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

Greetings. Welcome to Sutro Biopharma R&D Day 2025 Conference Call. [Operator Instructions] Please note, this conference is being recorded. I will now turn the conference over to Jane Chung, CEO. Thank you. You may begin.

Hello, everyone, and thank you for joining us today and for your continued interest in Sutro. We're excited to kick off our 2025 R&D Day, where we'll take a closer look at the science behind our platform and our growing pipeline of highly differentiated ADCs. As we move through today's program, we hope you come away with a clear sense of 3 things. First, for those new to the story, what is the new strategy for Sutro and why we have strong conviction in our differentiated pipelines based on the emerging scientific data. Second, how we have been executing on this new strategy with a new leadership team and with speed. Third, how our progress will drive more value for patients and all stakeholders over the next few years. We will show how our ADC technology translates to a rich pipeline of therapies that can change the trajectory of cancer. We believe Sutro is well positioned not just to participate in the ADC field, but our ambition is to define its future. Next slide. In the course of today's presentation, we will be making forward-looking statements, which should be interpreted as outlined here. Next slide. Joining me from Sutro are Dr. Hans-Peter Gerber, our Chief Scientific Officer; and Dr. Jonathan Fawcett, Vice President of Clinical Development. In addition, we are pleased to welcome Dr. Tony Tolcher, Co-Founder of NEXT Oncology and a key opinion leader in cancer treatments leveraging cutting-edge medicines such as ADC. For today's agenda, first, I will set the context for today's discussion with our strategic reset and steadfast execution to deliver our next-generation ADC pipeline. Then Dr. Fawcett will present the important progress of our lead program, STRO-004, our tissue factor ADC into the clinic, making Sutro a clinical stage company yet again. He will share more details on the ambitious clinical development plan to deliver initial data next year. Following that, we are very fortunate to have Dr. Tony Tolcher with us to share his expertise and excitement on what it takes to be a winning ADC and how Sutro's ADC can bring value to patients. And then Dr. Gerber will present an overview of our promising pipeline, including STRO-006, our integrin beta 6 ADC and our dual payload ADC platform, including the emerging data to support the reveal of our first dual payload program targeting PTK7. Next slide. Now I've been the CEO of Sutro since our strategic pivot back in March, and we have accomplished a great deal to transform the business in a short period of time, including rightsizing our team, extending the runway and delivering on our pipeline and getting us back into the clinic with STRO-004, our tissue factor ADC in just 6 months. We believe we have one of the most powerful ADC technologies capable of making highly differentiated ADCs that can help solve some of the toughest problems facing cancer treatment today. Our platform is differentiated by design. We can optimize every component of the ADC, the antibody, the linker, the payload. And in doing so, we can dial up the differentiation of our ADC design to pursue complex targets and dual payload ADCs that address significant clinical and commercial unmet needs from the start. In a short time, we have built an exciting portfolio of ADCs, developing multiple programs in parallel versus a single asset focus. We have promised 3 INDs in 3 years and are doing our best to bring time lines in even further with our initial dual payload ADCs planned for 2026, '27. At the same time, we've extended our cash runway 3 times this year, first to Q4 '26, then to Q1 '27 and now to the middle of 2027, which does not yet include all collaboration milestones. To achieve this, we have completed 2 restructurings, reducing the team from approximately 350 FTEs to about 130, thus rightsizing our organization to accomplish our goals effectively and efficiently. Further, we have fully externalized our CDMO network for supply chain resiliency and modularized manufacturing to reduce the burn compared to the previous strategy of made in-house model. And we have standardized our platform capabilities for speed of discovery, development and scalability. Importantly, we have a new senior leadership team who brings deep ADC experience and fresh perspective from outside Sutro, and we're compelled to join Sutro largely because of our promising technology and the desire to see that promise delivered for patients. Sutro today is a new company with a new strategy, a new team and new focus on execution and discipline to rapidly advance programs where Sutro is uniquely positioned to deliver differentiated best-in-class medicines for patients. We think we have achieved exactly that with our pipeline. Next slide. Let's take a closer look at how our ADCs are differentiated and why that's important. Again, what makes Sutro unique is our ability to optimize not just 1 or 2, but every component of an ADC, including the antibody, the linker and the payload and the way each of these elements are combined. We have optimized our payload system to deliver homogeneous DAR8 exatecan ADCs and have even achieved as high as DAR16 ADCs without compromising PK. This advance enables us to incorporate higher DARs with multiple payloads to deliver greater potency with our ADCs. We have also optimized the linker strategy with our beta-glucuronidase or beta-glu linker, which offers a better safety profile due to site-specific conjugation with our nonnatural amino acids. This design leads to better, more tumor-selective linker cleavage inside the tumor and less so outside the tumor. Finally, our antibodies are made in a cell-free system, making them Fc silent and are not glycosylated. This avoids Fc gamma engagement in normal tissue that's associated with certain liabilities commonly seen with conventional ADCs like interstitial lung disease or ILD or ocular toxicity, further improving the safety profile of our ADCs. Now despite the continuing progress made with conventional ADCs, the simple but persistent challenge to overcome is that efficacy is limited by toxicity. And altogether, Sutro's ADC technology enables greater flexibility in ADC design, increasing ADC drug exposure two to threefold higher than conventional ADCs, which we believe leads to improved safety and tolerability and then greater efficacy. Next slide. Now I don't want to steal too much thunder from our upcoming presenters, but there are some important developments in our programs that I cannot wait to share. Our pipeline consist of both single and dual payload ADCs. The strategy for single payload ADCs is to first validate the beta-glu DAR8 exatecan linker payload system on our cell-free platform and establish a greater therapeutic and safety window, which will enable the addition of a second payload system for our dual payload ADCs. So, the safety of our single payload ADCs in the clinic will be an important read-through to our dual payload ADCs. To address clinical unmet needs where there is still much room for improvement from current standard of care, our single payload ADCs tackle hard-to-reach complex targets with broad application across many tumors. We begin with STRO-004 on the left of this slide, our potential best-in-class tissue factor ADC. The emerging data you will see today underscore the potential opportunity for STRO-004 to redefine and expand the benefit of tissue factor ADCs in multiple solid tumors beyond cervical cancer and with much improved safety window seen with the GLP tox HNSTD of 50 milligrams per kilogram and antitumor activity in PDX models starting at doses as low as 1 milligram per kilogram. We are excited to share that the STRO-004 program is now active and enrolling with initial top line data expected in 2026. I would like to congratulate and thank the many Sutro lives involved in achieving this significant milestone. In the center of the slide, STRO-006 is our integrin beta-6 targeting ADC. Historically, this has been a difficult antibody target to make, which supports our clinical potential and differentiation. The integrin family of receptors is diverse, but we have engineered our ADC to be highly specific and selective for the alpha B beta-6 heterodimer involved in tumor genesis. Integrin beta-6 is highly expressed and has been clinically validated in lung cancer, which is a big clinical need. Sutro's ADC is well tolerated at 25 milligrams per kilogram. And at these doses, we do not see ILD or pneumonitis in nonhuman primates. And this is particularly important in lung cancer. The program is on track for IND next year in 2026. On the right, dual payload ADCs represent the next frontier, designed to overcome resistance, delay disease progression and potentially set a new standard of care. We believe there is significant potential here to transform cancer treatment by unlocking deeper and more durable efficacy. Again, we announced today PTK7 as the target for our first wholly owned dual payload program, and we're doing everything we can to accelerate entry to the clinic as early as 2026. Dr. Gerber will share the rationale for this target and the emerging data for this program. In addition to future program with our collaborator, Astellas Pharma, we're pursuing an exciting dual payload combination with our innovative immunostimulatory ADC or iADC program, which combines the cytotoxin and an immune stimulator, potentially providing a new treatment option for cold tumors and patients who do not respond to existing immunotherapies. We expect the first Astellas partnered iADC program to enter the clinic also in early 2026. As you can see, 2026 is lining up to be a very exciting year for Sutro. Next slide. As I just mentioned, we are particularly excited about the potential of Sutro's dual payload ADCs to overcome resistance and maximize clinical response with any ADC target. There still remains a significant need for better cancer treatments and ADCs as resistance often leads to tumor progression. What's next after exatecan payloads for ADCs? One challenge of ADCs is the development of resistance that we know is driven not by the loss of target, but by the payload class. We also know that combining chemotherapies with different mechanisms of actions can be more effective than an after single-agent chemotherapy and that dual payloads can deliver chemo combination in a targeted way. The other challenge with dual payload ADCs is safety or greater toxicity in combining 2 different payloads. Demonstrating a wider therapeutic window is essential for the viability of this modality, combining 2 different payloads at the right ratio to ensure the treatment is safe, as well as effective. It is very challenging to safely add payloads with ADCs that have HNSTDs of only or as low as 3 to 6 milligrams per kilogram. And if done right, dual payload ADCs can offer a better safety profile than combining 2 separate distinct ADCs. And that is our goal to safely overcome resistance and prolong and deepen clinical responses even in patients who have relapsed after prior treatments. Dr. Gerber will share how we have now treated tumor models to resistance on a weekly basis with both TOPO1 and microtubule inhibitor ADCs and are now seeing compelling responses with our dual payload ADCs, overcoming resistance to both payload classes. We are moving forward at pace to ensure that Sutro has the opportunity to be one of the first to validate the use of the multi-payload ADCs in the clinic. Next slide. For dual payload ADCs, the design flexibility of Sutro's unique ADC platform is particularly advantageous. We believe Sutro's dual payload ADCs are well differentiated in 3 ways. First, we are well ahead of others with more modalities of payloads, including TOPO1 inhibitors, microtubule inhibitors, DDRi or DNA damage response inhibitors, including PARP inhibitors and ATR inhibitors and immunostimulatory agents and even new payload classes we haven't yet disclosed. With the many different modalities of payloads, we have the ability to make dual and even triple payload ADCs that combine therapies with these distinct MOAs. Second, even more important is the control of payload ratios with our nonnatural amino acids in the cell-free system. Not all payload modalities are equal in terms of potency and safety. Therefore, a 1:1 [Technical Difficulty] ratio of each payload is not necessarily optimal for every combination. We can readily solve for this complexity driven by the fact that we have not 1 but 2 nonnatural amino acids to safely conjugate 2 different linker payloads to our antibodies. And third, as shared today, Sutro's ADC can potentially drive a wider safety window and are well tolerated at high doses. And this extends to our dual payload ADCs as well. We have seen with our dual payload exatecan MMAE combination, them to be well tolerated at doses as high as 25 milligrams per kilogram in nonhuman primates. Despite higher DAR and 2 different payloads, we do not see safety being compromised in these preclinical models. All this is in our words, protein engineering on steroids and why we believe the precise design capabilities of our ADC technology enable us to create disruptive and game-changing medicines with the potential to shape the future of the entire ADC field and bring meaningful benefits to patients. With that, I would now like to turn it over to Dr. Fawcett to review the exciting progress being made in our lead program, STRO-004, our tissue factor ADC that is now active and enrolling in the clinic with an ambitious plan to get to initial top line data middle of next year.

Thanks, Jane, for the great overview of Sutro and the emerging pipeline. I'm going to dive into the program for STRO-004 now, which is our tissue factor targeting ADC, which is just entering the clinic. Can we have the next slide? Tissue factor or TF is a strong target for ADCs. It's highly expressed on a variety of solid tumors with relatively modest expression in normal tissues, some of which are essentially nonproliferative such as the subendothelial layers of blood vessels. TF is a transmembrane glycoprotein with potentially important signaling properties in malignant cells, and TF has been associated with poor prognosis in some malignancies such as colorectal cancer. Tisotumab vedotin shortened TB is a TF-targeted ADC approved for the treatment of advanced cervical cancer. With an ORR of 17.8% and a PFS of 4.2 months in the pivotal innovative-301 study, it is an important advance for patients with cervical cancer, but also an important proof of concept for TF-targeted ADCs. However, TF is limited by inherent disadvantages shown on the left of this slide. The antibody does have an effect on the extrinsic coagulation pathway and bleeding events were seen in clinical studies. Payload, the microtubule inhibitor, monomethyl auristatin E or MMAE for short, is conjugated to antibody by an early generation linker that results in spontaneous deconjugation and there is off tumor on target as well as free payload toxicity. The resulting toxicity profile of TB affects the eyes, TF being expressed in the conjunctival and corneal epithelium, the nerves and also the bone marrow. These limit the therapeutic window as reflected by the HNSTD of only 3 milligrams per kilo in GLP toxicity studies. So, there is scope for developing an improved next-generation TFADC. Sutra has developed a new TFADC STRO-004 with several modifications that are anticipated to widen the therapeutic window shown on the right hand of this slide. First, the antibody has been selected for high affinity binding to TF with an affinity constant of only 5 nanomolar, good internalization on target engagement and also it's been selected for not having an effect on the extended coagulation pathway. Second, the Sutro manufacturing platform is based on antibody synthesis in cell-free XpressXB coli, ensuring that the antibody lacks glycosylation. Thus, STRO-004 has an intrinsic absence of Fc gamma receptor engagement, negating a binding pathway, which is believed crucial in the triggering of interstitial lung disease, or ILD, which has been a problematic issue for some exatecan-armed ADCs. Third, the linker payload assembly uses nonnatural amino acids in the antibody to precisely determine the point of attachment using click chemistry to conjugate the linker payload at optimal positions in the antibody molecule. Spontaneous deconjugation is effectively nil, so STRO-004 is not prone to an unscheduled disassembly to borrow language from the SpaceX folks from describing an unsuccessful rocket launch. Finally, the linker uses state-of-the-art [indiscernible] cleavage to release the payload, resulting in better intracellular exatecan release after internalization and shuttling into lysosomes and tumor cells. Residual linker moieties also modify the lipid solubility of exatecan to facilitate a strong bystander effect. Next slide, please. Underlining the favorable readout from our GLP tox study where we had an HNSTD of 50 milligrams per kilo, here are some supporting data from in vitro assays to examine ocular toxicity, which is an off-tumor on-target event. The left-hand panel shows better viability of corneal epithelial cells than an MMAE arm TFADC. Cathepsin such as exatecan are less toxic to the ocular epithelium than microtubule inhibitors. In the middle panel, a similar assay of human keratinocytes as a measure of potential skin toxicity is shown. And finally, the right-hand panel shows markedly reduced in vitro activation of the extrinsic coagulation pathway with STRO-004 compared to tisotumab vedotin. Next slide. When starting the TF-ADC program, Sutro made a DAR4 prototype for testing and subsequently also a DAR8 version, noting, of course, that our platform allows easy dial-up and payload conjugation by the placement of more nonnatural amino acids in the antibody peptide sequence. This slide illustrates the results of in vitro testing of our candidate TF-ADCs against the HCT-116 cell line, which has low to medium TF expression. You can compare the DAR8 results shown in purple against the DAR4, which is the green plot in a payload matched experiment. Even though the HNSTD of our DAR8 TF-ADC was 50 milligrams per kilo rather than the 100 milligrams per kilo seen with the DAR4 version, the DAR8 strongly outperformed the DAR4 prototype in antitumor activity, both exceeded the performance of an approved TF-ADC shown in this graph in blue. Our DAR8 TF-ADC now named as STRO-004, thus succeeded in antitumor activity without losing excessively in safety, and HNSTD of 50 milligrams per kilogram is still comfortably at the front of competitor assets in development. Alongside pharmacokinetics predicting a half-life of nearly 7 days, the development program draws a straight line connecting the preclinical science to our expectations for STRO-004 as we move into the clinic. Next slide. STRO-004 also showed strong activity in CDX models of non-small cell lung cancer and head and neck SCC. Both of these cancer types are ones in which TV also showed some activity, the latter, particularly, but it was especially encouraging that we observed strong tumor inhibition after a single dose of STRO-004 of only 1 milligram per kilo with growth only breaking away as drug levels decline towards 0. This speaks to the potential for the wide therapeutic window that STRO-004 was designed for with an HNSTD of 50 milligrams per kilogram in conjunction with antitumor activity kicking in as little as 1 milligram per kilo. If you can, please remember that 1 milligram per kilo dose because I will come back to it. Of course, you have seen these data before, but we do have some new results to share today. We're just beginning to get the first outputs from the PDX study testing STRO-004 against different tumor types, which we'll share in the next couple of slides. We have the next slide, please. We're testing STRO-004 against panels of head and neck cancer, non-small cell lung cancer, both squam and non-squam, pancreatic and colorectal cancers, 20 for each tumor type. The models chosen for testing were screened for TF expression and all of them show at least some TF expression ranging from low to high. The summary waterfall plot on this slide are the first results that we have, and it is anticipated that the rest will be mature in time for presentation next year. I want to point out that the Translational Medicine Group elected to administer a single dose of 5 milligram per kilogram in these experiments. As you may be aware, there has been discussion of what represents a relevant dose in the context of PDX studies since it is possible to dose in these models at doses well above what is likely to be tolerated in the clinic, and that decreases the likelihood that the results will be clinically relevant. The current consensus is that the optimal strategy is to administer a single dose of drug commensurate with a likely clinically tolerated dose. Most DAR8 exatecan-armed ADCs are dosed in the 4 to 6 milligram per kilogram range, which explains the decision here to use 5 milligrams per kilo. As you can see, strong regression of tumor growth has been seen so far with the best objective response of a 73% ORR, including some complete responses. At least partial responses have been seen in all tumor types tested. I could those have 100% response rate in CRC shown in purple, but to date, we've only got data from a single model tested. It is preferable to seeing 0% though. Note that the data from a substantial number of head and neck cancer models depicted in light blue gives a solid 65% ORR, which I'll come back to in a minute. First though, next slide. Here are the data from the non-small cell lung cancer and pancreatic models broken out into a rather less busy slide. It's encouraging that thus far, the results are strong in NSCLC with 71% showing at least a PR and 2 of these are squamous histology. The current data are better again in pancreas, where all the models so far have shown at least a partial response. If we can go to the next slide. Finally, since TV also showed activity against the head and neck cancer in the clinic, we took the opportunity to set up an identical set of PDX models where we compared STRO-004 and TV, remembering again that the models were selected in advance to have at least some level of TF expression. Dosing was again 5 milligrams per kilo. And going back to a comment I made earlier, that might be a little generous for TV. Nonetheless, it's interesting that the response rate for TV in this PDX experiment, 41%, came out close to the ORR observed in clinical studies using 2 weekly dosing, where an ORR of around 40% was impressive, but was hampered by suboptimal tolerability. The STRO-004 treated panel showed a 65% response rate, which is encouraging as we shift our focus to the clinic. The PDX models are still a study in progress, but the data look to be heading in a direction that will support development in tumor indications where there are still large numbers of patients in urgent need of new options. This is emphasized in the next slide. Here, you can see tumor demographics across some of the indications that are of interest in the STRO-004 program. Recent developments in the treatment of these cancer types are starting to show promise, but there is a lot further to be done. Really a very large number of patients just in the U.S. alone face a very limited future after relapsing on early line therapies. The numbers on this slide add up to nearly 0.5 million patients annually in need of new treatment options. So, now that's appropriate to turn to the mapping for the early development of STRO-004 on the next slide. Clearly, the first goal must be to determine a safe and well-tolerated dose of STRO-004 to take forward for further evaluation of antitumor activity. Helpfully, an HNSTD of 50 milligrams per kilo has permitted us to enter dose escalation at a dose of 1 milligram per kilo and get to a go-forward dose in a minimal number of steps. You may recall from an earlier slide that preclinical activity in CDX models was seen at doses as low as 1 milligram per kilo, and that's our entry level in dose escalation. So, we anticipate achieving therapeutically relevant exposure quickly. We're also restricting study eligibility to participants with tumor types that commonly express tissue factor. With a targeted treatment, it seems logical to enroll patients where there is at least some likelihood of the target being expressed. Plus, we also see it as relevant to look at safety and tolerability in patient populations with tumors from indications that are most likely to be onward developed. The aim in the dose escalation study is to determine one or more recommended go-forward doses for further dose optimization as needed, but we also aim to set ourselves up to get a first look at antitumor activity in patients. Our IND application is now cleared and the dose escalation study has been activated with the first wave of sites already initiated. More to come by the year -- come online by the year-end. If we go to the next and final slide. This slide sets out a high-level time line. It is important to set ambitious goals for development. We are working in a highly competitive environment, which ultimately is driven by the very large patient population who are hoping for better options and hoping for them quickly. There is no secret sauce to speeding up progress beyond attention to all the minor points of delay in clinical studies and working hard to optimize them so that they can add up to development moving more quickly. For example, as an observation, ADC toxicity generally kicks in abruptly at a certain dose level and time can be lost at the upper end of dose escalation in chasing every last small increase in dose when the conclusion will likely turn out to be that a lower dose is going to be better tolerated over the longer periods of treatment that are typical in dose escalation phases. With the wide therapeutic window that we're aiming for, strong efficacy is anticipated without straining towards MTD, and this should be leveraged to get a dose more quickly that could be taken into further development. In finishing, we need to remember that no sponsor can develop a drug wholly in the laboratory. We are utterly reliant on patients and their families who recognize the importance of new drug development and decide that they want to help to make a difference. Our biggest thank you goes to them. Another pillar of efficient development is the partnership with investigators who are deeply interested in giving a new asset the chance to demonstrate its potential. We would also like to say thank you to them for their collaboration, their enthusiasm and of course, their enormous expertise in keeping patients safe and helping to translate the work in the lab into clinical reality. We look forward to sharing data with you next year as we get the first results from this exciting clinical program. Now it's my great privilege to pass you over to the next presenter, Tony Tolcher. As the founder of NEXT Oncology and one of the leading Phase I development of oncologists in the U.S., he needs a little further introduction. Thank you very much for joining us today, Tony.

Thank you, Jonathan. As many of you are aware, I've been involved with antibody drug conjugates for approximately 30 years, having worked originally with the first antibody drug conjugate, the R96-doxorubicin. So, I've seen this field grow from many initial failures to now the most successful platform. When I was asked to join the Sutro Clinical Advisory Board, the important points were that the data that they showed me were very attractive. And this is important because I turn away about 50% of the advisory boards that I'm offered when it comes to antibody drug conjugates because I've seen sort of the past and the present, and I'm going to talk a little bit about the future today. So, I hope that you understand why I am excited, but also where I see innovation going. So next slide, please. What I'd like to do is outline what I believe to be practical innovation and what it actually looks like. Now many people actually ask me to sort of foretell the future about antibody drug conjugates or ADCs from this point on. And I oftentimes say there are several key features that I would consider modern and likely successful antibody drug conjugates will have to have. Now the first point is this, we are developing drugs, but transformative therapies, the way we actually lead to either excellent treatments or perhaps cures come from combinations. So, chemotherapy was used way back 40, 50 and 60 years ago, and we used to give single agents of cytotoxics. And the trouble with that ultimately was that we would put patients into some sort of response or remission, but they would quickly progress. It wasn't until we actually combined chemotherapy agents together that we lead to successful therapy. And the examples, of course, were MOP, which ultimately proved to be curative in patients with Hodgkin's disease; ABVD, which was an improvement again, CHOP for non-Hodgkin's lymphoma and in many different types of cancers, those that we don't necessarily think we can cure but are still important therapies in frontline therapies such as taxol and carboplatin for lung cancer and ovarian cancer, these all came about from putting drugs together. And these combinations usually came about because we combine drugs with non-overlapping mechanisms of action, and they didn't have overlapping toxicity. It's important to recognize that for us to move forward with ADCs, we need to start to consider combinations of payloads. Now we have a number of different payloads currently. These include the antimicrotubules, which almost everyone knows are either a maytansine derivative or an auristatin derivative. We have TOPO1, which have become, I'd say, revolutionary in the fact that we've been able to now have very effective therapy in cancers that are resistant to prior ADCs. And in some cases, for hematologic malignancies, we have the strong alkylators PPD. It's important to realize, though, that there are many novel payloads that are coming in the future. And these ultimately might be transformative because our limitation right now is that chemotherapy consists of about 5 different classes. So, we've not even touched all the classes of validated chemotherapy at this point. Again, one other thing as we look towards the future. Combining different payloads together is never going to be 1:1. It's a bit of a misnomer when we think about that. And if people tell you that they're actually combining equal parts of 2 different payloads, you have to remember that our combinations of chemotherapy were based on the safety and none of the agents in combination were given at equally doses. And that's important, and that's really important to understand that all of this is based on the safety and the effectiveness of various ratios, optimal ratios. And this requires something that we have not had until very recently, and that's tunable ADCs, where you can actually, through very complex chemistry be able to provide different ratios of payloads. Now this is nontrivial when it comes to a chemistry standpoint. And so that's what's held the field up to this point. Next slide, please. Now I'm going to remind you that most ADCs fail due to safety, whether it be such things as neutropenia or myelosuppression or as we've seen more recently, pneumonitis and interstitial lung disease, but several drugs have failed again because of liver toxicity. And all of these side effects that have caused drugs to fail is usually because we're not trafficking the antibody drug conjugate to the tumor selectively. The premise of ADCs was to deliver the payload to the tumor and improve the therapeutic index. But if we don't get the ADC correct, we will end up with trafficking to some of the normal tissues and experience the toxicity problem. Next slide. So, there are several truths about the current ADCs that can be improved upon. First and foremost, target antigens. We have essentially a finite number of tumor target antigens that are successfully internalized. Yes, there's some work going on, on noninterernalized antigens, but those are still in very early development. Now it's important to realize that spending much time trying to discover new internalizing target antigens is probably not a useful deployment of resources. And why is that? Well, first and foremost, the loss of the target antigen is not the usual mechanism of resistance to ADCs. Perfect examples are HER2. So, HER2 is a wonderful target antigen. It's been validated with naked antibodies such as trastuzumab. We had Kadcyla, which ultimately led to some responses in one of the more successful antibody drug conjugates. But even when we came along with in HER2, there was no loss of HER2 expression. And that meant that the target antigen persists even though patients became resistant to the payload on Kadcyla. Now that's an important point because you can actually reduce the risk of your development by using credentialed antigens, tumor-targeted antigens that are already being used and are internalized and then coming along with new payloads or combinations of payloads, and that might speed up proof of concept. Next slide. We have to keep in mind that you are developing a class of drugs and using an antibody as it would be developed as a naked antibody is not appropriate. We should be manufacturing and designing our antibodies to be suitable as an antibody drug conjugate. And hence, you want to make sure that it's optimal for trafficking. So, one of the first aspects that you have to look at when you're looking at a prospective ADC is, is it Fc silent. And this should be standard because there's no need for antibody-dependent cytotoxicity. In fact, actually, at this point, it's more of a hazard and a problem because an intact Fc region on an antibody increases the risk for interstitial lung disease, as well as liver toxicity, which we've seen more recently. Again, as I mentioned, one has to have the antibody design to be tunable because you need to be able to increase either the drug-to-antibody ratio, the DAR and you may not need high DAR, you may need low DAR depending on the payload or if it's a less potent payload, you might need high DAR. You also need to have sites where you can bring other payloads on if we're going to get the combinations. And we have to optimize for linker chemistry. The old Vaxcyte linker technology, I think, was important at the time, but is clearly not superior when it comes to stability. Next slide. And as I mentioned, the biggest problem about the older linker technology is it leads to off-target toxicity. The fact that the cytotoxic agent can come off the antibody leads to widespread distribution of a potent cytotoxic payload. And this is something that we've seen with many of the earlier ADCs, such as GI issues, most notably sacituzumab govitecan, where we see diarrhea, even though there's no expression of Trop-2 on the GI tract of any substantial degree. We also see neuropathy that has been seen with both Enfortumab vedotin and atezo. And in both cases, that's because the linker is not fully stable and some of the neurotoxic payload comes off and distributes widely. Next slide. The other point is, at this juncture, we're delivering cytotoxic payloads. And so we have to keep in mind all of the lessons from the chemotherapy era. And even though some of this wisdom has been lost, it's important to recognize that the problem for chemotherapy was that every patient routinely became resistant to the chemotherapy agent when it was administered as a single agent. So, with that in mind, you can say we're going to come up with novel payloads and go after currently available targets like HER2 and TROP2 with novel payloads that are not overlapping in terms of mechanisms of resistance. And that's an easy way to try to have proof of concept. As I mentioned before, it's important to recognize that the ratios of the cytotoxic chemotherapy agents in the past were designed by safety and around safety. And so, it is foolish to actually believe that we should have 1:1 ratios all the time. And it's remarkable at this point to say that other people have shown that to be very clear. A company many years ago called Celator developed an optimized ratio of donorubicin to ASC for elderly patients with a liposomal preparation of what we give for leukemia. And they struggled for a period of time, but then were ultimately successful because they hit the right ratio for that little nanoparticle. The same applies to antibody drug conjugates. And in the past, what led to those ratios, the combinations of drugs and what ratios were used, it was safety and always safety. Next slide. So, when I look at the work that Sutro has done and I look at the checklist that I go through each time when I'm looking at a different company or a different molecule, I have this sort of 5-point checklist. First and foremost, are they going for an antigen target that's credentialed or novel? And as I said, from a practical standpoint, it's much easier to go after a credentialed target. The antibody construct, it has to be Fc silent. And what is very interesting about the whole technology and the platform of Sutro is it's tunable. They're using modern linkers, and so we're having linker stability. Although we're still in an era where we're largely exploring antimicrotubules as well as TOPO1. We will ultimately get to a point where almost all tumors that can have antibody drug conjugate therapy -- patients will be resistant to those antimicrotubules in the TOPO1, so we need to look at novel payloads. And that in the next 3 to 5 years is going to be a big challenge. And finally, being able to look at different things about exposure, understanding the pharmacokinetics and ultimately pursuing that. And with that, I'd like to thank you for your time, and I'll hand it over to Hans-Peter.

Thank you, Tony. So, I wanted to start with this graph comparing the clinical response rate of tubulin inhibitor ADCs in grey and exatecan ADCs in blue, showing progression-free survival in the last column and objective response rate in the second last column. Across a variety of tumor targets and indication, there is a significant improvement in both endpoints by exatecan-based ADCs over traditional tubulin inhibitors, demonstrating how payload innovation can impact ADC pharmacology. However, while exatecan ADCs induced higher ORR, their impact on PFS remains modest with the notable exception of an HER2 in breast cancer, which clearly set a new benchmark for the field and started the turnaround of ADCs back in 2019. Importantly, the regulatory approval endpoint for ADCs is PFS, the time it takes the tumor to develop resistance and not ORR, which is a measure of how quickly tumors respond to treatment. Remarkably, other than the payloads, most ADC components of the exatecan ADCs and tubulin ADCs shown on this slide remain the same, including glucuronidase-cleavable linkers linkers, cysteine-based conjugation chemistry with all their known tox liabilities leading to ADC instability and platform toxicity. At Sutro, our goal is to build upon the improvements brought by the exatecan payload and to use our unique ADC manufacturing technology to improve all components of an ADC and to turn strong initial responses into long-lasting clinical benefits, such as shown by PFS. Next slide. So how can you achieve better antitumor activity, prolonged antitumor responses and the delay in resistant formation to ADCs. There are 2 different approaches being pursued in oncology and the core principle of each have been tested and validated in oncology and beyond. First, is to simply increase drug exposure by making ADCs safer, so more drug can ultimately get to the tumor. This is exemplified by STRO-004 and 006, which achieved industry highest exposure levels in [ cynos ]. Second is to combine payloads with different mechanism of action as exemplified by our dual payload ADCs. For STRO-227, we combine exatecans with a payload with complementary mechanism of action such as tubulin inhibitor MMAE. For our iADCs, we're combining exatecans with immune activators like STING. And finally, when we combine exatecan with our DNA double-strand repair inhibitors or DDRIs, we are boosting exatecan activity by blocking the tumor escape pathways. Next slide, please. This brings up the question, how can you identify winner ADCs early based on preclinical data, how do you -- how does success look like? Shown here are the 3 hallmarks of ADC pharmacology with all having a track record to predict success of ADCs in the clinic. Good PK is highly predictive of winner ADCs, in particular, long half-lives and low clearance. Good safety in cynos by means of high maximum tolerated dose and the highest nonseverely toxic dose. Good antitumor activity, in particular, in tumor models that are predictive for clinical responses known as patient-derived xenograft models or PDX and provided that ADCs are dosed at a clinically relevant level as already discussed by Jonathan for STRO-004. I want to point out that throughout our R&D from today, you will see industry-leading PK safety and activity data generated with our single and dual payload ADC programs. Next slide. As Jane already pointed out, our unique cell-free manufacturing system allows us to rapidly integrate and optimize multiple proprietary technologies to increase the therapeutic index of ADCs. This differentiation of our ADCs is different from conventional manufacturing approaches that have much less flexibility in improving the design of ADCs. For example, on the left graph, we exchanged each of the 450 amino acids in the heavy chain of antibody shown in blue and each of the 220 amino acids in light chain shown in green with our nonnatural amino acids. The site shown in gold provided optimal PK properties when conjugated to linker payloads. These sites are all different from the standard 8 predefined cysteine residues used for most conventional ADCs. On the right panel, we see the mouse PK of different DAR16 ADCs with different combinations of the golden nonnatural amino acids shown on the left panel. As you can appreciate, only one combination achieved optimal PK. If you are limited to the standard 8 cysteines, your chances of achieving optimal PK properties are limited, and I will show you that on the next slide. Next slide, please. On the left panel, we compared cyno PK data from 4 of our exatecan ADCs circled with an orange dotted line compared to conventional exatecan ADCs shown in green and DX derivatives of the payloads shown in blue. On the Y-axis on the left, we plotted the exposure levels per payload at the HNSTD and on the X-axis on the bottom, the payload dose per payload at HNSTD. So, ADCs with high stability are on the top of the graph and ADCs with low platform toxicity are on the right. So, you want to be on the upper right quadrant if you achieve the 3 hallmarks of winner ADCs. On the right panel, we went through a similar exercise with our dual payload ADCs. Here, the MMAE dose per ADC at the HNSTD is shown on the Y-axis and the MMAE exposure per ADC at the HNSTD on the X-axis. Again, you want to be on the upper right of the plot with a winner ADC. As you can appreciate, by applying our platform technologies to MMAE, we could increase MMAE exposure shown on the X-axis three to fivefold and increase the dose for DAR4 MMAE two to threefold, all in presence of additional 8 exatecans. These PK demonstrate that thanks to the versatility of our ADC platform, the PK improvements are not limited to exatecan payload, but applied to other payload classes. But most importantly, why does this high exposure matter? It is well known now after 20 years of ADC development that for ADCs, higher exposure drives better antitumor activity. Dual payload ADCs depend on high DAR when adding payloads on top of 8 exatecans and conventional ADCs display reduced PK and safety and exposure at higher DAR ratios. These PK data position Sutro as a leader in dual payload ADCs going forward. Next slide. STRO-006 is our integrin beta-6 targeting ADC, and this slide illustrates how we integrated our proprietary ADC technology to generate an ADC with two to threefold higher exposure and improved antitumor activity compared to conventional integrin beta-6 ADCs currently developed in the clinic. First, we took advantage of our phage display technology to identify binders that don't interfere with integrin beta-6 biology on normal healthy tissues. Our technology allows us to screen human antibody libraries that are millionfold larger than standard hybridoma approaches, enabling us to find better targeting antibodies faster. In addition, our ADCs don't engage Fc gamma receptor binding. So STRO-006 is not taken up by immune cells expressing Fc gamma receptors, which reduces the risk of interstitial lung disease, also known as ILD. It is a DAR8 exatecan ADC similar to STRO-004 with strong bystander activity, which allows us to target tumors with low and heterogeneous target antigen expression. We are using our proprietary beta-glu linker, which is not cleaved in the tumor -- in the bone marrow in contrast to the conventional cathepsin-B cleavable linkers. In addition, all our linker payloads include a hydrophilic group, which further minimizes platform toxicities. Our target IND filing date for STRO-006 is in mid-2026. Next slide, please. Integrin beta-6 is expressed in a large variety of solid tumor indications as shown on the right side of this slide. It has been clinically validated as an ADC target in lung tumors with over 90% of patients expressing integrin beta-6. Despite its prominent expression in multiple solid tumor types, there is only one competitor ADC in clinical development targeting integrin beta-6 due to its complex target biology. In addition to competitor ADC is a conventional MMAE conjugate with a significant platform toxicity reported in the clinic. Therefore, switching the payload to TOPO1, combined with our advanced engineering technologies keeps strong promise to improve ADC exposure and therefore, antitumor activity. Next slide, please. When comparing STRO-006 with competitor ADCs, including conventional MMAE conjugate, we noticed significant improvement in both safety and efficacy as shown in the table on the left. The minimum efficacious dose, MED, is about three to sixfold lower. The maximum tolerated dose in cynos is 4x higher and the half-life is twofold extended. There is no sign of neutropenia, lymphopenia or ILD in the pilot cyno tox study. The PK is outstanding with a half-life of 7 to 8 days and with 1 nanogram per milliliter of free exatecan shown on the right graph, which is about tenfold lower compared to competitor conventional exatecan ADCs. Next slide, please. In these xenograft experiments using lung PDX tumors, we noticed superior antitumor activity of STRO-006 shown in blue and dark blue compared to a tubulin inhibitor ADC shown in green. In bladder cancer, shown on the right panel, we found better antitumor activity of STRO-006 compared to the competitor exatecan integrin beta-6 ADC, both administered at the same dose. The superior antitumor activity of STRO-006 on the right panel is most likely caused by the improved stability of our exatecan ADC platform, resulting in higher exposure levels and better antitumor activity. Next slide, please. As mentioned previously, PDX models are highly predictive for clinical responses of ADCs when dosed at clinically relevant dose levels. Here, we compared the ORR of STRO-006 shown as a waterfall plot in blue to a competitor tubulin inhibitor ADC shown in green in a mouse clinical trial in head and neck PDX tumors. On the table on the bottom right, you can see that the overall response rate of the competitor ADC was 47%, which is close to the 40% reported for this ADC in clinical trials in head and neck cancer. For STRO-006, we report ORR of 71% in this mild clinical trial when dosed at the clinically relevant dose level of 5 mg per kg. An important detail is that the competitor ADC shown in green was dosed at 5 mg per kg, which represents double the clinically relevant dose for MMAE conjugates in the clinic. Next slide, please. This slide shows the same experimental data analyzed for durability of response relating to PFS in the [indiscernible] block. On the left panel in blue, a single dose of STRO-006 induced responses in most tumors that lasted over 40 days. In contrast, the responses induced by the tubulin inhibitor ADC shown in the right in green were less durable with most tumors relapsing after 20 days. These findings are consistent with the notion that switching the payload class from MMAE to TOPO1 not only increases ORR, but also PFS. Next slide, please. I mentioned that in addition to increasing ADC exposure, combining 2 payloads with different mechanism of action can help to delay the onset of resistance to ADC treatment. I will provide you with 2 examples how we achieved this goal when combining different payload types. The first example is for MMAE, the most successful ADC payload developed so far with over 40% of all approved ADCs. The second is an immunostimulating payload known as STING. Next slide, please. The PK analysis of a HER2 conjugate with 8 exatecans and 2 or 4 MME payload suggests rock solid PK properties similar to what we already reported for the single payload conjugate STRO-004 and STRO-006. Next slide. Importantly, the HER2 dual payload ADC was able to regress tumors that were resistant to either payload as shown on the left panel on this slide. In this experiment, we treated the tumor with weekly doses of Enhertu shown in gray and black until the tumor eventually became resistant to the exatecan ADC after 100 days. Then we switched the ADC payload to a tubulin inhibitor shown in green. And after initial response, the tumor relapsed again despite weekly treatment with the tubulin inhibitor ADCs. Then we switched to our dual payload ADC shown in blue and treated the double-resistant tumors again, which all responded with a durable complete response. These data demonstrate that dual payload ADCs can overcome resistance to each single payload ADC. On the right panel, we treated colorectal cancer, which historically don't respond to tubulin inhibitor ADCs with a single MMAE payload shown in green, confirming lack of responses. When treated with the single exatecan ADC at clinically relevant dose levels, we saw a moderate response, which is shown in dark blue. However, when we treated the colorectal cancer model with a dual payload ADC shown in light blue, the tumor responded significantly better compared to the single payload ADCs. Next slide, please. The next example demonstrating how we can improve the durability of response is with our dual payload ADC targeting PTK7. I am very happy to introduce for the first time the target of our first dual payload ADC with a target IND date of late '26, early '27. PTK7 is highly expressed antigen in a variety of different tumor types known to respond to either payload type, exatecan and MMAE. Most importantly, PTK7 is expressed on cancer stem cells, which are considered the root cause of cancer and PTK7 expression correlates with poor prognosis across a variety of tumor indications. Unfortunately, cancer stem cells express a lot of PGP drug efflux pumps and prior ADC attempts with MMAE type of payloads failed due to the short durability of responses. Exatecans are not substrate for PGP pumps, and it is time to revisit this clinically validated target with a dual payload ADC where the payload is not substrate for PGP pumps. Next slide. The anatomy of the STRO-227 ADC is shown here. It combines 2 MMAE payloads shown in orange with 8 exatecan payloads shown in blue. The rest of the design is similar to the features for STRO-004 and 6. The target IND date for STRO-227 was originally 2027, but due to the rapid advancement of the dual payload program, we are now targeting an IND filing date of late 2026. Similar to the data shown in the HER2 dual payload ADC, the PTK7 dual payload ADC shown in purple induced better ORR and PFS in breast cancer models compared to single payload ADC shown in light blue and pink. Even increasing the dose of the exatecan payload ADC shown in the right panel in pink, the dual payload induced better antitumor responses shown in purple. Next slide. In pilot cyno tox studies, we were able to dose the 8 plus 2 PTK7 ADC at 25 mg per kg without signs of toxicity. When compared to the reported HNSTDs of conventional MMAE conjugates, we were dosing at higher dose levels than reported for any MMAE conjugate despite the presence of 8 additional exatecan payloads on the ADC. These data demonstrate that we can apply our ADC platform technologies to other payload types and exatecan with the same increase in dose and exposure levels. Next slide. Here, we compare the HNSTD of STRO-227 with the reported HNSTDs of other exatecan platforms, and you can discern that we are not taking a significant hit in safety despite the presence of 2 MMAE payloads. Combined, these findings position us as a leader in dual payload ADC development and minimizing platform toxicity to increase overall exposure level with decreasing safety are key for success. I want to conclude my presentation with the preclinical data generated when combining exatecan payloads with immune agonist payloads known as STING agonist. Next slide. There's a strong body of scientific evidence that combining cytotoxic payloads with immune agonists can induce prolonged antitumor responses. First, immune agonists work best in minimal residual tumor settings after debulking of tumors. Exatecan payloads do exactly that. They debulk tumors, so immune agonists can be more effective. As shown on the right panel, immune agonists activate the innate and adaptive immune system to launch a second wave of attack mediated by CD8 T cells against the tumor following the tumor cell killing induced by exatecan. The basic concept was attractive to Astellas, and we launched a dual payload collaboration combining exatecans and immune agonists back in 2022. As a matter of fact, Sutro was the first ADC company to report dual payload ADC data back in 2022, enabled by our unique manufacturing process. Next slide, please. It is easy to see from this xenograft experiment that the relative fold improvement of the dual payload versus the single payload exatecan ADC are most pronounced with the STING payload, resulting in 8 out of 8 complete responses compared to the exatecan single payload ADC with only 1 out of 8 complete responses. Next slide. The HER2 iADC induced the cellular and molecular hallmarks of induction of the innate and adaptive immune responses similar to the changes observed with checkpoint inhibitors. Next slide. The combined -- the combination of exatecan and STING payloads induce complete and durable antitumor responses in HER2 refractory tumor models shown on this slide. Next slide. The safety of the HER2 iADC was assessed in an exploratory cyno tox study, revealing an MTD of 25 mg per kg. These data are particularly impressive in light of the Enhertu [indiscernible] reported in cynos of 30 mg per kg. Most importantly, the PK data revealed a highly stable ADC with no increase in cytokines and negligible ADA formation in the past. This was a major impediment for STING ADC development. Next slide. With that, I'd like to hand it back to Jane. Thanks very much for your attention.

Thank you, Dr. Gerber. And as we wrap up today's call, next slide, I want to summarize the ambition of the new Sutro story, driving execution and value to patients with our new strategy and pipeline. 2025 has been a year of transformation and execution, capped off with our reentry into the clinic with STRO-004, our tissue factor ADC and expected FPI or first patient enrolled by year-end. We look forward to 2026, getting to initial STRO-004 data by the middle of next year and continuing that strong momentum as we deliver INDs for STRO-006 in 2026 and our first PTK7 dual payload ADC in '26, '27. As mentioned, we also have an ongoing partnership with Astellas focused on 2 dual payload iADC programs. We are already seeing the fruits of this partnership, and we expect the first iADC program to enter the clinic in early 2026. Partnerships like these not only validate our platform, but also extend our runway and strengthen our ability to deliver. In closing, with transformative potential and scientific progress we are making, our team is all in to drive the future of Sutro and shape the future of ADCs. This is all about execution, innovation and delivering value to patients, to partners and to shareholders. Thank you for your attention, and we would now like to open it up for questions. Thank you, operator.

[Operator Instructions] Our first questions come from the line of Tara Bancroft with TD Cowen.

All these really exciting updates. You have a lot going on here. So I mean, I guess the first question that I think is most relevant is related to STRO-004. I'm curious if you could discuss a little bit what level of efficacy that you think would support moving it into later-stage development? And maybe a little bit on safety, too, your level of confidence that it should have similar safety to what you saw in the preclinical data.

Tara, thanks for the question. STRO-004, we believe, is designed to differentiate on both efficacy and safety. In terms of the safety question first, you heard us say repeatedly on this call that we are -- we have a very favorable toxicity or safety profile with a GLP tox HNSTD at 50 milligrams per kilogram. That's probably one of the highest doses we've tested for an ADC. And at those doses, we do not see the liabilities associated with the approved tissue factor program, namely the ocular toxicity, the skin and bleeding risk. So we feel very confident in that we have a very good or wider safety window. In addition, regarding your question on efficacy, I think it's important to note, and I think Jonathan emphasized that we were seeing in our PDX models antitumor efficacy starting at doses as low as 1 milligram per kilogram. That's really important as you recall also that we'll be starting our Phase I program at that dose and we'll be -- and that will help us get to therapeutic doses as quickly as possible. So -- and given the additional PDX models that we've done, and I want to just explain some of the background on the PDX models. We looked at 20 different PDX models for each tumor type. So this is not cherry-picking one model that would just look at our data favorably, but we span the universe of PDX models to really get a holistic look at what the potential differentiation could be with STRO-004 from an efficacy standpoint. And you've seen the data today that we see in the benchmarking even with the strong activity in lung, in head and neck, in pancreatic. These are high unmet need tumors that need additional and better options. And even when we benchmark against the Tivdak or approved tissue factor program, dosing them even higher a bit, we still saw very competitive activity there. So I will just ask Jonathan, if he wants to add any more.

Thanks, Jane. I mean this is the critical thing that the drugs are safe and that they make a meaningful difference. And we acknowledge that the PDX data we presented today is still a work in progress. I mean we didn't see -- we haven't got yet results for all [ 2020 ] models across all the tumor types tested, but the results do look very encouraging that we're going to have activity in the clinic that will make a real difference to patients. I mean we're not talking here about small effects. We expect real differences that make a difference to patients' lives. And that will be achieved, we anticipate without paying a safety penalty. I can't give you precise numbers because the data will drive the decisions as they emerge. But we've gone into this roots and all with the expectation of a strong result. Thank you.

Our next questions come from the line of Ted Tenthoff with Piper Sandler.

The presentation today, very, very interesting. I wanted to get a sense when it comes to the dual targeting ADCs, is there a potential -- how closely do you have to watch the tox? Obviously, you're delivering both. So it's going to be better than systemic dual chemotherapy. But how big of an issue do you have to worry about complementary tox between different agents?

Ted, I think we highlighted that challenge with respect to the dual payloads, the safety being the real challenge here. And it's not just a straight up 1:1 ratio, as Dr. Tolcher had mentioned, even when you combine chemotherapies, it's not the same dose of each chemotherapy. You have to tune these in a way that is safe to be delivered. And so with -- and what's unique about the Sutro platform to be able to have these 2 non-naturals that can actually tightly control the ratio of payloads is really important for us. We know that MMAEs and TOPO1s are not equally potent and equally safe. They have different toxicity profiles. So what you want to make sure is you can tailor the approach and adjust the dosing, if you will, in the payload combinations. I'll ask Hans-Peter to further elaborate here.

Yes. Thank you, Jane. And I think this is the critical point of dual payloads, how you minimize the toxicity between each of the 2 payloads. And as Dr. Tolcher alluded to, most of the tox of the DLTs in the clinic is platform tox. So with these conventional conjugate these payloads come up before they reach the tumor and they cause this bone marrow toxicity or ILD. And with our platform, we've now shown it for 3 payloads, that we reach very low free payload levels because we have different linkers. We have different conjugation chemistry. We have these hydrophilic modules to actually increase -- decrease platform toxicity. And when we now did these 2 payloads together, combined with all the technology advantages, we got to industry highest exposure levels and lowest toxicity levels across all the panel of dual payload companies that we are monitoring, and we actually reviewed now 13 of these at the recent World ADC and you can take a look at yourself. There is -- if you look at PK, which is the telling matter, if you look at those numbers and have them in front of me, there's nobody that comes to our numbers in terms of exposure. And we think that will ultimately translate into better antitumor activity of dual payloads and deeper responses resulting in better PFS. This is how we see our dual payloads moving forward. And again, we started with 3 payloads, and we have 2 more to go, and we will make sure we maximize the benefit for each indication, each target specifically.

And I think it's particularly noteworthy that we have shared today that both CTK7 as well as the -- which is the dual payload of the TOPO and MMAE and the iADC HER2 program were well tolerated at 25 milligrams per kilogram. So that is already getting to a very good dose level. And I see Jonathan wants to weigh in here as well.

Thanks, Jane. I think the tunability point that was made by Dr. Tolcher is a critically important one. If you don't tune right, you'll run into toxicity with one of the payloads before the other ones got into the zone where it's going to be active. To get the tuning right, and you can dial them up thoughtfully and carefully to a point where you see activity without being hit over the head by running a toxicity one of the payloads prematurely, if you will. And that's very, very high on our list of priorities to sort out. And as you can see from the work that Dr. Gerber presented, this has been -- the tunability is a thing that we can work with very well, and we have seen that we've -- the data show that we're in a really good HNSTD zone, and I think this is encouraging.

Our next questions come from the line of Roger Song with Jefferies.

Appreciate the updates. This is [ Nabeel ] on for Roger. A couple from us. Regarding STRO-004, so as we -- the trial is ongoing in dose escalation, is there any particular rationale for what lead indications we would then select for, assuming efficacy is on par? Is there a rationale to look at unmet need or anything particular there? Any more color would be helpful. And then I had a follow-up.

Yes. So thanks for the question on STRO-004. The goal for the tissue factor program is really to expand the tissue factor benefit -- tissue factor ADC benefit beyond cervical cancer. You've seen several of the tumors that we've highlighted in the PDX study were inclusive of lung, head and neck, pancreatic. And these are cohorts, these are tumors that we will -- that express tissue factor and that we will include in our Phase I program. And we'll also be looking at in our Phase I program, cervical cancer because I think it's important to actually show differentiation there as well to the approved tissue factor agent. And Jonathan, do you want to add here?

Yes. Thanks, Jane. I mean, the data from TV was an important path find to proof of concept. And we remember in the early cohort expansions, there were activity in other tumors besides cervical, head and neck and lung come to mind. And the [ Miracogen ] asset also showed that the activity in pancreas. And so there's a lot to build on here. And as one of my slides showed, there are a ton of patients out there who need something new. And we built a next-gen TF ADC exactly with the intention of going after those patients to try and give them a new option.

That's very helpful. My follow-up is on the xenograft model. So on Slide 15, again, looking at that waterfall plot, was there anything similar or different within the tumor types? Like, for example, I'm just curious on those -- the head and neck tumor types, the 2 bars on the left most on the waterfall. Any -- anything different about those? Or is that -- would we just call those outliers?

So I would say that the study is an interim look at the PDX models we have so far. We will continue to evaluate any kind of differences in these tumor models. We don't expect to get a 100% win on all of them. But maybe I'll pass it over to Hans-Peter, if you have any additional color to add.

Yes. Happy to add more granularity on those columns that have these dots. That means actually they are currently being on the treatment and the response could only improve from now on. So we, of course, do translational studies of these tumors. We have tumors before we implanted them, and we can take them at the end of the experiment, if there's any left. And we do gene expression profiling and we look for this sensitivity markers to each payload. I mean, here in this case, it's TOPO1, but for the dual payload, that is an important question. These tumors that do so well, are these both expressing high target and then the markers that predict response to the second payload. So we're looking at this in this collaboration with these PDX models to identify potential market to identify the patients that respond best early on.

That's really helpful. If I can sneak in one more question. Really excited about the PTK7 program, and I'm sure we're going to hear more later. I was just kind of curious about your inclusion criteria, like how you might be selecting for PTK7 expression. IHC, would that be an H-score percentage cells positive?

Yes. So we are excited about PTK7 as well. And we believe that PTK7 is already a validated target, while it's not approved, any agent isn't approved for that target yet. There are several companies going after this similar target as well with an exatecan single payload ADC. And we want to make sure that we're developing a program that is highly differentiated, and that's why we're introducing our dual payload program to go after this target. It's been validated in several tumors, whether it be lung, breast and ovarian. And there is an IHC in terms of enrichment strategy there as well. So we'll continue to evaluate.

I mean in terms of -- you had a question about the eligibility criteria. And I think we are starting to put those together. But we anticipate the usual balance between making sure you've got a patient population that stands a chance of demonstrating the potential of the asset versus patients do have to receive the approved therapies before they come into trial. And that's always a sort of tension in developing early drug development studies. But again, we think the dual payloads are incredibly exciting in terms of what they're going to offer patients. And in that case, you want to cast the net wide. You want to give as many patients a chance to take part as you can in principle.

I think upfront, we might do retrospective analysis in the Phase I just to see what the correlation is with target expression and response rate. But I think when we look at the enormous wealth of data that is already around that PTK7 target, this is now a different target space, which is known to be associated with cancer stem cells. And 10 years ago, this was the root problem of cancer that we need to take care of. But I think 10 years ago, we didn't have the right payload. With these exatecans, you can actually go into these root causing cells of cancer because they're no longer being effluxed by these pumps. And that is the most exciting aspect of this. This is in addition to the delay in resistance formation which because of the dual payload, we can now go into the root problem of cancer and get rid of those cells. And it's already been shown in a paper in 2019. If you take these PDX tumors and you eliminate the PTK7 positive cells and you put the tumor back in mice, the tumors don't form. So we know when we get rid of these cells, there will be no more tumor growth. And we knew with the tubulin inhibitors before we actually that's published, we couldn't get rid of these cancer stem cells. There was always 10% left, and they reformed the tumor. So this is a super interesting experiment now going into the clinic and see how these new more advanced platform technologies can help the patient.

Our next questions come from the line of James Shin with Deutsche Bank.

This is Sam on for James. I'm just wondering if Dr. Tolcher could share his thoughts on integrin beta-6.

Dr. Tolcher, maybe he couldn't join us for the Q&A, sorry.

We only have the Sutro team available for the Q&A.

Okay, right.

Can you repeat your question

Yes. We didn't hear your question. Could you repeat your question?

I was just -- I wanted to hear Dr. Tolcher's thoughts on integrin beta-6. Yes, that was my only question.

I'm happy to address the question. We are excited about the integrin beta-6 program. It has been a target that's historically been difficult to make. Peter knows as well when he was working at another company that took many years to actually formulate that target. Reason being is that it is just grouped with a lot of other targets in the integrin beta family that you don't want to get -- you don't want to interfere with. And I think we have made with our Sutro technology and protein engineering, a highly specific antibody or ADC targeting this alpha-v, beta-6 heterodimer that is involved in tumor genesis and also avoids the other sort of target biology associated with this target as well. So that helps us get a cleaner profile. And already, we're seeing doses that are well tolerated at 25 milligrams per kilogram for this program. And we believe that it is -- well, actually, we know that it is highly expressed in lung cancer and has already been validated in lung cancer with a competitive program, but there's opportunities for improvement in terms of the safety as well as the efficacy. And so we're excited about this program. In fact, the one competitor that has been investing in this target is now tripling down on this target. They have 3 assets going after the same target, which I think is really -- speaks to their excitement and bullishness around this opportunity and supports our excitement around it as well. I'll pass to Peter to add.

Yes. Thank you, Jane. So to add some additional data around this point that among the top 35 targets being pursued by ADCs now, integrin beta-6 is ranked #32 sort of one being the most competitive like HER2, integrin beta-6 is on #2 out of 35. The reason for that, it's so hard to get an antibody to target that integrin beta-6 without interfering with the biology. And that is really in contrast to the enormous value of the target indication lung. In fact, our competitor went out with 3 agencies into that space because they have an antibody that is safe. We are having the same or better antibody that is safe with a TOPO1, and we're looking forward to actually see how much more we can dose and how much better antitumor activity we can achieve with these kind of new enabled ADC that lets us dose at higher levels. And we already have compared our exposure levels with competitors, and we're very confident that we have good reasons to believe that we will see very good antitumor activity with this ADC.

Are you expecting activity to correlate with target expression here?

So the thing about integrin beta-6 that is highly, highly expressed in lung cancer, upwards of 90%. So we know that the target speaks poor prognosis in cancer patients. Whether or not we'll need a biomarker for this program is TBD. We'll further evaluate. The competitor program that's already in the clinic is an all-comer strategy without a biomarker or enrichment strategy. And so this could be quite a sizable clinical and commercial opportunity for this program. And even if we were to share this market in lung cancer, it's quite sizable for Sutro and high value.

Yes. I mean the thing about the biomarker piece is if the prevalence of the marker is very high, then the biomarker approach is less important in terms of achieving efficacy. And the other sort of side of that page is that if you need biomarker expression, patients don't have tissue, they then face a new biopsy and that's -- there are issues around that. Some patients are reluctant or frightened even to undergo another biopsy. So if you can show that you've got a drug that's working well without the biomarker enrichment, that actually, in the end, is a service to patients. And I think perhaps sometimes people don't always appreciate what it's like to be on the receiving end of a biopsy needle.

Yes. And the biopsies are tend to be a bit more challenging to get in lung cancer versus like other solid tumors.

[Operator Instructions] Our next questions come from the line of Tazeen Ahmad with Bank of America.

If you think about areas where companies like to differentiate in the ADC space, one of those, as you mentioned and most other companies have mentioned, would be payload. So in your decision to select MMAE as your second payload to add to exatecan, can you talk about why that is the best combination and maybe what other payloads you might have considered and how this could be particularly differentiated?

Thanks for the question, Tazeen. It's an important question because -- and it's a strategic one, right? So when we think about PTK7, it's been validated with the previous program. There has been some efficacy shown, but the PFS was limited to about 1.5 to 3 months. And so the program itself was limited by the toxicity of an MMAE design. And I think for us, when we think about a target that's been validated, but not yet approved, still needs -- still is sort of a novel -- somewhat novel target. We want to then think about how do we combine and derisk the program to some extent with how we design sort of payloads. The payloads for both TOPO1 and MMAE are a bit more validated, right? They're more validated, they're credentialed according to Dr. Tolcher and historical payloads that we have seen very active in the tumor types that we just mentioned in lung, breast and ovarian. And so the combination of those 2 payloads derisk sort of this program going forward going after a validated but not approved target. So that's kind of how we think about putting these combinations together. If we went for a -- like we did for the HER2 program and wanted to dial up the differentiation for the payloads like an immunostimulated payload, we chose purposely to go after a validated target, right, because then you can really see the differentiation of the payloads and the activity and the contribution of those payloads and the new payload. So that's really kind of the reason behind the design. And we think that because PTK7, the target is being sought after by several companies with a single payload exatecan approach, we want to differentiate our program with a dual payload with an exatecan plus MMAE that has already been shown active in these tumors that we're going to be looking at for that program. Anything else, Peter?

I can add a little bit more color to that statement. So yes, this is, of course, we are looking at 5 different payload combination with TOPO1. And that is the most important question. What's the biology behind one versus the other. And for -- there's basically 2 principal approaches. One is empirically to combine 2 different payloads with different mechanism of actions. And that's based on strong signs that it will take the tumor at least double the time to develop a resistance against 2 payloads with different mechanism of action. Now among those, MMAE is the most widely approved payload industry-wide for most of the time. TOPO1 is maybe the one behind, but will overtake. So we take the 2 most successful linker payloads in a kind of an empirical way because, a, they are validated and b, they have different mechanism of action. And then add 5 more categories that we put into the selection. The other one is we know already in the target indications for PTK7, each linker payload on its own has shown very prominent antitumor activity in an ADC context. And then in addition, again, that cancer stem cell, now it's time to revisit those cancer stem cell target because PTK7 is one of those. This could give an additional boost in progression-free survival. And last but not least, and I don't want to go through all the rationale here, but this is -- this MMAE combination. If you listen to the presentations from people that develop MMAE, the induction of immunogenic cell death by this payload is a very important differentiator that you then can combine these MMAE conjugate with checkpoint inhibitors. So by adding 2 of those MMAE to a TOPO1, we should then make these tumors super sensitive to an additional checkpoint inhibitor. So on top of all of these possibilities that we build into this ADC, you could then basically super boost if needed, even the T cells to go after the tumor and then further improve PFS. So that was very attractive for this MMAE combination. And I don't want to go into all the details with the other payload. Just the concept is why we're taking a DDRI, for example, which we didn't really discuss, but we're very advanced with those as well because there, it's the other one. We -- this is called -- it's in the context of synthetic lethal. It's our old principle of oncology development. You use a drug and that drug has all the pathways that the tumor will utilize when you press the button on that load, and they will find an alternative pathway to overcome that pressure. And the DDRIs will actually cover all the remaining pathways for tumor to escape to the TOPO1 pressure. So that's more like a biology, synthetic lethal biology approach to overcome the rescue pathways. And the third one, of course, is the iADC where we ask an entire arm, different -- your own arm of antitumor response to the rescue after we debulk the tumor with the exatecan. And so these are 3 buckets, all different rationale. And as you know, in cancer biology, there's different ways to get there, and we have to explore the space in the clinic where we get most benefit for the cancer patient.

Our last questions will come from the line of Andres Maldonado with H.C. Wainwright.

Kind of want to dig into a little bit of the nitty-gritty on the engineering front. First question, I guess, as we look across targets, can you speak on what is the variance of rates of internalization kinetics, maybe half-life of internalization across the targets? And if that variance is wide, how have you been able to counteract that with your cell-free conjugation? And do you feel that the more engineering you had to do to kind of normalize or increase the rates of internalization, you'll be leaving some efficacy on the table? And then a follow-up question for the dual payload engineering, really cool stuff here. So curious, given that the dual ADC constructs employ a DAR 8+2 or DAR 8+4 combinations, can you speak to maybe from a synthetic chemistry perspective, how reproducible are those stoichiometry batch to back? Just curious on how you guys controlling the scale up in the future.

Okay. So thanks for those questions. Maybe I'll tackle the dual payload one and then hand over the internalization of the target to Hans-Peter. So I think for the dual payload process on the ADCs, whether it's 8+4, 8+2, the reason why we have such tight control of the stoichiometry is because we have these non-natural amino acids that is further stabilized with our quick chemistry within our cell-free platform. This is really unique for Sutro. And I believe what this platform was made to do, not necessarily me to conventional ADCs like everybody else, but actually really differentiating what we do in the dual payload space. We -- and so I think the 8+2, 8+4 rationale to be able to control the ratios will be very essential for us to ensure the safety window and the therapeutic window we want to achieve with these dual payloads. With that, I'll hand it over to Hans-Peter to address the stoichiometry as well as internalization of the target.

Yes. Happy to add more color here, Jane. So with regard to the preciseness of how we can conjugate single and dual payload in a DAR 8+2, 8+4, you may have seen our collaboration that we initiated with the FDA, where actually the FDA reached out to us because they have seen the profiles of our ADCs and said they could become industry standards for how to precisely make ADCs. So we're very happy actually when we heard from them. And so we collaborate with them. That says maybe more than I could explain in the next 5 minutes about why we have these highly precise conjugates. But with the internalization, that is a good question. It came up many times. I want to frame it a little bit, starting with one extreme version. As you know, there's now currently being developed ADCs against targets that don't internalize at all and extracellular matrix actually was one of those that I started originally when back at Pfizer. So you do not need actually with these new technologies when you have good cleavable linker, you have bystander effect. All you need is a high copy number target and something that cleaves the payload in the tumor environment. Now in vitro internalization, everybody shows this internalization data. You can have like half of the ADC internalized in 30 or 60 minutes or sometimes 2 hours. And people read a lot into that. But if you think that these ADCs now with our half-lives, they are in these animals or patients for weeks. It really doesn't matter how quickly internalized because they all will have plenty of time to internalize. In fact, I'm going to give you some clinical evidence that it doesn't matter. The biparatopics that were designed to get a target too fast or internalize to get more drug into the tumor. Yes, biparatopics always worked very well in preclinical experiments in vitro, maybe under certain conditions in vivo. But now the first readout in the clinic, it turns out it doesn't matter because the residence time of these ADCs in the circulation is so long, whether you internalize in 30 minutes or 60 minutes over 3 weeks, it doesn't matter. What really matters is whether your ADC is stable, that's how you get more payload into the tumor and not how quickly you get it in. I give you a little bit -- I'm sure all the people have different opinions, but I'm really referring to clinical reports where this now didn't translate into better antitumor responses, though in preclinical models, they did. So these are some of the [ PSs ] in ADC development. If you list this, you know about that. If you come new to the field, all these things look very interesting, but only a few of them are actually translating from preclinical into the clinic. One among those is certainly PK. PK that usually translates into the clinic, and that's a really important thing to look for in these early preclinical data sets.

Yes. I think important to add is on the point on PK, we enjoy describing our assets and programs as having rock solid PK in that it has low clearance, high longer half-life and higher ADC drug exposure. And that's achieved in many different ways with the optimization of our design features for the ADC where we optimize every element of the ADC. And then in terms of your question on stoichiometry, I'd like to keep things simple because I love the technical explanation that HP just gave. But if you can imagine when you think about dual payloads, when you have 2 different payloads competing for the same site of conjugation, it becomes very -- it can become a bit messy. And so how do you keep that super clean. The way we do it is through our non-natural amino acids that work well in our cell-free platform that does not work so well in the conventional CHILL-based manufacturing process. And so it has an impact of decreasing the yield there as well for those programs. So this is what gives our dual payload programs a competitive advantage. Any further questions, operator?

There are no further questions at this time. I'd like to hand the call back over to you, Jane, for any closing comments.

All right. Well, thank you, everyone. Thanks, everyone, for tuning in and for your questions and your active engagement. I want to thank the Sutro team for all the progress being made. We're building a lot of momentum into this year and into next year. And just -- we appreciate you following our progress.

Thank you. This does now conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.