO-003 IND and eventually our first iADC IND, which may well come from our collaboration with Astellas. From here, I would now like to hand the microphone over to Trevor for additional comments about our pipeline, and then to begin to walk you through what we've done. Trevor, over to you.

Thank you, Bill, and good afternoon, everyone. It's a pleasure to talk to you on our latest innovations and where we believe our emerging portfolio is going to go. Just while we're on this slide, as Bill just mentioned, we have 6 different clinical studies going on so far -- clinical candidates in development, 4 of which are ADCs. One at a vaccine conjugate packaging with Vaxcyte and the other is cytokine variant. The one thing they all have in common is that they're all designed and manufactured using this unique platform that Sutro has advantage of. And this is a cell-free synthetic biology platform effectively where we can design proteins incredibly quickly going from DNA to protein in 12 hours. That allows us to place very precisely and with varying numbers of precise conjugation sites in these molecules. So the common thing about all of these different biologics is the precision with which they're designed and the specificity and fidelity of the conjugation site. This ability to design fit-for-purpose is really, I think, a unique differentiator for Sutro, allowing us to conjugate very precisely into completion to result in homogeneous molecules in a drug, which is quite unusual in complex biologics to be able to get that precise and also our ability to conjugate sites, which are not predesignated by natural amino acids like cysteines or lysine, but where we have the flexibility to roam around the protein to find the best performing site. So for ADC, that's all about a really efficient site that's optimized to be able to deliver a cytotox into a tumor cell. For conjugate vaccines, it's all about the efficiency and precision of conjugation to allow as many as 24 different strains of pneumococcus to be represented in the tumor and retaining the balance between a full protein and those things that are conjugated to it to optimize immunogenicity. And for cytokine variant like MK-1484, there are a number of advances where we're able to directly conjugate to get best performance out of those cytokines. So without further ado, I'm going to talk you through our next up, which is STRO-003. This ROR1 ADC, Bill just mentioned. And also then for the rest of the presentation, I'm going to talk about this inherent integrated combination of new processes and new products that come together and they're designed to give us for increasingly complex biologics, actually an increasingly simple, straightforward and efficient manufacturing solution. So I'll get going with STRO-003. I can't find the toggle for the next slide. STRO-003 is a ROR1 targeting ADC. Why are we so excited about ROR1? Well, for one thing, the ROR1 biology makes an attractive ADC target in that it has an active role in cancer progression, and is expressed in tumor and tumor-initiating cells. Perhaps the more important thing, though, is that it's that specificity of expression on tumors and its restricted expression on normal tissue, means that there is low potential for on-target toxicity. So the second thing that's really quite interesting of ROR1 is its broad expression on many different tumors. There are -- there is an expression of ROR1 in wide hematological malignancies as well as a broad solid tumor expression as well. And that includes large indications, which is non-small cell lung cancer and breast cancer. So the trick to getting this is to getting an ADC that's really performing as best as can be with the relative component parts is to recognize that a lot of these tumors do express ROR1, but there is a combination of heterogeneous expression across the different indications and a fairly low copy number too. So that favors therapies that are very potent in their ability to cause tumor cell death with low antigen density or low copy number of the target antigen, in this case, ROR1. You have to make sure that if for an antibody drug conjugate, it's going to deliver those cytotoxins in sufficient quantity on each individual tumor cell to fit that over into a cell death. And of course, that's more complex with low antigen density, needs greater efficiency in the design, and that's where our site positioning comes in, but it also potentially needs payloads, so mechanisms of cytotoxicity that are really very potent. So this favors the more potent DNA disruptors rather than the more common tubular inhibitors as a potential mechanistic target. That doesn't mean to say that tubular inhibitors kind of an affecting factors some pretty reasonable clinical validation for both efficacy and safety in hematological tumors, with an MMAE-derived ROR1 ADC, and which is also being expanded into solid tumor indications. But we feel certainly there's an opportunity here to engage with some of the newer mechanisms that have been targeted in ADCs to be able to get to it. Now potent DNA disruptors like cross chain collagen like benzodiazepine can be a challenge from a tolerability perspective, although are very active even on cells that are not dividing rapidly. So we've gone with an exatecan class, which is Daiichi-Sankyo, has had great success with drugs like Enhertu. And we think this will provide that sort of ideal ability to tackle cells that are dividing slowly. The exatecan class has got good bystander effects. So potentially a drug that's released in the antigen-expressing -- ROR1-expressing tumor cells that exatecan can actually also kill surrounding cells. But it's not as potent as some of these things. So the tolerability which Enhertu enjoy is very attractive in being able to dose up. And what will finally be important to believe is that every internalization [indiscernible] has really got to count and deliver the optimal amount of payloads because of the low antigen density. And so we've now developed technology with our site-specific precise conjugations that can load DAR8 and above by positioning nonnatural minerals, and we'll talk about that technology. So this just is a prevalent chart across many different tumor indications, and the highest prevalence being at the top with mantle cell lymphoma. And you can see that the prevalence is -- can be quite variable depending on clinical indication. And in large commercial opportunity like lung cancer, you'll see towards the 1/3 of this table. In lung cancer, that prevalence can vary quite considerably from somewhere north of 45% to around 93%, 94%. And in addition to prevalence, which is really the number of -- the percentage of samples that prove to be positive for ROR1 in these indications, this chart also grades them in terms of percentage high. So if you were to look at prostate cancer, for example, that's a 90%-and-above prevalence. It's certainly 15% high grade. That relates to the antigen density, and that's a critical number for ADCs in that you want a number of binding and internalization events to deliver optimal output of payload. So the lower that number is the more potent -- the more warhead, the more efficient the antibody drug conjugate. So with the design, this is why we've designed a DAR8 specific exatecan class to go after a broad range of clinical indications. This slide shows the design of STRO-003. It's a -- I think this is the first site-specific DAR8 ADC in that these sites are chosen for optimal performance, not just the stability and PK, but also the most efficient way in which we know that this exatecan payload is going to be released in the tumor or in the tumor microenvironment in that those linkers are designed to work with these sites of conjugation to give really optimal release once bound to the antigen. So the targeted ROR1 epitope is clinically validated in that we know that epitope is expressed in a wide range of diverse hematological tumors. We expect that to be the case also for solid tumor indications. The precisely positioned nonnatural amino acid that we use as a proprietary p-azidomethyl-L-phenylalanine molecule, which is tremendously efficient in conjugation because it's a complete conjugation in just a few hours. So we can generate this start conjugation in several hours with very little more excess, which cause extremely important to cost of goods and manufacturing efficiency. We've chosen a different sort of linker from the fairly normal copeptin B cleavable linker. We've chosen a beta-glucuronidase cleavable linker. These are several examples of these new linkers in clinical studies. They are thought to be more specific to hypothermal endothermal space and can give a potentially more tumor-specific release, which has the promise of adding to tolerability. One particular improvement with beta-glucuronidase is that these linkers are designed, and are not as liable to cleavage by neutrophil-derived proteinases like neutral assays, for example, where some of the CatB linkers can be found. And there are papers out there which link that susceptibility to neutrophil-derived proteinases to their own demise, so that potentially can cause neutropenia. That's not entirely proven and of course, site of conjugation can make a big difference to that. In addition, TOPO summarize class have been known when paired with Cathepsin B linkers, like, for example, with Enhertu and others, to have long tolerability issues. And that is something, of course, we also want to avoid, the pneumonitis and interstitial lung disease seen in patients. So the exatecan is a fantastic payload, we believe, it elicits that potent tumor cell killing and by standard activity. But it also sends up a flag from the tumor cell that's under stress, and the so-called immunogenic cell death which, a lot is made of it these days, but it potentially is a very important aspect of this, and that it sends up a flag DNA immune system to go after the cell. So we believe these elements working together could potentially give us an ability to go after low level expression of ROR1, deal with the heterogeneity through bystander effect of the exatecan, and also be really very tolerable with this new combination we've been [indiscernible] So the first proof of the pudding really when the first test was to put STRO-003 and challenge some patient-derived non-small cell lung cancer tumors by way of xenograft, which -- and this is a representative of 4 such PDX models, which express low and heterogeneous amounts of ROR1 antigen level on that tumor [indiscernible] So if you look at this, what we're looking at, these are 4 separate PDX models, 4 separate tumors, which are representative of these lower level ROR1 antigen levels. And we're challenging them either with vehicle with STRO-003, which is the beta-glu exatecan linker payload or an alternative Sutro design, which is the same DAR8 capable antibody against ROR1 STRO-003. But in this case, we've conjugated to accepting [indiscernible] as an alternative development candidate actually, but also to see which of these might develop best. And this is a great test of whether the beta-glucuronidase in the human tumor system is going to do the job. So as you can see in all of these, in dark green, you can see -- sorry, in black, you can see the vehicle. So that's the normal tumor growth in each one of these tumors. And in dark green, you see that 4 doses of 10 mg per kg a week apart are able to completely cause tumor regression, at least in 3 out of the 4 of these, but pretty significant responses in all 4. By contrast, the alternative design, the [indiscernible] exatecan in light green, does really well in 3 out of the 4. And the other one, you can see a little bit of growth on the second from last -- so not quite as efficacious. And actually, that was not too much of a surprise in that we know that the active catabolite from the Cathepsin D linker is slightly less potent than the active cable that is derived from the beta-glucuronidase sensitive linker. So all in all, efficacy falls out the way we wanted it to or we're hoping to with the beta-glucuronidase into a really fantastic job in the low-level expression system. And the next question, this is actually looking at a breast -- human breast cancer model with moderate ROR1 expression, and looking to see the effects of the DAR8 beta-glucuronidase exatecan system here. So this -- so what we're looking at here in dark green is the DAR8 beta-glucuronidase exatecan targeting ROR1. So that does very well. Now in this particular inserters 4 doses of 5 mgs per kg, so a slightly lower dose a week apart. And you can see a very good response out to day 50 or so with those doses. In light green, you can see the DAR8 Cath C exatecan for comparison, which is, again, less efficacious. And for those of you that are interested in what a DAR4 CatB and NAE linker-payload would look like on a similar affinity antibody, that's in blue. So you can see -- you do see some tumor growth inhibition, not quite as significant as the beta-glu DAR8 exatecan. Now this slide demonstrates that actually the killing by STRO-003 is ROR1-dependent. An important point we believe, in terms of tolerability. On the left side, you can see a comparison between 2 cell lines, 1 ROR1+++, so high level of expression of ROR1 and then the other one, a ROR1-, the MCF-7 cell line. And the reason for doing this in red, you can see the effect of STRO-003 on the relative cell viability of[indiscernible] . We incubate these cells of 4 days. We're looking at the viability and the presence of either STRO-003 or an isotype-controlled ADC. So an ADC that doesn't bind to anything human but is loaded with the same DAR8 exatecan, and that does not kill the ROR positive cell, STRO-003 does, and you can see the doses curve there. The incomplete killing is because this cell line is heterogeneous. So those cells that do express ROR1 on average express quite a high level, so there is a certain population that do not express. And then the last one in blue, we've actually shown you what STRO-003 will do, but now in the presence of micromolar of an anti-ROR1 antibody. And that is there to completely block the ROR1 site to prevent the ADC doing its thing. Now if you have a linker that's not very stable and that comes apart, you will still see killing in this sort of -- in this sort of experiment. And on the right-hand panel on the left side is just to show that when we incubate the STRO-003 for 4 days in a ROR1- cell line, we see no decrease in viability. So we conclude that this is indeed antigen-dependent and a stable linker. On the right-hand side, we just show that again a 2 mg per kg 3 doses, a week apart. We see some good tumor growth inhibition in the ROR1+ xenograft model, which we've just showed you before. So it seems to be quite well-behaved. It is antigen dependent, and the linker is stable in these models. So tolerability and safety. This is key. So STRO-003 is comprised of a monoclonal antibody that targets ROR1. And if we chose this particular antibody, not least because it was stable or good PK and all the rest, but also because it had cross reactivity, not just to nonhuman primates, but also to rodents. So this allowed us to do a full analysis with a different link, not only the linker [indiscernible] -- not only to check to see how tolerable they were in an off-target manner, but also whether there are any antigen-dependent target tolerability issues we needed to consider. And we were thrilled to see that STRO-003 in rat at high doses up to 60 mg per kg, we observed no neutropenia and no elevation of liver enzymes. So that was really extremely good. For a nonhuman primate studies, which is a multidose non-GLP nonhuman primate study, and we observed no neutropenia at all or thrombocytopenia to dose of 45 mg per kg top dose. No changes observed in white blood cells generally. So that was phenomenally good news too. Now one of the things we did do because of the experience with Enhertu and other ADCs using exatecan payloads, it was to have a look to see what the liabilities might be for lung toxicities. And again, STRO-003 at 45 mg per kg showed no changes, no pneumonitis, no infiltrates, no damage at all in the lung, which will be indicative of a developing pneumonitis or interstitial lung disease with this beta-glucuronidase linker payload. In contrast, the Cathepsin B linker exatecan, and you'll remember that the active payload with the Cathepsin, although it's the same exatecan class, the active catabolite is slightly less potent than STRO-003. We expected that this construct would actually be slightly more tolerable because of that less potent exatecan. In fact, that's not the case. With the Cathepsin B linker, we also saw some lung findings, which were consistent with developing pneumonitis and potentially ACD at that 45 mg per kg dose. So going from Cathepsin B to glucuronidase linker, we both increase the potency because we had a more active catabolite in there. But at the same time, we made it more tolerable than a conventional Cathepsin B linker. So the beta-glucuronidase was clear that, that was our most efficacious, most tolerated and therefore, the widest therapeutic window with this particular construct. It should be noted -- and I said before, the other CatB linker ADCs including associated with a significant rate of clinical pneumonitis and ILD, although drugs like Enhertu are remark -- fantastic overall response rate in solid tumors, but this is a serious concern. So improvements on that could really extend us to be considered best-in-class. So we believe STRO-003 enables a broad clinical development strategy because we've got efficient killing of tumors with low-level ROR1 expression and a very favorable safety profile, is an expansive indication space. And so we'll be looking certainly to explore the fullest number of indications that we think makes sense. Of course, ROR1 is validated in both hematological and broad solid tumors. The opportunity is there. Tougher ones, however, have only really been showing compelling clinical validation in solid tumors at the moment. Although there's no reason they I believe that they shouldn't also do well in hematological tumors too. It's just that, that is not properly validated to share. There certainly are DNA payloads of the benzodiazepine class, for example, that do -- that are finding great efficacy in liquid tumors. So we believe that the benzodiazepine demonstrates impressive pace potentially reducing lung and neutropenia tolerability. I haven't spoken much about that, but that is completely clear. So -- and those things are associated with TOPO-1 class payloads. So we look forward to moving that forward. Our clinical programs. Our strategy is going to be exploring when we get into the clinic, both the prime indication space, but certainly, for solid tumors, this looks like a really excellent [indiscernible]. Now I wanted to move from there and talk a little bit more about these advancements and the impact on our emerging research portfolio, and also talk about some recent news, some of you may have seen with the collaboration with Astellas. So let's just talk through our platform as it is at the moment. So we've been developing the platform, the component parts of this platform and our manufacturing strategy to give us a number of different tactical component parts that we can bring to bear. We already know that Sutro's precision design, its ability to flexibly and iteratively choose best possible sites for conjugation outside of the normal constrained natural amino acids targeting sites can improve efficiency of killing. We also know -- so the conjugation sites do matter. We've also used our system to be able to balance the relative binding affinities within a bispecific antibody to actually improve specificity of the agent to go after carcinomas. And we've used the fact that epithelial cells are normally polarized -- healthy epithelial cells are polarized, so they have membranes where proteins are expressed specifically on one side of the cell or the other. Of course, as the epithelial cell transforms into a carcinoma, that polarization is lost. So we can use that by designing a bispecific antibody that has to bind to one of each antigens to give it the sufficient ability, to internalize and kill as an ADC. You can use that specificity to sidestep some of the common tolerabilities that you would get, for example, with EGF risk binding. And that's indeed something we've done with EMD Serono, and that's a clinical development candidate in EGF for ADC. We've now enabled the TOPO-1 inhibitor payload with new linker, new very promising cleavable linker chemistries, which promise or we aspire, we hope that when we get into patients, they're going to have better tolerability and retain such great efficacy. That DAR8 has been a critical element of getting -- that shown well on other molecules. And we managed to get to DAR8 and above in a homogeneous way and a site-specific, not compromised by having to go to existing natural positioning on the antibody, but finding new space. And then lastly, we've been evaluating how to use these sorts of technologies and our ability to make dual conjugate on the same antibody, which opens up the opportunity to conjugate 2 different mechanisms of payloads. We need to be smart about this, choosing payloads that are mechanistically synergistic, and it makes sense to deliver in the same temporal and geographical location, is obviously the way to go. And we feel this technology is going to open the lid on some new therapies. These are going to be new modalities that we've not really seen before, which move us beyond best-in-class. I want to talk a little bit about that now. So our platform then this is a good summary. I guess, on the left-hand side, where we're looking at different modalities, the ADC on the left, the bispecific see on the right which I just talked about as the example being M1231 and MUC1 EGF. So in the middle, we have this dual conjugation opportunity. And we've got 2 little subscriptive. iADC for immunostimulatory ADC and ADC2, which is we're not going to reveal at the moment, but this is really targeting modalities in dual conjugations, which is really focused on getting optimal ADC activity but also doing something about resistance pathways at the same time to really potentially enhance durability of response and depth of response. So we have options at each time. Because we manufacture and design these things in such a faster and iterative way, we can put these things together and make some fairly late discovery choices on exactly what modality we want to go with. So let me walk you through. On the right-hand side, these are actually a bit of a reveal on the antigens that are on slow simmer at the moment -- or not so slow. But the ones that we're very interested at that moment. Tissue factor, PTK7, Integrin B6, LIV-1 and CEACAM5 are all active programs within Sutro. We're looking at these both as monospecifics, a single antigen targeting potential but also as potential bispecifics in combining one with another. And that's our first choice. Which ones do we go? How do we pair that with the indication? Do we need that improved specificity by combining into a bispecific targeting agent or coming out with them on a specific. So once we have that, then we have choices about how we recognize these things. We now have a toolbox of linker payloads, non-cleavable tubulin, cleavable tubulins and cleavable DNA targeting lasers, including the CEACAM, but also including [indiscernible]. So in addition to that, we've also been developing a number of different in modulators, including Sting agonist TLR7, TLR7/8 joint agonists, and other mechanistically synergistic payloads, that we've already talked about the proprietary cleavable or non-cleavable linkers that we combine with all these. So the question is, what do we want? We can actually go to select a clinical indication on antigen of choice. We can decide whether to tighten that up in terms of specificity. We can then decide -- at a late stage once the antibody is designed, what do we actually want to do in terms of conjugation sites and how do we want to put something together? What payloads do we want to combine? So I'm going to give you an example, which is the basis of the Astellas' collaboration we revealed publicly late last month. An example of combining a cytotoxin with an immune stimulus and to give us a longer lasting response. So we've turned this an immunostimulatory ADC an iADC, and it is a dual conjugation of cytotoxin and immune modulator. So this is a great opportunity to completely new modality, and I want us to think about this rather differently from an ADC. From ADC, you're really interested in precise targeted antigen and how can you get the optimal amount of killing of the tumor by targeting that single antigen. In this case, it might seem a minor adjustment to just add in an immune stimulus as well as the cytotoxic payload, but actually, the concept is very different. What we're looking to do here is mimic some of the very old knowledge that bacterial infections can affect tumor growth. It goes back, I think, several hundred years or at least as far as William Coley, who did some of the first bacterial extracts and put those into cancer patients and got some reduction in tumor size. And that was the whole basis, really the immunotherapy. Of course, these days with the FDA approval of things like BCG, for non-muscle invasive bladder cancer, this whole area of toll-like receptor agonist and patent recognition responses has come to the floor. So we're very much looking at this from a conceptual basis of wouldn't it be good if we could try and stimulate an anti-immune response from the tumor itself? So if one could disrupt the tumor, release too many antigens and equip that with also agonists that would mimic those stimulators in an immune system, could you set up an adaptive response that would give you a far long-lasting response? So we set about trying to do this with the cytotoxin, which we knew we could disrupt and release tumor antigens, but also the hemiasterlin that we did a concept molecule with, of course, is on a couple of our clinical development including STRO-002. And what we did here was reduce that particular warhead because we knew it caused immunogenic cell death, which is a bit of a popular phrase these days. But as an interesting phenotype as the cytotoxin puts the tumor cell in distress, this tumor cell starts -- engages a very natural physiological mechanism of signaling to the immune cells, it's under duress. And this is by [indiscernible] expression on the surface release of HMGB1 and other proteins, which are able to stimulate patent recognition risk. And in addition to this, we wanted to put an immune stimulus, and we used a TLR7 agonist as a prototype, and plant that in the tumor cell. So what we envisage happens in these circumstances is that you are injecting or effectively, systemically administer an antibody, which delivers both the cytotoxic payload as well as the innate stimulus, and that will release the antigens. It will cause an immunogenic death response, which preps it up. Innate immune cells will come in after those released tumor antigens and the debris from those resected tumor cells. When those macrophages and other cells tromp down on that to clear that debris, they will find an activator. And that activator will then stimulate cells, send up the flare, the beacon, and that's what sends in the T cell responsiveness and stand up the adaptive immune response. So what we're aiming to do here is set up a longer-lasting memory response. So does it work? So this is the construct of a systemic administered monotherapy that drives anti-tumor immunity. This is a prototype molecule. Let me stress, this isn't a development candidate, but it shows you what we can do and how we can do it. So the purple stars on this graphic are really the hemiasterlin cytotoxin conjugated to the antibody in a very precise way. So we know something about this is a hemiasterlin tubulin inhibitor on a cleavable CatB linker. And in red, we've put in a TLR7 agonist, which is actually conjugated to the light chain you're seeing another CatB linker. The way in which we construct this is that we are able to make a prefabricated light chain with a nonnatural amino acid, and then around that run a cell-free synthetic construct of the heavy chain, which contains a different nonnatural amino acid. So we can get very precise conjugation and any stoichiometry we want on the same antibody. So on one part conjugation at the end of all this in manufacturing delivers the precise ratio of payloads that we've chosen to these specifically chosen sites and is very high fidelity for those different sites for each payload. I'll come back to this a little later because this is the basis of the sort of modular manufacturing data. So when we look at molecules such as this, you can see here, we have a -- these are MC38. This is a tumor -- a mouse tumor. We're looking at mouse tumors in an immune-competent mouse -- mice system. And then on the top left, you can see the vehicle. So that's the [ seed rate ], and how well the tumor grows very quickly and aggressively. And it's this MC38 mouse tumor is transfected with the human tumor-associated antigen that our iADC is coveted. If you were to look at the ability of an ADC that targets that antigen on the mouse tumor loaded with just the hemiasterlin DAR4. So this is in blue, top right. You can say, these are individual mice. You can see most do quite well after a single injection of the ADC. The ADC does reasonably well, but -- and some of them do very well. They are 3 complete responses in this group. At bottom left, you can see, if you do the same thing with the same antibody now conjugated with 2 TLR7 agonist on the light chain, you can see there is a little bit of a delay in tumor growth, but there is nothing like the response you get with the ADC. When you combine both of these things in red on the same antibody now, so 2 TLR7 agonist on the light chain for hemiasterlin cytotoxic on the heavy chains to give you 4 plus 2 iADC. Now you can see that directionally, it's going in the right way. We're getting 5 out of 7 complete responses just after a single dose. Now if you take those surviving animals and now you rechallenge with the same tumor, that's on the right-hand side, what you see is that you cannot regrow that tumor. Now is this because the iADC hangs around for a long while, and that's 60 days out when these rechallenges mice. And the naive animals are age-matched mice showing that, that tumor will grow. We know that that's not due to residual amount of the initial therapeutic there because we know that if we try and rechallenge with the MC38 cells, which don't have the initial tumor antigen, the human tumor antigen transfected into them, we still get complete inability to grow those tumors. So effectively, what we're saying is that there's likely a cross epitope learning, a memory response to an adaptive immune response, which gives these mice protection from further regrowth will be challenged. A further experiment we've actually done show that this is dependent on CD8 cells, and if we deplete CD8 cell, these tumors regrow. So that's pretty exciting to understand, and directionally points to the fact that these combinations may work well for us if we can optimize them for efficacy and tolerability. Now if we look at those tumors, and we ask the question of what was -- compared with vehicle, what's happening to dendritic cell activation in the tumor. And you can see on day 1 on the left, the dendritic cells are activated by an ISAC that just targeted TLR7 alone, but not by the ADC. And they are targeted, of course, by the iADC, which also helps the 2 TLR7. And if we switch across to the right-hand side, you can see that although that innate response, as you'd expect, it's a day 1 of that. It's an early event. We're not seeing any change on day 1 in the adaptive, so the CD8 component part. But you can see at day 5, there's a developing response in the CD8 T cell in the iADC population, not so much in the ISAC population of TLR7 alone. And indeed, if you look at the CD8/Treg ratio, again, that seems to be enhanced which is exciting. Now if you -- I like visual. So if you look at the staining of the CD8 cells in these different tumors treated with these different treatments, you can see that the iADC population of CD8 has increased. So that's very promising. Just quickly trying to make sense of the iADC versus these other sort of modalities. You can see that we think it's pretty important to have both the antigen released to direct tumor cell killing as well as the ability to try and stimulate innate in order to drive T cell recruitment of this adaptive response. So from that perspective, I think this new modality covers the Gamba really and the ability to be able to drive an in situ immunization from a systemic administration. The thing that's really different, I think, though, is that what we're now seeing as potential for bystander effect, not driven by a cytotoxin, which leads out into the grounding tumor microenvironment kills surrounding cells. This bystander effect is caused by the immune system. So you're giving it the 1, 2 of both antigen as well as late activator, which potentially sets you up to get almost like there I say, vaccination-type response in response to a systemic administration, and it's obviously personalized to that individual patient tumor. So this is quite complicated. And clearly, the reason why I'm talking to you about a concept molecule rather than a development candidate is that there are a lot of moving parts and a lot of things we've had to cover to get that combination precisely at the right levels of each component payload place in the right way. So -- but there's great promise in here, and this is the basis of a very exciting new collaboration with Astellas to find out whether to push these candidates through to the clinic as quickly as we can. Now I want to go from there and just talk to you a little bit in the final few minutes and talk about our product and process design and how the integration and relationship between the product design is integrated entirely with the processes, and how that then converts for what are seemingly really complicated molecules into a very measurable component part modular manufacturing base where things become quite straightforward as we go forward whether it's predictable manufacturability. So I'll cover the key aspects. So we effectively have an open system. If you think of a large organization with maybe 100 different products, each of those biologic products is manufactured in a separate cell line. It's like having 100 manufacturing solutions. What we can do is generate 100 different things with a much smaller number of component part. The reason for that is, we don't need a separate cell strain for every product because we make everything in our portfolio to date with 1 cell strain, which -- from which we derive an extract and that extract, of course, is clear. There are no living cells there, it's just the raw transcription and translation operators, which we're harvesting. That extract can be used for all of the products in our portfolio today and everything that you've seen in the future from what I've just described. So that ability to break open the sell and use that as an extra gives us an ability to spot, probably expect to use it at any time. It's 12 hours from a protein when you add DNA to this extract and support it with the reagents, energy and immuno acids, of course. And you can do that at any scale. So the link between design and what you will do from a manufacturing base is incredibly close. You're choosing from many different protein variants, which are going to be a lead. It could be an antibody discovery, trying on new CDRs and a fully folded IgG for the first time. It's for a synthesis, and you can pick already which ones are going to fold up well, behave well very quickly. And they -- so your choice of starting point, your choice of antibody leads is biased by how manufacturable it is because it's the same exact reaction, which we foresee even at 20,000 liters. So we've already demonstrated this transferability from microliter 5 ml, 10 ml, 8 liter level expression in our research labs through to larger scale in our process development labs and out to 1,000 liter single-use bioreactor in Sutro's own GMP facility in San Carlos. And from that sort of scale, it's derisking the further scale to 20,000 liters and beyond, if we so wish. So this idea of an integrated synthetic biology enabled by the fact there are no live cells or membranes gives you an open platform for different modular component parts to play in your design. So we've already talked about one example, which is a prefabricated light chain, which we can actually put in and then build the rest of the antibody around it, and that can change how you conjugate to it. The way in which we build this, of course, we're designing aspects of this, which carry through and are common in process development. So the fact that we always use the same strain means we always have the same host cell protein background. And so many of these component unit operations become very familiar and very straightforward and same again every time we treat the same. So I'm going to try and get a summary through how we do this. Now on the left-hand side of this diagram, we talk about how we design. So we're looking at patient needs, where the limitations are really, whether treatments are really limited. Where are the precedent mechanistic things we could try out really quickly, and of course, we have interest in commercial opportunity as well as the medical need. But the speed with which we can put something together is really cheap because that means we can make many versions of something to optimize. We can look at different things quite quickly and engineer them very fast as proof-of-concept things, where we can scale quickly as well to be able to do in vivo pharmacology and efficacy of these contents as well as go fast into nonhuman primates. And if we don't like to look at something, we can redesign it, go back in 2 to 3 months. And that's really novel in terms of biologics and the year-long process. It normally takes to get a stable cell time to equip those sorts of studies with decent quality and quantity of product. The continuity is key. So I mentioned the whole cell-free reaction that we do at very small scale is exactly the same as we do at large scale. So because ADC is a complex molecules, ultimately, the clinical profile depends on all of these features coming together. There are attributes well-behaved [indiscernible]. Those attributes can change. If you have to design an antibody and you express it in a stable transaction, then you migrate to a stable cell line in time and then commit to all of the difficulties in conjugation, the quality control and so on. That -- the spec of that molecule can change in time and sometimes that can compromise what was originally started up as quite a nice reserve tool. For our system, we don't change it. It's the same system. So not only are we able to preserve the integrity of the product profile, but we're also able to see how we will get cost-efficient gains. We're able to see that what we choose to go forward with is actually biased for the ability to be able to manufacture because it's the same system. So that seamless scalability from milliliter scale to thousands of liters, I think, is really key with no formatting changes. The second part I wanted to just call out was the rapid process development. So we know we can get a cell-free reaction, which can be quickly deployed to produce new molecule within days. It's almost an on-demand system because we can stockpile that. And beyond that, we have a number of components we can bring to there. So we have a core cell-free product agnostic manufacturing process, the extract and sell-through reaction. We also have off-the-shelf reagents, which are specific to this cell-free reaction to support it as well as -- and I've mentioned before, stockpiled GMP-ready prefabricated light chain. So where common light chains are used across different antibodies, we already have that component part. We can bring them in. Linker payloads, we used to -- we're all used to thinking of linker payloads as components so we can switch and to change across different products, but the modularized process options by selecting from these now is really interesting. And we can take pretested, pre-optimized versions of these component parts and combine them in new products without having to repurchase everything from scratch as you would. Lastly, the standardized control strategy because it's a same strain. It's producing the same extract. We're able to actually produce packages to refer to by health authority review, which are familiar. I mean the predictable CMC packages using the same component part. So I just want to give you one example, and this is very relevant in Sutro relation, prefabricated light chain. Now for 2 of our molecules in clinical development, we've shown that premanufacturing a prefabricated light chain that's common to both antibodies is actually quite useful because we can add it into the cell-free reaction. So the cell-free reaction itself is only making a heavy chain and placing nonnatural amino acids or an ADC. If they place it, they're positioned in the heavy chain. So just the wild-type sequence. So native amino acid-only prefabricated light chain was very familiar with having that as a component part that's prefabricated. We actually make it in an intact on the same background strain as from the extract. So they're not confusing or contributing to the complexity of the GMP process. On the middle one, there's another variation. So think common light chain, same prefabricated light chain, but now with a nonnatural amino acid. So this is exactly how we're using ROR1. Again, it's on a common light chain. So we could take a number of different antibodies that use a common light chain and substitute this component part in with a nonnatural amino acid late-stage discovery just to ask the simple question. So in this case, do we want DAR4 or do we want DAR6 that you could do on the left-hand side or do you want DAR8? You do that for this middle things. And then lastly on the right, now if we can do that, we can also use the common light chain, but now have already equipped it with a different nonnatural amino acid for an orthogonal conjugation chemistry, which allows you to do, in this case, 6 on the heavy chain plus 2 on the light chain, 2 different payloads. So that's how we think of putting things together using this modular production process. And so actually just to add a little bit more complexity to it. You have to balance the 2 payloads. There's no point in having one very potent and the other not so. It's not going to work. It will -- that molecule, obviously, will -- one payload or the other will dominate. So the ability to do what we do and part of our optimization process is exact as I've spoken. We can switch the ratio. In this case, on the left-hand side, are red payloads to yellow payloads. It was a 3:1 ratio on the left-hand side, and a 1:3 ratio on the right-hand side. So this can be done by modular components and done very quickly, also looking at different sites to actually end up with the right balance together with the chemistry input. So we've got a strong medicinal chemistry outset that's absolutely critical to everything we do. Although we're known for our engineering, we're also a medicinal chemistry company that basically ties into synthetic biology and medicinal chemistry and make complex molecules like this. So this is another key aspect of the flexibility of our system. Now lastly, I just want to touch on very quickly on CMC and supply chain strategies for both 2 important aspects of what we do, faster clinic and commercialization. So the first thing, we have experienced in it. We have our own GMP facility where 6 product candidates have gone through. 3 monospecific ADC's, a bispecific ADC, a Cytokine bio-conjugate and a conjugate vaccine. So establishing -- what we've been doing is establishing and doing a robust external supply chain for these -- for clinical supplies of these molecules. So we have linker-warhead process chemistry and GMP manufacture. We have conjugation established with external that can do that and form drug -- product from drug substance for both ADCs and bio-conjugate. We obviously are doing fill and finish. So drug product and vials, clinical packaging. And so our extra and customer reagents, which are the rapid common agnostic platform can be applied very quickly to antibody-based and cytokine product development and manufacturing. So in the future, now we've got put themselves through these processes and support, we can move quickly through the clinic. And lastly, our strategy to CMC commercialization. So Shabbir Anik is on the Q&A panel, well, I'm sure would be happy to answer your questions, if I don't do this justice. What Shabbir and colleagues have been doing is establishing a CMO network for all of the components that we need to deliver scalability, notably extract and then the sell-through action itself, but also including things like the prefabricated light chains and customer agents to support this whole thing. And really, that scalability that comes with the CMO network is going to allow us to build an inventory, minimize risk and to support clinical studies and commercial launch in the future. So we talked about the extra, we can take down now. It's quite phenomenal that you can take a biomass extract and dry it down, add water and get all the attributes back, all the transcription, translation and the capability to generate energy in situ from -- by feeding it low-cost energy. The scalability that's now being put in place externally is 10x the capability or capacity the Sutro's San Carlos facility has, which is great for vendor Phase I clinical trial material. But this scale will now allow us to do registration studies in commercial. And then GMP batches for the extract are in process and will be coming through in the last half of this year. For customer reagents, we already have large-scale GMP batches manufactured, and prefabricated light chain have already exemplified with large-scale GMP batches manufactured for at least the clinical trial. I will cover that right now. And then the cell-free reaction itself, the production of protein we've selected a CMO, the GMP batches on track for the end of next year. So with all of this in place, the supply chain should produce over 250 kilograms of antibody per year. So lastly, just to conclude, we have a number of unit parts of our design and process and manufacturing, which are impressive. We know the rules. In other words, we don't have to do an iterative design of every component. We know where we're going now. We have rules that we now go-to sites for conjugations and that convergent optimization of product design makes everything more efficient going forward. The modular process development, I hope I've done justice to kind of accelerate our process development and the way forward to have a predictable manufacturing platform. So the other aspect of our manufacturing platform is that it's very simple to outsource and produce on demand. It's flexible. So it allows us to move technology around the world or to, obviously, to partners, allowing them to control their own CMC schedule. Lastly, just to conclude, I'm really excited that we've been able to turn the platform now into something that can come up with new modalities, targeting combinations now, but targeting to tumors to reduce their combined tolerability issues to really play into getting the immune system to go after tumors that are cold, in other words, introducing cytotoxic T cells into there to [ create ] that, and also to address other aspects that have presently been done in combination where targeted therapies could do so much better and to deepen responses by targeting resistant pathways at the same time. So with that, I'll turn it over back to the operator for a Q&A session. Thank you for listening.

[Operator Instructions] Our first question comes from Roger Song with Jefferies.

Great. I appreciate the detailed presentation for 003 and ADC and CMC. So I have a couple of questions related to 003 ROR -- ROR1. So the first one, is the magnitude of the cancer-killing also 003 ROR1 expression level dependent? Because I see the small cell PDX model seems not clear, works pretty well even in the low expression level. But have you done any other model as a cancer model NSCLC consistent without?

Trevor, if you can handle that, please?

Roger. Yes, I mean, the -- what we were showing there is relatively high dosing. In fact, when we run these studies we were having a real good look. This is a 10 mg per kg, 4 doses. So if you give lesser doses or lower doses, you do see less efficient killing but still remarkably good. I think in terms of the -- I tend to think of antigen dependency and antigen density, as long as the antigen dependency and the antigen density is more predictable in terms of dose. So you either get the dose or you get with an antigen density for a given dose. So I think there's an intricate relationship between the numbers. What we're really trying to look at though is whether clinically, this is in the relevant place for efficiency of killing. So if you combine this slide, looking at the antigen density itself being low, we're giving good killing. And you remind yourself that actually the killing is absolutely antigen dependent, and I think the rationale follows that the antigen will have a relationship with what you're dosing, it just depends on whether you're going low enough and dose to demonstrate that. And from what I've shown you, I'm not sure that, but that's our expectation. I'm not sure if I answered your question.

No, no, I think that answered. If you go some dose lower enough you will see the difference. Obviously, if you go higher dose, basically everyone kills those cancer cell regardless of the antigen expression level. Okay. I got it. All right.

The things that confuse it, Roger, is the linker is unstable and you've got a systemic play of active catabolite or payload lasting systemically in -- at the same time as you're trying to get an antigen-dependent response. So with ADCs, which are poorly behaved and are shedding active payload as soon as you dose, you're going to lose that because it's almost like a slow relief chemotherapy. This isn't one of those. This is a stable ADC. And so they're also a little bit more straightforward.

Yes. Got it. I see that in the second slide, we see the no killing in the ROR1 negative cancer model, so that speaks to the stable. Got it. All right. So that's good. And then -- so I know you just announced candidate, maybe a little bit too early to talk about the clinical plan, but just maybe just broad stroke, what will be your time line or the plan for the R&D filing and the potential clinical indication in the study?

Roger, this is Bill. I'll let you know that this is a target that we're excited about because we believe there is tremendous potential not only in hematologic malignancies but also in solid tumors. As we're moving through the IND-enabling work and the CMC processes, we'll be refining what our clinical strategy is, but I think you could anticipate a relatively traditional dose escalation process in a basket trial looking at a wide variety of different tumor types. There is tremendous validation for this target, we believe, in hematologic malignancies, and we're excited about its potential as well in solid tumors. So stay tuned, we'll be revealing more of that strategy and our thinking probably next year as we get closer to when we're ready to enter the clinic.

Excellent. Okay. So maybe just one last one. Obviously, we know Merck acquired VelosBio $2.8 billion for the DLBCL ROR1 ADC. Maybe I see you have data from 1 PDX model showing some superiority. But just the way you design your molecule, is that one of your benchmark where you try to be in the preclinical? And also, have you seen consistent preclinical data across different models where you compared to your competitors?

Trevor, why don't you go ahead with that, please?

Yes. Roger, that's not that -- what I showed you was the VelosBio linker payload to a different antibody. It's not supposed to be anything like the VelosBio's antibody. We were just comparing antibodies with the same properties as STRO-003, but charged with different payloads. So it's DAR4, MMAE versus the other equity conversions. So I mean, I think that what we're looking for, for duration of response is beyond where the tubulin enablers have gone in terms of -- or at least to date and what I've seen publicly in solid tumors. So we're looking to get much deeper responses, longer duration. We're obviously keen to make sure we're seeing what we believe are strong benefits of immunogenic cell death, those sorts of innate cell stimuli caused by sufficiently long and stressed tumor cells that the innate immune system has a leg up to go after. And we think that's going to be particularly important in solid tumors for combinations with things like checkpoint inhibitors. So is tubulin the optimal payload? No, I don't think it is. I think the data to date with the top 1 inhibitors is really impressive. And that, to my mind, I wanted to ensure that Sutro had the full benefit and is playing on the same -- well, same level playing field as some of the other opportunities now where the ADC field has gone, but can bring our own unique differentiation of both everything else as well using our engineering plans. So yes, so really what we're looking at is how do we get the best possible response with the best possible tolerability for solid tumors, payload, linker and then the overall design, dollar rate and where you currently stand because they all play with each other to give you the widest possible therapeutic index and the deepest response.

Our next question comes from Nick Abbott with Wells Fargo.

First of all, just sort of kind of following up on that last theme. I think you said in the past, Bill, that in order for a product to become a development candidate, it has to be clearly best in class. So maybe just summarize for us going back to VelosBio product, ADC, what do you think the advantages are over that product?

Trevor, do you want to talk a little bit again about the new design elements we're bringing?

Yes. Nick, I mean I've had a little look about what's publicly around about VelosBio and it sounds very interesting. And they had a recommended Phase II dose of 2.5 mgs per kg every 3 weeks coming out of the hematological cancers. And I think Merck saw that and probably saw some solid tumor data as well and made the decision to go. I was interested in changing in the sort of dosing the dose fractionation it seemed late last year to go for a 3.5 mg per kg dose for solid tumors split into 2 times 1.75 at day 1, day 8 per 3-week cycle. I know the 2.5 mg per kg, we're seeing neutropenia north of 2.25 mg/kg. So I would expect that trying to push up from 2.5 mg per kg may have some limitations. And I think that neat way of fractionating the dose like that may give them the opportunity to load up the solid tumor higher to get to higher hair doses, high levels of efficacy, while managing a neutropenia response. At least that's my interpretation without knowing anything from what they've done. So neutropenia is clearly an issue there. One of the key aspects that we wanted to do is get out of some of the CatB related neutropenia liabilities that can occur. And we also noted that although exatecan seem to be very tolerated. They're still not -- they still do have some impact on the tolerability as well through the CatB linker. So we wanted to get away from that just to see what we can do. And so I mean, one notable is that we don't see neutropenia at very high doses in the monkey. Just to give you an idea, we expect to see, if we go from mice efficacy to humans, we think those sorts of exposures, the efficacy is going to be in the 2 to 3 mg per kg range. I hope we don't get too surprised, but somewhere around there for Phase III. I think in the efficacy on the non-human primates at 45 mg per kg, while we're free of neutropenia and free of institutional lung disease and even other symptoms, at least in the short-term pre-IND GLP studies -- sorry, non-GLP studies in non-human primate. That translates with exposures to about 15 mg per kg or so. So that gives us quite a wide window from 2 to 3 for efficacy up to maybe 10 to 15 for where you start -- where we know we're clean at the moment. And of course, that's not the same thing as doing chronic dosing and where we will eventually go. So -- but it's very promising and it's exciting. And the fact that we're seeing an improvement on our own designs for CatB exatecan going to the beta-glu exatecan is even more exciting because the CatB exatecan are clinically validated, and we do have data points now.

Perfect. And then maybe a follow-up. I just want to make sure I fully understand the comments you made about this cross-species activity, the antibody. Are you saying that it has the same antigenicity profile? And that the lack of lung tox is occurring in the context of no or low neutralizing antibody development?

No, I'm not saying that. I'm talking about the ROR1 ability of the antibody to bind ROR1, either rat ROR1 or monkey ROR1. So it's easy to see good tolerability sometimes when your antibody doesn't bind to anything. And it's the purest form of does your payload fall off and cause some collateral damage. Where it does bind, you've got the other things. So what mechanisms are the low levels of antigen density express in some tissue, which normally you wouldn't see if the antibody can't bind to. But now the antibody can and it signals that there may be a flag there in that particular tissue. So that's why it's useful to have across the activity to ROR1 because you can get an early look without needing to go to monkeys. But in this case, even though the antibody could hit both ROR1, so rat ROR1 as well as non-human primate ROR1, we didn't see any flags there that would indicate if there were anything other than known tolerability issues associated with targets. And we were looking very hard and even though we expect to see lung, we expected to see maybe some neutropenia because of the nature of the payload. And it's been demonstrated before, we didn't see any at these high doses. And so that's a testament to the design of stability, the link of choice and so on.

So just going back to your long-term stability, that would be highly differentiating. I guess how robustly can you test for that outside of a human?

Sorry, Nick, I didn't quite catch your question.

Yes. Just going back to the issue of the exatecan, I guess, related to lung toxicity, how robustly can you test for that outside of a human? I mean how confident are you that you avoid that liability?

You never worry. At the end of the day, it has to be in human. But there are some aspects of similarities that we can see from what's published before and what's the patient's experience and what's been seen preclinically, which we control. The close relationships are there, then we can -- we could make the conclusion that, that does translate. It might be wrong, but we could. And so improvements like this, I think really as we can do in terms of reassuring ourselves that we're not seeing some things that do translate. So like anything -- and of course, it's different again because site-specific conjugates were not using SYSTANE, we're using non-naturals. We're using a different linker compared with Enhertu. Any of that might change and throw our translatability off, but we do these things for a reason. We go into monkeys for a reason. We don't want to go with an unsafe drug. And we have an antibody that recognizes ROR1, and we're not seeing -- it's very well tolerated. We're very excited about going forward. So that's all you can glean really.

Okay. And then just I guess, just the last one for me. I know Enhertu is not an antigen on your list, but presumably, given the data you have, there could well be some interest in Enhertu version, you are leveraging that beta-glucuronidase linker and exatecan platform. What are your thoughts about business development and co-development opportunities around this exciting platform?

Thanks, Nick. I'll let Bill answer.

Thanks, Trevor. We've had a lot of interest from a lot of different partners on both our antibody drug conjugate platform as well as on the iADC platform, not just limited to Astellas. So we think that there are tremendous synergies to be found with a number of different companies that are interested in different targets than we may be interested in. And we're open for business in that vein and looking forward to continuing those discussions. And hopefully, today gives people an even broader appreciation of the breadth and depth of our platform technology and the various ways in which we can rapidly advance molecules forward so that we have the best-in-class opportunity or people are interested first in class and be assured of manufacturability. So it's an exciting time for us, and we're delighted to be engaged in so many different conversations. We don't guide, as you know, on any particular deal objectives, but we are actively in conversations as we speak here today.

Our next question comes from Boris Peaker with Cowen.

I'm just curious, is there any competitive data on ROR1 in the horizon we should be paying attention to or that may impact your development strategy for 003?

I think, Boris, people are still waiting to see how the VelosBio data comes out. That's probably going to be the next most significant bit of data for us to look at. And one of the advantages being where we are in terms of the development of this asset is we've learned a lot in the field in order to design better reach. We've now got this new linker and this new [ Hemiasterlin ]. And so we'll be following as we have historically the evolution of programs like the VelosBio, like perhaps the MBE molecule as well and really understanding what the opportunity is, what the desire and, frankly, also what the liabilities are because we have such a significantly differentiated molecule. We think we can learn quite a bit and adopt a very fast follower strategy here once we move into clinical development. But I would keep an eye out looking particularly for the Merck program from VelosBio.

You mentioned ADC square, if that's how we refer to it. When are we going to get an update on what that really is or any kind of programs out of that?

I'll let Trevor, since he's the one who put out the terminology, to handle.

It just my sense of humor, I guess. But no, it's really meant to capture other systemic mechanistically synergistic mechanism we might put together. And there are a few of them out there. We're not ready to reveal those yet. But yes, stay tuned.

I think we had enough for everybody today. So we'll just save that for a future date for us.

Our next question comes from Asthika Goonewardene with Truist.

First of all I want to say thanks for putting this very informative discussion together. This is very helpful to us. And I really appreciate all the detail and color that you provided here. And congrats on disclosing more on 003, which we've been waiting for. Maybe some questions on 003 and also get your thoughts on how it compares to the other competitors, VelosBio and the NB-02. Maybe I'll start with the targeted epitope and the binder. I want to know if you guys -- how is the epitope and the binder that you're targeting with 003 is differentiated from the others? And then I've got a couple of follow-ups.

Thanks, Ash. I'll go to Trevor.

Hi Asthika. Yes, there was some background -- there was some information around CAR-Ts at one point in certain indications where there was some concern over whether a binding appetite was too far out from the surface of the cells to be retained. In that particular indication there was evidence that there was some shedding of the ROR1 and the epitope of the particular the CAR-T would bind to. So of course, that would be compromising. So we're aware that there are those sorts of discussions going on. But that was an immediate concern for us when we embarked on this program. With the VelosBio program, we believe we have an epitope which overlapped, if not identical, but I think that it's pretty -- it's going -- I think it performed pretty well similar to the same -- in the same epitope with the VelosBio antibody. So from that perspective, I will be watching the VelosBio Merck program very closely and to see whether that is reproduced or whether they see large amounts of dissociation. So we are pretty excited with where we are. We think we've made the right decisions in terms of epitope choice.

Okay. And then I just want to confirm, Trevor, the warhead that you use is exatecan itself, or is it a modified version of exatecan?

The Enhertu warhead is a direct exatecan. Our STRO-003 catabolite is exatecan. And the one on the CatB linker releases a slightly different catabolite again. So hence, this discussion around slightly different potencies and seen with the different things and slightly different tolerabilities of the ADC in its entirety. We're not sure whether that's driven by the difference in the catabolite or the difference in the linker release or liabilities or whatever. But the bottom line is we're very happy with the choice of the active catabolite we derived from STRO-003 and its linker mechanism.

Okay. And then if you were to maybe benchmark the membrane permeability of this versus, let's say, DXd, would you expect them to be sort of similar? Or how do you see those circumvent, Trevor?

We expect us to be very potent. I haven't done a direct comparison.

And then have you benchmarked the level of immunogenic cell death that the warhead drives versus, let's say, [indiscernible] and hemiasterlin.

I think that, TOPO-1, which is exatecan itself is known to be a very potent name in immunogenic cell dose stimulus. So I think it's -- it looks very well. The hemiasterlin itself is really quite good. I think the exatecan is even more potent.

Got it. Okay. I just want to try and understand the specific differences between these different ADCs here. Maybe if I can squeeze in a quick question on MK-1484. I just want to get some thoughts on what the next milestone payments have been or what milestone payments have been recently triggered by Merck kicks into a Phase I study.

Thanks, Ash, for talking about that asset. We're excited that it's moving forward with clinical development. And when we're ready to talk more about that, we'll be in a position to do so. So I would say, stay tuned, but it's not something we're going to be discussing today.

Our next question comes from Reni Benjamin with JMP Securities.

Congrats on 003 and this presentation. I guess I'm most interested in any sort of combination work that you might have performed and how we should be thinking about the development of this asset going forward in terms of either add-on combinations or given kind of what Trevor went through is how it's easily modified, whether or not you can drop the DAR down to, let's say, 6 and add on, let's say, 2 TLR7 molecules or a TLR7 and TLR8 molecule, essentially get a combination within one molecule. Can you give us some thoughts as to how we should be thinking about that?

Trevor, over to you.

Of course, it might be. So yes, I mean -- are you talking about ROR1 specifically here?

Yes, ROR1 specifically.

So I mean -- yes, so it's all about the indication of the antigen combination, of course. And also whether treatment paradigms, standard of care, what sort of tumor are we looking at? Is it cold? Is it hot? Is it one where there's a great deal of resistance of particular mechanism of that you're driving with the payload and so on. So there are already clues precedented, of course, in clinical practice with some of these things, with some of the payloads and different things in combination. We expect the iADC constructs to be extremely good when combined with checkpoint inhibitors. We're providing a component part, which is enriching CDA-positive cell populations and driving an adaptive immune response. It would be astounding if we can't reproduce some of the exciting preclinical data we have, that this doesn't actually -- if it acts the same way and it is driving that bridge from the innate immune cell stimulation or activation through to adaptive immunity, then we would really expect to see a great contribution from checkpoint inhibitors there. And so those are opportunities to further define and further move. And the fact is we have now a foundation of tolerability that we've begun to build with a DAR8 exatecan ROR1 and all the component parts are pretty well, will be GMP ready in a short period, it's relatively straightforward to switch, say, the light chains with a different on natural to do as you say, if we so wish. Of course, it's all about money and where we think the opportunity is to generate value for the company.

Right now, we're really focused on driving this asset, the ROR1 ADC into the clinic as quickly as possible. And certainly, the possibilities of combination therapy and/or modifications to make this more of an iADC player are downstream. But we want to start with what we think is a very exciting opportunity as an ADC. And with an exatecan DAR8 and this new linker, we think we've got a really great molecule that can benefit patients. But I appreciate the creativity, and we'll be thinking through that stuff as we continue to progress this program.

Got it. As we look at both the low and heterogeneous ROR1 antigen levels, right, like on Slide 9, am I reading too far into it? When I look at the ROR1 2+ mouse model, it doesn't seem to achieve the same sort of tumor -- antitumor activity as the ROR1 1+ levels. And so it would seem to suggest that maybe a biomarker strategy might be important in developing this further in the clinic and maybe selecting against high expressers. Is that too much of a read? Or is this more of a mouse model sort of artifact?

Both. I think it is too much of a read. I mean these are chosen to be sort of representative. I mean, I'm just looking at -- okay, we got good everything? Yes, great. That qualifies a different linker because that was a concern about beta-glucan expression, for example, across human tumors and so on. So -- but I think you're absolutely right. I mean we're absolutely -- we would be planning to be doing a basket trial in heme and solid tumors, for example, 2 separate baskets, then we will, of course, evaluate whether we need to enrich. And -- but I think it is too deep a read on these particular PDX models. They're fraught with lots of other factors going on, you can't really quite control for across by comparison. So I wouldn't read too much from there. To me, it's validating in terms of linker choice and nice to see good efficacy at low antigen density.

Got it. And I guess just one final one for Bill. When do you think -- you may have answered this, but when do you think we might file an IND for 003? Would that be next year or the year after?

Yes. I wish it was this year, but it's not going to be. At this stage, we're working through the process development and the IND-enabling work. I think we've not guided to when this is going to be in the clinic. Typically, molecules at this stage -- and remember, this is a brand-new design for us. It takes about 18 months or so to get into the clinic, but we're going to certainly work hard to beat that. And when we're ready to announce the time line, you'll be one of the first to hear it, Reni.

Our next question comes from David Nierengarten with Wedbush Securities.

Most of might have been asked, but I wanted to ask a question maybe a little more on the heterogeneous expression and what does that mean for cell killing? Is there -- or do you think there's a threshold of kind of 0 expressing cells and you can still see an effect? And does that change with general expression level of 1+ or 2+? I know it's kind of a tough question to answer probably in the PDX models, but I'm curious because it might be reflected in the confidence levels of tumor types that could be treated by Bio3 in the future, looking at some of the papers of expressing levels and proportion of tumor cells that express and things like that. So I was just curious if you had any thoughts around proportion of expressing versus level of expression in different tumor types.

Trevor, over to you.

Yes, it's a little too early to know. We've done -- we do studies where we go from sort of 2-dimensional projects a 3-dimensional project, which is sort of in the cell-killing area where I showed to you, there was no bystander effect. So it's all antigen-dependent as a 2D culture where any released payload is relatively diluted away. If you go to a 3D culture, you can build up some of the concentrations around there, and you can start to get a feel for how much primary tumor cell processing, there is a stable ADC to release enough payload to then have a knock-on effect of those sort of [ next ]. It's quite competitive. I'm not totally sure it predicts either. But you're right, somewhere in the middle there. There's a scenario. I think it's actually rather difficult to -- well, one, I could establish it, but then I know what your question would be of me if I did show you that, you'd say, "Well, how can you translate [ Azinova ], how do you know that?" So it's a no win game for me. Suffice it to say, there is good -- there are good -- there is a good bystander, strong bystander effect there. We know from -- I mean, the more important thing for me is it can we're getting sufficient killing of a heterogenous ROR1 PDX. So it's obviously giving a good strong response. And I do -- we do know from the other things we've done, that we are able to ensure that we're not killing immune cells straight out of sites -- those systems are populated. So we'll be doing more than that. I think the designs and efficiency we have with our system allow us to be very, very sparing with the level of payload with dosing and that reach the tumor because each payload can efficiently get to the tumor and to the tumor cell. And I think like with STRO-002, those, what we're able to see there is good efficacy preclinically and in MC38 models, where you're able to see, in combination with checkpoints, we've demonstrated with STRO-002 that we see good enhancements of CD8 populations. There's no apparent clear-out because you're using an ADC in some of those systems. You're enriching the tumor for CD8 cells. So there's not such a strong bystander effect that you're wiping out all immune cells, which [indiscernible]. So it's just a bit of a tight road though. And our key design is let's get this really efficient. Every internalization event is optimal. Every molecule is optimal. And with that, that's homogeneous, and it's the right conjugations and the right number for the right potency for the right linker to ensure that every internalization event is optimal.

There are no further questions at this time. I'll turn the floor back to Bill Newell for closing remarks.

Thank you all for joining us today. Trevor, thank you for such an extensive presentation and discussion both of our next molecule wholly owned ROR1 ADC will be STRO-003. We don't talk about these molecules until we're highly confident of our ability to deliver on them and to bring them to the clinic. So this is a DAR8. It's the first DAR8 from Sutro's platform. It's site specific with a new and exciting exatecan warhead and a beta-glucuronidase cleavable linker. We also had a chance to talk a little bit today about what our platform is and how we've been building it so that we really have a modular approach with the most advanced linkers, the most advanced warheads, the ability to do dual conjugations to mono or bispecific targeting. All of that is really up to the research team here, and they've done a tremendous job of breaking new territory in protein engineering design and chemistry that no other company, we believe, is capable of doing and certainly not a company nearly our size. And then to actually extend that into an integrated manufacturing system where our biochemical synthesis really works well because we premade many of the component parts. And so we've got rapid scalability broad flexibility and a path to commercialization. So happy to really dive more deeply on all of this with others in the coming days and weeks. This is really a summer break for us in a sense that we get to talk about the underlying platform technology and our next assets. That doesn't mean that we're not hard at work at advancing STRO-002. That continues to move forward. And we look forward to having an opportunity to speak with you all later this year about what our conversations with FDA are, our path forward to a registration-directed study, what our final data sets are and really what our clinical design is. So this is more of a scientific lecture in some respects and presentation. I'm looking forward to actually getting back to clinical dialogue with you all later this year. So thanks so much for tuning in today, and appreciate your interest in Sutro and your time today. And that's it, operator.

Thank you. This concludes today's conference. All parties may disconnect. Have a good day.