Good afternoon, ladies and gentlemen, and thank you for standing by. Welcome to Xencor fourth quarter and full year 2021 conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. Please advise that this call is being recorded at the company's request. Now, I would like to turn the call over to your speaker today, Charles Liles, Head of Corporate Communications and Investor Relations. Thank you. Please go ahead. Thank you and good afternoon. Earlier today, we issued a press release which outlines the topics we plan to discuss today. The press release is available at www.xencor.com. With me on the call are Bassil Dahiyat, President and Chief Executive Officer, Allen Yang, Chief Medical Officer, John Desjarlais, Chief Scientific Officer, and John Kuch, Chief Financial Officer. After remarks, we'll open up the call for your questions. Before we begin, I would like to remind you that during the course of this conference call, Xencor management may make forward-looking statements, including statements regarding the company's future financial and operating results, future market conditions, the plans and objectives of management, future operations, the company's partnering efforts, capital requirements, future product offerings, and research and development programs. These forward-looking statements are not historical facts, but rather are based on our current expectations and beliefs and are based on information currently available to us. The outcome of the events described in these forward-looking statements are subject to known and unknown risks, uncertainties, and other factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements, including but not limited to those factors contained in the Risk Factors section of our most recently filed annual report on Form 10-K. With that, let me pass the call over to Bassil. Thanks, Charles, and good afternoon, everyone. Today, we released our earnings results, and now, in a bit of a change from past calls, we'll only make a few brief comments before spending the majority of today's call on questions. We've used our array of modular protein engineering tools to create our internal development portfolio in oncology and autoimmune disease, and we use the breadth of this portfolio to take multiple simultaneous shots on goal in the clinic. The proof of concept data we generate guides which programs we advance, which we terminate or which we partner. We focused our efforts in 2021 making key portfolio advancement decisions, specifically initiating phase II studies for vudalimab, our selected PD-1/ CTLA-4 bispecific antibody in prostate cancer and gynecologic tumors based on promising phase I data. We entered a collaboration with Janssen for the development of plamotamab, our CD20 x CD3 bispecific antibody, to add their expertise and resources to the program and enable novel combination trials in a highly competitive therapeutic area. We terminated development of vibecotamab, our CD123 x CD3, due to a challenging clinical profile in a changing treatment landscape. Of course, we're continually applying our engineering tools to build drug candidates that tackle new or hard-to-address biologies, and several of our early stage programs are advancing into clinical studies and reporting data this year, led by our reduced potency cytokines and our 2+1 CD3 and CD28 T-cell engagers. Our goal is a well-balanced portfolio of late and early stage programs in development that we can potentially advance to approval and ultimately the market if the data supports that. Now, supporting our development work is the growing partnership portfolio, including three marketed products producing royalties for us, such as sotrovimab, the Vir/GSK antibody for treating COVID-19. We also have a broad clinical pipeline with our partners, such as the exciting new 2+1 CD3 T-cell engager, AMG-509, that we created for prostate cancer with our partner Amgen, in which they released early but very promising data for this month. Our own XmAb819 shares the same 2+1 format and will start a clinical trial in renal cell carcinoma this year. Now we'll turn to Allen Yang, our Chief Medical Officer, who will review a few recent highlights of our clinical programs and upcoming plans. Allen. Thanks, Bassil. Today, we'll review two of our wholly owned programs, vudalimab and XmAb564. First, we're wrapping up our phase I study with vudalimab. At SITC, we reported data from maturing expansion cohorts, primarily metastatic castration-resistant prostate cancer, renal cell carcinoma, and a basket of other potential indications. We observed a consistently tolerable profile, predominantly immune-related adverse events, including rash, pruritus, and liver enzyme elevations. We have observed a low incidence of adverse events like colitis and pneumonitis that have been typical with historical combinations of PD-1 and CTLA-4 antibodies, which supports our hypothesis that vudalimab is selective for binding double positive cells. Importantly, this could make it easier to use in patients. For a more complete discussion of the results, I would point you to our press release last fall, and the posters are available on our website. Though within the analysis, we want to highlight our prostate cancer cohort. Prostate cancer is a heterogeneous disease, and we enrolled mostly late-line patients. Eight patients had measurable disease. That is some kind of metastatic lesion in a visceral organ or lymph node that could be measured by RECIST for response. In four, we were able to evaluate response, and two of these four had durable, impressive six- and nine-month partial responses. It has encouraged us to advance vudalimab in prostate cancer. The first phase II study, which started last fall, is in patients with metastatic castration-resistant prostate cancer who are post-androgen deprivation therapy and post first-line chemo. We are using standard genomic profiling to find actionable risk phenotypes, which would guide us to either a chemotherapy regimen or PARP inhibitor, and vudalimab is dosed on top of that. Patients with no actionable mutations will receive vudalimab monotherapy. Later this year, we'll present early initial data from the study. We will only have a few months of on treatment data for a portion of patients, but it will allow us to get a first look at the safety of vudalimab in combination with other therapeutic agents that can have significant toxicities of their own. Historically, combination therapy with PD-1/ CTLA-4 dual blockade has been challenging, and we hope that vudalimab can improve on that. Of course, we will share whatever efficacy data we have collected at the time. Ultimately, we hope that this study defines combination strategies and subsets of patients with high unmet need that could define a simpler development path than previously available for prostate cancer. We are also initiating a second phase II study evaluating vudalimab monotherapy in a differently defined slice of prostate cancer. That is a clinically defined high-risk metastatic castration-resistant prostate cancer, where we saw two out of four partial responses in the phase I. In addition, this study will examine select gynecological tumors as well. We do not anticipate data from this second study in 2022. Next, our wholly owned cytokine, XmAb564, a reduced potency IL-2 that we are developing for an autoimmune disease. In contrast to cytokines being developed in oncology, it's engineered toward the IL-2 alpha receptor, CD25, which is over-represented on regulatory T cells compared to other T cells. We've also reduced the affinity for the beta gamma receptor. While the Treg hypothesis is just that, a hypothesis that more regulatory T cells can result in clinical benefit for autoimmune disease, it was a perfect fit for our cytokine platform and represents an enormous opportunity to enable new treatment modalities based on Tregs. Currently, we're conducting a single ascending dose study in healthy volunteers, and this year we'll present our first data from that trial consisting of T-cell and other biomarkers, safety and pharmacokinetic data, all critical information for determining our potential product profile. We also plan to initiate, in parallel, a multiple ascending dose study in select patient populations. Now, as we wrap up, we wanted to briefly mention three other studies we are planning to initiate in 2022. First, the potentially registration-enabling phase II study evaluating plamotamab in combination with tafasitamab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Second, as Basil mentioned, the phase I study evaluating XmAb819 in patients with renal cell carcinoma in the first half of this year. Third, following the submission of an IND, the phase I study of the B7-H3 x CD28 bispecific XmAb808 in patients with advanced solid tumors in the second half of this year. Now, with that, I'd like to hand the call over to John Kuch, our CFO, to review our financial results. John? Thank you, Allen. Xencor's broad portfolio of partnerships, collaborations, and licenses continue to generate strong cash flows in 2021. During the year, we received over $200 million in upfront payments, milestone payments, and royalties, which helps offset our growing investment in our pipeline as bispecific and cytokine candidates. A breakdown of 2021 proceeds was $80 million in royalties, including $52 million from our Vir partnership, a $100 million upfront payment related to our second Janssen collaboration, and $20 million milestone payments. These proceeds strengthen our balance sheet, and we ended 2021 with cash equivalents, receivables, and marketable debt securities of $664.1 million, compared to $610.2 million at the end of 2020. We estimate that we'll end 2022 with between $500 million and $550 million in cash equivalents, receivables, and marketable debt securities. Based on current operating plans, we expect to have cash to fund research and development programs and operations through the end of 2025. I refer you to our press release this afternoon and our SEC filings for further information about our recent financial results. With that, we'd now like to open up the call for your questions. Operator? As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question or if your question has been answered, press the pound or hash key. Your first question comes from the line of Jonathan Chang from SVB Leerink. Your line is now open. Hi, guys. Thanks for taking my questions and congrats on the productive year. First question on vudalimab. Can you discuss reasons for confidence in the safety profile of the drug and its potential in combination treatment? Sure. I'll let Allen take that. I think it's basically just from what we've observed. Yeah. If you look at the data from the phase I study that we presented at SITC, and you look at the AE profile, you know, traditionally with PD-1/ CTLA-4 combinations, you'd expect a lot of discontinuations. About 1/3 of the patients discontinue the product. We did not have those problems, and it's primarily due to colitis and GI symptoms, and we don't have those problems. The GI toxicity rate was around 10%. If you look at the AE profile, the most common immune-related adverse event in about 1/3 of patients was rash, which is, you know, a milder AE. We believe that even though we're targeting both PD-1 and CTLA-4, it's a highly tolerable profile compared to the two drugs independently. Understood. Second question on your cash guidance, can you provide some color around what assumptions are being made, in terms of receiving potential milestone payments and royalties from partners? Yeah. Well, I'll let John take that, but I think the word of the day here is that we're very conservative in future revenue flows when we do our planning. Thank you, Bassil. Yes, Jonathan, as you know, we're very conservative as far as forecasting milestones, only near-term milestones that we have visibility from our partners. With respect to royalties, we look to, again, the guidance that's provided by our partners. For example, GSK has provided some guidance as far as potential sales of sotrovimab in 2022, which I believe are somewhere in line with 2021. We're gonna forecast quota levels may be a little bit discounted. Generally, that's how we look at things, and we do not forecast any new revenue. When we think about the year-end cash position, we do include some potential revenue, but again, it's conservative, and it assumes certain spending levels based on starting out certain clinical programs. Understood. I'll just sneak in one last one. On XmAb306, are you able to provide any additional color on the tumor types and combination strategies of interest? Thank you. No more than what we've said in the past, which is that we think there's a lot of potential in both NK cell-mediated therapies for combination as well as T cell- mediated therapies. Of course, Genentech's already running the Tecentriq combination in the dose escalation, and we're looking forward to them starting the expansion cohorts with Tecentriq soon. I think NK cell-mediated therapies are very promising, and I mean, the top of the list of NK cell- mediated therapies are all the traditional antibodies that people have been using for now a number of years. You know, the Rituxans, Herceptins, and daratumumabs of the world are all things that are possible. What we have, we're making plans now. We'll be very specific when we kick off those trials, which we do hope to be able to announce all of that this year. Got it. Thanks for taking my questions. Thank you. Your next question comes from the line of Kaveri Pohlman from BTIG. Your line is now open. Yeah, good afternoon. Thank you for taking my questions, and thanks for the update. My first question is related to XmAb306, the cytokine program again, and its applicability in combination with NK cell therapies. There was a recent publication in Blood Journal that showed that exogenous IL-15 administration led to faster NK cell therapy rejection in AML patients compared to patients who received low dose IL-2 with the cell therapy. Just to get your thoughts there. Is it more like a different biology or just a dosing play? Well, I think the complexities that happen when you give a cell graft to a patient, it makes it hard to understand even how the growth factors like IL-15 or IL-2 are working. I think you continually see these kinds of challenges with cell therapies, whether they're auto transplants or allo transplants. The power of an exogenous cytokine therapy when you're not basing your efficacy on a cell that you're infusing, but rather on another drug, is that you can count on the intrinsic biology of the natural NK cells that are in there, and it's a whole different game. I don't know that that paper really reads very much on the approaches that we're taking, which is combining XmAb306 with other drugs, rather than the challenges and unknowns of experimental cell therapies. Got it. Can you talk about your rationale for combining vudalimab with PARP inhibitors? Is there a biology there, or it's just data-driven? It's empiric based on the what's being treated. Patients with prostate cancer that have homologous recombination deficient, the PARP inhibitor is sort of the standard of care. We want to demonstrate that we can add on to that and see if we can synergize with that therapy. It's mainly empirically driven, as all the combinations. Got it. I don't know, John. I mean, there is a concept out there that, you know, if you're repair deficient, you give a PARP inhibitor, that you might generate more neoantigens. That's true. Right? Have more of a T-cell response to build on. Got it. Thank you. Your next question comes from the line of Gregory Renza from RBC Capital Markets. Your line is now open. Hi, this is Ying Lu for Greg. Thank you for taking our questions, and congrats on the progress. Maybe just first question on the vudalimab. I was wondering, as we expect to see some initial data from the trial this year, how would you characterize, you know, the benchmark for each molecular subtype to be clinical, clinically competitive? And what will the go, no-go decision making process look like when you have some data from the trial? Yeah. Before I hand this to Allen to talk about benchmarks, I will say that the data we're gonna have this year is gonna be a pretty early slice. It's gonna be only partially enrolled, of course, and pretty early on in follow-up for most of those folks or all of those folks, I should say. We're gonna get a very clear read, I think, from a small number of patients on some of the combination therapy safety. As for the benchmarks, that'll have to wait for the full trial data, which is not gonna be this year. I'll just preface it with that. We're not gonna have really a good efficacy read this year, but maybe you can go to the benchmarks, Allen. I think if you look at the expectations in castration-resistant prostate cancer for checkpoint inhibitors in general, the benchmark is fairly low. If you look at the KEYNOTE-199 study, the response rate in chemo-refractory patients, which will probably be most of the patients that we see, is probably about 5% or less, depending on what their expression of PD-1 was. If you look at the CheckMate, I forget the number of the CheckMate study, I wanna say 650 or something, which looked at nivolumab and ipilimumab in combination, depending on the population you looked at, the response rate was probably approaching 10%, right? The expectation of checkpoint inhibitors in prostate cancer is fairly low. We think there's clearly synergy when you compare those two studies. The expectation was low. Now, when you looked at our study, granted it's still small number of patients, we're seeing a higher response rate, but the numbers are too small. We think we will add to chemotherapy as well as PARP inhibitors, as well as, you know, other therapies, or excuse me, monotherapy, in certain populations. I think anything above that should be pretty exciting. Depends on the population. Like the marker negative group with chemotherapy, we would expect a higher response rate, but chemotherapy is not that effective. Yeah. Great. Thank you. Just one more, if I may, on plamotamab. I think Roche Genentech is investigating their CD20, CD3 in combo with Polivy. What are your thoughts on that combination approach and, you know, potential impact on the positioning opportunity for plamotamab? Yeah, I mean, Polivy is, of course, being combined with it also in combo with other things. It's not just those two things. Really, as a targeted chemotherapeutic agent, I think it shares some of the same challenges in treatment that traditional chemo has. That's why we're going to a chemo-free approach in our combination studies. I think we're trying to get to where the field wants to go. I don't know that that changes the landscape for us dramatically in our thinking. It's really another chemo. Yeah. I have to agree, Bassil, that, you know, polatuzumab, you know, is an ADC like chemotherapy, and, you know, the convenience for them is that they own that and can combine them. I'm actually more excited about some of our potential combination opportunities. You know, I think tafasitamab, lenalidomide, and plamotamab scientifically makes more sense, and there's a much better scientific rationale for synergy, right? Great. Thank you very much. Your next question comes from the line of Mara Goldstein from Mizuho. Your line is now open. Great. Thanks very much for taking the question. If I can just ask another vudalimab question, and that really is coming off of some of the data that came out at ASCO GU, particularly around the PROPEL study and looking at combinations with PARP inhibitors. Can you maybe just help us understand sort of positioning of vudalimab from a combination perspective, at this point, looking at where the standard of care may be going? That's my first question. Then I did have a second question on plamotamab, which we can come back to. Sure. Allen, you wanna take that? Yeah. I just wanna remind everybody that it's still early in our phase II. I think clearly the trend in prostate cancer is to sort of molecularly define prostate cancer, and we have several buckets of aggressive molecularly defined, you know, the homologous recombination-deficient, the MSI-unstable group, as well as those that are biomarker negative. You know, and I think, you know, PARP inhibitors are gonna be used. I think chemotherapy will still have a role as well, docetaxel and other agents. And so the question is, checkpoint inhibitors have limited activity. Can we add on to those therapies? I think that's the first question that we hope to address, hopefully later this year, that what we can safely combine, you know, a PD-1/ CTLA-4 or targeting agent with other therapies. This has traditionally been very difficult. It's been tried in melanoma, and I think the AE profiles were very discouraging. We're excited if we can put these together. I think if we are successful, then that will sort of change the different sort of subtypes of prostate cancer and how you treat them, in earlier stages of disease still within the castration-resistant population. Okay. Then if I could just ask, on plamotamab, in looking at a combination trial with lenalidomide and tafasitamab, I'm just curious as to what your thoughts are around enrollment, just given the, I think, some of the challenges that tafasitamab has had in terms of picking up traction in the market, and if you can speak to that. I'd say we are very aware that enrollment in relapsed/refractory DLBCL is very challenging 'cause of the intense competition for many agents. You know, the tafasitamab having a bit of a slow pickup in their commercialization, I don't think that's our primary worry. I think it's just the competitive landscape among clinical trials sort of fighting for that same patient. I think that the unique scientific approach, the chemo-free approach, and the mechanistic rationale is actually quite exciting for the physician community that we're talking to. That said, I mean, part of the reason why we think the Janssen partnership last fall or last winter for us was such an important move for plamotamab is that they have the kind of resources that I think it's gonna take to really put the pedal to the metal in a really challenging development competition environment. Yeah. I would just add, Bassil, that our investigators are very excited about the scientific strategy of the combination. Currently, we're still enrolling our phase I study in the expansion cohorts in diffuse large B-cell lymphoma, and that cohort is enrolling rather well. That's only in two regions, the United States and France, and we plan to go global with this study, so I'm confident that we can execute. All right. Thank you. I appreciate it. Your next question comes from the line of Charles Zhu from Guggenheim. Your line is now open. Hey everyone, congrats on the progress and thanks for taking the questions. If I may ask my first question, though, just one more on vudalimab. I guess, you know, regarding your upcoming data or I guess in context of your trial, what sorts of prostate cancer subpopulations do you think are potentially most interesting? And also how should we think about that in context of the broader landscape that continues to shift with things like ADT intensifications or new therapies like radioligands, you name it. How applicable will the data you generate in the coming days might be to a potential patient population perhaps a few years down the road? Thanks. Yeah, I think the big picture answer on that is we're gonna find out how well we work with things like chemo and PARP inhibitors that are certainly gonna have an important role in the future landscape. We're gonna do that in a way that's correlated to the molecular subtype that's determined from the standard genotyping that's happening now in mCRPC post-chemo. We think we'll be well-positioned to make decisions, but this trial is about making decisions and understanding which way we can go scientifically. As that landscape changes, we're fully anticipating adjusting to it. I think the benchmarks you're talking about are the COSMIC study by Exelixis. Depending on whether you believe the sort of site review or the central review, the response rate was less than 20%. For the radioisotope from Novartis, you're talking about the response rate if you look back in the most recent study was approaching 30%, I believe. Those are high bars. If you talk about what subsets we're interested in our studies, I don't think we've publicly disclosed what the molecular phenotyping is, but we are doing two different studies, and we are looking at aggressive phenotypes. The aggressive phenotype, either molecularly defined or clinically defined, and we believe that from our phase I data, the early exciting data, is that we had two patients with very aggressive disease that had good responses. We think that that could be a population for us as well. Again, I think our data is still early. We wanna cast a wider net, and that's why we're doing this phase II, and then we can focus in based on the data we see later on. Got it. That makes sense. Thanks for that, detail and color. If I may ask one more, shifting gears a little bit onto XmAb564, the IL-2. I guess, what's your thinking around, near-term clinical development of this particular asset? How should we think about the potential patient populations that may benefit most, from your, Treg targeted approach? Thanks. Yeah. I think the early clinical development is, of course, first establish the pharmacodynamic profile, tolerability profile of the agent. That's single ascending dose, and also the multiple ascending dose will help with that. The SAD data that we're gonna have this year should really give us a quick early read on are we being selective? Are we amplifying Tregs in that selective way to a magnitude that's at least benchmarked against competition, but that's also promising? Critically is durability of that effect 'cause this is autoimmune disease and frequency of dosing can be a hugely important thing and of course good tolerability. With that SAD data going into the MAD, we're looking for two things. We're looking for one, a clear way to look at if you're causing disease-modifying activity. Because this whole hypothesis that enhancing Treg number and function is going to treat disease is still just a hypothesis. Some exciting early glimmers of data from some programs and of course the old competing programs that we've seen, but also the old LOTUS IL-2 data supports that. We wanna have with our molecule in indications where we can clearly see or not see disease activity because of well benchmarked endpoints, we wanna look at that in our MAD study. As for selecting indications, we think that it's gonna be a big exploration, but we wanna go after ones that have both clear development paths, albeit competitive ones, potentially large indications, as well as we're identifying some small indications that we can maybe go with a niche approach. That's a very strategic type question without a lot of science in it. Did you have a more scientific aspect to what you were getting at? I can let Al or John weigh in. Yeah. I would just- Oh, go ahead. No, go ahead. Oh, yeah. No, I was just elaborating and just, you know, just scientifically or medically, I guess, what are perhaps some of the indications that, you know, Treg expansion might work better or worse for inflammatory diseases? Thanks. Yeah. I mean, there's a number of autoimmune diseases. You know, there's the literature's rife with publications showing imbalance of Treg versus effector T cells in various autoimmune diseases, including diseases like lupus, but also a number of more, you know, niche indications as Basil mentioned. But ultimately, I mean, it's Tregs are a pretty important, you know, way of achieving homeostatic, you know, immune balance and, you know, it could be incredibly widely employed if it's actually, you know, effective. Yeah. From an operational standpoint, I would just sort of reiterate, you know, we know that it's a competitive space, and I think that's why we're doing our SAD and our MAD in parallel. Some of the thinking that went into the disease selection for our MAD was not only about a good model system where we can figure out the multiple ascending dose and our schedule, but also one that we could execute quickly on and sort of have an advantage and proof of concept as well. Got it. Great. I guess just one more on this one. How are you thinking about this asset as it fits into your portfolio? You know, are you thinking about in-house development, out licensing or maybe some sort of a partnership? Thanks. Right now, this is an asset that we think has extremely high scientific promise. Like all the other assets we put into the clinic, we hope that we can do the full development path and market it ourselves one day. Deviations from that hoped-for path are always driven by data, and it could end up anywhere. Our goal is not to partner. Our goal is to make drugs. Got it. Thanks for taking all the questions. Your next question comes from the line of Arlinda Lee from Canaccord. Your line is now open. Hi, guys. Thanks for taking my questions and congrats on the progress. I was thinking about your Amgen data from earlier this month, and I guess I had a couple of follow-ups. Can you remind me what happened with I think Amgen also had rights to your CD38 that returned? Is that moving forward? Maybe secondarily, can you talk about how many other targets they can be going after and then how that progress is moving along? Thirdly, can you talk about other two-to-one formatted things that you might have in the works? Thank you. Sure. I'll take that first set on the Amgen collaboration part quickly. They don't have any more targets they can choose out of the collaboration. The timeframe to choose targets ended a couple years ago. The CD38 program that was returned to us is now in an investigator-sponsored trial that we're collaborating with in hematologic malignancies, and you know, that one's moving along. They have no other target rights, and there aren't going to be any more programs from that collaboration. They have, at this point, just the STEAP1 AMG 509 program. Now for the other 2+1s, I mean, I'll let John start talking about that. Yeah, I mean, I think we've publicly even had posters on multiple of our other 2+1s that we've created. claudin-6 x CD3, that's a 2+1. Of course, we have our XmAb819 program, the ENPP3 x CD3. I think just maybe a glypican-3 x CD3 that we publicly disclosed. You know, we're of course, Arlinda, we're working to generate a whole pipeline, but there's a few of them that have been disclosed, and you kinda get the sense of where we're going with that. Recall, we also have our Atreca collaboration. We're working closely with them to see what comes out of that in terms of new targets. Yeah. I think for us, we see that initial bit of validation from the AMG 509 program for this 2+1 format, in particular, its ability to really attach strongly to tumor target, tumor antigen and afford CD3 activation in a way that is tolerable, and at least in this instance, in solid tumors, really gives us a lot of confidence to really double down on solid tumor targets for CD3s and using the selectivity we can potentially achieve here as the backbone. We're excited to start XmAb819 in the clinic imminently in renal cell carcinoma. Great. Thank you. Your next question comes from the line of Peter Lawson from Barclays. Your line is now open. Hey. Thanks so much for taking the questions. Just, I guess, another question on vudalimab. The second half readout, appreciate all the detail around, you know, kind of safety and early in the response cycle. As we think about responses, should we be thinking about PSA 50 reductions, or is it? Do you think we can potentially see shrinkage of tumors? And then kind of how difficult are these patients to treat? Is it kind of like bony disease that we should be thinking about? You want me to take that? Yeah. I think it depends on the molecular subtype, Peter. You know, I think for some patients, depending on molecular subtype, you know, they'll have more bony lesions or occult metastases, and you would wanna look at PSA. Some of the more aggressive phenotypes will have lymph node metastases or even visceral liver lung metastases, and I've seen brain metastases. Those you would try to look for traditional tumor shrinkage. I think it depends on the subgroup. Again, the way that the study was designed, there's different molecular subtypes. You can imagine some of the subtypes, like MSI, microsatellite unstable will be very difficult to enroll, so we may not have a lot of data. We do have a bucket for those that don't qualify for any of those groups, and that group will probably be early data, but it'll be a mix of different genetic phenotypes. That group is also in combination with chemotherapy, so we'll see how that looks. Gotcha. Thank you. How many patients do you think we could see? I don't know if you mentioned that before. We're guiding to probably, on the order of, a dozen or two at that point. Perfect. Thank you. Maybe a question for John, just around, you touched upon, guidance being conservative. Any kind of near-term milestones that we should be thinking about, in the 2022 number? Nothing that. Oh, other than possibly the only one I can think of would be possible sales milestone from Alexion. You know, the sales ramps up. We do have a $20 million sales milestone, which we expect possibly 2022, if not 2023. The rest of them are all development. You know, obviously, you know, we're excited if Amgen advances the program, but we don't have any timelines to their next steps. Gotcha. None of those are in the guidance. We shouldn't be thinking about any of that in the guidance. I'm sorry, what was that? Are any of those in your kind of cash year-end guidance? Yeah, the Alexion would be. Like I said, the Amgen. We don't have any more information than what they've disclosed publicly. Gotcha. Thank you. Just finally, on the B7-H3, what tumor types are you hoping to enroll in that study? We're not disclosing that yet, but I will say that it'll probably be a mix. I will say that we're obviously keenly interested strategically in prostate cancer. Our vudalimab program, our collaboration with Janssen, which gives us access to a number of their clinical stage and commercial stage prostate cancer agents. But I think what we also wanna do is we wanna be thoughtful about the different mechanisms we can potentially benefit here, both checkpoint inhibition as well as CD3 bispecifics. We're gonna be guided by sort of the availability and quality of combo agents as much as by the theory on which tumor types. Great. Okay. Thanks so much for all the details. Your next question comes from the line of David Dai from SMBC. Your line is now open. Yeah, hi. Thanks for taking my questions. I have a question for vudalimab. Phase II data is expected in second half of this year. Besides the genetic subsets, can you also share with us any biomarker strategies that you're exploring to further identify predictive biomarkers that will support the benefits of vudalimab combinations in mCRPC? Could you also just comment on the cadence of data release? Would you expect to report the data at a medical meeting, or would it be a press release? Thanks. I'll answer the second one. Our goal is at a medical meeting, but of course, it's still well before abstract submission timeline. We consider that an aspirational goal. We're hopeful, optimistic we can get there, but we'll see. On the other one about predictive biomarkers, I mean, you can get into the science of it. We're gonna be looking at a lot of immuno-oncology-type biomarkers. I am not certain that we are really gunning for predictability here. We're gonna use the existing bucketing of the clinical genotypes and even the clinical definition of high risk. Biomarkers are, I think, something to strive for but not count on in your development program in immuno-oncology. All right. Thank you so much. Your next question comes from the line of Etzer Darout from BMO Capital Markets. Your line is now open. Great. Thanks for taking the question, and congrats on the progress here. The first one is really more a point of clarification for me. The plamotamab combos with Monjuvi and lenalidomide, would that be with the sub-Q or the IV formulation as you sort of open up these sites here? A second unrelated question. Back to sort of guidance, just was wondering whether or not you expect any meaningful step up in R&D spend associated with plamotamab combo with Monjuvi specifically, or just kind of, you know, the regular way as you kind of advance these multiple programs into the clinic. Thank you. Maybe, Allen, you wanna take the. Yeah, I'll take the first one. It will be IV, not the sub-Q form. Got it. On the spending, you wanna take that one, John? Yeah. As far as the spending, the spending we have in the next two to three years anticipates these trials. Basically early look into the potential, but we do not have large multinational 200-patient type trials budgeted at this time. It does include the cost for the initial run-in for these, but, you know, we've not at this time budgeted larger trials. Got it. Awesome. Thank you. Your next question comes from the line of Zhiqiang Shu from Berenberg. Your line's now open. Great. Thank you. Good afternoon. I wanna ask about the new program you're going to put in the clinic, XmAb819. I guess, what gives you the confidence of this program in RCC, any valid targets that you want to highlight here? I guess broadly for this program to succeeding the indication, any thoughts around combination approaches later on? That's the first question. That was two questions. That wasn't your first question. I'll let John take the one on confidence, maybe the mechanistic and the historical confidence- Yeah. -going on the, uh- Yeah. Sure. -confidence. You know, there was historically in fact an Astellas Agensys ENPP3 drug conjugate program. We had also independently identified the target really just from bioinformatics analyses of you know different targets that are overexpressed in various cancers. ENPP3 emerged as one that is like very nicely selectively overexpressed in renal cell carcinoma. To some extent in papillary as well, but we're gonna focus on clear cell. Other than that, you know, we've also done immunohistochemistry analyses. We see you know really nice bright staining in renal cell carcinoma. We've also talked to various academics that are working with the RCC cells, and they say ENPP3 is one of the cleanest markers of that tumor population. That's what's driving most of our confidence in this, is that, you know, that it was sort of safely targeted with a drug conjugate coupled with the overall expression pattern and high expression in kidney cancer. I would just add from a clinical perspective, you know, I think now there's clear proof of concept data that these T-cell engagers will work in solid tumors. There was AMG 757 in small cell lung cancer, as well as AMG 509. There's early data. I think we're clearly gonna work in solid tumors as well. I would remind people that in renal cell cancer, it is responsive to immunotherapy. Checkpoint inhibitors are the standard of care in frontline. In the second part, in terms of combinations, I think we have to wait to see the data. I think for kidney cancer combinations, it's sort of the game with a checkpoint inhibitor and a TKI for frontline, but, you know, we still need early data. You know, T cell engagers do have CRS, but I think they're more manageable in solid tumors, so we'll have to see how good that data is. Whether we combine with something that accentuates the T cell engager or just empirically has activity like a TKI has to be seen till we see the phase I data. Great. That's helpful. I guess maybe the third question for me, given I asked to either Bass or John, in terms of capital allocation, now you have $600 million in the bank. It's very comfortable in today's market. I guess, how would you think about spending the money? Obviously, you have a lot of programs and a lot of 2+1 format T cell engagers in pre-clinical stage, but also you do have mid-stage assets like vudalimab. How would you think about, you know, either to push the mid-stage to the finish line or more kind of pushing more pre-clinical assets into the clinic? Appreciate any color here. We look at the data. If we think the data that we see so far in a clinical program merits us putting down the money to go forward all the way to the finish line ourselves to try to get an approval ourselves, we'll do it. We'll continually feed programs into the phase I, you know, exploratory phase and see whether they merit further advancement. We're gonna judge every program against what exists in our portfolio at that time. It's all gonna be data-driven, and we do wanna be thoughtful about making sure we have something that we really truly believe has a competitive profile before we put all our chips down. For example, vudalimab, the phase II studies we're doing now are actually fairly contained and modest in scale relative to something that would be registrational because we're still looking for how we now fit in the complex prostate cancer combination treatment landscape. We're gonna be data-driven. We're not at the point of committing to registrational studies, but when we do, we'll tell you. I would also say that, you know, we're very careful and thoughtful about managing our cash because money's never easy to come by, even in the so-called easy times. Great. Thanks very much. Your next question comes from the line of Dan Wu from Raymond James. Your line is now open. Hey, guys. This is Dawen, on for Dan. Thanks for taking our question, and congrats on the pipeline progress so far. On XmAb306, can you kind of guide, you know, when we could see kind of a comprehensive data from the phase I trial, maybe a presentation or publication? On the combo trials for XmAb306, you know, you mentioned that you're interested in NK cells and T-cell mediated, but kind of curious if you can provide any additional color, what color is left there on any potential guidance on the combo trials. And then, lastly on 564, kind of what are you looking for in the phase I healthy volunteer trial that could kind of shape the MAD trial initiating? Thanks. Yeah. First on the XmAb306, it's really has to be agreement between Genentech and us when we present. I think a natural point would be when the phase I is done, and we go to a medical conference. Though the phase I, we are hopeful is wrapping up soon, I can't imagine we'd have a publication ready given Genentech's timeframes for that being this year. I'm hopeful for next year, but I can't even guide on that. We'll give you guidance on when. But it would be when the phase I's wrapped up, and that's gonna be a discussion with Genentech. You know, on the combo trials, I really can't offer any more color until we announce them, unfortunately. I do think that the NK cell boosts we saw were remarkable, notable for their magnitude, the durability, the kind of control that suggests we could have by varying dose and varying schedule. That's there. For XmAb564 on the SAD, what can we get out of that healthy volunteers in this IL-2 Treg space to guide the MAD? I think the key there is the durability of our Treg expansion and how that helps us select the dosing frequency in the MAD, right? Longer is better. I know that our competitors seem to be settling in on every other week, and we're gonna be looking hard at how well we do in frequency. I think that's the biggest impact on the MAD. Got it. Thanks, guys. Your next question comes from the line of Mike King from H.C. Wainwright. Your line is now open. Hey, good afternoon, guys. Thanks for taking the questions. Just a financial question at first. Just wanted to see if you guys would be willing to give more color on the spend out to 2025, what the drivers of the burn. I don't know if you'd be willing to talk about the different components of spend, you know, on the particular programs. No, because we budget pretty carefully. I'd rather not carefully. We always budget carefully. We budget pretty specifically in a near timeframe, the next year or two, when we have clarity on what the clinical trial is gonna be, and then we keep placeholders for next stage trials, depending on which program we decide to promote. I think that's as much as we can say in terms of granularity. Okay. Sorry. On vacation with the fam, and I just came back to the room. I wanted to also explore five six four a little bit more. Can you just talk about have you compared the molar activity against a native IL-2? 'Cause, you know, we've talked a lot about your competitors and Nektar has basically been dosing at similar levels to what the tolerable levels of native IL-2 are at. Is there any difference between five six four and native IL-2 or the Nektar three five eight program? Marked difference, in fact. You know, as we learned with our XmAb306 program, the IL-15, this class of cytokines, IL-2 and IL-15, and to a large extent, most of the cytokines, when they signal, they get internalized. There's an inverse relationship between their potency and their exposure. Mm-hmm. We found out that basically the way to turn these cytokines into really good drugs is to actually reduce their potency dramatically. XmAb564 is potency reduced by at least a hundredfold compared to native IL-2. However, it actually lasts at least a hundredfold longer in terms of exposure. Right. You've got it sitting around a lot longer. It makes it a more tolerable drug. It can do its job longer than the native can. Okay. I know we recently launched, and you guys, but you have a tremendous amount of scientific data to process. Remind me if there is. Well, two questions I would have, I guess, is one is the selectivity for the alpha receptor on the T reg versus a T effector cell, number one. Number two, I don't believe there's any modifications that would keep it away from endothelial cells in the periphery, but I guess your response to that would be you're detuned, so you shouldn't have the same kind of cyto- or the, you know, the outside cytokine release syndrome, but you wouldn't have the. Absolutely. Periphery that. Yeah. Yes. In the periphery. Could you just go into that a little bit more detail? We engineer it so it has a slightly higher affinity for CD25. We want it to be CD25 biased in its activity. Most of the potency reduction comes from the IL-2 receptor beta reduction. That again helps with the selectivity. You know, based on what we've seen in our own assays and you know, looking at making other people's molecules, characterizing them, we're you know, pretty much top of the class in terms of Treg selectivity versus effector T cells. Mm-hmm. You know, we think overall we've got a great profile in terms of Treg selectivity as well as, you know, the potency tuning and the long half-lives. Okay. Great, guys. Thanks so much for taking the questions. Hey, thanks. It's great to have you covering us after all these years of knowing each other, Mike. It's a pleasure. There are no further questions at this time. I'll turn the call back to Bassil Dahiyat. Thank you very much, and thank you everyone for joining us today. We look forward to updating you more over the course of the year, and have a wonderful evening. This concludes today's conference call. Thank you for participating. You may now disconnect.