Good day, and thanks for standing by. Welcome to the NextCure Investor and Analyst Oncology Pipeline Update. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one on your telephone. If you require any further assistance, please press star zero. As a reminder, this conference call is being recorded. I would now like to turn the call over to Mr. Timothy Mayer, Chief Operating Officer at NextCure. Please go ahead. Thank you, operator. Good afternoon. My name is Timothy Mayer, Chief Operating Officer. Welcome to NextCure's Virtual R&D Update Conference Call and Webcast. You can also join this conference call on NextCure's website at nextcure.com. We're using slides to accompany our remarks today, which also can be accessed from the investor relations section of our website. A replay of this conference call will also be available on our website following today's presentation. I'd like to introduce NextCure's President and Chief Executive Officer, Michael Richman, our Chief Medical Officer, Dr. Han Myint, and Dr. Roy Herbst, a key opinion leader in lung cancer from Yale University, who will also provide remarks today. Michael, Han, Steve Cobourn, our Chief Financial Officer, Solomon Langermann, our Chief Scientific Officer, Dr. Herbst, and I will be available to answer questions as needed. Before I turn the call over to Michael, I'll remind you of the following safe harbor statement. The matters we are discussing today include projections or other forward-looking statements about the future clinical, preclinical, and operating results, research and development goals, and future financial performance of NextCure. These statements are estimates based on management's current expectations and involve risks and uncertainties that could cause them to differ materially from actual results. We refer you to risk factors discussed in our filings with the SEC, including our annual report filed on Form 10-K for the year ended December 31, 2020, and in NextCure's other filings with the SEC. These filings identify important risk factors that could cause actual results to differ materially from those in our projections or forward-looking statements. We undertake no obligation to provide any updates to these forward-looking statements even if our expectations change. Now I'll turn the call over to NextCure's President and CEO, Michael Richman. Michael? Thanks, Tim, and good afternoon to everyone. Thank you for joining the call today. Following our update to SITC, we thought it was an opportune time to host a call and provide further information on our programs in the company. This slide is a brief summary of NextCure's highlights, which focuses on what we call the three P's, our Pipeline, our Product strategy, and our People. In particular, we will be providing updates on two of our lead programs today, NC318 and NC410. I guess you've been hearing a lot about these candidates over the last few days. Also, we have a third program, NC762, that is currently in phase I and working its way through the early dose escalation cohorts. We look forward to providing an update on the clinical data in mid-2022 for this program. In addition, we have continued to push forward our research and development, and we are pleased to introduce a new program today. We call this NC525. NC525 is based on strong science and aligns with our focus on developing next-generation immunomedicine to treat cancer and other immune-related diseases. It also builds on our understanding of LAIR biology. Preclinical data will be presented at the upcoming ASH meeting next month. From a product development standpoint, we are applying a triangulation strategy that focuses on three aspects, one, patient selection to increase the probability of success, two, biomarkers for detecting immune activity, and finally, three, evaluating combination approaches. Finally, the last P, People, include our team of professionals, including our fully integrated GMP manufacturing group, responsible for producing clinical material to support our three ongoing trials. This next slide shows the breadth of our current pipeline, which has occurred in a bit over five years. In fact, by the end of next year, we expect to file yet another IND for our fourth program, NC525. More on that later. Given the continued productivity of our discovery efforts, we also anticipate filing yet another IND in 2023. Finally, our discovery platform continues to generate novel targets, and we look forward to disclosing additional programs in the future. Let's touch base briefly on today's agenda. In terms of today's agenda, our CMO, Dr. Han Myint, will be discussing the recent updates on NC318 and NC410. I'm also excited and pleased to introduce our collaborator and friend, Dr. Roy Herbst, who will be speaking on the unmet medical need in lung cancer today. Lastly, I will provide a brief introduction on NC525 and some additional closing remarks. I will now turn it over to Han to provide an update on NC318. Han, take it away. Thank you, Michael. This slide shows the previous phase I and phase II design. On the left, I will remind you that the phase I portion of the study with 49 patients has been reported previously at the SITC 2019 conference. The original phase II study, consisting of four cohorts of non-small cell lung cancer, ovarian cancer, head and neck and b reast cancer were depicted on the left-hand side in the bottom half. We treated those 47 patients with 400 mg of NC318 every two weeks in a Simon two-stage design. Now let me draw your attention to the right-hand side. Today, we are going to report composite data of the phase I and phase II, including the disease control rate and biomarker findings. The lesson that we learned from the phase I and phase II give us the confidence to change the protocol to enrich patient population using S15 staining, alter the dose of NC318 to 300 mg every week to increase drug exposure and return to non-small cell lung cancer. Now in this slide, I want to show you the historical clinical outcomes from the phase I and phase II. You may recall that we reported previously in the phase I study, one CR and one PR amongst the non-small cell lung cancer patients. We also remember that we showed you in the phase II part of the study, there were two PRs reported, including one head and neck and other with triple-negative breast cancer. Today, however, I want to concentrate on the 28 patients with stable disease, 18 from the phase I, 10 from the phase II, and their progression-free survival together with the biomarkers such as S15 staining, PK and PD data, and soluble S15 levels. Here, a similar plot depicts the time to and the duration of disease control. We are also showing you in color-coded fashion so that you can see the important diseases clearly. I want to draw your attention to the top colors. You can see that that represents lung patient population and the top two rows that you can see that the CR patient and the PR patient with lung remain on study at 2.8 and 2.3 years respectively. There are total of 28 stable disease patients that I mentioned earlier, and several of those stable disease patients have the duration longer than six months. Now we will show you next three slides, the analysis of all patients. First of all, I want to draw your attention on the disease control results. Disease control is defined as CR and PR and stable disease together. All patients that we have treated in the phase I and II, we have 37% disease control rate. We also tabulated for the other diseases as well. Notably, however, in the lung cancer population, the disease control rate is highest at 45%. That also give us the confidence to return to this indication. More importantly, progression-free survival is around five months in all cancer types. This Kaplan-Meier curve depicts the progression-free survival, and you can see clearly that CR and PR group has 18.5 months, the SD group has 4.5 months, and progressive disease group has 1.7 months respectively. It is critical to point out that this is the totality of the patients, and it is a mixture of those patients with S15- positive, S15- negative, as well as those with S15 unknown status. I'm gonna show you in a few more slides about the analysis of S15 staining. Here, we treated a total of 96 patients. Among them, we have 39 biopsies available for us to do immunohistochemistry to stain for the clear, validated S15 staining. This is, remember, a retrospective analysis. As I also remind you that biopsies were not available for the S15 staining for the CR and PR patients. However, there were 15 biopsies were positive for S15. 24 were S15- negative. More importantly, I want to draw your attention to the bottom left and right of the slide. Among those patients with S15- positive, 40% of them achieved disease control, whereas only 12% among the S15- negative achieved disease control. Now I want to show you the soluble S15 changes associated with the NC318 dosing. As you can see from the graph, after NC318 is given, a soluble form of S15 in the serum increases within 24 hours. It does increase by several fold from the baseline. Couple of points I want to make. Progressive disease was seen in patients with a higher fold increase of soluble S15 24 hours after the post infusion. We also noted that in the preliminary data suggests that progressive disease may also correlate with a higher baseline S15 level prior to treatment with NC318. We will be collecting more data prospectively in the currently amended protocol, and it may determine that low baseline level of S15 prior to NC318 treatment could be a means for optimal selection for patients in the future. In short, soluble S15 may serve as the NC318 biomarker for patient selection as well as monitoring in the future. Here I will show you the reason for us to increase to 800 mg every week. This is derived from the PK/PD modeling, showing that NC318 at 800 mg every week would result in tenfold increase in the drug exposure, as shown on the left-hand side of the figure, compared to 400 mg every two weeks in the phase I and II study, as shown in the right bottom of the figure. By increasing the dose to 800 mg every week may impact the overall drug exposure as well as clinical outcomes. Here I would like to summarize the learnings from the phase I and phase II studies. As I shown you earlier on, disease control rate, even at 400 mg every two weeks among the lung population was 45%, with the median progression-free survival around 5.2 months. If we look at across all tumors, we have 37% disease control with the median progression-free survival of about five months. We also showed you that S15 selection could enhance patient outcomes. We also learned from the PK/PD modeling that 800 mg every week will result in tenfold increase in the drug exposure. That led us to come with the final conclusion that we have amended our protocol as follows. Number one, we're going to select patients by S15 auto-staining using CLIA-validated assay. Number two, we're going to increase the dose 800 mg every week. Finally, we're very happy to bring back non-small cell lung cancer as an additional cohort into this study, together with head and neck and breast cancer. I also like to remind you that we are collaborating with Yale University on an investigator-initiated trial where they are conducting a three-arm study in non-small cell lung cancer. It gives me a great pleasure to introduce Dr. Roy Herbst, who will speak about the unmet medical needs in treating lung cancer patients and provide a high-level overview of Yale trial. Roy. Thank you, Han. There's still significant remaining unmet need in the treatment of lung cancer. Clearly, novel therapies are needed. We need more personalized immunotherapy for this disease, especially in resistant settings. Siglec-15 was identified as a novel immune suppressor and potential target for normalization in cancer immunotherapy. Here at Yale, this target was characterized extensively through a collaborative effort between Lieping Chen and colleagues at Yale and NextCure, and I've been fortunate to have worked with them. It was identified through screening an extensive gene library for molecules that modulate immune activity in a platform first developed in Dr. Chen's lab and later expanded to NextCure. As you see on this slide, the target is expressed in both tumor cells and macrophages in the tumor microenvironment and has structural similarity to PD-L1 and potentially suppresses T cell activity. NC318 was developed by NextCure as an antibody against Siglec-15 that blocks immune suppression and restores immune function, leading to antitumor responses. You can see that this swimmer plot depicts the time to and the duration of disease control for the lung cancer patients in the phase I and phase II trial. Note two lung cancer patients remain on study at 2.8 and 2.3 years respectively. In addition, some stable disease remains on study for greater than six months. NextCure has developed a CLIA-validated diagnostic assay to select Siglec-15-positive patients. The antibody used in the test was identified and characterized through a close collaboration between NextCure and Dr. David Rimm's lab here at Yale. Based on the data Han Myint just showed you, Siglec-15-positive patients had a higher disease control rate than the Siglec-15-negative patients. Therefore, selecting Siglec-15-positive patients for treatment could enhance the likelihood of providing overall clinical benefit to patients treated with NC318. NC318 has been well tolerated across multiple dose levels. Adverse event profiles are consistent with other approved immunotherapies. NC318 has shown encouraging single agent antitumor activity in PD-1 refractory non-small cell lung cancer, with one CR, one PR, and stable disease in 13 of 32 evaluable patients, with a median progression-free survival of 5.2 months. Durable stable disease greater than 24 weeks was observed in multiple tumor types. Phase II enrollment is underway with a revised protocol using 800 mg every week in S15-positive patients. Yale is currently a collaborator in a phase II investigator-initiated trial of NC318 in combination with pembrolizumab in patients with advanced non-small cell lung cancer. We anticipate results from this trial, which is ongoing, in the first half of next year. Thank you, Roy. Let's move to the second program, NC410. Now, let me introduce you to the players in the LAIR biology, starting from left to right. As you can see, LAIR-1, LAIR-2 in the middle, and NC410, which is our molecule, and I'll explain to you in a minute. LAIR-1 is an immunosuppressive receptor. It is expressed on T cells and myeloid cells, such as dendritic cells. You can see from the cartoon that it binds to the collagen as well as to the C1q. When it binds to the collagen, this is a barrier to the T cell migration and suppress the T cell activation. When it binds to the C1q, it enhance the cancer cell proliferation. The cartoon in the middle showing the LAIR-2. LAIR-2 is a natural decoy. It is produced by human to modulate the LAIR-1-mediated immune suppression, and it also maintain normal immune function and homeostasis in humans. It differs from LAIR-1 in two respects. One, it is soluble. Two, it has a great affinity for collagen and C1q. Now, let me introduce you NC410. It is a fusion protein of dimeric form of LAIR-2. It remodels collagen and normalize the immune system. Here, I will give you a brief introduction of the NC410 design on the left-hand side and the swimmer plot on the right-hand side. Let's start from the left. As you can see, it's a 3+3 design. There are eight cohorts in the study. As you can see, we are in the middle of the enrollment of this study. The disease consists of advanced metastatic solid tumors. Our primary endpoint is shown as safety and tolerability. We're also looking at efficacy and other extensive biomarkers. On the right, you can see the swimmer plot that depicts the cancer type as well as the duration of disease control in different cohorts of NC410 with the doses highlighted. What I'm very encouraged from this very early part of the study is the duration of stable disease amongst these patients, and also shown at the bottom of the slide with the duration in weeks and the different cohorts on the swimmer plot that you can see. Now, I want to introduce you to the biomarkers that we have done and show you in order as C1q, collagen-derived fragments, LAIR-1, soluble LAIR-1, and the number of CD4 and CD8 T cells. Here you can see that there is a transient reduction in the C1q level on the left-hand figure. At two hours, it started to come back up, and then it stays up after 24 hours. If I draw your attention to the right-hand side, that the baseline level of each cycle, it seems to be level out nicely. What is the importance of that? Number one, when the C1q's bound to NC410, that shows that it is target binding as an early biomarker that we can look at. More importantly, on the right-hand side, as I shown you, the returning to normal levels implies that there's no safety concern regarding the complement activity in the circulation. Now, this cartoon depicts the understanding of ECM remodeling. There are two important parts to understand in ECM remodeling. Number one is ECM formation. In other words, fibrosis formation, collagen deposition. Whereas ECM degradation is breaking down of those collagens that you can see. When you form, the degradation is less. When the degradation is higher, the formation is less. How do we measure that? It is quite easy to measure it on the serum because these serum biomarkers have been published by a few groups. Here we show you the example. PRO-C3 and PRO-C6 are the markers that we were looking at collagen deposition. When there is an increase in the PRO-C3 and PRO-C6, it is associated with tumor progression. On the right-hand side, when the ECM degradation occurs, there is an increase in the level of C4G. This C4G is a product generated by cleavage of collagen with Granzyme B, an enzyme produced by activated T cells that is associated with immune activation. Here we give you an example from three patients who have been on stable disease. You can see from the image that there is a trend in the increased level of C4G, a marker of immune activation. On the two graphs in the middle, you can see that there is a trend in the reduction of PRO-C3 and PRO-C6 which are the markers of ECM formation and tumor progression. We also show you an example from the NCI poster, the remodeling of the collagen in the non-tumor model. There you can see the control and the NC410 showing the denatured collagen staining on the bottom two images. Here we show you the LAIR-2 level in the peripheral blood on the left-hand side. As you can see, the LAIR-2 level increases in a dose-dependent fashion. One thing that I want to remind you that current assay is being optimized to discern the endogenous LAIR-2 and NC410 level. The right-hand picture depicts the baseline LAIR-2 level, and you can also see that there is an increase in the baseline LAIR-2 level with the dose-dependent fashion. Here we show you the soluble LAIR-1 in the peripheral blood over time. Unlike LAIR-2, soluble LAIR-1 does not change over time. We will continue to monitor at higher dose to assess the mechanistic role in reduction of immune suppression. Here I show you the FlowJo plot from a patient who had stable disease for some time. You can see very clearly that both CD4 and CD8 cells increases almost double from Cycle 1, Day 1 to Cycle 3, Day 1. Left top FlowJo plot depicts the CD8 and the bottom one depicts the CD4 that you can see very clearly. The right-hand image or graphic is very important to understand that despite the total number of CD4 and CD8 has increased, there is no concomitant increase in expression of LAIR-1 on those CD4 and CD8 cells. As you know, LAIR-1 expression on those cells are immunosuppressive, therefore it is important to know that there is no increase in LAIR-1 expression on CD4 and CD8 cells, despite the total increase in CD4 and CD8 cells on the left-hand side that I showed you. To conclude, NC410 in subjects with advanced and metastatic solid tumors is safe and well-tolerated with no DLTs up to Cohort five. It is being studied in the higher cohort at the moment. I also showed you that NC410 by binding to C1q and collagen, it modulates and restores immune function by increasing T cells that you saw earlier and also ECM remodeling. I'm going to turn over to Michael to discuss LAIR biology and introduce our new program, NC525. Michael? Thanks, Han. As Han has described what we call the ECM, which is the extracellular matrix, not the equity capital markets that many of you are familiar with. The ECM contains dense collagen, and it's these dense collagen regions that serve as barriers to immune cell infiltration. Basically, one can envision it representing a lock and preventing T cells from reaching the tumor. Based on existing biology, NC410 has cleverly been engineered to bind the collagen matrix, remodel the collagenous tissue, and actually change the architecture of the ECM. This is aligned with the collagen-derived products Han just mentioned. In other words, NC410 acts as a key that unlocks the collagen barrier through remodeling and normalizing the immune system. Over the last few years, we have been studying LAIR-1 and LAIR-2 biology to create novel immunomedicines to treat different diseases. Through our understanding of the LAIR pathway, we have applied our tools and immune expertise to now go beyond NC410, which is a LAIR-2 fusion that binds collagen, and now into developing a monoclonal antibody against LAIR-1 itself. Our new molecule, NC525, is such a monoclonal antibody and specifically binds to LAIR-1 to functionally kill AML blast cells and leukemic stem cells. In other words, we have leveraged our understanding of LAIR biology to develop, one, two distinct candidates, two, separate targeting mechanisms, and three, different cancer indications as it relates to focusing on solid tumors versus liquid tumors, and in particular, AML. Let me tell you a little bit about our new program, which will be our fourth program in about 5.5 years, NC525, which is a LAIR-1 monoclonal antibody. Currently, AML therapies do not differentiate between leukemia stem cells and normal hematopoietic stem cells. Quite interestingly, we took advantage of the LAIR-1 being overexpressed on leukemia cells, including leukemic stem cells, and being minimally expressed on normal blood cells. Most importantly, the NC525 monoclonal antibody kills AML blast cells and leukemic stem cells, while most importantly preserving normal blood cells, including hematopoietic stem cells. We will be presenting preclinical data at the upcoming ASH meeting in December and expect to file an IND in the fourth quarter of 2022. I'd like to now have several closing remarks. Finally, I'd like to first thank Dr. Roy Herbst for participating in today's call. Also thank Tim and Han for their presentations too. I'd like to just briefly touch on GMP manufacturing. As previously mentioned, we have a fully integrated GMP manufacturing infrastructure that supports our clinical trials. In the era of COVID, this is a strategically important asset to mitigate manufacturing risks affecting the industry as contract manufacturing organizations prioritize COVID vaccine production. To keep up with our own demand, we previously announced that we added additional capacity and currently manufacture at the 2,000 L scale. We have utilized our GMP facility to produce all of the material for our clinical trials. In fact, NC318 is in the bioreactor today and is being produced as we speak. As mentioned earlier, our product development strategy has evolved, and we use a triangulation strategy across all of our programs that focus on three key areas. One, patient selection to increase the probability of success. This is in the form of CLIA-validated immunohistochemistry assays. Two, biomarkers for detecting immune activity. Han has nicely described soluble Siglec-15 in the NC318 program and walked through a number of biomarkers for NC410. Three, combinations based on rational design. Such a strategy is being applied to all candidates in our pipeline moving forward. I'm now returning to our pipeline slide to highlight the anticipated near-term milestones for our programs, which include, one, providing an update on the NC318 phase II monotherapy solid tumor trial in the fourth quarter of next year, and Yale providing initial data on the combo trial in the first half of 2022. Two, reporting additional NC410 phase I data in the second quarter of 2022. Three, reporting initial NC762 phase I data in the middle of next year. Four, finally, filing an IND for NC525 in the fourth quarter of 2022. In summary, we continue to make progress on all of our clinical programs and look forward to reporting data in 2022. In conclusion, I'd like to thank everyone for joining the call this afternoon. With that, we'll now open the call for questions. Thank you. Thank you. As a reminder, if you have a question at this time, please press star one on your telephone keypad and wait for your name to be announced. If your question has been answered or you wish to remove yourself from the queue, press the pound key. We kindly request that you limit your questions to one and one follow-up. Your first question comes from the line of Alec Stranahan with Bank of America. Please go ahead. Thanks for taking our questions and for hosting the call. I guess just to start on your approach to AML, obviously this is your first liquid tumor study, so are there any unique considerations you're applying through the design or of the antibody or from a formulation perspective? Is it correct to assume that it'd be reserved for patients who failed maybe induction chemo and bone marrow transplant, or are you thinking of pushing it for earlier use? And then I've got a follow-up. Yeah, great question, and thanks Alec, for joining the call. I think I'll pass that question to the chemo expert at the table, Dr. Han Myint. Han? Thanks, Alec. Great question. Of course, you know, this is the first time we're going to AML here, but just you know that in my whole life, this is what I did for a living in academia as well as when I was at Celgene, developed many drugs in AML space. Of course, the difference that what we're seeing here is the expression level of LAIR-1 on the leukemic stem cells compared to the hematopoietic stem cell. What we're looking at is going to be a lot safer than the current regimen that's available today, whereas you know, whenever we give treatment, chemotherapy, bone marrow transplant, as you mentioned. You wiped out all the normal cells at the same time, and you got to rescue them in transplant with normal HSCs, whereas in the normal chemotherapy, you have to wait for them to recover from the natural HSC recovery kinetics. In the AML here with our product, we're expecting that the safety will be less. We've done quite a number of preclinical work with the preclinical data with the normal healthy donor cells as well as with the AML cells. You know, only time will tell when you start in the human studies. To answer your first question regarding how do we go after, I think initially we need to find the first in human dose that we're still working on in the lab, but then we start, you know, as usual, dose escalation to find out the safety dose. What we were looking at is to go after the myeloid leukemia population, the older age group where they can't go for bone marrow transplant. Depending on the results of what we see in the safety, the goal is to move into the first line of therapy in December 3, a normal chemotherapy, so-called intensive chemotherapy regimen. Transplant, we don't know yet at this moment in time, but I think your thinking is absolutely spot on. I think we will get more data as we start treating patients. Okay, that's perfect. Thanks. Thanks, Han. Maybe one for Dr. Herbst, if he's still on the line. I guess how scalable in your view is the S15 selection test? Just thinking about transferability of the technique to other treatment centers. Looking ahead to the first half 2022 update from the SPORE study, should we expect that any of the patients from the trial will be S15 selected? I know the study does have a safety run-in. Thanks. Right. Still here. Couple of questions. While this is an immunohistochemistry, and, as you've seen, a great deal of work has gone into developing this assay, still a work in progress, but I think it's coming along quite nicely. Immunohistochemistry can certainly be done at the point of care, and that would be one option. The other option is that this could be done at central facilities and sent out. I do think that the early biomarker data that was shown, you know, does suggest that we will move towards using this biomarker in the future. Of course, with the current phase II trial, including the one we're doing at Yale, we'll further validate this marker, you know, with, hopefully, you know, more responders and stable disease patients versus those who progress. Right now, the trial that we're running, which is the one I can speak for, is not selecting because it's our feeling that we still need to gain more information regarding the biomarker, regarding the cutoffs and so forth. Yes, the ultimate goal would be that we could use this in the future, to select patients for this drug. Thank you. Thank you. Your next question comes from the line of Jeff Hung with Morgan Stanley. Please go ahead. Hi, Jeff. Yeah, go ahead. I think we can- Pardon me, Mr. Hung. Your line is open. Can you hear me? Yes, we can hear you now, Jeff. Thanks. The first question is for Dr. Herbst. I'm wondering in these patient populations, what kind of PFS do you think would be clinically meaningful? Often in oncology, a lot of attention is given to CRs and PRs. How meaningful do you find stable disease in these patients and duration of disease control? I have a follow-up for the company. Well, you know, one of the things, of course, is sure you wanna see, you know, a PR, and there have been some, you know, to see that there is clear evidence of activity. That said, you know, if someone who's progressing pre-trial, you know, on immune therapy, and then they go on the agent and they stabilize, I think that's quite useful as well. You know, typically in the refractory setting, you know, one wants to see a drug have a median PFS in a five to six month range, with that type of durability, of course, tolerated reasonably well. I think Han showed some of that with some of those swimmer plots where the patients have been on for a long time. Just like to see a few more of them. Great. Then for the company, you're now dosing patients at the higher, 800 mg once weekly dose. Can you talk about your expectations on safety at this higher dose, and what gives you confidence that there won't be significant increases in Grade 3+ adverse events? Great. Thanks, Jeff. Han, do you wanna deal with that dose question and what we saw in the phase I adding in the mix? Thank you, Jeff, for the question. We have dosed four patients with 800 mg every two weeks in a phase I, and we have no Grade 3 toxicity at all in those four patients. We also dosed four patients with 1,600 mg, and I'm sure you already remember that we showed one DLT with Grade 3 pneumonitis and Grade 3 muscle weakness in that particular patient in the past. Because of the PK data that we know with our drug, when we look at everything, we thought that giving weekly will not have an issue. However, to be, you know, safe, and that's always we have to do, after we treat three patients, we have to pause for the DLT period. That's what we do. Now, we also sent the amended protocol to FDA for approval, and we were allowed to proceed with our study. For that reason, I think we're quite confident that we will not be seeing a lot Grade 3 toxicity. You know, as you know, time will tell. You know, when we treat more than we have to be cautious in looking at all the safety profile all the way along. So far, and I could say that so far so good, we haven't seen anything alarming. Do I answer the question? Yes. Thank you. Thank you. Your next question comes from the line of Ted Tenthoff with Piper Sandler. Please go ahead. Guys, thanks for the update. A lot going on here. I guess the first question is, just with so many things going on, how do you kind of prioritize things, obviously data driven? Is there the opportunity to even have NextCure, wholly owned combinations? Final part of this would be, how does partnering ultimately fit into, your calculus as you advance these programs? Thanks so much. Yeah, thanks, Ted, and nice to hear from you. A great question with respect to prioritization and our partnering strategy. As you point out, we have full rights to all of our ongoing programs. These programs continue to advance and will require additional resources, and in particular, input with respect to global expansion from a clinical and regulatory perspective, we're certainly going to need to entertain some strategic partnerships along the way. How we actually position each program or portfolio program with respect to partnering activities is yet to be seen. As you can imagine, we have a very proactive business development team here at NextCure. We're constantly in discussions with both pharmaceutical and biotechnology companies around the world as it relates to a specific program or group of programs, and also as it relates to oncology or perhaps some of the efforts going on outside the cancer space. Your point is well taken. As we move forward as an organization and knowing our discovery platform that acts as an engine to feed the pipeline, we're certainly going to need partnerships along the way to support these programs in the future. Great. Thanks. Thanks, Mike. Thank you, Ted. Thank you. Your next question comes from the line of Gil Blum with Needham & Company. Please go ahead. Good evening, everyone, and thanks for taking our questions as well. The first one about the soluble S15. Is there a potential for some sort of shedding going on here? I'm just trying to understand if the soluble S15 and the tumor expressing S15 are related or correlated. Thank you. Yeah. Han, would you like to take that question? I know you've been living in the shadow. So, I'm sure you'll provide a perspective on that. Yeah. Thank you very much for the question. I'll start first, and I'll turn over to Sol to chime in a bit more. Yes, you're absolutely right in saying that we have done some work in the lab and it's still ongoing, I must say. It looks like it's shed from the surface, as you can imagine. This is not new to us, right? It has been shown in many other checkpoint inhibitors, as well as with the HER2, which is well known back in probably about nearly a decade ago, right? People have seen this phenomenon. Then all in the CAR-T BCMA world as well, that you've seen that BCMA has been shed, rather, from the surface. We're still doing a lot of preclinical and in vitro and in vivo modeling to understand this and how the function's functioning is. I think, I hope I answered your question, but I'll let Sol see whether we want to add anything more. Yeah. Thank you, Han. I think that's a great question. I think there's a lot of evidence for many checkpoint inhibitors that they produce soluble forms of the protein, including PD-L1 and PD-1. The whole family, including LAG-3, TIM-3, I mean, basically all the plays that you're familiar with. With regard to the shedome, where those are areas of active investigation, whether it's actually shed or I think another possibility which really relates to what we're seeing in the clinical trials, is whether our antibody actually mediates the release of that soluble form, which would lend further support to it being a very good biomarker. Those studies are ongoing as we speak, and I think will be very informative in supporting using the soluble factor as potentially a selection marker for those patients. All right. That's a very comprehensive answer. Maybe another one just on NC410. Is it likely or is there a possibility that NC410 will be insufficient as a single agent to achieve the kind of immune activation you guys are looking for? I mean it does modify the collagen microenvironment, but would you also consider combining it with a checkpoint or an agonist, either targeting T cells or NK cells? Thank you. Yeah, thanks. Great question, Gil. Han, you've been thinking a lot about combinations these days. Thank you. Thank you very much, your question, Gil. As you know, you know, we already shown you that even at the very early in our phase I study, we're seeing durable stable disease with a single agent. We show you all the trends in the, you know, ECM remodeling, the T cell infiltration, et cetera. As we go up to the dose that we expect to get a good therapeutic level, we are hoping to see responses in addition to those stable diseases. Nevertheless, because as you just pointed out, and we have done number of preclinical modeling in-house, NCI and the Netherlands groups, so we've done, you know, three different things, and others have shown that combination with checkpoint inhibitors or other, you know, like, fusion molecules may be very useful and perhaps optimal effect of the drug may be seen when we do that. We are planning all these things. As we go along, we will be presenting those as we go along in the next year. You may also have seen the NCI poster last year as well as this year, and they presented their preclinical data using NC318 model and showing the activity when they combine with NC410 and with interferon alfa and showing amazing results. Especially in the NC318 model, not only the tumor is eradicated when the tumor is rechallenged with the same tumor to those animals and the tumor is rejected and showing the memory T cell might be rejecting the tumor. Very compelling data from the NCI. We're definitely considering all these combo studies that I highlighted earlier. All right. Thank you for taking our questions and continue with the good work. Thanks, Gil. Thank you, Gil. Thank you. Your next question comes from the line of Reni Benjamin with JMP Securities. Please go ahead. Hey, good afternoon, guys. Thanks for taking the questions. Maybe just to start off for Dr. Herbst. I'm kinda curious, you know, what got you excited to get this IST underway. I'm sure you get your choice of a ton of experimental, you know, drugs that are out there that are in development to evaluate in combination with checkpoints, you know, why NC318? And just related to the data that we've seen so far, I continue to be amazed by, you know, the long duration of response of those two non-small cell lung cancer patients. Have you seen super responders like this? And do you have an idea as to what could be driving this kind of a response? A couple of things. You know, why did I get excited about this? Well, you know, remember, you know, we're you know an academic institution, a hospital, and we wanna take science to the lab, the best science to the lab, and we're very fortunate we have Lieping Chen here, probably one of the top leaders, if not the one in the field. We have some grants, NCI grants in lung cancer. In the first five years of that grant, while we were studying the standard PD-1, PD-L1 inhibitors, it was quite obvious that the standard doesn't work for 80% of patients. Even those that do respond to those agents in lung cancer still become refractory. We're very excited, you know, about the screen that Lieping did and then collaboration with NextCure to close out Siglec-15. That actually happened under, you know, our collaboration. It was very nice because that gave us some time early on to work with NextCure, and David Rimm got involved, helping to develop the biomarker. We've been engaged and following this for quite some time. Certainly, it didn't hurt that the phase I data were promising, with the responders, with the stable disease. You know, it takes work. You know, think about how many years it took to develop, you know, pembrolizumab. We knew that we needed to do more. We needed a trial where we had reliable biopsies. We knew that we had some work to do with the dosing. We knew we had some. We wanted to look at combinations, you know, with PD-1 inhibitor pembrolizumab. We actually did what it's really only possible to do at an academic center because we actually brought together an investigator-initiated trial. We were able to partner with Merck, who are providing the drug for that. No easy task, I'll tell you. We're working with NextCure, and we're holding the IND for this trial. It's a very important trial because this trial is continuing to increase the cohort in lung cancer. We're looking at the new dose level. You heard the rationale for that. Here at Yale, I know we can very meticulously get the biopsies. You know, even in the best of circumstances, sometimes you just don't get a good piece of tissue, but we're getting the biopsies. We're looking at the combinations. Then just to make it even a little bit more exciting, we added a frontline combo of pembrolizumab plus the NC318 because, you know, certainly, you know, will this enhance activity in the frontline setting? We're all very excited. I'm part of a team, Dr. Gettinger, Dr. Rimm, Goldberg and others. We've been accruing to this trial and, you know, even during, you know, what admittedly has been a very tough year for medicine and for clinical trials, but we've been doing that. That's why we're interested. We believe in the science. We're following the science. You know, if you don't follow the science here, you're not gonna be successful. There's amazing science behind this. Otherwise, I wouldn't be involved. Now we're seeing the You know, what we need to do early on, but it needs, you know, it needs that careful refinement. That's why we're working with it, and we're happy to be partnering. Now, you asked me a second question. Can you remind me what that was, please? Yeah. About the super responders. You know, you're an academic institution. You've worked with a lot of different compounds. Have you seen this before, even with just the checkpoints and maybe just your thoughts as to what could be driving it? Well, like the super responder, like the patient who's had the CR? Yeah, the CR and the PR and the length of duration, which I think is pretty profound unless, you know, you've seen this multiple times before. Yeah. I was trained by the late Judah Folkman. Some of you might remember him, and he used to always tell me, you know, "Your first patient will always be your best, you know, best." You know, early on in the trials, you see that first patient, you know, responded and has gone for a long period of time. Why you have that, you know, we don't know. Wish we had some tissue on that patient to look and see. But again, it speaks to the fact that, you know, immune response is multifactorial. It's not just blocking one target. It's whatever else is going on in the immune microenvironment. Might have something to do with the genetics of that patient-specific tumor. Yes, we see this from time to time. We actually have, you know, just to the PD-1 inhibitors here at Yale, you know, a library of 25 samples from exceptional responders, five, 10 years. Then we have just as many people who didn't. They didn't go more than a few months and didn't or even less. That's a mystery. That's the science we have to unravel. I would say the fact that we see that's the hope, that's the proof of concept that we're moving in the right direction. Now we have to unravel exactly what that is. That's why I do believe the serum plasma biomarker and the tumor biomarkers are gonna be so critical. You know, now, of course, we can follow ctDNA as well, and we're gonna start doing that as well. Terrific. Okay. Just a follow-up for the company. It seems like you're doubling down on the LAIR biology, and I'm just kinda curious. Does, you know, now going after LAIR-1, does it wind up becoming redundant? Have you maybe looked at NC410 in the leukemic setting to kinda get a sense as to how that targeting that biology might work? Or do you feel that, you know what, yeah, they're part and parcel of the same coin, but they're different enough that you really can't take NC410 into hematological malignancies. You need a separate molecule, you know, like NC525 to interrogate the hematological malignancies. Yeah, that's a great question. Dr. Herbst mentioned, you know, we're driven by the science. When we started studying LAIR biology, we developed a number of reagents that ultimately could be developed as product candidates with respect to our understanding on how best to interact in this pathway. As we talked about earlier, NC410 and now NC525 work distinctly through two separate mechanisms of action, where NC410 is a dimeric version of LAIR-2, a fusion protein that focuses mainly on binding the ligand, as we talked about earlier, remodeling collagen. That has a much different biological effect versus NC525, which is specifically recognizing LAIR-1 expressed on T cells and various myeloid cells in the context of AML. Again, being driven by the science, we're happy to see that we could see two distinct molecules focusing on two different specific applications. For example, years ago when they were developing CTLA-4, you could see Ipi being developed in the oncology setting, yet Orencia, which is a CTLA-4 fusion protein, being developed in autoimmunity. Again, it speaks to the richness of the science and how we leverage our understanding of pathways, targets, ligands, and how to intervene through various structures. Han, would you like to add anything? No, thank you. You did a great job of explaining. I think I just want to summarize very short, a summary. NC410 binds to collagen and C1q, remodel the ECM, and activate the immune cells to treat solid tumors. NC525 binds to LAIR-1 directly. LAIR-1 expressing leukemic cells and leukemic stem cells do the direct killing of those cells. That's the difference between the two, and that's what we are trying to achieve with NC410 in the solid tumors, you know, and NC525 in the liquid tumor. Did we answer the question? Yep. Thanks very much. Appreciate it. Thank you. Thank you. Your next question comes from the line of Asthika Goonewardene with Truist Securities. Please go ahead. Hi, guys. Thanks for taking my question. I'd like to ask Dr. Herbst something please. Dr. Herbst, to run Reni Benjamin's question earlier, you said you're seeing what you need to see early on. I'd like to ask you what exactly is it that you're seeing, and maybe ask, are you seeing any responses? I got a follow-up. Well, you know, You know, I've done a good number of phase I trials in my day. What are you looking for in a phase I trial? You're looking for safety, so we've got that. You're looking for efficacy, you know, and there are responses now in you know, four of them, you know, three different tumor types. We're seeing some stability of disease. It's phase I. You know, would I love to see more responses? Sure. You know, realistically, we know that we need to personalize immunotherapy just like we've been spending years personalizing targeted therapy, what I showed in my slide. I'm just saying that right now we're at the step now where we need a larger cohort. Get the dose, you know, the dose could have a big role here. Get the dose up, you know, get the biopsies pre and post, understand the mechanism. That's why we've taken a deep dive here at Yale into it. That was what my point was. Got it. Okay. It wasn't specifically to the Yale study. It was just, you know, the extensive phase I data that's been produced so far. Right. You know, yeah, just the whole body of work. Got it. Okay. Next, can I just ask, what is your personal hypothesis on the relationship between PD-1, PD-L1 expression and S15 expression? Maybe tell us a little bit more about what kind of analysis you're specifically looking to do in your Yale study to help answer this. You know, we know that, you know, the whole adaptive immune response is predicated on the fact that interferon is upregulated after PD-1, PD-L1 interaction, and that of course through the JAK-STAT, you know, upregulates more PD-L1 and causes the adaptive upregulation of the microenvironment. We actually know that Siglec-15, as opposed to being stimulated by interferon, is actually downregulated by interferon. Initially, you know, we were even selecting high PD-L1, assuming low Siglec-15 and vice versa. That's complicated though, because we know that even though PD-L1 is a reasonably good marker, you know, there is heterogeneity and other problems with measuring it. In our Yale study, you know, what's different, you know, by doing it at a single site, you know, we have, you know, a large team that does these biopsies. I'm hoping we'll get more usable biopsies. The biopsies can be sent to multiple places. Some of the sample can go to a central lab, some can go to the NextCure scientist, some stays here with Lieping in our lab, David Rimm. We're hopefully getting adequate tissue to answer the whole panel of scientific questions we wanna answer. You know, then, you know, I'm looking forward to, you know, having our own experience with this. I think the combination with pembrolizumab, you know, just because, you know, a resistant patient, you know, what do you do with someone who's resistant to immunotherapy? Do you stop the PD-1, PD-L1 inhibitor or keep it going with the next drug? Admittedly, you know, the science on this still needs to be developed. We have to see what's happening, you know, with Sig 15 and as we move through this. You know, the sense is that maybe the combination could be effective, so that's why we're trying it, you know, in our trial here at Yale. We're also looking at it in a frontline setting as well. Could be that there are multiple pathways involved. You know, one drug is not necessary. It's necessary, but not sufficient. That's why we're doing the combo. Got it. You're looking to do serial biopsies as well, pre and post and further down off the treatment as well to help answer these questions? Yes, we have serial biopsies, exactly. Which as you probably know, are extremely hard to do, and I certainly wouldn't try to do that in a trial that's open. If a person's doing a five,six site trial, I wouldn't expect that many of the sites would be able to do that. But we can do that here in New Haven. You know, admittedly a little harder than usual because, you know, some of the restrictions over the last year, but we're getting back to normal. Got it. If the company articulated that they wanna present or have this data in the first half, Dr. Herbst, would you like to present this at an AACR and ASCO, or is your focus to get this published in a journal first? I think it's a little too soon for me to speculate when the study will be completed. Of course, I always like to publish in journals, and I always like to present. Don't worry, as soon as I have something or actually it's my group. You know, I'm just the leader of an amazing team with Dr. Gettinger and Goldberg and others. As soon as there's something worthwhile, we'll get it out. Don't worry. The sooner the better. Right now the study's ongoing. We were able to start, you know, during this difficult year and we're accruing, but nothing to report yet. As soon as we can, we'll try to get it to the best venue. Awesome. We look forward to it. Thanks a lot for taking my questions. Thank you. Thank you. Your next question comes from the line of Bert Hazlett with BTIG. Please go ahead. Thank you. Thank you for all the comments and for taking the question. One or two just points of clarification. With regard to Siglec-15 expression, soluble expression, did you comment that soluble expression was correlated with tumor expression or and/or macrophage expression, or do we not know that yet? Yeah, thanks, Bert. Han, you wanna address that? Yes. I think there is no direct correlation between the tumor membrane staining or the immune staining with the you know in the tumor microenvironment staining versus the soluble factor. Because as Sol alluded to earlier on, we haven't completely sorted it out where those S15s coming, soluble S15 coming from. As mentioned earlier to the earlier question, we're doing both in vitro and in vivo modeling to understand that. Sol, you want to add anything? No, I think you covered the answer very well. Thank you. I have a question for Dr. Herbst. Nice to hear your voice, Dr. Herbst. I'm curious about the dosing, if I'm reading this correctly, is NC318 monotherapy in Arm 1A, is it the revised dosing levels? It looks like the Arm 1B and Arm 2 are at the prior dosing levels. First of all, is that correct? Then secondly, how are you thinking about that? Or is that something that's under consideration for a potential modification of the study? Yes. We, when we began the study, we didn't have the information about the revised dosing. That's being done now in the, as a single agent. We do plan to modify to do the combination in the same way. That's under consideration right now. Absolutely. Okay. Thank you. Just one other quick one. With regard to NC410, were the Grade 3 AEs of anemia lymphopenia seen at higher doses? Have you disclosed that? If not, if you would, that would be great. We have not disclosed that and which dose. The report that we give you is between cohort one to five, but we have not disclosed which particular cohort. We have not seen that, you know, other patients. Were they generally, reasonably well managed, those patients? Well, that's very easy to answer. I think that the lymphopenia patient came in with Grade 2 lymphopenia already, and that went down to Grade 3 lymphopenia transiently and then come back up. Because of the pre-treatment the patient had from existing disorders for the tumors, the patient was heavily pre-treated with chemotherapy. The other one that you were mentioning regarding anemia transfusion sorted out quite easily. It was not an issue. Okay, terrific. Thank you. I look forward to more data. Thank you very much. Thanks. You're welcome. Thank you. Your next question comes from the line of Tony Butler with ROTH Capital. Please go ahead. Han, first, thank you. Han, just a little LAIR biology, if I may ask. First, is there any evidence that the LAIR receptor on collagen is downregulated in the presence of either LAIR-1 or LAIR-2? And second, would you or is there any evidence or would you speculate that that receptor is in fact shed as well as Siglec-15 at any point in time during therapy? And then just a tangential comment. What do you think if Granzyme B is produced from activated T cells? It was my understanding that at least Tregs in the presence of Granzyme B and perforin could actually suppress any activated CD8+ T cells. And I'm just curious because I'm trying to close that loop of that understanding. Thank you very much. Great question. I think let's go back one step at a time. I think you got three questions lumped together. Let's start with the first one. As alluded to earlier on, LAIR-1 expressing immune cells bound to collagen and C1q. If I borrow the term from Michael, who used to say Mother Nature cleverly produced LAIR-2, which is a soluble form, as a percent homology to LAIR-1, and those LAIR-2 that as a soluble form has a better or higher affinity to bind to collagen and C1q. They go and bind so that they give away the LAIR-1 expressing T cells to become activated. In the tumor, however, is not good enough, right? The normal endogenous LAIR-2 is not good enough. They were overcome by the immune suppressor states. The LAIR-2 may not be overcoming the T cell to be activated. What we do, we take the LAIR-2 and make them a dimeric form as a fusion pro-protein with the Fc. What we get is more affinity to collagen and C1q. When it binds, of course, the T cells are activated. As I show you with the FlowJo plot for one of the example, the CD4 and CD8 goes up. In addition, we also see there's no concomitant increase in the LAIR-1 expression in CD4 and CD8 cells, even though the number increased almost double. That tells us that whether it's a downregulation or, you know, not overexpressing those LAIR-1 is quite good for us. That means those T cells can be activated and do the job. To link to that, those T cells then when they are activated, they produce Granzyme B, as you know. Then of course, Granzyme B can come from NK cells as well, right? When they do that's what happened. It breaks down the barrier. When it does, that's where you get C4G, which is the collagen-derived product coming out from the Granzyme B induced collagen breakdown of Collagen IV, and that's what we get. To sum up the loop that you ask, I think that's what happened. LAIR-2 is secreted by the activated T cells. Now, how much LAIR-1 is shed that you were asking? We don't know that. If you look at so far in the study, the LAIR-2 levels, soluble LAIR-2, LAIR-1 level seems to be stable, not going up or down. We will know when we get, you know, more, higher cohort and can keep collecting those data. To answer all your three questions lumped together, I hope. Han, thanks very much. Thanks, Tony. You're welcome, Tony. Thank you. We have no further question at this time. I will now turn the call back to the company for closing remarks. Thank you very much, everyone. We greatly appreciate you taking the time to participate this evening, and thanks for sharing your questions. Have a nice evening. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.