Please be advised that today's conference is being recorded. I would now like to turn the conference over to Bill Newell, Chief Executive Officer of Sutro. Please go ahead. Thank you, operator, and welcome to all. Thank you for joining us for today's Sutro Research Forum. As many of you know, we are presently conducting two pivotal trials for Luvelta tazevibulin, one in platinum-resistant ovarian cancer and the other in a pediatric leukemia. We look forward to sharing updates on Luvelta with you around year-end. For today's presentation, we are focusing solely on our emerging research pipeline. In the course of today's presentation, we will be making forward-looking statements, and we refer you to the text of this slide as it pertains to such statements. For over twenty years, Sutro has been innovating on our world-leading cell-free technology. Today, we want to showcase how we are using our technology to give cancer patients more and less. The next-generation antibody drug conjugates, or ADCs, that we'll be discussing today are being designed to give more patients more efficacy with less toxicity or side effects. Sutro's cell-free protein synthesis platform is an elegant solution for what has been a long time challenge in the biotechnology industry, the production of complex biologics using cell-bound techniques. Our cell-free platform is highly flexible, allowing the modular design of complex biologics in a way no other company can, and the ability to efficiently scale up to commercial scale under good manufacturing practices. In today's research forum, we are focusing on the application of our platform to the design and development of next-generation ADCs. We can mix and match different payloads in different locations on the antibody and in different ratios, using non-natural amino acids in a way that is not possible with cell-bound approaches. The result is the ability to build a pipeline of ADC candidates specifically designed to move beyond current standards of care and to treat a broader range of patients by improving safety and efficacy. We're really excited about the programs we will discuss today, and also about the long-term potential of our platform to attract world-class partners like Astellas and Ipsen, and to continue bringing unique innovation to do more for patients. Cell-free design and manufacturing has come of age, and we are now at the precipice of the most dynamic period of pipeline advancement and new INDs in the company's history. To that end, today we are announcing goals for our proprietary pipeline. Three INDs over the next three years, with a significant number of programs coming after that, giving us the potential to be highly selective in the programs we pursue and the optionality for robust business development. We are confident in our ability to deliver this growth based on the proven ability of our cell-free platform and our research and development team. So let's get to it. The agenda for today is as follows: Dr. Hans-Peter Gerber, our Chief Scientific Officer, will provide an overview of Sutro's approach to design and develop next generation ADCs. Dr. Gerber joined us just over a year ago and is a luminary in the field of ADCs. He brings over twenty-five years of drug discovery and development experience to Sutro, with extensive scientific background and expertise in ADCs, targeted oncology, and novel biotherapeutic platforms. Then, for the first time, we will share details and new preclinical data on the three main approaches we are taking to improve ADC performance. Dr. Alice Yam, our Vice President of Drug Discovery, will introduce our tissue factor targeting ADC, STRO-004, which leverages our cell-free platform to increase the drug-to-antibody ratio and mitigate against toxicity seen with current ADCs. Next, Dr. Daniel Calarese, our Senior Director of Innovation and Strategy, will spotlight our dual payload ADCs, what we call ADC squared. We will finish our early-stage pipeline update with a special guest from our partner, Astellas, Dr. Peter Sandor, Executive Vice President and Head of Corporate Strategy at Astellas Pharma. Dr. Sandor will highlight the rationale and opportunity for immunostimulatory ADCs, or what we call IADCs. Jane Chung, our President and Chief Operating Officer, will conclude with brief closing remarks, and then Jane, Dr. Gerber, and I will be available for Q&A. I will now turn the call over to Dr. Gerber. Thank you, and hi. It's great to be here today. My name is Hans-Peter Gerber, and I'm the CSO at Sutro, and I look forward to sharing with you our highly differentiated ADC platform and the promising preclinical data in support of strong efficacy and safety profiles of our next gen ADCs. I've been involved in ADC development for over twenty-five years now, from the early days at Seagen to the recent renaissance of ADCs that was enabled by the dramatic increase in their therapeutic index, as shown graphically on this slide in the gray area. TI improvements can be achieved in two ways, either by making ADCs better outside the tumor, resulting in an increased maximum tolerated dose or MTD. We will provide several examples of how we achieve this goal with our Topo1 platform today. The other way to improve the TI of ADCs is to make ADCs better inside the tumor by lowering the minimum efficacious dose, or MED. We have four speakers today that will explain to you how we achieve this goal using our proprietary ADC platform technologies. I'd like to point out that most of the data you will see today has not been previously disclosed, so you are in for a real treat today. Looking back, ADC development has primarily focused on developing payloads with increasingly higher potencies, represented in the gray area of the graph. I personally spent most of my time developing ADCs at Genentech, Seattle Genetics, Pfizer, and other biotechs, with high-potency payloads shown in the gray area. During this time, I was fortunate to advance more than a dozen ADCs to IND filings and to support BLA of five of the fifteen approved ADCs. The main reason for the initial focus on high-potency payloads is that the very first generation of ADCs were conjugated to the low-potency doxorubicin, shown in the blue area of the graph, and failed in the clinic due to lack of efficacy. However, while the ADC field was heading towards higher-potency payloads, the breakthrough data for Enhertu in two thousand nineteen was achieved with a lower potency exatecan Topo-1 payload, shown in the green area of the graph, and for many of us at the time, this came as a surprise. So how comes that ADCs with lower-potency payloads induce higher antitumor activity? That sounds somewhat counterintuitive. To explain this conundrum, I wanted to remind you of the fact that only 1% of injected ADC ultimately reach the tumor. The other 99% remain outside the tumor, where they can cause toxicity in normal tissues, known as platform toxicity. And it is this platform toxicity that became the dose-limiting toxicity of almost all high-potency payload ADCs in the clinic, and it prevents administration of higher doses. The key difference with Topo-1 ADCs is that they do much better outside the tumor, making these 99% of ADCs less toxic to normal cells, so they can be dosed higher. So why does this matter? The simple rule of ADCs, and perhaps most oncology drugs, is that more is better, and higher doses and exposure levels drive their antitumor activities. So why did it take twenty years to get to this breakthrough moment for ADCs? The main reason is that platform toxicity were less well understood and different for each individual linker and payload type. So it was more convenient to optimize ADCs for efficacy because these models were readily available, but unfortunately, they do not predict ADC toxicity. So the good news is, however, that almost all platform toxicity can be detected in non-human primates. However, these studies are late stage and resource intensive, and it is difficult to stop programs that late in their development cycle. Therefore, safety took a back seat in ADC development until recently. So the most impactful progress made in ADC research during the past five years or so, is the development of in vitro surrogate assays that are predictive for platform toxicities, as shown on the bottom of this slide, including interstitial lung disease, which is a type of lung inflammation known as ILD, skin, liver, kidney, and eye tox. In the next couple of slides, I will give you examples how we used our tools successfully to reduce platform toxicity based on these surrogate assays. The first example here demonstrates how our proprietary click chemistry generates highly stable bonds between the antibody and the linker payload, compared to conventional conjugation chemistries, leading to lower platform tox. The Sutro conjugates using click chemistry are shown in black, blue, and green, and all induce lower rates of neutrophil cell death compared to the competitor ADC, shown in orange, which is using standard maleimide chemistry known to induce neutropenia in the clinic. The second example highlights our ability to precisely position the linker payload at specific sites on the antibody, which do not interfere with the natural recycling of antibodies in endothelial cells via the FcRn receptor. The site-specific Sutro ADC, shown in blue, did not induce endothelial cell death, in contrast to conventional random conjugates, represented by Mylotarg and Kadcyla, which are both approved ADCs known to induce vascular damage and thrombocytopenia in the clinic. The third example here is how we take advantage of our cell-free manufacturing process to reduce Fc gamma receptor-mediated toxicity. On the left side of the graph, we show that a Sutro HER2 DAR exatecan ADC in blue induces lower Fc gamma receptor-mediated cell death compared to the Enhertu benchmark, which is the ADC that triggered the ADC renaissance back in 2019. So consistent with these preclinical findings, we have not detected ILD or iTox in our safety studies in non-human primates with our exatecan and tubulin conjugates. To summarize this part, in vitro surrogate assays to detect platform toxicity are now commonplace to guide ADC development. I provided three examples on how we use Sutro's platform technology to minimize platform toxicity to make ADCs better outside the tumor. Additional examples can be found in the appendix of our slides today. Most importantly, we can measure success in making ADCs better outside the tumors in a very simple and reliable preclinical assay, the PK assay in non-human primates. So this here is my favorite slide. Because PK is so important for ADC development, I asked our PK scientists to compile all published PK data for ADCs in non-human primates, and they came back to me with the graph shown on the left side. On the y-axis, the ADC exposure levels are shown in payload equivalents, and on the x-axis, the HNSTD, which is the highest non-severely toxic dose, is shown also in payload equivalents. Topo-1 ADCs are represented in blue dots. The ADCs with the best PK properties are in the upper right corner, circled here in a dotted line, and they turned out to be Sutro's ADCs. So by using our unique ADC design tools and selecting for ADCs that do better outside the tumor, based on the surrogate in vitro assay, we were able to generate high DAR exatecan ADCs with industry-best PK properties. So why does this matter? As I pointed out previously, for ADCs, exposure drives efficacy, and we cannot wait to see how our topo-1 ADCs will perform in the clinic. Dr. Yam will give you a more detailed information on the PK and efficacy properties of our first exatecan ADC, STRO-4, which will enter the clinic next year, and the PK data of which is shown here in the upper right corner of the graph. So I shared with you how we utilize our platform technologies to make ADCs better outside the tumor. The following presentations will focus on the progress made to make ADCs better inside the tumor. For our next generation ADCs, we identified three focus areas to make them better inside the tumor in the post-topo I era. First, we want to improve ADC potency by increasing the drug-to-antibody ratio, known as DAR, with the goal to reach patients with lower copy number target expression, which can amount to over 50% of patients within certain indications. Second, in the middle of this slide, we want to combine payloads with different mechanism of action in one ADC, known as dual payload ADCs or ADC squared. This approach carries strong potential to not only deepen responses, but also to overcome resistance to mono payload ADCs. And thirdly, we want to combine the most successful modalities in oncology, cytotoxic compounds and immune activators, to activate both the innate and the adaptive immune system, with the goal to induce antitumor immunity and preventing tumors from regrowing. Before I get to how we differentiate from other ADC platforms, I want to emphasize that our platform is not just incrementally different, but fundamentally. This is because we manufacture proteins in prokaryotic cells, as opposed to eukaryotic cells, which are most commonly used for ADC manufacturing. And as you can see, we are not the only ones with this bold vision, because Genentech, when founded back in 1976, had the same goal to manufacture proteins in prokaryotic cells. So Genentech manufactured their first three products in prokaryotic cells by means of DNA vector engineering, which was state-of-the-art at the time. These products were all short peptides like somatostatin, insulin, growth hormone. So there is precedence for the success of prokaryotic cell manufacturing since more than 50 years. However, for more complex proteins like antibody, the technology was not ready at the time. Now, in the meantime, with the advancement of genome sequencing and genome engineering, complex proteins could be manufactured. Sutro went even one step further and developed a proprietary cell-free extract manufacturing method known as cell-free. And we are happy to report to you today that a couple of months ago, we completed the largest-ever reported cell-free manufacturing run of 4,000 liters for GMP manufacturing of our phase III ADC, Luvelta. And it is this unique, scalable manufacturing platform that enables us to engineer ADCs in ways conventional manufacturing approaches cannot. And this is shown on the next slide. So in this differentiation slide, if you look across Sutro's engineering tools compared to other non-prokaryotic ADC platforms, you will see that Sutro checks every box. Our cell-free manufacturing platform puts us in a unique spot to tackle the challenges of current topo-1 ADCs, putting us in a leading position to develop next-gen ADCs with fewer safety events and to improve their antitumor activities, such that more patients can ultimately benefit from them. So the entire ADC team at Sutro is extremely enthusiastic about the new, previously unpublished data that we will present today, and we plan to share more data at upcoming meetings, including ADC World, PECs, and AACR. So stay tuned for more progress updates in the near future. To summarize, we have developed a unique combination of Fc gamma receptor deficient ADCs, containing exatecan payloads with a beta-glu linker, and conjugated via click chemistry that resulted in reduced platform toxicity and industry-best PK properties. We also made tremendous advancement in scaling up manufacturing and recently completed a 4,000-liter GMP run, the largest ever reported for prokaryotic cell manufacturing. Based on the promising preclinical data presented today, we plan to advance several ADCs towards clinical development at the frequency of one ADC per year. More details on our pipeline will be shared with you at the end of today's presentation. With that, I'd like to introduce Dr. Alice Yam as our next speaker. Thank you, Dr. Gerber, and good afternoon, everyone. Thank you for the opportunity to share with you exciting preclinical data we've generated for STRO-004 in the last year. I'm Alice Yam, Program Lead for STRO-004. I've been at Sutro for 12 years now and intimately involved in building this really innovative portfolio. We're excited to share with you some of our results today. We've heard from Dr. Gerber about three focus areas that we've developed within our portfolio. The first is focused on pushing to higher potencies with high DARs. Now, of course, this is only possible when you have technologies that allow you to do this safely. Today, I'm going to take you through a deep dive of how we've done this for STRO-004, a next-generation tissue factor-targeted ADC, where we focus on three key areas to enhance therapeutic potential: the payload, the linker chemistry, and bringing it all together with optimized site conjugation on an antibody to deliver a really well-behaved molecule with a better safety profile and greater efficacy. First, let me introduce the target. Tissue factor is broadly expressed across multiple solid tumor indications. It's clinically validated, with tissue factor-targeted ADCs now approved in metastatic cervical cancer and showing promising early activity in areas of significant need, like head and neck cancers. However, some of these earlier therapies have been limited in their therapeutic potential by both systemic and on-target toxicities and have had to really thread the needle to achieve a therapeutic window. Tissue factor is also expressed in the skin and the eye, so on-target toxicity in these tissues is a concern. Additionally, its primary role is in the initiation of blood clotting, so any interference in that function can increase the risk of bleeding. There's an opportunity here to develop a differentiated next-generation ADC with reduced susceptibility to systemic toxicities like neutropenia, reduced on-target toxicities like bleeding or ocular tox, all while maintaining the potency to achieve good antitumor response. Tissue factor is broadly expressed across multiple solid tumor indications. On the left, we see that it's expressed not just in cervical cancer, but in many other cancers, generally at high prevalence and high copy number. On the right, we see that overexpression is associated with poor prognosis, consistent with studies implicating it in protumorigenic processes such as proliferation, survival, and metastasis. This suggests that tissue factor is an important driver in cancer progression and an excellent target for drug targeting. In this next slide, I'd like to introduce you to STRO-004. The backbone of the molecule is a high-affinity, high-internalizing tissue factor antibody engineered to avoid interference with tissue factor-mediated blood clotting, reducing the potential for bleeding. In the upper left panel, we have exatecan, the payload that's delivered by the antibody. Exatecan is a potent Topo one inhibitor with strong bystander activity and reduced susceptibility to drug efflux, which means STRO-004's activity will be less impacted by resistance mechanisms that allow the tumor to pump the drug out, rendering it inactive. Moving to the right, the payload is linked to the antibody with a beta-glucuronidase cleavable linker. The beta-glu linker is a really important component that not only lends the molecule the hydrophilicity that makes the ADC a really well-behaved molecule in circulation, but it also imparts a strong tumor selectivity for the payload release, as the beta-glu enzyme is highly upregulated in tumors, as seen in this rainbow-colored chart. Importantly, the linker payload is conjugated to the antibody using our site-specific technology at sites that are optimized for enhanced stability and performance. We can see in these lower panels that all of these components come together to enhance PK, which are the drivers of safety and tolerability and may help us push the boundaries of how much payload we are delivering in an ADC. So why go for a high DAR in an ADC? Studies have shown that the more payload you can deliver to the tumor, the better the anti-tumor response. This is exemplified in this Enhertu dataset from their pan-tumor trials, where they're seeing enhanced activity in high HER2-expressing tissues across a broad range of indications. In essence, high levels of tumor antigen translates to more payload delivered to the tumor, which means better responses for longer periods of time. We also want to consider the lower target-expressing tumors. In context of low target expression, we're limited in how much payload we can deliver by the target copy number, which is limiting how much payload we can internalize into the cell with each binding event. So in this scenario, a higher DAR may be favored because we're internalizing more payload with each antibody. To illustrate this, we focused on a colorectal model, HCT116. On the right, we see that the tumors express low and heterogeneous levels of tissue factor. On the left is a study we ran comparing DAR4 and DAR8 exatecan ADCs, evaluating their ability to suppress growth in this colorectal tumor model. Both exatecan ADCs outperformed an auristatin ADC in yellow. When we compared the DAR4 and a DAR8 ADC to each other in green and blue lines, we see that the DAR8 significantly outperformed the DAR4, even at half the ADC dose. So because we wanted to reach a broader patient population, including even low tissue factor-expressing tumors, we've decided to move forward with the DAR8 ADC in development. We've now evaluated STRO-004 in xenograft models of lung and head and neck cancers, most of which have medium to high levels of tissue factor expression. In these models, STRO-004 has potent dose-dependent activity, with significant tumor growth inhibition at doses as low as 0.25 mg per kg. With only a single dose of one mg per kg, we achieve sustained tumor regressions that persist out to three to four weeks, as shown in the dark blue lines at the bottom. We're in the process now of further evaluating STRO-4 in patient-derived xenograft models of head and neck and lung cancer. The dataset includes hard-to-treat tumor models, such as squamous cell carcinomas. Nevertheless, we're still observing quite good responses in this interim dataset, with more than 50% of the tumors responding to STRO-4, despite dosing quite conservatively with just a single five mg per kg dose. How about safety? Based on the toxicities observed for other tissue factor-targeted ADCs, we were particularly concerned about the eye and the skin, both of which express tissue factor at significant levels. We looked at STRO-004's impact on these tissues in vitro relative to a clinical benchmark with known levels of toxicity observed in the clinic. We were excited to see that STRO-004, in blue, showed more than a tenfold shift in cell viability compared to the clinical benchmark in yellow, suggesting it would have a significantly improved safety margin in the clinic. Given this promising result, we decided to take STRO-004 into a non-human primate safety study. Here, we wanted to understand if a DAR-8 ADC had greater on-target toxicity risk than a DAR-4 ADC, in particular, for tissues like the skin and the eye. We had seen strong safety profiles with this linker payload platform in earlier studies. Here, we wanted to push to much higher doses to understand when toxicity would occur. We were pleasantly surprised to see the strong tolerability profile for both molecules at the highest doses tested, dosing 50 mg per kg for STRO-4, the DAR-8 ADC. For the DAR-4 ADC, we were able to achieve 100 mg per kg dosing, which to our knowledge, are some of the highest doses achieved in the ADC space. Importantly, we saw no evidence of eye toxicity and only mild signs of skin toxicity in both the DAR-4 and the DAR-8 ADC, despite these very high doses. Moreover, we saw no differences in the tolerability profile between the DAR-4 and the DAR-8, which really cemented our decision to progress the DAR-8 ADC to the clinic. I'd like to also draw your attention to the PK profiles on the right, which really highlight all the attributes of a well-behaved ADC. In the blue line, we see we have ADCs that stay in circulation for long periods of time, which means we're able to minimize the ADC catabolism that drives payload release and toxicity. We can also see that our ADCs stay intact while in circulation, with superimposable levels of antibody and ADC, shown in open and closed blue circles. All of this supports the very low levels of free drug, in green, that we find in circulation at six logs lower concentration than the ADC. So all of these properties, the payload, a stable and hydrophilic linker, optimized sites of conjugation, these all contribute to improved therapeutic performance, which in turn allows us to drive towards higher tolerability, higher drug exposure, and greater efficacy. Compared to a clinical benchmark, we're able to achieve 50 times greater exposure with an HNSTD of 50 mg per kg, as shown in the bar graph on the right. Combine this with the potent activity we observed even in low tissue factor expressing tumors. We believe we've widened the therapeutic window for tissue factor-targeted therapies and the patient population that will benefit from this medicine. We believe tissue factor presents a significant clinical opportunity for pan-tumor targeting, with clinical validation in cervical cancer and signs of early activity in head and neck, pancreatic cancer, and multiple other solid tumor indications. To access the full potential of this target, we've designed STRO-004 for broad therapeutic benefit, with a novel linker payload chemistry that delivers potent tumor-selective activity. What makes this molecule differentiated is not only the linker payload, but how we've brought it all together with the conjugation chemistry and optimized sites of conjugation to make a really well-behaved molecule with enhanced safety profile. Based on these very exciting preclinical data, we will be submitting an IND in the second half of twenty twenty-five, and we'll be updating you on our clinical development strategy in the near future. I'd like to now introduce our next speaker, Dr. Daniel Calarese, who will be introducing our dual payload platform. Thank you, Dr. Yam. Good afternoon. My name is Daniel Calarese, and I've been at Sutro for ten years, working in protein engineering and research strategy. I'm excited today because, for the first time, we are going to pull back the curtain on the dual payload ADCs we are working on at Sutro. By a dual payload ADC, we mean an ADC that delivers two different payloads. Our goal is to make ADCs better inside the tumor and overcome the emerging trend of payload resistance being observed in clinic. There are many potential advantages to a dual payload approach. I have four listed here. First, many ADCs are being combined with small molecule therapeutics in clinic. These small molecule therapeutics have their own toxicities. However, by delivering these compounds via an antibody, we can reduce the systemic toxicity, leading towards more effective targeted therapies. Second, using a dual payload ADC can reduce clinical complexity. Instead of managing a combination of therapies, a dual payload ADC allows for dose escalation like a traditional ADC, simplifying treatment. Third, a dual payload ADC ensures simultaneous delivery of both payloads to the same cancer cell. We believe this is crucial for overcoming resistance, the last point. So why is overcoming resistance so critically important? An emerging trend of payload resistance has been reported at major clinical meetings. This clinical data, illustrated at the top of the slide, demonstrate that when patients relapse after receiving an ADC, they are less likely to respond to a second ADC with the same type of payload, even if the target antigen is different. In contrast, as illustrated on the bottom, when patients are treated with a second ADC that uses a different payload, they may respond as if they hadn't been treated with a prior ADC. This opens the door to delivering both payloads simultaneously on one ADC, achieving anti-tumor activity regardless of prior lines of therapy. Another possible dual payload approach is to use one payload that potentiates the effect of the other payload, with the aim of restoring sensitivity to cancers that have stopped responding. These dual payload ADC approaches will not only have the potential to improve outcomes for relapsed patients, but we also believe they can benefit treatment-naive patients by proactively addressing the onset of resistance. It is harder for cancer cells to evade both therapies. We plan to advance multiple dual payload ADCs, as we believe a dual payload ADC approach can expand treatment options for both treatment-naive and relapsed patients, and our cell-free platform is ideal for making these dual payload ADCs. By site-specifically incorporating different non-natural amino acids at selected sites and using different conjugation chemistries, we can efficiently generate dual payload ADCs. Here is a real experiment to demonstrate this, so on the right is an SDS-PAGE gel, and we can site-specifically conjugate a blue dye to the light chain and see the blue band for the unreduced IgG. We can conjugate a red dye to the heavy chain, and now you see the red band, and then we can conjugate both the red and blue dyes and see the unreduced IgG band is now purple. In the reduced gel, we see the blue light chain and the red heavy chain clearly. This demonstrates we have precise control over our ADC design and this precise control is what is truly special about our cell-free platform, as we can easily optimize the stoichiometry between payloads. When you consider different linker payloads and their dosing in clinic, combining those linker payloads in a strict one-to-one ratio would be impractical. Different drugs have different potencies. With our cell-free platform, we can fine-tune this ratio, not just one to one, but two to one, three to one, three to two, five to one. This is something very few others can do. Our cell-free platform enables us to design dual payload ADCs with optimized safety and efficacy so far, this has all just been a demonstration of our capabilities. Let's take a look at some practical examples of dual payload ADCs we are working on. Let's consider the combination of TOPO1 inhibitors with microtubule inhibitors.... Most clinical ADCs use one of these two types of payloads. We now understand that these payloads do not have cross-resistance, and there are many clinical indications that are sensitive to both. If you look at the purple column in the middle, you'll see non-small cell lung cancer, bladder, ovarian. There's a significant potential in these indications for a dual payload topo one inhibitor, plus a microtubule inhibitor to enhance the clinical efficacy. The concept of combining these two payloads in the clinic has been validated through simultaneous delivery of two different ADCs in a clinical trial. In the double antibody drug or DAD trial, they use Trodelvy, which delivers a topo one inhibitor payload, with Padcev, which delivers a microtubule inhibitor payload to treat metastatic urothelial cancer. Both ADCs target antigens which are highly expressed in this cancer type. The trial observed an additive effect in the response rate, highlighted in green, with no new toxicities reported. This confirms that targeting two different payload classes can enhance patient outcomes. By hitting the tumor with two different mechanisms, mechanisms of action, you allow fewer paths for the tumor to escape. For our own proof of concept designs, we selected MMAE, a clinically validated microtubule inhibitor payload, attached to a PEGylated beta-glucuronidase cleavable linker. Our technology enables us to make dual payload ADCs that are eight plus two and eight plus four. This means one ADC has eight topo one inhibitor payloads, illustrated in pink, and either two or four microtubule inhibitor payloads, illustrated in blue, and this is all on the trastuzumab backbone. It's important to note here that these ADCs are higher DAR, a DAR higher than you typically see on ADCs, with overall DARs of 10 and 12. Now we're going to see results from a number of different experiments we haven't shown before. We see that these dual payload ADCs demonstrate promising in vitro efficacy. We observed improved cell killing in certain cancer cell lines. In these cell killing plots, the black line represents a HER2 benchmark, while the purple indicates our eight plus two dual payload ADC, and we see greater cell killing than with the dual payload ADC approach. The dual payload ADCs also exhibit desirable in vivo pharmacokinetics. Here are the results from a twenty-one-day study in C57BL/6 mice. Both the eight plus two and the eight plus four dual payload ADCs demonstrated favorable PK profiles with low clearance and long half-lives. In the same study, we observed the dual payloads have rock-solid stability. Here you can see the DAR 10 and DAR 12 are maintained throughout the twenty-one-day study. This stability is important. It means the ADC remains intact while in circulation, increasing our potential to deliver more payload to the tumor. We are currently evaluating these dual payload ADCs for in vivo efficacy. Another dual payload approach involves combining two payloads where one can potentiate the other, in this case, PARP inhibition with topo one inhibition. There is a well-established synergy between these inhibitors, as PARP is directly involved in the DNA damage repair pathways that address the DNA damage caused by topo one inhibition. So there's a strong biological rationale for their combination. We can see this synergy with our own in-house data on the right. In this in vivo efficacy, the systemically delivered PARP inhibitor talazoparib, shown in purple, has no significant tumor growth inhibition. The DAR four topo one inhibitor ADC, shown in blue, has some tumor growth inhibition. However, the combination of the topo one inhibitor ADC with the systemic PARP inhibitor, shown in orange, has greater tumor growth inhibition and even tumor regression. However, despite the synergy, the combination of PARP and topo one inhibitors delivered systemically at the same time has not been realized in clinic due to dose-limiting myelosuppression. There are now multiple ongoing clinical trials combining an ADC with a topo one inhibitor payload with a systemic PARP inhibitor. However, PARP inhibitors do have toxicities. There's a hematological toxicity and an increased risk for advanced malignancy, such as AML. So we decided on a pioneering approach to develop a dual payload ADC that specifically targets the PARP inhibitor with the topo one inhibitor. For this proof of concept ADC, we chose a potent pan-PARP inhibitor, again, with a similar PEGylated beta-glucuronidase cleavable linker. As it is less potent than the microtubule inhibitor we saw previously, we first started off with a four plus two dual payload ADC approach on an anti-tissue factor backbone. That is, there are four topo one inhibitor payloads, illustrated in pink, and two PARP inhibitor payloads, illustrated in blue. This dual payload ADC has shown compelling end results, both in vitro and in vivo. On the left is the in vitro cell killing, where the dual payload ADC, shown in purple, has better cell killing than the single payload PARP and topo one inhibitor ADCs, shown in blue and pink. On the right is the in vivo efficacy data, where we see the topo one inhibitor ADC alone, in pink, does have some tumor growth inhibition, but the dual payload ADC, shown in purple, has greater efficacy, and we observe some complete responses. We are currently optimizing the linker payloads and the stoichiometry between them. So we are working on multiple different dual payload ADCs, and we believe we have a best-in-class platform for creating dual payload ADCs, as we can optimize both the conjugation sites and the stoichiometry between the payloads. With these dual payload ADCs, our hope and intention is to overcome resistance mechanisms that are currently being observed in clinic... Another dual payload ADC approach we are working on, in collaboration with Astellas, incorporates immune agonists as a combination partner, and it's my pleasure to introduce Dr. Peter Sandor from Astellas to share this data with you. Thank you, Dan. It's a pleasure to be here. Thank you for having me at the research forum. My name is Peter Sandor, Head of Corporate Strategy at Astellas. In my previous role at the company, I oversaw the immunology efforts at Astellas, including the formation of the partnership between Astellas and Sutro Biopharma to develop the next generation immunostimulatory ADCs or iADCs. I will talk very briefly about the technology, what made us excited about this, and then talk a little bit about our partnership with the Sutro team. Astellas is a global specialty pharma company with significant presence and market-leading position in oncology, including an ADC in urothelial cancer treatments called Padcev. We are very much focused on developing emerging cutting-edge science and turn these into value for patients. Our R&D approach is based on the so-called focus area approach. What it means, that we are exploring the unique combination of the disease biology linker and the most relevant modality to create maximal impact on the disease, hence improving the outcome for patients. Especially in immuno-oncology, we are exploring the so-called multifunctional modalities, which can address multiple cancer drivers or pathways at the same time, leading to improved clinical outcomes. This is exactly what the IADC does, and that's why we got very much interested in the technology what Sutro has developed to allow precise conjugation of different payloads on the same antibody. As the slide illustrates, combining an immunostimulatory payload with cytotoxic one, disrupts the primary tumor driver, effector T cell infiltration, and it activates the innate immune response as well, and overall bridging innate and adaptive immune responses to deliver better outcome. Beyond the strong strategic fit of the iADC, the combined dual payload, we have seen strong data supporting this hypothesis even at the time when we were forming our partnership. The experiment on the slide compares ISAAC, the single payloads, immune-stimulating antibody conjugates, the immunostimulatory antibody conjugates, or iADC, and ADC with a single simple chemo payload, compares them with vehicles. As you can see very early after the application, the innate immune system, then the T cells get activated both by the iADC and the ISAAC, but then longer term, by day five, the T-cell infiltration, as well as the CD8 T regulatory ratio, start to increase, driven by the iADC primarily. If you compare the same modalities in the tissue or the effect of the same modalities in the tissue, the iADC has demonstrated superior increase of the CD8 T cell count in the tumor microenvironment, and we compare it to ISAACs and ADCs. The next slide, the in vivo experiment shows superior and durable antitumor response, which has been demonstrated by the combination of a cytotoxin and TLR7 immunostimulatory agents on the iADC, compared to the ADC alone. On the right side, you can see how the prolonged immune response or immune effect is preventing the tumor regrowth in the rechallenge model after applying MC38 cells in this model. As you have seen in the previous presentations, and also in this summary, there is strong advantage of using combined payloads on a single antibody. We believe in that the Sutro platform, including the iADC programs, have many advantages compared to other modalities. It can prevent Fc gamma-related toxicity, as you have seen before, and it combines direct tumor killing with the activation of antigen-presenting cells, as well as T cell effect or T cell recruitment, and it does as a single modality with a single-step delivery. In summary, the iADC offers a new, highly promising treatment option as monotherapy, given its dual mechanism of action. It can also synergize with other immune therapies... and it also has the potential to offer treatment for patients who have hard-to-treat cancer. I would like to thank the Sutro team for the innovation, what they do, the hard work, which makes it possible to start to create these programs. It is a great privilege for us to work with this very talented, innovative Sutro team, and our collaboration is progressing rapidly, and I really look forward seeing these programs to move into the next phase of research or development, in the future. With this, I hand it over to Jane for closing remarks. Thank you. Thank you, Dr. Sandor, for the important scientific update and very strong partnership with the Astellas team on the exciting IADC strategy. And thanks to all of you for your full attention today. I'm Jane Chung, Chief Operating Officer here at Sutro, and I'd like to share why we are frankly bullish about our growing pipeline. We certainly have lots of love for Luvelta that's already in a late-stage phase III trial, and now more love for our early-stage pipeline. We are doubling down on innovation that's made possible by two things. First, you heard a lot about the power of Sutro's unique cell-free technology today, and second, our incredibly talented people. I wanna give a big thanks to the Sutro team and the presenters on this call for the tremendous progress you're seeing here made on our science, innovation, and technology. The team is working at pace to accelerate and move these important medicines into the clinic, and we're on track to deliver three INDs in the next three years. First, with our tissue factor DAR 8 Exatecan ADC in the second half of 2025, followed by the higher DAR Exatecan and dual payload ADCs in the next several years, and this doesn't even account for our partnered programs listed on the bottom of this slide. Now, as a commercial leader at heart, this is my favorite slide. We've already done the commercial assessments based on the new target level expressions of our early pipeline, and I can tell you these are very high-value targets. We look forward to confirming these results in patients and having these next-gen ADCs benefit exponentially more patients across many solid tumors, including lung, colorectal, breast cancers, and many others. One finer point I want to illuminate and make sure you take away is this: While many companies are seeking value in only new ADC targets to differentiate, we don't have to. With targets, with our dual payload ADCs, what's old is new again. As all ADC targets, whether validated or not, old and new, are back on the table to address, as our dual payload ADCs are intentionally designed to overcome resistance to single payload ADCs. This will be game-changing for the field. Here's what you heard today. With significant advances of our science, technology, and manufacturing, Sutro is on a mission to fundamentally change the way these medicines are made, not just to make a me-too or small incremental benefit, but to fundamentally transform what science can do and the treatment paradigm for cancer patients. By translating our unique design advantage from cell-free to dramatically improve the therapeutic index of ADCs and avoid unwanted platform toxicities, we can safely dial up the potency with higher DAR and dual payloads to work better both outside and inside the tumor, to overcome resistance to conventional ADCs, and to deliver best-in-class targeted medicines that can benefit far more patients. There was so much great science presented today, much of it for the very first time. The team did a great job differentiating Sutro's design advantage of ADCs, enabling greater exposure, leading to greater safety and efficacy. Thanks again for tuning in, and we'll now open it up for Q&A. Thank you, Lisa. Thank you. As a reminder, if you would like to ask a question, please press star one one on your telephone. If you would like to remove yourself from the queue, please press star one one again. One moment while we compile the Q&A roster, and our first question for the day will be coming from Roger Song of Jefferies. Your line is open. Please proceed. Great. Thanks for sharing all the very promising data from your research programs. Maybe two questions from us. One is more scientific, the other one is more strategic. On the scientific side, just curious, given you're adding more payload in terms of DAR and also potentially using different payload, dual payload to the ADC, how should we think about the impact to the internalization, given it is to ADC, the internalization matters a lot for the in vivo efficacy? Thank you. Thanks, Roger. Hans-Peter, why don't you take that, please? Yes, and happy to do that. Thank you for the question. And so we've been looking at internalization of low versus high DAR ADCs, and consistent with earlier reports, that unless you really have massive load of ADCs, which we don't have, of ADC linker payload, internalization is not affected by the numbers of DAR. So we don't see any issues, and we haven't seen any issues going to as high as DAR 16 on that aspect, so I don't think that's gonna be rate-limiting. In contrast to that, what usually is the problem when you do too many linked payloads on an ADC, that you have less exposure. And there we had a very pleasant surprise, that the more payloads we added, the PK stayed rock solid, in some cases, even got better than the naked antibody. This doesn't always happen, but when it happens, you know, we took that we were very happy to see that. We don't have a problem with that, and we're continuing to look for, you know, best PK in the industry to have less off-target and on-target toxicity. Yeah, Roger, and I think the strategic piece is that it's a very unique and differentiated modality. Very few companies can have the precise protein engineering design to enable dual payload, you know, structures. And so I think this will be very, very game-changing for the field. Thank you. Yeah, we do see some PK data, but just curious how consistent the PK is. But seems you know, you don't see the rate limiting for the PK. And then another thing is related to you know, you will have this IND filing every year, you know, come up with those earlier pipelines. So how should we think about your cash, and then what is the funded through your current cash? And then also, how should we think about you will allocate your capital, balancing your pivotal program versus the early pipeline? Thank you. Thanks, Roger. That's a very important question, and, you know, we continually assess what our available resources are today and what we project them to be in the future, so right now, we've got a lot of capital going towards our REFRaME-01 and REFRaME-P1 trials, as well as the non-small cell lung cancer. We're confident of our ability to put STRO-004 into the clinic with the capital that we have available, and as you know, we continue to work on adding capital into the company, so our projection of being able to do three INDs over the course of the next three years really takes into consideration the amounts that we're going to be spending on our pivotal trials, as well as our ability to add capital to our bank accounts over the course of that same time period. As you know, we've been pretty good at raising capital through strong collaborative partnerships, like our deal with Astellas, like our deal with Ipsen, and we project that we will have more deals on an ongoing basis in the future. So we do take seriously the requirement to make certain that we're adequately balancing risk and capital, and I want to make certain that I assure everyone we plan to have sufficient capital to move forward with these very exciting programs that we've given you a preview of today. Excellent. Thank you, Bill. Thank you, everyone. Thank you. One moment for our next question. And our next question will be coming from Tazeen Ahmad of Bank of America. Please proceed with your question. Okay, I think that's me. Hi, guys. My first question to you is about safety profile as it relates to how you're thinking about combining different modalities. So, for example, you talked about combining ADCs with PARP class. The PARP classes in general is known to have safety observations to be slightly different depending on the PARP. But based on the data that you've collected so far, what do you think will be something to look for in terms of tolerability for patients as you think about what indications to pursue? And then I have a follow-up. Great. Thanks, Tazeen. Hans-Peter, would you please answer that? Yes, happy to do that. Yeah, so for the PARP inhibitors, the toxicity is well explored in the clinic. We know what to look for. For the safety, we do have a linker in place and a chemistry in place that we have the best stability in the industry, so we lose less payloads in the circulation, so we shouldn't run into this systemic toxicity problem that you see with PARP, and so the art actually to get the right PARP inhibitor in the right ratio to an exatecan is going to be the main focus from the efficacy point of view, and as you can see, we can dial in PARP versus exatecans all the way from one to four to higher, and that ratio will determine how we can maximize the efficacy and how we then also can balance that with the safety. But again, that dual linker that we have, you could see that a one millionfold difference between how many molecules are on the ADC and in the circulation should really drive that safety profile for us. So I'm pretty confident on the safety side. The efficacy side is what we're doing best, so I'm looking forward to finding that sweet spot. Okay, thanks for that color. And then related to that, because of what's likely to be a more tolerable profile, does that open up more indications for you to pursue that other companies have not been able to do? And can you share what potential indications those could be? Yes, that is exactly the case. So we're looking now at targets where we can apply the dual payload concept that have these BRCA type mechanisms, this ovarian that is breast and that is prostate. So we select our targets right now according to where we're gonna go with the dual payload, and we have three to choose from. So really, this is reopening the book again, but looking at validated targets and where in this combination we can go where others couldn't go. That's a pretty interesting and exciting activity that we're conducting here as a team. Do you have a- Jane, if you'd like to refresh on slide sixty-four? Yeah. On the slide sixty-four, it should- Sorry, go. We basically look at a whole list of opportunities here for the early pipeline. Some of them do overlap, and we'll let the preclinical data really guide us in terms of which tumors to go after for each target. But it does show exponentially more patients that could benefit from the early pipeline. Last question for me is, when do you think you'd start to have color on those indications? We already are deliberating internally about which are the most important tumors to go after. But we also recognize that it is a competitive field. And so we will be disclosing that information as we move forward. You know, and we wanna make sure that we maintain our lead in some of these areas as well. Yeah. Okay. Thank you. Thank you. One moment for our next question. And our next question will be coming from Asthika Goonewardene of Truist. Your line is open. Hi, guys, thanks for taking the questions, and I appreciate the color provided today. So I want to focus a little bit on, first question on STRO-004. A neighbor of yours in San Francisco, looking across the bay, aimed to develop a tissue factor-targeting ADC that contained an MMAE payload, but found, to your point about payload and chemotherapy resistance, that the efficacy didn't pan out. They have since brought forward a new asset that uses a topo-1 payload, with a precise DAR, site-specific conjugation, et cetera. So it sounds like the field is appreciating the aspects of what is also in STRO-004. But I want to ask, how does your -- how does... What else does STRO-004 have to differentiate itself from these emerging other ADCs that for tissue factor? Thanks, Asthika. Peter, you want to take that, please? Yeah, happy to do that. Yeah, so of course, we are familiar with the activity of our next-door neighbor in this space. And we looked at them very carefully. So as the design, as it relates to the design of their tissue factor ADC, they do have a different derivative of exatecan, known as belotecan. So there may be difference there in the pharmacology, but most and importantly, they're using a cathepsin B linker. And this is the linker that has been used for twenty years now. The liability is very clear, and that is going to be cleaved in the bone marrow. We learned that all in this field over the last 20 years. And when you do have these VC linkers, when you lose your payload in the bone marrow, you are likely to use neutropenia and cytopenia. So we monitored that in our tox studies, and that's why we have our link, which is a beta-Glu, which does not have that bone marrow liability. So we will have, expectantly, based on what we've seen preclinically, less of that bone marrow toxicity. So there's differentiation on the link, a payload level. And in addition, we mentioned that the way we manufacture the antibody in E. coli, we do not glycosylate the antibody, and that's basically Fc gamma receptor silencing. And that means much less uptake in normal tissue, including the eye, the bone marrow, again, and also the lung, ILD. The ILD for conventional topotecan ADCs that are Fc gamma active is reported across the field, whether it's a belotecan, exatecan, DXD. We haven't seen ILD with any of our conjugates in cyno, and we think this has to do, and that's reported by Daiichi, Fc gamma receptor immediate uptake into lung alveolar cells. We do not have that because we do not engage the Fc gamma receptor. That's on the antibody design side. Then, of course, we selectively choose our sites to conjugate the link of payloads to sites that do not interfere with normal recycling of ADCs. This is a conventional ADC that is conjugated to the cysteine, that is not selected. That's basically stochastic random conjugation. So there may be liabilities on that end that we don't have, because we carefully, over the last year, selected these sites where we have minimal impact on PK properties. Ultimately, that reflects in better PK, as I just walked you through that collection. So we have reason to believe we are differentiated on the ADC linker payloads, on the antibody, manufacturing side, and linker chemistry and conjugation chemistry. How much that will translate into differences in the clinic will remain to be seen, but again, our PK properties are making us very, very positive and bullish about seeing how far we can go in the clinic in terms of those. All right, so shots fired across the bay there. On the, maybe if you can dig a little bit into the dual payload design. ... the assets that you have in plan here. You highlighted using Trop-2 and MMAE in, well, in one of the slides that you covered, with the Trop-2 being linked with a beta-glucuronidase linker. And we, from what we understand, MMAE typically is with the Val-Cit linker. We know Val-Cit also has some of this cleavage by elastases outside of, in the bone marrow. So I guess my question is, when you think about repurposing payloads like MMAE, will you be taking on additional steps to maybe engineer the linker as well, that's normally traditionally associated with them? Yes, good question. And yes, we started from the get-go not to use the VC linker. We went with the beta-glucuronidase right away for that liability of VC linker that I explained already. So working with beta-glucuronidase MMAE and beta-glucuronidase exatecan and any other payloads later on, beta-glucuronidase. And just to remind everybody, it's not just the standard off-the-shelf beta-glucuronidase, that's a proprietary engineered beta-glucuronidase that has better release kinetics in the tumor. So, that's just the update there. Yeah, but you're right, one shouldn't go in with a VC-MMAE ADC when you can dose up at 100 mg/kg in this cyno. Because if you were to do that with a VC-MMAE, you have to stop at 6 mg/kg, 24-fold below where you can be with a different linker, so we wouldn't do that. Awesome. Last question, guys. I'm just gonna build on Raj's previous question on capital allocation here. Bill, you mentioned that you're open to doing more deals to fund your targets of an IND per year for the next three years. Just want to clarify, is a deal for Luvelta also on the table, or should we think about these as deals with more the the these early pipeline assets? Thanks, Asthika. You know, we're very bullish on Luvelta and continue to think about the prospect of meeting the needs of eight in ten women who have platinum-resistant ovarian cancer, as well as potentially non-small cell lung cancer patients. You know, our ideal deals, as we've discussed in the past, really are the platform deal opportunities, but you know, as you can imagine, we have conversations on all sorts of deals from time to time. We don't comment on them, but I feel confident in our ability, as we have done over the last five to seven years, our ability to do a robust amount of deal making that continues to fuel the continued development of our proprietary pipeline, so stay tuned for further developments, and we'll keep everybody posted as they occur. Great. Thanks for the color, guys. Thank you. Thank you, and one moment for our next question. Our next question will be coming from Jay Olson of Oppenheimer. Your line is open. Please proceed. Oh, hey, congrats on the progress, and thank you for providing this update. I have one question about your three new INDs and then a follow-up on zero zero four. So for the new INDs, how are you prioritizing those, and should we expect the first to be a dual payload IND? Thanks, Jay. I'll answer that the first one is gonna be STRO-004, so that's the DAR exatecan with the beta-glucuronidase linker. That's really, we have line of sight on that. As to prioritizing the other two, if you return to slide sixty-three, you'll see that it's more likely than not that there will be an exatecan-based ADC following the tissue factor ADC, and then the dual payload ADCs following that. So that's our current projection as to the molecules and the order in which we'll be moving them forward into the clinic. Okay, got it. That's clear. Thank you. And then, as you plan for the clinical development of STRO-004, since AstraZeneca has a biomarker strategy they're advancing using their QCS algorithm for Trop-2, is that type of biomarker strategy something that Sutro is considering for tissue factor or other antigens? I think I'll ask Jane to respond to your question. Yeah, you know, there is already a commercially available tissue factor ADC, and there is a commercially available biomarker already for tissue factor. So, you know, it will be interesting to see whether an additional, you know, what AZ is doing will be applicable or not. We can always consider and take a look at that. I think what we've seen is that we can leverage the commercially available biomarker at this point and get to lower copy numbers. Yeah, I think there's the AI biomarker assays are all evolving, and so we'll see how this all plays out. Okay, great. Thanks for taking the question. Thanks. Thanks, Jay. Thank you. One moment for the next question. Our next question will be coming from Rennie Benjamin of Citizens JMP. Please proceed with your question. Hey, guys. Thanks for taking the questions, and, thanks for the presentation. A couple from us. I guess starting off, Hans, I think you mentioned in the beginning that you had conducted a 4,000-liter GMP run. I mean, given this is a cell-free extract, can you just give us a sense as to how much product that can produce and ultimately maybe what you need to get to, if you haven't gotten to it already, what you need for commercial product? Yes, I'm happy to do that. So we, of course, like everybody, continuously increase the titer of what we can produce in cell-free, same as for CHO. We are now at the point where the overall cost of goods for our cell-free manufacturing of ADCs are about the same as in CHO cell extract produced ADCs. So we kind of reached that tipping point. I think we keep doing that. Actually, we have actual collaborations with academic groups to further improve our titers, our productivity of our cell-free extract. So Rand, let me also add to that. We are anticipating putting out some either a paper, white paper, or publishing on that production run, and so I just ask you to stay tuned for that. Okay, fair enough. Switching to STRO-004, can you talk maybe a little bit about the biological mechanisms that you may be aware of, that could cause, you know, resistance, or any sort of a rebound that you see when the drug is no longer being either administered or when the drug is being administered? And any combinations that you think, you know, might actually, you know, help even enhance the activity of STRO-004, especially, you know, given the, I guess, heterogeneity of expression across various tumor types. Thanks, Hans-Peter. I'm gonna go there. Yeah. No, happy to comment on that. So when back at Pfizer, we actually wrote a manuscript on how resistance towards ADC develops, and at that time it was tubulin inhibitors, but it's the same what happens now with exatecan inhibitors. And it's important, it's different from what happens to the chemotherapy alone of the same payload. With ADCs, the resistance mutations and changes that happens in the tumor cells are related of how that antibody bound to the target antigen internalizes through the cell, endosomal-lysosomal trafficking, and then release of the payload, and then reshuffling back to the cell surface of the antigen. These processes, and it's critical that that complex goes to endosome and lysosomes to release the payload. So the cell finds ways around that cell trafficking, that, that complex never gets to the lysosome. The payload is not released. For chemotherapy, it's first and foremost, anything that makes the chemotherapy get to the target protein, and these ways are different from an ADC. So when you become resistant to the chemotherapy, you are likely not resistant to the ADC with a payload of the same chemotherapy. So this resistance mutations are different. So after you get chemo, you still respond well to an ADC. Now, how you can overcome that resistance to an ADC, it turns out if you just change the payload, you become sensitive again. And that has to do, though, so payload goes to different parts of the cell into areas where one is still transported when you become resistant to the first. And the other way to overcome that is from the get-go, and that is the current theory about how tumors become resistant. If you have two payloads that target two different mechanism, biological mechanisms, the cell is less likely to find those two mutations in each of these pathways to become resistant. So you respond much longer to a dual payload treatment, you expect a more deeper response and a very much slower onset of resistance when you treat with dual payloads. If that is answering your question. Yeah, so I definitely understand the point or the advantage of the dual payloads. I guess before that even makes it into the clinic, do you anticipate or do you think about potential combinations with approved, you know, approved targeted therapies or IO combinations with, let's say, something like O4? Oh, yes, of course. That is, naturally, something that we're looking very intensively, so I give you one of the areas where a lot of that is happening. It's MMAE tubulin inhibitors with checkpoint inhibitors. In bladder cancer, they do very well, and of course, if you have a dual payload and you have a tubulin inhibitor in there, you'd expect more of that as well, so this is one way to maybe go with a dual payload in an indication where checkpoint inhibitors don't do as well, especially in an exatecan ADC, because with the tubulin payload, we might induce that immunogenic cell death, and then you get responses to checkpoint inhibitor that you didn't see with an exatecan or lone ADC. Other areas of combinations is what Dr. Calarese talked about. It's when you bring two inhibitors of two parallel pathway, all involved in DNA repair. So when the cell finds a way around your exatecan blocker to actually still repair the DNA, you have another blocker, like a PARP inhibitor, that it cannot repair the DNA and the cell will die. So this is like the synthetic lethal approach that is being published in the literature widely across academia and biotechs. And so this is a second way of combination. And of course, there's plenty more of these chemical groups and classes that combine well with each other and have a very active screening going on in research to find those two components that synergize with each other to maximize the anti-tumor efficacy, and then to build this onto an ADC. ... Got it. Just a final question. How does, unless I missed it in the slides, as I was focusing on the comments, how does STRO-004 compare to something like Tivdak? You know, the product is approved. I imagine you can, you know, get it and run the preclinical studies. I'm kind of curious if you've done that. And as a path forward, do you steer clear of cervical cancer and go after, you know, other cancers where the expression of tissue factor is quite high? Or do you, you know, since it's established in cervical cancer, you know, you have an approved product, do a head-to-head, and try to prove, you know, either superiority or non-inferiority? Peter, why don't you answer the first, and then Jane will answer the cervical question. Yeah, happy to do that. So yes, Tivdak is the tissue factor with a tubulin inhibitor, and you may have seen that when Dr. Yam presented, she used Tivdak as a benchmark. We like to do that here, to have our feet in reality, to know where we are with our safety and efficacy, and you may have noticed that, you know, that exposure that I explained why the exposure is important, that we have a fifty-fold higher exposure with our ADC compared to Tivdak. I've never heard of any of that kind of difference, so we kind of can't wait to see what that would do in the clinic, and then in addition, we have fifty-fold higher exposure, but efficacy-wise, every time we do a test, we're better than Tivdak, so we have better safety, better efficacy. I mean, we know how we have to go to the clinic to see what that does, but we are, of course, very forward-looking, and also the patients, that they might actually get a drug here where we match the tumor biology. Cervical is very sensitive to topotecan and Exatecan, and the right target that is known to be tumorigenic. We're finally zooming in on the key aspects of what drives tumor and targeting exactly those, the root cause of tumor. So this is very, very, very bullish on this program. And in addition, any of these targets that you haven't seen, we selected them for being tumor drivers. So the cells don't like to lose that target. So when we target these targets, the tumor will not down-regulate the targets, and they're involved in tumorigenic behavior or cancer stem cell survival. So we're really going after the root cause of cancer with these mono payload, but in particular, dual payload. Yeah, and then in terms of development, as you know, tissue factor is highly expressed in cervical, so it makes sense to really see a signal there. And in terms of future development, I will ask you to stay tuned with respect to how we design the trial, whether it would be head-to-head or, or some other way of actually designing that trial. But there are a number of tumors that express tissue factor that we will be pursuing. Excellent. Thanks very much, guys. Thank you. Thank you. And one moment for the next question. And our next question will be coming from James Shin of DB. Your line is open. Please proceed. Hi, guys. Thanks for the question. I have one for Hans and his team on therapeutic index. Does Sutro's next gen ADCs have you guys looked into the cell trafficking and whether there's any recycling and serial killing capabilities? And then I have a follow-up on payload type. Great. Hans here. Yeah, I heard you asking about recycling of ADCs? Yes, serial killing capabilities for the next gen assets. Oh, yes. Yes, yes. So we've seen, but we selected the payloads for having bystander activities. So once, the ADC has internalized, it's being released in the lysosome. When it kills the cell, it actually has the capability to transfer the membrane of the dying cell and kill the next cells. It's known as bystander activity. And exatecans have more of that compared to deruxtecan, for example, which is the Enhertu payload. So we can actually get into tumors where maybe 5%-10% of all the cells have the antigen, and we kill the other cells without the tumor antigen because of bystander activity of the payload when it is released. So yeah, we see that we can kill cells that don't have the target antigen because of bystander activity. MMA is the other well-known molecule that can do that. Is that answering your question, or? Yes, yes, yes. And then the other question I have is, the click chemistry platform, is that amenable to ADCs at all? Yeah, it likely is, but can you repeat what DAD is? ADCs, the next generation antibody conjugates. The degrader antibody conjugate. I mean, so in general, we can integrate those non-natural amino acids into any protein. We've done over eight or 10 different protein conjugates using non-natural amino acids. There's a review out there, so we're not limited to antibody drug conjugates, if that answers your question. Yeah, I just was trying to see how the breadth of the click chemistry can go. So that's it. Thank you, Hans. You can use that to actually conjugate an antibody to another protein and things like that. That's like the Lego principle is- Yeah. Chemistry. It's great. Mm-hmm. Thanks, James. Thank you. Thanks, guys. I'm showing no more questions in the queue, and I would like to turn the call back over to Bill Newell for closing remarks. Please go ahead. Thank you all for joining us for today's Research Forum. You've learned a lot about what we've been able to achieve and where we're going with our next-generation antibody-drug conjugates. This is the tip of the iceberg. As Hans-Peter explained, we'll be presenting more evidence at upcoming scientific conferences, and we look forward to engaging with you and revealing more as our exciting pipeline of next-generation ADCs unfolds over the next few years. Thank you again for your time today, and we appreciate your listening. This does conclude today's conference. Thank you for participating. You may now disconnect.