Good afternoon, and welcome to the Sutro Biopharma Virtual Deep Dive Research Forum: NextGen Innovations in ADCs. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up for your questions. 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, 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. Shabir 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 six 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 spin-out 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 through today, Sutro has averaged more than one IND filing per year from products emerging from our platform technologies, and we look forward to adding to that with the 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 gonna go. Just while we're on this slide, as Bill just mentioned, we have six different clinical studies going on so far, clinical candidates in development, four of which are ADCs, one a vaccine, conjugate vaccine with Vaxcyte, and the other a 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 number precise conjugation sites in these molecules.
The common thing about all of these different biologics is the precision with which they're designed and the specificity and fidelity of their conjugation site. This ability to design fit for purpose is really, I think, a unique differentiator for Sutro, allowing us to conjugate very precisely and to completion to result in homogeneous molecules in a drug, which is quite unusual in complex biologics to be able to get that precise. Also our ability to conjugate sites which are not predesignated by natural amino acids like cysteines or lysines, but where we have the flexibility to roam around the protein to find the best-performing site. For ADC, that's all about a really efficient site that's optimized to be able to deliver a cytotoxin to 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 vaccine and retaining the balance between a core protein and those things that are conjugated to it to optimize immunogenicity. 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. Without further ado, I'm gonna talk you through our next up, which is STRO-003, this ROR1 ADC Bill just mentioned.
For the rest of the presentation, I'm gonna talk about this inherent integrated combination of new processes and new products that come together in their design to give us for increasingly complex biologics, actually an increasingly simple, straightforward, and efficient manufacturing solution. I'll get going with STRO-003. If I can 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.
The second thing that's really quite interesting of ROR1 is its broad expression on many different tumors. 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 such as non-small cell lung cancer and breast cancer. The trick 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.
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 gonna deliver those cytotoxins in sufficient quantity on each individual tumor cell to tip that over into a cell death. 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. It also potentially needs payloads, so mechanisms of cytotoxicity that are really very potent. This favors the more potent DNA disruptors rather than the more common tubulin inhibitors as a potential mechanistic target. That doesn't mean to say that tubulin inhibitors can have an effect.
In fact, there's some pretty reasonable clinical validation for both efficacy and safety in hematologic tumors with an MMAE-derived ROR1 ADC, which is also being expanded into solid tumor indications. We certainly feel there's an opportunity here to engage with some of the newer mechanisms that have been targeted in ADCs and to be able to get to it. Now, potent DNA disruptors like crosslinkers like pyrrolobenzodiazepines can be a challenge from a tolerability perspective, although are very active even on cells that are not dividing rapidly. We've gone with an exatecan class which 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, drug that's released in the antigen expressing ROR1-expressing tumor cells, that exatecan can actually also kill surrounding cells. It's not as potent as some of these things. The tolerability, which ENHERTU enjoys is very attractive in being able to dose up. What will finally be important, we believe, is that every internalization event has really got to count and deliver the optimal amount of payloads, because of the low antigen density. We've now developed technology with our site-specific precise conjugations that can load DAR 8 and above, by positioning non-natural amino acids, and we'll talk about that technology in a moment. This just is a prevalence chart across many different tumor indications, and the highest prevalence being at the top with mantle cell lymphoma.
You can see that the prevalence can be quite variable depending on clinical indication. In large market, large commercial opportunity like lung cancer, you'll see towards the bottom third of this table in lung cancer, that prevalence can vary quite considerably from somewhere north of 45% to around 90%, 93%, 94%. Now in addition to prevalence, which is really the number, the percentage of samples that prove to be positive for ROR1 in these indications, this chart also grades them in terms of percentage highs. If you were to look at prostate cancer, for example, that's a 90% and above prevalence. It's only 15% high by grade.
That relates to the antigen density, and that's a critical number for ADCs in that you want a number of, you know, binding and internalization events to deliver optimal amounts of payload. The lower that number is, the more potent, the more effective, the more efficient the antibody-drug conjugate has to be. With the design, this is why we've designed a DAR 8 site-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 DAR eight ADC in that these sites are chosen for optimal performance, not just for stability and PK, but also the most efficient way in which we know that this exatecan payload is gonna 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. 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 non-natural amino acid that we use as a proprietary para-azidomethyl-L-phenylalanine molecule, which is tremendously efficient in conjugation, goes to complete conjugation in just a few hours. We can generate this DAR 8 conjugation in several hours with very little molar excess, which of course is extremely important to cost of goods and manufacturing efficiency. We've chosen a different sort of linker from the fairly normal cathepsin 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 lysosomal and endosomal 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 neutrophil elastase, for example, where some of the CatB linkers can be quite susceptible. There are papers out there which link that susceptibility to neutrophil-derived proteinases to their own demise, so potentially can cause neutropenia. That's not entirely proven, and of course, site of conjugation can make a big difference to that. In addition, topoisomerase class have been known when paired with cathepsin B linkers, like for example, within HER2 and others, to have lung tolerability issues. That is something of course we also want to avoid, the pneumonitis and interstitial lung disease seen in patients. The exatecan warhead is a fantastic payload, we believe.
It elicits that potent tumor cell killing and bystander activity, but it also sends up a flag from the tumor cell that's under stress and this so-called immunogenic cell death, which a lot is made of it these days. It potentially is a very important aspect of this in that it sends up a flag to innate immune system to go after the cell. 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 with beta-glucuronidase. The first proof of the pudding really, the first test, was to put STRO3 and challenge some patient-derived non-small cell lung cancer tumors by way of xenograft.
This is representative of four such PDX models which express low and heterogeneous amounts of ROR1 antigen level on that tumor cell surface. If you look at this, what we're looking at, these are four separate PDX models, four separate tumors, which are representative of these lower-level ROR1 antigen levels. We're challenging them either with vehicle with STRO3, which is this beta-glucuronidase exatecan linker payload, or an alternative Sutro design, which is the same DAR 8 capable antibody that against ROR1 that we use on STRO3. In this case, we've conjugated to a cathepsin B exatecan, to see whether as an alternative development candidate actually, but also to see which of these might develop best. This is a great test of whether the beta-glucuronidase in the human tumor system is gonna do the job.
As you can see in all of these, in black, you can see the vehicle, so that's the normal tumor growth in each one of these tumors. In dark green, you see that four doses at 10 mg per kg a week apart are able to completely cause tumor regression, at least in three out of the four of these, but pretty significant responses in all four. By contrast, the alternative design, the CatB exatecan in light green, does really well in three out of the four. The other one, you can see a little bit of growth on the second from left. Not quite as efficacious.
Actually, that was not too much of a surprise in that we know that the active catabolite on the cathepsin B linker is slightly less potent than the active catabolite that is derived from the beta-glucuronidase sensitive linker. All in all, the efficacy falls out the way we wanted it to or were hoping to, with the beta-glucuronidase seems to do a really fantastic job in these low-level expression systems. On the next question, this is actually looking at a human breast cancer model with moderate ROR1 expression, and looking to see the effects of the DAR8 beta-glucuronidase exatecan system here. What we're looking at here in dark green is the DAR8 beta-glucuronidase exatecan targeting ROR1. That does very well.
Now, in this particular instance, this is four doses of 5 mg per kg, so slightly lower dose a week apart. You can see a very good response out to day 50 or so with those doses. In light green, you can see the DAR4 CatB exatecan for comparison, which is again, less efficacious. For those of you that are interested in what a DAR4 or CatB MMAE linker payload would look like on a similar affinity antibody, that's in blue. You can see, you do see some tumor growth inhibition, not quite as significant as the beta-glu DAR4 exatecan. 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 two cell lines, one ROR1 3+, so high level of expression of ROR1, and then the other one, a ROR1 negative, the MCF7 cell line. The reason for doing this, in red, you can see the effect of STRO-003 on the relative cell viability of those cells. We incubate these cells for four days. We're looking at their viability in the presence of either STRO-003 or an isotype control ADC. An ADC that doesn't bind to anything human, but is loaded with the same DAR exatecan. That does not kill the ROR1 positive cells. STRO-003 does, and you can see the dosage curve there.
The incomplete killing is because this cell line is heterogeneous, although those cells that do express ROR1 on average express quite a high level, there is a certain population that do not express. 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 experiment. On the right, the right-hand panel of the left side is just to show that when we incubate the STRO-003 for four days in a ROR1 negative cell line, we see no decrease in cell viability.
We conclude that this is indeed antigen dependent and a stable linker. On the right-hand side, we just show that again, at 2 mg per kg, three doses, a week apart, we see some good tumor growth inhibition in a, in the ROR1 positive, xenograft model, which we just showed you before. It seems to be quite well behaved. It is antigen dependent and the linker is stable in these models. Tolerability and safety, this is key. STRO-003 is comprised of a monoclonal antibody that targets ROR1, and we chose this particular antibody, not least because it was stable and good PK and all the rest, but also because it had cross-reactivity, not just to non-human primates, but also to rodents.
This allowed us to do a full analysis with the different linkers, not only to check to see how tolerable they were in an off-target manner, but also whether there were any antigen-dependent target tolerability issues we needed to consider. We were thrilled to see that STRO-003 in rat at high doses, up to 60 mg per kg, we observed no neutropenia at all and no elevation of liver enzymes. That was really extremely good for non-human primate studies. We did a multi-dose non-GLP non-human primate study, and we observed no neutropenia at all or thrombocytopenia up to doses of 45 mg per kg top dose. No changes observed in white blood cells generally. 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. Again, STRO-003 at 45 mg/kg showed no changes, no pneumocytes, no infiltrates, no damage at all in the lung, which would be indicative of a developing pneumonitis or interstitial lung disease with this β-glucuronidase linker payload. In contrast, the cathepsin B linker exatecan, and you'll remember that the active payload of the cathepsin B, although it's the same exatecan class, the active metabolite is slightly less potent than our STRO-003 active metabolite. We expected that this construct would actually be slightly more tolerable because of that less potent active metabolite.
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 ILD at that 45 mg/kg dose. Going from cathepsin B to a glucuronidase linker, we both increased the potency because we had a more active metabolite in there, but at the same time, we made it more tolerable than a conventional cathepsin B linker. Beta-glucuronidase was clear that that was our most efficacious, our most tolerated, and therefore, the widest therapeutic window with this particular construct. It should be noted I said before, the other CatB linker exatecan ADCs, including ENHERTU, associated with significant rates of clinical pneumonitis and ILD. Although drugs like ENHERTU are remarkable and fantastic overall response rates in solid tumors, but this is a serious concern.
Improvements on that could really extend us to be considered best in class. 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. It's 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. TOP1s, however, have only really been showing compelling clinical validation in solid tumors at the moment, although there's no reason I don't believe that they shouldn't also do well in hematological tumors too. It's just that that's not properly validated as yet. There certainly are DNA payloads of the pyrrolobenzodiazepine class, for example, that are finding great efficacy in liquid tumors.
We believe that the dual design of this that demonstrates impressive activity with potentially reduced lung and neutropenia tolerability. Haven't spoken much about that, but that is completely clear. Those things are associated with TOP1 class payload ADCs. We look forward to moving that forward. Our clinical programs, our strategy is gonna be exploring when we get into the clinic both the prime indication space, but certainly for solid tumors, this looks like a really excellent candidate. Now, I wanted to move from there and talk a little bit more about these advancements from the impacts on our emerging research portfolio, and also talk about some recent news some of you may have seen with a collaboration with Astellas. Let's just talk through our platform as it is at the moment.
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 acid targeting sites, can improve efficiency of killing. We also know 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. We've used the fact that epithelial cells are normally polarized, healthy epithelial cells are polarized. 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. We can use that by designing a bispecific antibody that has to bind to one of each antigen to give it the sufficient avidity 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 receptor binding. That's indeed something we've done with EMD Serono, and that's a clinical development candidate that's an EGF receptor ADC. We've now enabled the TOP1 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 gonna have better tolerability and retains this great efficacy. The DAR 8 has been a critical element of getting shown well on other molecules.
We've managed to get to DAR 8 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. Lastly, we've been evaluating how to use these sorts of technologies and our ability to make dual conjugates on the same antibody, which opens up the opportunity to conjugate two different mechanisms of payload. 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. We feel this technology is gonna open the lid on some new therapies.
These are gonna be new modalities that we've not really seen before, which move us beyond best-in-class. An example of combining a cytotoxic with an immune stimulus to give us a longer-lasting response. We've termed this an immunostimulatory ADC, an IADC, and it is a dual conjugation of cytotoxic and immune modulator. This is a great opportunity. This is a completely new modality, and I want us to think about this rather differently from an ADC. For an ADC, you're really interested in a 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, you know, 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. That was the whole basis really of 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 agonists and pattern recognition receptors has come to the fore. We, you know, we're very much looking at this from a conceptual basis of, wouldn't it be good if we could try and stimulate an antitumor immune response from the tumor itself?
If one could disrupt the tumor, release tumor neo-antigens, and equip that with also agonists that would mimic those innate, you know, and stimulate those innate immune systems, could you set up an adaptive response that would give you a far long-lasting response? We set about trying to do this with a 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 candidates, including STRO-002. What we did here was we'd use that particular warhead because we knew it caused immunogenic cell death, which is a bit of a popular phrase these days.
There's an interesting phenotype as the cytotoxin puts the tumor cell under stress, this tumor cell starts to engage as a very natural physiological mechanism of signaling to the immune cells it's under duress. This is by calreticulin expression on the surface release of HMGB1 and other proteins which are able to stimulate pattern recognition responses. 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. 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. That will release the antigens, it will cause an immunogenic cell death response, which preps it up.
Innate immune cells will come in after those released tumor antigens and the debris from those disrupted tumor cells. When those macrophages and other cells chomp down on that to clear that debris, they will find an activator, and that activator will then stimulate the cells, send up the flare, the beacon, and that's what sends in the T cell responsiveness and sets up the adaptive immune response. What we're aiming to do here is set up a longer-lasting memory response. Does it work? This is the construct of a systemic administered monotherapy that drives antitumor immunity. This is a prototype molecule. Let me stress that this isn't a development candidate, but it shows you what we can do and how we can do it.
The purple stars on this graphic are really the hemiasterlin cytotoxin with a conjugated to the antibody in a very precise way. We know something about this. This is a hemiasterlin tubulin inhibitor on a cleavable CatB linker. In red we've put in a TLR7 agonist, which is actually conjugated to the light chain using another CatB linker. The way in which we construct these is that we are able to make a prefabricated light chain with a non-natural amino acid, and then around that, run a cell-free synthetic construct of the heavy chain, which contains a different non-natural amino acid. We can get very precise conjugation in any stoichiometry we want on the same antibody.
A one-pot 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 it's very high fidelity for those different sites for each payload. I'll come back to this a little later 'cause this is the basis of a sort of modular manufacturing base. When we look at molecules such as this, we can see here we have MC38. This is a tumor, a mouse tumor. We're looking at mouse tumors in an immunocompetent mouse/mice system. In the top left you can see the vehicle. That's the seeding rate and how well the tumor grows very, very quickly and aggressively. It's this MC38 mouse tumor is transfected with the human tumor-associated antigen that our IADC is targeted to.
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 see 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. There are three complete responses in this group of eight. The bottom left, you can see if you do the same thing with the same antibody now conjugated with two TLR7 agonist on the light chain, you can see there is a little bit of a delay in tumor growth, but there's 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 agonists on the light chain, 4 hemiasterlin cytotoxics on the heavy chains to give you a 4 plus 2 iADC. Now you can see that directionally it's going in the right way. We're getting five out of seven complete responses in just after a single dose. Now, if you take those surviving animals and now you re-challenge 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? This is 60 days out when these are re-challenged, these 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 re-challenge with the MC38 cells which don't have the initial tumor antigen, this human tumor antigen, transfected into them, we still get complete inability to grow those tumors. Effectively what we're saying is that there's likely a cross-epitope learning, a memory response now, an adaptive immune response, which gives these mice protection from further regrowth or re-challenge. Further experiments we've actually done show that this is dependent on CD8 cells, and if we deplete CD8 cells, these tumors regrow. 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 the, you know, compared with the vehicle, what's happening to dendritic cell activation in the tumor? You can see on day 1, on the left panel, that the dendritic cells are activated by an ISAC that just targets the TLR7 alone, but not by the ADC. They are targeted, of course, by the IADC, which also has the 2 TLR7s. If we switch across to the right-hand side, you can see that although that innate response, as you'd expect, is a day 1 event, it's an early event, we're not seeing any change on day 1 in the adaptive immune, so the CD8 component part.
You can see at day five, there's a developing response in the CD8 T cells in the IADC population, not in, not so much in the ISAC population of TLR7 alone. Indeed, if you look at the CD8 Treg ratio, again, that seems to be enhanced, which is exciting. Now I like visuals, so if you look at the staining of the CD8 cells from these different tumors treated with these different treatments, you can see that the IADC population of CD8s has increased. That's very promising. Just quickly trying to make sense of an IADC versus these other sort of modalities.
You can see that, you know, we think it's pretty important to have both the antigen released, so direct tumor cell killing, as well as the ability to prime and stimulate the innate cells in order to drive T cell recruitment and this adaptive response. From that perspective, I think this new modality covers the gamut 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, you know, what we're now seeing is potential for bystander effect, not driven by a cytotoxin, which bleeds out into the surrounding tumor microenvironment, kills surrounding cells.
This bystander effect is caused by the immune system, so you're giving it the one-two punch of both antigen as well as an innate activator, which potentially sets you up to get almost like a, dare I say, vaccination-type response in response to a systemic administration. It's obviously personalized to that individual patient's tumor. 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 placed in the right way.
But there's great promise in here, and this is the basis of a very exciting new collaboration with Astellas, who've signed up with us to push these some 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 process design. 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, where there's predictable manufacturability. I'll cover the key aspects. 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 parts. 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 one cell strain, from which we derive an extract. That extract, of course, is clear. There are no living cells there. It's just the raw transcriptional and translational 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.
That ability to break open the cell and use that as an extract gives us an ability to stockpile extract and 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 amino acids, of course. You can do that at any scale. 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 gonna be a lead. It could be an antibody discovery, trying your new CDRs in a fully folded IgG for the first time as per synthesis. You can pick already which ones are gonna fold up well, behave well, very quickly.
Your choice of starting points, 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 scale. We've already demonstrated this transferability from, you know, 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 a 1,000-liter single-use bioreactor in Sutro's own GMP facility in San Carlos. From that sort of scale, it's de-risking the further scale to 20,000 liters and beyond if we so wish. This idea of an integrated synthetic biology enabled by the fact there are no live cells or membranes in there gives you an open platform for different modular component parts to play in your design.
We've already talked about one example, which is the 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. The fact that we always use the same strain means we always have the same host cell protein background. Many of these component unit operations become very familiar and very straightforward and same again every time we change the product. I'm gonna try and run through how we do this. Now, on the left-hand side of this diagram, we talk about how we design. We're looking at patient needs, where the limitations are really.
where the treatments are really limited. Where are the precedent mechanistic things we could try out really quickly? Of course, we're always interested in commercial opportunity as well as the medical need. The speed with which we can put something together is really key 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 determinations, as well as go fast into non-human primates. If we don't like the look of something, we can redesign and go back again within two to three months.
That's really novel in terms of biologics and the year-long process it normally takes to get a stable cell line to equip those sorts of studies with decent quality and quantity of product. The continuity is key. I mentioned that the whole cell-free reaction that we do at very small scale is exactly the same as we do at large scale. Because ADCs are complex molecules, you know, ultimately the clinical profile depends on all of these features coming together. There are attributes in a well-behaved antibody. Those attributes can change.
If you have to design an antibody and you express it in a stable transfection, 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. Sometimes that can compromise what was originally started off as quite a nice research tool. For our system, we don't change them. It's the same system. 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.
That seamless scalability from milliliter scale to thousands of liters, I think is really key with no formatting changes. The second part I wanted just to call out was the rapid process development. 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 extract. Beyond that, we have a number of components we can bring to bear. We have the core cell-free product agnostic manufacturing process, the extract and cell-free 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. Where common light chains are used across different antibodies, we already have that component part, we can bring them in. Linker payloads, we're used to...
We're all used to thinking of linker payloads as components we can switch and change across different products. The modularized process options by selecting from these now is really interesting. We can take pre-tested, pre-optimized versions of these component parts and combine them in new products without having to reproduce everything from scratch as you would conventionally. Lastly, the standardized control structure, 'cause it's the same strain that's producing the same extract, we're able to actually produce packages to refer to by health authority for health authority review, which are familiar. I mean, they're predictable CMC packages using the same component parts. I'm having problems advancing forward. I just wanna give you one example, and this is very relevant to an observation. Prefabricated light chain.
Now, for two of our molecules in clinical development, we've shown that pre-manufacturing a prefabricated light chain that's common to both antibodies is actually quite useful 'cause we can add it into the cell-free reaction. The cell-free reaction itself is only making the heavy chain and placing non-natural amino acids for an ADC if they're placed, if they're positioned in the heavy chain. Just the wild type sequence for a native amino acid only prefabricated light chain, we're very familiar with having that as a component part that's prefabricated. We actually make it in an intact E. coli strain on the same background as from the extract. They're not confusing or contributing to the complexity of the GMP process. On the middle one, here's another variation.
Think common light chain, same prefabricated light chain, but now with a non-natural amino acid. This is exactly how we're using ROR1. Again, it's on a common light chain. We could take a number of different antibodies that use a common light chain and substitute this component part in with a non-natural amino acid late-stage discovery, just to ask the simple question. In this case, do we want a DAR 4 or do we want a DAR 6? You could do that on the left-hand side or do you want a DAR 8? You do that by this middle process.
Lastly, on the right, well, if we can do that, we can also use the common light chain, but now have already equipped it with a different non-natural amino acid for an orthogonal conjugation chemistry, which allows you to do, in this case, a 6 on the heavy chain plus 2 on the light chain, two different payloads. So that's how we think of putting things together using this modular production process. To actually just add a little bit more complexity to it, you have to balance the two payloads. There's no point in having one very potent, the other not so. It's not gonna 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 exactly this.
We can, we can switch the ratio, in this case, on the left-hand side of red payloads to yellow payloads. There's a 3-to-1 ratio on the left-hand side and a 1-to-3 ratio on the right-hand side. 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 inputs, and we've got a strong medicinal chemistry outfit 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 in synthetic biology and medicinal chemistry to make complex molecules like this. This is another key aspect of the flexibility of our system.
Now lastly, I just wanna talk, touch on very quickly our CMC and supply chain strategies for both two important aspects of what we do, faster clinic and commercialization. The first thing, you know, we have experience in the clinic. We have our own GMP facility, where 6 product candidates have gone through, 3 monospecific ADCs, a bispecific ADC, a cytokine bioconjugate, and a conjugate vaccine. What we've been doing is establishing and doing a robust external supply chain for these, for clinical supplies for these molecules. You know, we have linker warhead process chemistry and GMP manufacture. We have conjugation established with external suppliers that can do that and form drug product and drug substance for both ADCs and bioconjugates. We obviously are doing fill and finish, so drug product and vials, clinical packaging.
Our extract and custom reagents, which are the rapid common agnostic platform, can be applied very quickly to antibody-based and cytokine product development manufacturing. In the future, now we've equipped ourselves with these processes and support, we can move quickly to the clinic. Lastly, a strategy to CMC commercialization. Shabbir Anik is on the Q&A panel, will, I'm sure, be happy to answer your questions if I don't do this justice. But what Shabbir Anik and colleagues have been doing is establishing a CMO network for all of the components that we need to deliver scalability, notably extracts, and then the cell-free reaction itself, but also including things like the prefabricated light chains and custom reagents to support this whole thing.
Really, that scalability that comes with this CMO network is gonna allow us to build an inventory, minimize risk, and to support clinical studies and commercial launch in the future. We talked about the extract. We can write 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 10 x the capability or capacity that Sutro's San Carlos facility has, which is great for our end of phase I clinical trial material. This scale will now allow us to do registration studies and commercial.
GMP batches for the XpressCF are in process and will be coming through in the last half of this year. For custom 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 two clinical trial candidates right now. The cell-free reaction itself for the production of the protein, we've selected a CMO with GMP batches on track for the end of next year. With all of this in place, the supply chain should produce over 250 kilograms of antibody per year. Lastly, just to conclude, we have a number of unique 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 set. We have 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 some justice to, can accelerate our process development and the way forward and to have a predictable manufacturing platform. 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 our technology around the world or, obviously, to our partners, allowing them to control their own CMC schedule.
Lastly, just to conclude, I'm really excited that we've been able to turn this 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 those there to equip that, and also to address other aspects that are presently being done in combination where targeted therapies could do so much better and to deepen responses by targeting resistant pathways at the same time. With that, I'll turn it over back to the operator for our Q&A session. Thank you for listening.
Thank you. At this time, we'll be conducting our question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate that your line is in the question queue. You may press the star key followed by the number two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Once again, to queue up for a question on the phone, press star followed by one on your telephone keypad. We'll pause for a moment to poll for questions. Thank you. Our first question comes from Roger Song with Jefferies. Please state your question.
Great. Thank you for taking the question, and appreciate the detailed presentation for STRO-003 and IADC and CMC. I have a couple questions related to STRO-003 ROR1. The first one is the magnitude of the cancer killing also on the ROR1 expression level dependent? Because I see the non-small cell PDX model seems to work pretty well even in the low expression level. Have you done any other model as a cancer model and to see consistent results?
If you could handle that, please.
Hi, Roger. Yeah, I mean, you know, what we were showing there is relatively high dosing. In fact, when we ran these studies, you know, we were having a real good look. This is at 10 mg per kg four 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 you know, as long as there's antigen dependency, then the antigen density is more predictable in terms of dose. So you either get there with dose, or you get with the 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. If you combine this slide looking at the antigen density itself being low, but giving good killing, and you remind yourself that actually the killing is absolutely antigen dependent, then I think the rationale follows that, you know, that the antigen density will have a relationship with what you're dosing. It just depends on whether you're going low enough in dose to demonstrate that. I, from what I've shown you, I've not shown you that. That's our expectation. Sorry, I'm not sure I answered your question.
No, no, I think that answered, you know, if you go 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, are the linker is unstable, and you've got a systemic release of active catabolite or payload that's acting systemically, you know, at the same time as you're trying to get an antigen-dependent response. With ADCs, which are poorly behaved and are shedding active payload, as soon as you dose, you're gonna lose that because it's almost like a slow-release chemotherapy. This isn't one of those. This is a stable ADC, and so the rule's a little bit more straightforward.
Yeah, got it. I see that in the second slide, you see the no killing in the ROR1-negative cancer model. That speaks to the stable linkers. Got it. All right, that's good. I know you just announced the candidates may be a little bit too early to talk about a clinical plan, but just maybe a you know, a broad stroke, what will be your timeline or the plan for the IND filing and the potential clinical like indication in the settings?
Roger, this is Bill. I'll let you know that, you know, this is a target that we're excited about because we believe there's tremendous potential not only in hematologic malignancies but also in solid tumors. You know, as we're moving through the IND-enabling work and the CMC processes, we'll be refining what our clinical strategy is. 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. 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. Thank you, Bill. Okay, 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 one PDX model showing certain superiority. But just when you design your molecule O3, is that one of your benchmark you try to beat in the preclinical? Also, have you seen consistent preclinical data across different models when you compare to your competitors?
Trevor, why don't you go ahead with that, please?
Yeah, 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 VelosBio's antibody. We were just comparing antibodies with the same properties as STRO-003, but charged with different payloads. It's a DAR four MMAE Val-Cit versus the, you know, the other exatecan versions. I mean, I think that, you know, what we're looking for duration of response is beyond where the tubulin inhibitors have gone in terms of or at least to date and what I've seen publicly in solid tumors. 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. We think that's gonna be particularly important in solid tumors for combinations with things like checkpoint inhibitors. Is tubulin the optimal payload? No, I don't think it is. I think, you know, the data to date with the TOP1 inhibitors has looked really impressive and that, to my mind, I wanted to ensure that Sutro had the full benefit and was playing on the same, well, same level playing field as some of the other opportunities now where the ADC field has gone.
can bring our own unique differentiation above everything else as well using our engineering platform. 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, DAR 8 and where you place them, because they all play with each other to give you the widest possible therapeutic index and the deepest response.
Excellent. Thank you. Okay. That's all for that. Thank you.
Thanks, Roger.
Our next question comes from Nick Abbott with Wells Fargo. Please go ahead.
Hey, great. Thanks for taking my questions. First one, you know, just sort of, kind of following up on that last theme. I think you've said in the past, Bill, that for an order of product to become a development candidate, it has to be clearly best in class. Maybe just summarize for us, you know, going back to that VelosBio product, an ADC, you know, what do you think the advantages are over that product?
Trevor, you wanna talk a little bit again about the new design elements?
Yeah.
We're bringing to this?
Yeah. Hi, Nick. I mean, so I've had a little look about what's publicly known about the VelosBio, and it sounds very interesting. You know, they had a recommended phase II dose of 2.5 mg per kg every three weeks coming out of their hematological cancers. I think Merck saw that and probably saw some solid tumor data as well, and made the decision to go. I was interested in a changing in the sort of dosing. They had a dose fractionation, it seems, late last year to go for a 3.5 mg per kg dose for solid tumors split into two times 1.75 at day one, day eight per three-week cycle.
I know the 2.5 mg per kg, they were seeing neutropenia north of 2.25 mg per kg. I would expect that, you know, trying to push up from 2.5 mg per kg, may have some limitations. I think the neat way of fractionating the dose like that may give them the opportunity to load up a solid tumor higher to get to higher doses, higher levels of efficacy while managing a neutropenia response. At least that's my interpretation without knowing anything from what, from what they've done. Neutropenia is clearly an issue there. One of the key aspects that we wanted to do is get out of some of the Cat B related neutropenia liabilities, that can occur.
We also noted that although, you know, exatecans seem to be very well tolerated, they're still they still do have some impact on other tolerabilities as well. To the cathepsin B linker. We wanted to get away from that just to see what we can do. 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 gonna be in the 2-3 mg per kg range. I hope we don't get too surprised, but somewhere around there for STRO-003.
I think in the efficacy on the non-human primates at 45 mg per kg, where we were free of neutropenia and free of interstitial lung disease and pneumonitis-type symptoms, at least you know in the shorter pre-IND non-GLP studies in non-human primates, that translates with exposures to about 15 mg per kg or so. That gives us quite a wide window from 2-3 for efficacy up to maybe 10-15 for where you start you know where we know we're clean at the moment. Of course, that's not the same thing as doing chronic dosing and where we will eventually go. It's very promising and it's exciting.
The fact that we're seeing an improvement on our own designs for Cat B exatecan going from the beta-glucuronidase exatecan is even more exciting 'cause the Cat B exatecans are clinically validated, and we do have data points now.
Perfect. Thank you. Then maybe a follow-up. I just wanna make sure I fully understand the comments you made about this, you know, cross-species activity, the antibody. Are you saying that it has the same antigenicity profile and that the lack of lung co-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. You know, it's easy to see good tolerability sometimes when your antibody doesn't bind to anything, and it's.
Yeah.
Pure, the purest form, does your payload fall off and cause some collateral damage? Where it does bind, you've got the added thing. What mechanism? Are there low levels of antigen density expressed in some tissue which normally you wouldn't see if the antibody can't bind to it? Now the antibody can, and it signals that, you know, there may be a flag there in that particular tissue. That's why it's useful to have cross-reactivity to rodents, because you can get an early look without needing to go to monkeys. In this case, even though the antibody could hit both rodent ROR1, so rat ROR1, as well as non-human primate ROR1, we didn't see any flags there that were indicative there were anything other than known tolerability issues associated with targets.
We were looking very hard, and even though we expected 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. That's testament to the design, the stability, the linker choice, and so on.
Mm-hmm. Just going back to this issue of lung tox, 'cause obviously 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.
Yeah. Just going back to this issue of, you know, the exatecan, I guess, related lung toxicity. You know-
Right.
How robustly can you test for that outside of a human? I mean, how confident are you that, you know, you avoid that liability?
Well, you're never very confident. At the end of the day, it has to be in human. There are some aspects and similarities that we can see from what's published before, in what's the patient experience and what's been seen pre-clinically, which we can draw on. If those relationships are there, then we can, we could make the conclusion that that does translate. It might be wrong, but we could. Improvements like this I think are really, as we can do in terms of reassuring ourselves that we're not seeing some things that do translate. You know, like anything, and of course, it's different again 'cause it's like specific conjugates. We're not using cysteines, we're using non-naturals. We're using a different linker compared with HER2.
Any of that might change and throw our translatability off.
Mm-hmm.
You know, we do these things for a reason. We go into monkeys for a reason. We don't wanna go with an unsafe drug. We have an antibody that recognizes ROR1, and we're not seeing. You know, it's very well-tolerated. We're very excited about going forward. So that's all you can glean, really.
Okay. Thanks. Just, I guess just the last one for me, I know HER2 is not an antigen on your list, but presumably, given the data you have, there could well be some interest in a HER2 version, you know, leveraging the beta-glucuronidase linker and exatecan platform. You know, what are your thoughts about, you know, business development and co-development opportunities around, you know, this exciting platform?
Thanks, Nick. You know.
I'll let Bill. Yeah.
Thanks. 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. 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. We're open for business in that vein and looking forward to continuing those discussions. 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 if people are interested first-in-class and be assured of manufacturability.
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.
Great. Thank you very much.
Thanks, Nick.
Thank you. Our next question comes from Boris Peaker with Cowen. Please go ahead.
All right. Thanks for taking my question. I'm just curious, is there any competitive data on ROR1 on the horizon that we should be paying attention to or that may impact your development strategy for STRO-003?
You know, I think, Boris, people are still waiting to see how the VelosBio data comes out. That's probably gonna be the next most significant bit of data for us to look at. One of the advantages of being where we are in terms of the development of this asset is we've learned a lot in the field as to how to design better. We've now got this new linker and this new class of warhead. We'll be following, as we have historically, the evolution of programs like the VelosBio one, like perhaps the NBE molecule as well, and really understanding what their opportunity is, what the chances are, 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. I would, you know, keep an eye out looking particularly for the Merck program from VelosBio.
You mentioned ADC squared, if that's how we refer to it. When are we gonna get an update on what that really is or any kind of programs out of that?
Oh, I'll let Trevor, since he's the one who put out the terminology, handle.
It's just my sense of humor, I guess. No, it's really meant to capture the systemic, you know, mechanistically synergistic mechanism we might put together. There are a few of them out there. We're not ready to reveal those yet. Yeah, stay tuned.
I think we had enough for everybody today, so we'll just save that for a future date for us.
Got it. All right. Well, thanks very, very much for taking my question.
Thank you.
Thank you. Our next question comes from Asthika Goonewardene. Please go ahead with your question, with Truist.
Hey, guys. First I wanna say thanks for putting this very informative session together. This is very helpful to us, and really appreciate all the detail and colors that you provided here. And congrats on disclosing more on STRO-003, which we've been waiting for. Maybe some questions on STRO-003. Also wanna get your thoughts on how it compares to the other competitors, the VelosBio and the NBE-002. Maybe let's start with the targeted epitope and the binder. I wanted to know how the epitope and the binder that you targeted with STRO-003 is differentiated from the others. I got a couple of follow-ups.
Great. Thanks, Asthika. Trevor?
Yes. Hi, Asthika. There was some background. There was some information around CAR T at one point in certain indications where there was some concern over whether a binding epitope 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 CAR T that the CAR T would bind to. So of course, that would be compromising. We're aware that there are those sorts of discussions going on. That was an immediate concern for us when we embarked on this program. With the VelosBio program, we believe we have an epitope which overlaps. It's not identical, but I think the. It's pretty. It's gonna.
I think it'll perform pretty well, in the same epitope as the VelosBio antibody. From that perspective, I will be watching the VelosBio and the programs very closely and to see whether that is reproduced or whether they see large amounts of dissociation. We are pretty excited with where we are. We think we've made the right decisions in terms of epitope choice.
Okay. Just wanna confirm, Trevor, the warhead that you're using is exatecan itself, or is it a modified version of exatecan?
You know, the ENHERTU warhead is deruxtecan. Our STRO-003 catabolite is exatecan, and the one on the CatB linker releases a slightly different catabolite again. Hence this discussion around slightly different potencies and, you know, seeing with the different things and slightly different tolerability 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 the set of liabilities or whatever. You know, 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. 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 would you see those combined, Trevor?
We expect ours to be very potent. Haven't done a direct comparison.
Have you benchmarked the level of immunogenic cell death that the warhead drives versus, let's say, the auristatin?
I think the top of one of them, which is exatecan itself, is known to be a very potent immunogenic cell death stimulus. I think it's
Okay.
It looks very well. The hemiasterlin itself is really quite good. I think exatecan's gonna be even more potent.
Got it. Okay. Yeah, just wanna try and understand the specific differences and between these different ADCs here. Maybe if I can squeeze in a quick question on MK-1484. I just wanna get some thoughts on what the next milestone payments have been or what milestone payments have been recently triggered by motixafortide to a phase I study.
Thanks, Asthika, 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. I would say stay tuned, but it's not something we're gonna be discussing today.
Got it. All right. Thanks a lot, guys. Appreciate all the color.
Thank you.
Thank you. Our next question comes from Reni Benjamin with JMP Securities. Please go ahead.
Hey, thanks, guys, for taking the questions, and congrats on STRO-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, you know, the development of this asset going forward in terms of, you know, either add-on combinations or given, you know, kind of what Trevor went through as to, you know, how it's easily modified, whether or not you can, you know, drop the DAR down to, let's say, 6 and add on, let's say, 2 TLR7 molecules or a TLR7 and TLR8 molecule. You know, 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.
Thought it might be. Yeah, I mean, are you talking about ROR1 specifically here?
Yeah, ROR1 specifically.
I mean, you know, it's all about the indication, the antigen, combination, of course, and also where the treatment paradigms are, standard of care, what sort of tumor we're looking at. Is it cold? Is it hot? Is it one where there's a great deal of resistance to a particular mechanism of that you're driving with a payload and so on. There are already precedents, 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. You know, we're providing a component part which is enriching CD8-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, you know. If it acts the same way and 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. You know, those are opportunities to further define and further move. The fact is we have now a foundation of tolerability that we've begun to build with 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 unnatural 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.
Okay.
Thanks for giving me ideas. Right now we're really focused on driving this asset, the ROR1 ADC, into the clinic as quickly as possible. Certainly the possibilities of combination therapy and/or modifications to make this more of an iADC player are downstream. We wanna start with what we think is a very exciting opportunity as an ADC. With exatecan, DAR8, and this new linker, we think we've got a really great molecule that can benefit patients. 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 nine, am I reading too, you know, too far into it when I look at the ROR1 2+, you know, mouse model? It doesn't seem to achieve the same sort of tumor, you know, anti-tumor activity as the ROR1 1+ levels. It would seem to suggest that maybe a biomarker strategy might be important in, you know, 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, have we got good efficacy? Yes. Great. That qualifies a different linker 'cause that was a concern about β-glucuronidase expression, for example, across human tumors and so on. So, but I think you're absolutely right. I mean, we would be planning, if we were doing a basket trial in heme and solid tumors, for example, two separate baskets, then we will, of course, evaluate whether we need to enrich. You know, 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, you know, by comparison. I wouldn't read too much from there. It's to me, it's validating in terms of linker choice and nice to see good efficacy at low antigen density.
Got it. 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 STRO-003? Would that be next year or the year after?
Yeah. I wish, I wish it was this year, but it's not gonna be. You know, 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 gonna 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 gonna certainly work hard to beat that. When we're ready to announce a timeline, you'll be one of the first to hear it, Ren.
Excellent. Thanks very much, guys.
Thank you.
Our next question comes from David Nierengarten with Wedbush Securities. Please state your question.
Hey. Most of mine 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 zero expressing cells and you can still see an effect? You know, like, and does that change with a general expression level of one plus or two plus? I know it's kind of a tough question to answer probably in the PDX models, but I'm curious because it might, you know, be reflected in the confidence levels, you know, of tumor types that could be treated, you know, by STRO-003 in the future, you know.
Looking at, you know, some of the papers on expression levels or proportion, you know, tumor cells that express and things like that. I was just curious if you know, had any thoughts around, you know, proportion of expressing versus, you know, level of expression in different tumor types.
Trevor, over to you.
Yeah. It's a little too early to know. We do studies where we go from sort of two-dimensional culture to three-dimensional culture, which is sort of, you know, in the cell killing area where I showed to you there was no bystander effect, so it's all antigen dependent. That's a 2D culture where any release payload is relatively diluted away. If you go to a three-D culture, you can build up some of the concentrations around there, and you can start to get a feel for how much, you know, primary tumor cell processing there is of a stable ADC to release enough payload to then have a knock-on effect to those that are next. It's quite complicated. I'm not totally sure it predicts either. You're right, somewhere in the middle there. There's the ideal 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? How do you know that?" You know, it's a no-win game for me. Suffice it to say there is good payload. It's very potent. There is a good bystander, strong bystander effect there. We know from. I mean, the more important thing for me is it can, you know, we're getting sufficient killing of a heterogeneous ROR1 PDX, so it's obviously.
Mm-hmm.
giving a good strong response. We do know from the other things we've done that we are able to ensure that we're not killing immune cells, you know, straight out of sight if those systems are populated. We'll be doing more than that. You know, I think the designs and efficiency we have with our system allow us to be very, very sparing with the level of payload we're dosing and that reach the tumor, because each payload, it can efficiently get to the tumor and to the tumor cell. I think like with STRO-002, those, you know, 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 know, you're enriching the tumor, the CD8 cells. There's not such a strong bystander effect that you're wiping out all immune cells, which is one thing to see from. It is a bit of a tightrope though. Our key design is let's get this really efficient. Every internalization event is optimal. Every molecule is optimal. With 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.
Thank you.
Thanks, David.
Thank you. 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, anti-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. This is a DAR 8. It's the first DAR 8 from Sutro's platform. It's site-specific with a new and exciting exatecan warhead and a β-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 do 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. Then to actually extend that into an integrated manufacturing system where our biochemical synthesis really works well because we pre-made many of the component parts, and so we've got rapid scalability, broad flexibility, and a path to commercialization. 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 up 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. This is more of a scientific lecture in some respects in presentation. I'm looking forward to actually getting back to clinical dialogue with you all later this year. Thanks so much for tuning in today and appreciate your interest in Sutro and your time today. That's it, operator.
Thank you. This concludes today's conference. All parties may disconnect. Have a good day.