Again, it's Michael Schmidt from the biotech team at Guggenheim. The next presenting company is Bolt Biotherapeutics. With us today, we have Willie Quinn, CFO, as well as Edith Perez, Chief Medical Officer. Welcome, guys. Thank you. All right. Why don't we dive right into the Q&A, perhaps for Edith. ISACs has been a somewhat challenging category for some companies. On the other hand, there have been a number of partnerships in the last few years, in industry which, you know, suggests there is strategic interest in this technology. Maybe talk about your platform technology and how it's differentiated from others out there. Yeah. I mean, as you said, Michael, there is interest in the technology because one of the reasons for this is that it makes biological sense for us to target, you know, a, an abnormality in the tumor cells and then bring activation of the innate immune system right to the site of the tumor. They have had different molecular structures compared to what we've developed at Bolt. Our ISAC technology includes the monoclonal antibody, with a linker payload that is non-cell permeable and non-cleavable that is attached to an activator of toll-like receptor 7 and 8. By having this non-cleavable, non-cell permeable linker, we allow the activation of the immune cells to occur right at the site of the tumor instead of systemic release of an immune activation, which will be associated with potential cytokine release syndrome. Yeah. If I can just add to that, I think for us, what we've really discovered is that it's not one size fits all. You can't just take a linker payload and copy and paste it over to other antibodies. What we've developed is a pretty deep toolbox that has different conjugations, different linker lengths, and then most importantly, different payloads. We match the payload, linker payload to the purpose. The antibody matters, the linker payload matters, and most of our work is TLR7/8, as you know, but we've explored a lot of other options as well. Yeah. Some companies have had issues with that tolerability. Presumably if their payload dissociates, or, you know, derives some other systemic exposure. You guys had the opposite issue, I think, in your study of BDC-1001, where we've seen low exposures. Maybe just if you step back a second, can you just remind us where you are with your BDC-1001 study, which is your HER2 ISAC program? Yeah. They're very good. We, first, you know, continued to look at our preclinical data even before we started the study, and then we continued doing more preclinical work as we initiated the clinical trial. As you nicely alluded to, we started with our strategy, and we showed low exposure levels when we were administering our anti-HER2 ISAC once every three weeks. We learned from the pharmacokinetic evaluation that we needed a different strategy to be able to increase exposure, and that's why we proceeded with evaluation once every two weeks and then once every one week. I'm very pleased to say that we've completed accrual to the dose escalation portion of our trial. Now we're in an excellent position to continue to aggregate the information from this now completed dose escalation trial to be able to share information related to the top-line results from this study, along with a discussion related to our plans related to the phase II portion of the program. Okay. Great. You know, again, if we step back a second, you know, I guess what gave you confidence that the weekly dosing schedule, you know, achieved sufficient exposure to potentially drive efficacy? Yes. We looked at the pharmacokinetic profile of the once every three week schedule at increasing doses. We did population PK modeling to determine or predict what would be the levels that could be achieved with once every two weeks and with once per week scheduling. Obviously, after having the models, we needed to test the hypothesis in the clinic. We felt that it was achievable and that we've been successful to get to the levels that we anticipate are the appropriate levels to take to the phase II portion of the trial. It was all based on the data once every three weeks, population PK analysis, and then conducting the clinical trial to determine if our modeling would pan out. Okay. Then what should the investors expect from this upcoming phase I data update? Maybe talk a bit about, you know, what types of patients are enrolling in or have enrolled in the study, and sort of what types of data are you trying to, you know, disclose to, you know, support next steps? Yes. We've enrolled, you know, patients, with 16 to 17 different solid tumor types, and these tumors have to express HER2, either the HER2 low or the HER2 positive, degree using ASCO/CAP guidelines. These patients needed to have tumors refractory to standard of care. In terms of the specifics of the patient population, when we had disclosed data on the initial group of patients even a year and a half ago, you know, more than half of the patients had already received prior anti-HER2 therapy. When we share the top-line data from the now completed dose escalation trial, you'll hear about all the different tumor types that the patients had, number one, the safety, and pharmacodynamic data at different dose levels, as well as the clinical activity observed at different dose levels and for the different tumor types. What are some of the key pharmacodynamic, you know, assessments that you're conducting and also, you know, considering that many of these patients have had already prior treatment, I guess? Yes what level of clinical activity would you think supports, you know, phase 2 development? Michael, you know, one thing I would like to clarify is that, you know, we're gonna have top-line data of, you know, this is Q1 of 2023, but at the same time, we anticipate submitting an abstract to a medical meeting where we will then disclose details of the specifics-. Okay ...of the tumor types enrolled and things of that nature because we want to abide by the rules of the big meetings. We want to be able to share, again, the top-line information with the high level findings from this study. In terms of looking at clinical activity, we want to be cognizant that this is the first in human trial with this compound, where we've enrolled, again, patients in 18 different cohorts attempting to seek the right exposure level, the right dose and schedule that we will take to the phase II portion of the program. Even though it's a phase I dose escalation trial, we are very cognizant, and we have been paying attention to the clinical activity because that gives us the confidence that it, we should move to phase II. In terms of your other very good question related to what pharmacodynamic markers we're looking at, again, we're taking the example of what we found in the preclinical models, but we're evaluating markers related to myeloid activation, markers related to T cell migration and activation. We're also looking at any data related to systemic inflammation, such as IL-6. Those are the three main components. Are we modulating myeloid cells? Are we activating and migrating T cells? Are we leading to any systemic inflammatory response that would be of concern? Gotcha. All right, cool. You're also doing a study in combination with Opdivo. Just remind us again where you are in the process of enrolling that study and again, what investors should expect in terms of forthcoming updates. Yeah. Michael, so when we at least release the top-line data, this quarter, it will include both the monotherapy and the combination with nivolumab because we've completed both portions of the dose escalation, trial. Okay. That makes sense. Great. You know, I know you're gonna talk about it soon, but in terms of next steps, I guess where do you see the best opportunity to potentially differentiate from other options in the HER2 space? You know, one thing is our mechanism is very different. You know, we are bringing the activation of the immune system right at the site of the tumor, we are striving to not only activate the innate immune system but actually adaptive immune system with long-term memory from the T cells to be able to reject, you know, the development of new tumors. This immunological memory is very unique in terms of mechanism of action compared to other anti-HER2 agents in the market. The second aspect that is differentiating for us is that we don't have chemotherapy with the associated side effects of chemotherapy as part of our molecule. At the same time, the safety that we've observed, you know, allows us the opportunity to not only certainly proceed with the combination with nivolumab, but also seek other opportunities for combination. Yeah. I meant more sort of, you know, are we thinking as, you know, in terms of histology, you know, are we thinking, you know, are we moving to the breast cancer space or are there other HER2 tumors where there's perhaps a better opportunity for this? Yeah, very good. One of the things we've learned over the years is that HER2 can be overexpressed in a wide range of solid tumors reflected, you know, by the patients who were enrolled in our study. The opportunities are quite broad. Again, as we've enrolled patients with so many different tumor types, we've gotten the glimpse of the tolerability and activity, although at different dose levels. I think we believe there are opportunities both for tumor types for which there are already anti-HER2 agents approved, but there are other tumors where there's still not an approval of the HER2 space, I think that provides us with additional avenues to consider. Makes sense. All right, great. We'll look forward to this data soon. Great. Maybe switching gears to BDC-3042, which is your second, product candidate targeting Dectin-2. Yes. could you just remind us of the mechanism of action of Dectin-2 activation? We- Yeah, I'll jump in there. Dectin-2 is an agonist antibody, and it targets Or Dectin-2 is the target on the surface of the tumor-associated macrophage. What we've found is that this is expressed in most TAMs, and it tends to be upregulated across different solid tumors. It's a pattern recognition receptor, not too dissimilar from TLR7 or TLR8, it's on the surface, and it's really functioning to recognize fungal infections. The natural ligand is mannan. When you stimulate Dectin-2, you actually polarize or repolarize the TAM, it becomes an inflammatory phenotype, which is exactly what you want in that tumor microenvironment to have a productive immune response. We're really excited about that program. It's on track to get into the clinic later this year. Then, you know, TAMs also have been, I would say, a mixed, you know, a mixed experience so far with other programs. You know, where do you, would you expect this to have the most benefit? You know, are there any sort of, you know, histologies or biomarkers that you could evaluate? Yes. You're absolutely correct about, you know, there's wide interest in repolarization of macrophages. There are several companies attempting this strategy, looking at different targets. We are fortunate that we identified, you know, Dectin-2 targets, so we're the essentially the first ones pursuing that approach. The way to think about the potential tumor selection is based on the combination of gene expression data, protein expression data available in multiple databases, which we're utilizing as we conduct our pre-IND work and make decisions so of the tumor types we will take to the clinic. Okay. I guess, how are you tracking towards IND filing for this? We're on time. We anticipate we will submit, you know, the first half of this year, and then, start in the clinic, the second half. Can you talk about the design of your planned phase one study? We're working on that right now. Okay. I guess, mechanistically, is Dectin-2 a target where one would expect single agent activity or is it more something that would be positioned as a combination agent? We- That's actually a really interesting question. We've done a number of preclinical studies where we create humanized mice models, and we use PD-1 inhibitor as a control and see better tumor growth inhibition than PD-1 inhibitor. I think there is still a good potential for monotherapy activity, but certainly this mechanism seems like it'd be something that would combine well with other modalities, and ISACs could be one. If we've made good progress with BDC-1001, you know, maybe it'll be something we combine down the road with BDC-3042. Yeah. All right. Super interesting. Then, you know, you guys do have a number of collaborations with other companies. Perhaps could you highlight just how you leverage those to advance the platform or pipeline? Yeah. I'll highlight two of them. Genmab is one we have where we're exploring bispecific antibodies. This is interesting because you could imagine having two arms of the antibody to increase specificity in terms of the tumor targeting. You could imagine having one arm targeting a tumor antigen and one arm involving some immune cells or mechanistic help for the ISAC modality. That's progressing well, and we're bringing all the linker payload expertise to the party, and they have the bispecifics. The other collaboration is Innovent. Innovent has a deep library of different antibodies, and we've decided on the initial target that we're pursuing, and that is also progressing well. Again, it's bringing our linker payload expertise, combining with their antibodies. Going back to the platform point, everyone is different. We're really finding out that you can have a toolbox with maybe your top half dozen candidates, but this one will do much better in that situation and a different one will do better in a different situation. It's great that we're able to continue to advance our toolbox and platform, and the collaborators are the ones funding a lot of this early work. They help us fund this through clinical proof of concept. At that point, depending on the program, we have the ability to opt in to some of those and add those to our pipeline. We're very excited about the collaborations. Perfect. I guess, you know, in terms of news flow, will there be any announcements coming out of any of the collaborations in the next year or so? I sure hope so. We haven't, you know, put a stake in the ground yet on any of those, but I do think that later this year we'll probably be in a position to make some... at least one announcement between the three-plus collaborations we have. Okay. Then maybe just to wrap up, just remind us of your cash balance and guided runway. We ended the Q3 with $210 million, and that puts us in a really strong position. As you know, there are a number of companies that aren't as fortunate, but the runway takes us through the end of 2025. All of the program for 1001 that Edith was talking about and the new program for 3042 that we're starting later this year, those are all baked in to the financial projections. We'll be able to get a lot of good milestones between here and there. Great. Yeah. Well, thank you so much, Willie. Yeah. Edith. Really appreciate the time. With that, I think we can wrap up. Great. Thank you. Thanks, Michael. Thank you.