NovaBridge Biosciences (NBP) Earnings Call Transcript & Summary

Good morning or good evening, everyone. Welcome to the 2021 I-Mab Biopharma R&D Day. My name is Jielun Zhu, Chief Financial Officer of I-Mab. I will be your host today. First, I would like to welcome everyone on behalf of I-Mab. Thank you very much for joining our discussion this morning or this evening. Since 2016, I-Mab has continued to develop into an innovation-driven global biotech company focused on the discovery and development of novel and highly differentiated biologics in immuno-oncology and autoimmune diseases. And now we are well on our way to becoming a biopharma with the near-term commercialization prospect of our first clinical assets. Now let me introduce the senior management team with me today. We have Dr. Jingwu Zang, Founder and Chairman; Dr. Joan Shen, Chief Executive Officer; and Dr. Taylor Guo, Chief Scientific Officer. They will share with you our overall R&D strategy and the latest progress of I-Mab's key pipeline assets, including some new clinical data we have yet to present before today. For today's event, we have also invited 3 leading industry experts to present to you cutting-edge sector insights as they relate to our clinical programs. Now without further ado, we first welcome opening remarks from our Founder and Chairman, Dr. Jingwu Zang. Dr. Zang, over to you.

Thank you, Jielun. Hi. Good morning -- actually, good evening. I'd like to thank you for joining us today for this R&D Day. At I-Mab, we have made remarkable progress since IPO last year, January 2020. I hope through this -- the next presentation by the management team, we'll be able to share our excitement around pipeline and the science behind innovative assets. And then without further ado, I'd like to start by giving you a short introduction of the company. Yes. There are 3 highlights about I-Mab. The first highlight is about innovation. Innovation is really our differentiation. By innovation, we mean we only focus on biologics, innovative biologics that have first-in-class or best-in-class potential. In I-Mab, in our discovery, we take time to build points of innovation or differentiation into our molecules, into the drug properties. And one of the best examples is our CD47 antibody, lemzoparlimab, where we selected a unique CD47 antibody that is highly differentiated from other clinical-stage CD47 antibodies. So our CD47 antibody, lemzoparlimab, on one hand, retains superb antitumor activity. At the same time, it has a minimum bond into red blood cells to avoid commonly seen anemias -- severe anemia commonly seen in the clinic with most of the clinical-stage CD47 antibodies. Last year, we successfully closed a global partnership with AbbVie. The total deal size is around $1.9 billion for CD47, for lemzoparlimab with upfront of $180 million and $20 million as the first milestone payment. And that was the largest cross-border transaction for the past many years in China. Now the second highlight I'd like to mention is that even though we put so much focus on our discovery, on our early-stage assets, we're able to build a mature and advanced pipeline through 2 mechanisms. One is to rely on our internal R&D capability to build early stage, mostly now in Phase I, Phase II clinical trials both in U.S. and China and an in-licensing strategy where we focus on clinical-stage assets in U.S., Europe and South Korea to bring those innovative clinical-stage assets and leverage our strength -- R&D strength in China to move those assets quickly to the late stage and then to launch the products in China. Now by the end of this year, we will have 16 clinical programs, and among them, 2/3 of those assets will be in late stage, either Phase II or Phase III clinical trials. And the pipeline is progressing rapidly. And also, I'd like to mention that our most advanced asset, CD38 monoclonal antibody, felzartamab, for multiple myeloma, we are scheduled to submit our NDA by the fourth quarter this year. And we're very excited about this milestone because it signifies the company is moving from a clinical-stage company towards a commercial-stage company. Now the third highlight about I-Mab is our ongoing transition from a clinical-stage company to an integrated global biopharma. For that goal, we are in the process of building a manufacturing capability in Hangzhou, China. We will have our pilot plants in operation by 2022 and our commercial-scale production by end of 2023. At the same time, we have been building rapidly our commercialization capability to prepare for the first product launch for our CD38 monoclonal antibody and additional assets thereafter. Now we started in 2016 as a discovery company. Now today, we're a clinical-stage company. And we spent 3.5 years from a start-up to get listed in NASDAQ, and going forward, we have plans to be listed in either Hong Kong or STAR board in China. And we are very excited about all the progress we have been making that will bring the company to the next stage. Now on Slide 4, I'd like to share with you our scientific rationale behind our pipeline and behind our innovative assets. Now in our discovery, we focus on 2 classes of antibodies. One is monoclonal antibody. The other is a bispecific antibody. Now for monoclonal antibodies, we focus on highly differentiated monoclonal antibodies. We leverage our expertise in immunology, years of expertise from the academic base and also from pharma experience to identify emerging immuno-oncology targets around critical immune cells such as T cells, B cells, macrophage, NK cells because they are important part of the immune system. For example, we focus on T cells. We focus on B7-H3, interleukin 7 and a few other emerging targets. For macrophage, we focus on CD47, GM-CSF because they are important pathways involved in the antitumor activity. For B cells and plasma cells, we focus on CD38 because it is an effective pathway to target B cell lineage tumors. And as a part of the strategy, we also look at targets or pathways like CD73 to modulate tumor marker environment in order to increase patient response to PD-1 or PD-L1 therapies. And as a result, now we have built a very exciting globally competitive, highly differentiated monoclonal antibodies, which I'm going to spend some time to talk about. Now for bispecific antibodies, through our antibody engineering platform, we generate bispecific antibody [ molecules ] to specifically address unmet clinical need. When I say unmet -- clinical unmet need, I mean, in today's oncology, there's a high percentage of patients -- cancer patients who do not respond to PD-1, PD-L1. And this is a very important unmet medical need for us to address. Now at I-Mab, we focus on this particular unmet medical needs through bispecific antibody. And our rationale is to engineer novel bispecific [ molecules ] in order to convert cold tumor commonly seen in patients who do not respond to PD-1 or PD-L1 therapy to hot tumor in order to increase clinical response to current immunotherapy. And we rely on our biology and proprietary sequences we generated in the past several years to build this panel of bispecific antibodies with one arm as a tumor engager to target tumor tissue and with the other arm to activate immune cells through defined immuno-oncology targets such as 4-1BB, CD73 and many others. So that has been the science we built over the years to discover and generate either monoclonal antibodies or bispecific antibodies. Now in this slide, Slide #5, I'd like to deliver this message. In our discovery, innovation comes in 3 waves. The first wave is represented by highly differentiated monoclonal antibodies such as lemzoparlimab, our CD47 antibody; uliledlimab, our CD73 antibody; and few others. And they are engineered to build a point of innovation or point of differentiation. Now this cluster of highly differentiated monoclonal antibodies are now in Phase II clinical trials both in U.S. and China. We are very excited about this group of monoclonal antibodies because they are globally competitive. Now the second wave is represented by novel bispecific antibodies, as I mentioned earlier. The 2 best examples, leading programs are PD-L1/4-1BB bispecific, Claudin 18.2/4-1BB bispecific antibodies. Both are already in Phase I clinical trial in the U.S., and these 2 bispecific antibodies are followed by a panel of 4 or 5 novel bispecific antibodies designed to have one arm as a tumor engager and the other arm as immune system -- immune cell activator. And we hope this group of bispecific antibody will help us to achieve our goal to convert -- through converting cold tumor to hot tumor in order to increase patient response to current immunotherapy. Now the second wave is followed by the third wave, the newest wave of our innovation. And our discovery strategy for this wave is so-called super antibody, where through antibody engineering, we will engineer or enable antibodies -- or super antibodies to perform unique tasks that otherwise cannot be achieved by monoclonal antibodies or bispecific antibodies. Now with this strategy, we like to work with informative technology platform companies around the world, in U.S., Europe and South Korea and China, and to identify those novel platforms in order to engineer those so-called super antibodies. Now the 2 examples I can give you, recently, we signed agreements -- global partnership agreements with 2 companies. One is EU-based Complix. With that partnership, we'll be able to access their cell-penetrating antibody platform in order to generate a panel of novel antibodies that are able to penetrate into cells to target otherwise intractable targets -- immuno-oncology targets. And we're very excited about this opportunity that we are working with Complix, the scientists at Complix to start to generate cell-penetrating antibodies. Now the other example is with Shanghai Affinity, a biotech company that has a platform technology to generate masked antibody. To make a complicated story simpler, through this collaboration, through this transformative platform, we'll be able to generate a set of novel antibodies that can only be active at the tumor site. And with that unique property, we'll be able to avoid systemic toxicities and to enrich the antibody at the target site inside the tumor in order to increase efficacy and also avoid systemic toxicities often seen in other antibodies. And we also have plans to work with companies that have messenger RNA technology -- technologies in order to generate -- using our proprietary antibody sequences, to generate molecules that can directly -- since it can be synthesized within the patient system in the liver to deliver therapeutic antibody within the system. And we're very excited about those opportunities. And we hope by the end of this year, through multiple global partnerships, we'll be able to build extensive panel of so-called super antibodies, and that will bring us to the next level of innovation. Now those drug candidates mostly are at a candidate selection stage or CMC stage. And we expect those super antibodies will get to U.S. for IND application and start up Phase I around 2021 and 2023. And this is how we build our pipeline through 3 waves of innovation, to build stage by stage our innovative assets. Now next slide. On Slide 6, I'd like to say a few words about our pipeline strategy. Our pipeline strategy is also innovative. We take a dual strategy to operate in parallel. Our main strategy is to rely on our internal R&D capability based in Shanghai, Beijing in China. We generate novel molecules or differentiated molecules, whether they are monoclonal antibodies or bispecific antibodies, and we work with global CDMOs like WuXi Biologics and bring those molecules to U.S. for clinical validation. We have specialized clinical development team based in Maryland to operate in collaboration with clinical CIOs, U.S. hospitals and clinical sites to bring our innovative molecules into Phase I, Phase II clinical trials for validation. And this is a very important step because we consider our molecules are innovative and we consider our molecules are highly differentiated. And we wanted to use the U.S. clinical trial system to validate the differentiation, safety and early efficacy signals. So the second purpose for the development in the U.S. is that after clinical validation, we choose to work with big pharma groups for our partners -- for our global partners to carry on with the clinical development of those innovative molecules into Phase II, Phase III and the launch of products in the global market. And we will always retain the China rights and leverage the clinical data generated in the U.S. back to China and facilitate our clinical development process, getting the molecules into Phase II, Phase III and the launch of products in China. So that has been the main strategy, and the best example really is our lemzoparlimab, our highly differentiated CD47 antibody. After validation in Phase I, we had a deal with AbbVie for global rights for development, manufacturing, commercialization, and we retain the China rights. And we work together with AbbVie, and we think this partnership will help us to facilitate global development as well as development -- clinical development in China. And this is considered as one of the best examples to illustrate how we rely on our internal R&D capability and utilize the strengths or advantages in China, both in China and U.S. to facilitate our clinical development program. Now the other strategy is different. We rely on our capability to work with global biotech companies or big pharma groups in U.S. and Europe to identify clinical-stage -- innovative clinical-stage assets, and our strategy is to in-license. Through in-license, we own the China rights for development, manufacturing and commercialization for those exciting innovative clinical-stage assets. And we leverage our strength in China to quickly bring those assets into registrational trials and before we launch the products in China. Over the past 3 to 4 years, we have in-licensed 5 clinical-stage assets. Now they are all in Phase II, Phase III clinical trials in China. And we are about to bring those assets into the market in China and bring this company from a clinical stage to a commercial stage. Now there, the best example is felzartamab, our CD38 monoclonal antibody for multiple myeloma. We in-licensed these assets from MorphoSys who completed a Phase IIa clinical trial in Germany with 148 patients. We were able to bring this molecule into China into a CMC process and also clinical development. Now today, we are running 2 registrational clinical trials for this molecule, and as I mentioned earlier, by fourth quarter this year, we will submit an NDA for this molecule. So at the pipeline level, this is the strategy that goes hand in hand to balance innovation from our internal R&D capability and development risk to have this balanced pipeline. And also, we'll be able to bring this pipeline closer to the market while we remain focused on innovation. Now based on this pipeline and through years of R&D efforts, now we have a very exciting, globally competitive, innovative pipeline. On Slide #7, I'd like to spend a few minutes to quickly go over this pipeline that we are very excited about. Now the top 2 assets are most advanced. Our CD38 monoclonal antibody, as I mentioned earlier, we are in 2 registrational clinical trials, and we'll be able to file NDA by the fourth quarter this year. We are actually in preparation of product launch, expecting to launch the product by 2022. Now the second asset is our long-acting growth hormone, which has a huge market in China. This particular asset is already in a registrational Phase III clinical trial, and we aim to complete patient enrollment by the end of this year or the beginning of next year in order to bring this molecule very quickly to the market. And this Phase III clinical trial involves about 165 patients. It's a relatively small Phase III clinical trial, and we hope to complete this trial quickly to move our assets into commercialization. Now coming down the list, there are 3 very exciting core assets. They are all at the clinical stage. TJ107 is a long-acting interleukin 7 that is positioned as oncology care product to treat patients who developed lymphopenia after chemotherapy and radiation therapy. And this indication has a broad application in oncology space because a high percentage of patients -- cancer patients who received chemotherapy and radiation therapy will develop lymphopenia, reduction of lymphocytes. Currently, there's no treatment for this indication. And we hope that our asset, long-acting interleukin 7 will be able to address this unmet medical need because through Phase I, Phase II studies by Genexine and by us, we have seen that this molecule performs to increase T cell count, which is a very exciting marker to indicate that the drug works to address lymphopenia. Now at this point, we have already started a Phase II clinical trial in China in patients with GBM, a very difficult cancer indication to treat, and those patients are often developing lymphopenia after chemotherapy and radiation therapy. Now in the second half of this year, we will start a new Phase II clinical trial in patients with solid tumors. This is based on Genexine's data in the U.S. where they combined TJ107 with KEYTRUDA to treat patients with cancer, and they have seen some very promising clinical signal -- efficacy signal in patients with triple-negative breast cancer. And based on that, in the second half of this year, we will start our -- a new Phase II clinical trial in combination with a PD-1 antibody in patients with selected solid tumor. And the next one is CD47. I'm going to spend some more time in a few minutes to come back to tell you about our excitement about these assets in terms of clinical developments and our plan to bring this molecule to registration in China. And this is followed by CD73 monoclonal antibody, which we just completed a Phase I clinical trial in the U.S. in combination with a PD-L1 antibody, atezo, in patients with solid tumor. And in a few minutes, I'm going to tell you about some of the high-level data which we are very excited about. Now coming further down the list, we have 6 clinical-stage assets that are in development, both in U.S. and China. Most of those assets are in Phase II or Phase III -- Phase II or Phase I clinical trials in U.S. and China. Now I'd like to mention a few in that list. Plonmarlimab, TJM2 is a GM-CSF neutralizing antibody, which is in Phase II clinical trial for patients with cytokine release syndrome associated with severe COVID-19. We are in the middle of this Phase II clinical trial. Within the next 2 months or so, we'll be able to get to the point for interim analysis, and we're quite excited about this time point to see how the data would look like and how we're going to move forward with this exciting molecule for multiple indications. And in a few minutes, Joan will come back to give you a more detailed data and our plan going forward. Now the next one is olamkicept, TJ301. This is a selective interleukin-6 inhibitor. This is a very unique -- it works through a unique pathway. Most of the IL-6 antibodies or receptor antibodies marketed or in late-stage clinical development work through a so-called classic pathway. Now olamkicept is the only asset that works through a different pathway called trans-signaling pathway. The clinical advantage of this pathway is that, on one hand, this molecule retains the clinical efficacy. On the other, this molecule will have the differentiation in safety because this molecule can avoid most of the side effects seen with the marketed interleukin-6 or interleukin-6 receptor antibodies. Now we just completed Phase II clinical trial in China in patients with ulcerative colitis. The data are positive. The Phase II met both primary and secondary endpoints, and we're very excited about the outcome of this Phase II clinical trial. In a few minutes, Taylor, our Chief Scientific Officer, will come back to discuss some of the detailed data why we are excited about these assets and how we're going to move forward with these assets. And enoblituzumab is another exciting monoclonal antibody. This is the most advanced B7-H3 antibody in the world. We in-license from MacroGenics. In the second half of this year, we will start a Phase II clinical trial in China in patients with solid tumor. We're putting together our clinical development plan in terms of selection of partner drugs for the combination therapy. And then just a few words about TJ210. Again, it's an innovative monoclonal antibody targeting C5a receptor, a novel immuno-oncology target. We already started Phase I clinical trial in the U.S. to see safety and perhaps some early efficacy signal. The last 2 in the middle are the 2 leading bispecific antibodies, and we just got IND approval and started to initiate Phase I clinical trials in the U.S. and also in China. Now this pipeline is really followed by additional panel of novel, early-stage assets that are still in the preclinical stage. And we hope that within the next year or so, those -- some of those assets will advance into a clinical trial. So in our view, this pipeline is balanced. On one hand, we have most advanced assets, clinical-stage assets that are very close to the market, CD38 monoclonal antibody, long-acting growth hormone. Now in the middle, we have globally competitive monoclonal antibodies or bispecific antibodies that are in Phase II and Phase I in U.S. and China. And we are advancing this group of assets into Phase III or registrational trials within the next 12 months or 18 months. We're very excited about this process. Now on the early slides, as I mentioned earlier, we are focusing on the second wave, bispecific antibodies; and the third wave, super antibodies, to sustain this pipeline with even more innovative antibody [ molecules ] into this pipeline. Now with this introduction, I'd like to now take a deep dive into some of the most exciting assets in our pipeline. The first one I'd like to talk about is our lemzoparlimab, our differentiated CD47 antibody. As you know, most of the clinical-stage CD47 antibodies have safety issues because most of those antibodies bond strongly to red blood cells, and our antibody is differentiated. Our design from the early days, in 2016, when we started this program, we purposely built a system in our screen campaign to select, by design, unique CD47 antibodies that have a superb antitumor activity and at the same time, have minimum bonding to red blood cells, and we succeeded with one CD47 antibody. Now it's called lemzoparlimab. And as you can see on Slide 8, with this antibody, we were able to demonstrate over the years that lemzoparlimab maintains superb antitumor activity in the preclinical setting in all the animal models that we used to evaluate antitumor activity. Now on the other hand, this is even more exciting, is the differentiation. And over the years, with the -- at a preclinical setting, in animal models and in monkeys, we were able to demonstrate our antibody has a minimum bonding to red blood cells, unlike some other clinical-stage CD47 antibodies that are in development. And this is an important differentiation because this would address the unmet medical need where most of CD47 antibodies naturally can bond to red blood cells and induce severe anemia. And over the years, we made a lot of research efforts to understand why lemzoparlimab can maintain superb anti-tumor activity at the same time as minimum bonding to red blood cells. Now to make a long story short, through protein crystal structure, we were able to identify lemzoparlimab has epitope -- a unique epitope on red blood cells that is surrounded by sugar groups, by glycosylation. As you know, red blood cells are highly glycosylation cell type within our body, and lemzoparlimab happens to engage or recognize a unique epitope that is located in an area on the red blood cells that is surrounded glycosylation, heavy glycosylation. And that prompt us to hypothesize that perhaps because of this glycosylation in red blood cells, that prevents lemzoparlimab from engaging fully to its epitope on red blood cells. Now the final proof is the experiments in the middle on Slide 9 where we use enzyme -- a particular enzyme to remove glycosylation on red blood cells, to make de-glycosylated red blood cells. And our antibody -- and then we identified that our antibody can bond strongly to red blood cells. So after we removed the red blood cells, lemzoparlimab is found to bond strongly to de-glycosylated red blood cells, and this is a final proof that the underlying mechanism is related to glycosylation of the epitope on the red blood cells. And this mechanism is very important because it will help us -- will guide us through future clinical development. It will also help us to develop perhaps biomarkers in the future to select patients and also to guide clinical development. Now my next slide, on Slide 10, I'd like to spend a few minutes to tell you where we go from there. First of all, I'd like to mention the Phase I clinical trial we completed last year in the U.S... Now this clinical -- Phase I clinical trial is a dose-escalation study with a single agent. We went from 1 milligram per kilo all the way to 30 milligram per kilo to evaluate safety of this molecule, PK profile and clinical activity of this molecule in patients with solid tumor. Now I'd like to summarize the clinical data of the Phase I clinical trial conducted in the U.S. First of all, we validated the clinical advantage, the safety advantage of this molecule in such clinical setting in patients with cancers. Through the entire clinical study, we have not observed severe anemia. And we -- oftentimes, we observed a small decrease or small dip of red blood cell counts that would not constitute anemia clinically. And we're very excited about this validation of the clinical advantage in safety, and this is related to the minimum bonding of lemzoparlimab to red blood cells. Now the second future -- feature we demonstrated in our Phase I clinical trial is that unlike other clinical-stage CD47 antibodies, we do not require priming dose in order to prepare the patients with smaller dose of CD47 antibody before we can get into -- before we can give patients a high dose. Because our antibody lemzoparlimab behaves just like a regular antibody because it has a minimum bonding to red blood cells, so we use, as such, as a regular antibody that does not require priming dose. Now the third feature is around PK. Because our antibody has a minimum bonding to red blood cells, at the middle dose and high dose, we did not see sink effect. Sink effect meaning if anybody has a strong bonding to red blood cells when you give the drug, most of the drug will be absorbed by red blood cells. Hence, you see a sink effect -- a drop of free drug concentration in the blood. Now because of the differentiation, at the middle dose and high dose, our PK is linear, we did not see sink effect. And we think that this feature is important clinically. It's important -- it's related to efficacy because with this feature, our antibody can maintain sufficient dose level in the patient system in order to achieve sufficient efficacy. And we also determined around 20 milligram per kilo and 30 milligram per kilo, we pretty much reached saturation of the receptor occupancy, 100% receptor occupancy. There were also -- this also is an indication that at the 30 milligram per kilo, this is the dose that we like to move forward with in future clinical development. Last but not least, even in this limited clinical trial, we have observed clinical activity -- single-agent clinical activity of lemzoparlimab with PR and stable disease. And from there, next slide, we want to continue, move forward with this exciting molecules. And our clinical development plan is designed along 3 lines of development. Our ambition is to launch lemzoparlimab as the first CD47 product in China. How are we going to achieve that? We're going to be focusing on 3 parallel lines of development. The first line will focus on hematologic malignancies, MDS, AML and non-Hodgkin's lymphoma. There, we hope to achieve the first registration in China. Now currently, in China, we are in a combo study with AZA in patients with AML, MDS, and we hope to achieve full enrollment by the end of this year, 2021. And we hope to start a registrational clinical trial next year in patients with MDS. And that trial perhaps will help us to achieve our registrational goal in China as the first CD47 product registration. With that, next year, we'll be working together with AbbVie globally. We will participate a global clinical trial led by AbbVie to focus on patient -- focusing patients with AML with different combo therapies. Now on non-Hodgkin's lymphoma, we have an ongoing combo study with rituximab, a CD20 monoclonal antibody, in patients with non-Hodgkin's lymphoma. We are in the process of expanding the patient cohort in order to get more patients into the trial in order to see clinical efficacy. Now I'd also like to mention, in addition to clinical sites in the U.S., now we have clinical sites in China to combine patients from both sides, China and U.S. And our goal is to achieve the full enrollment by fourth quarter this year. The likelihood is that by the end of this year, 2021, we may have data readouts from this clinical trial. And based on the data readouts, by the end of this year or latest, by the beginning of next year, we'll be able to initiate a registrational trial in China in order to move forward with this indication. The second line of clinical developments, we will be focusing on solid tumors. Currently, we have an ongoing combo clinical trial in the U.S. with KEYTRUDA, lemzoparlimab with KEYTRUDA in patients with solid tumors. And we are collecting more data, and hopefully, by the end of this year, fourth quarter of this year, we'll be able to have sufficient data qualifying for data readouts. So by the end of this year, we hope to disclose clinical data in patients with solid tumor in combination with PD-1. In the second half of this year, we will start a Phase II clinical trial in China in combination with a PD-1 therapy in selected solid tumor and most likely, patients with lung cancer, with ovarian cancer and melanoma. And the third line of clinical developments, we will be focusing on combination. And our first attempt is to combine lemzoparlimab with felzartamab, our CD38 monoclonal antibody. In the second half of this year, we will start a new clinical trial to combine lemzoparlimab with our CD38 monoclonal antibody for multiple myeloma. And our attempt is to assess or to evaluate the possibility, based on efficacy signal, to see whether we could have the opportunity to move third-line, second-line treatments to first-line treatment, if approved. Now let me quickly turn to my last few slides. Here, I'd like to talk about another exciting monoclonal antibody, differentiated CD73 monoclonal antibody. As you know, CD73 antibody is another promising immuno-oncology target today. And our antibody, uliledlimab is among the global frontrunners together with BMS, AstraZenca, Corvus, Surface Oncology, Novartis. And recently, as you heard, Arcus published some very exciting data with their small molecule drug for CD73 target. Now I'd like to mention that in addition to the competitiveness of our CD73 antibody as one of the global frontrunners, our antibody is highly differentiated to address a drawback of CD70 -- most of CD73 antibody in development. On Slide 12, you can see in the middle where we designed our CD73 antibody to avoid the so-called the hook effect. The middle curve, if you focus on the red line, as you can see, a competitor CD73 antibody has the so-called the hook effect. At a low dose, it has a low effect. In the middle dose, around 10 to the -- around 10 milligram per mL, you see a high effect. But at a high dose, this molecule behaves abnormally to have a low effect, and this is so-called the hook effect. Now the hook effect is associated with this so-called intergamma bonding. So most of the CD73 antibodies have this mechanism of action. Now our antibody by design has a different mechanism of action. It's a so-called intra-dimer bonding. And to make a long story short, it does not have this hook effect. And this is illustrated in the blue line in the middle figure. So the advantage is that clinically, we'll be able to use our CD73 antibody according to the dose. At a low dose, we expect this molecule to perform with a lower effect. But at a high dose, we expect this molecule to perform with a higher clinical efficacy, unlike other CD3 (sic) [ CD73 ] antibodies that people have to identify an optimal dose between the low dose and high dose. So this differentiation, we have done a very extensive research. The data are actually published at the recent AACR meeting in the U.S., and we're happy to share the data with you. Now where are we with this molecule, uliledlimab? We just completed a Phase I clinical trial in the U.S., and this Phase I clinical trial was designed with a monotherapy run-in for 3 weeks; followed by a combination with atezo, a PD-L1 antibody, in patients with solid tumor in order to evaluate safety, PK profile and clinical activity. And we just completed this study. Now we have a high-level data. The data package has been accepted by ASCO. And our presentation has been accepted -- has been selected for oral presentation at ASCO in June, so we will be able to discuss more detailed data at ASCO in June. Now here, I'd just like to share with you, without breaching the embargo policy by ASCO, some high-level data. First of all, in this Phase I study, we have demonstrated this molecule is safe and well tolerated at a dose range that is -- that was tested. This molecule has an expected PK profile and reached receptor occupancy -- 100% receptor occupancy around 10 milligram per kilo. And that pretty much got us what -- the dose that we're going to carry forward. Now most importantly, we're quite impressed by the clinical activity that we have seen with this molecule. And clearly, this molecule with a 3-week monotherapy run-in and followed by subsequent combination with atezo, we see a clear clinical signal, efficacy signal, which we will talk about at the ASCO meeting in June. Now I'd like to turn the presentation to Taylor, who is our Chief Scientific Officer. He's going to talk to you about our bispecific antibodies and olamkicept -- Phase II data with olamkicept, hopefully, to give you more color on those assets. Taylor?

Thank you for waiting. Can you hear me now? Okay. So as I was saying, bi-specific molecules dominate our second wave of drug discovery. So currently, we have 2 T cell engagers leading the pack of this second wave. Working with ABL Bio, we've been generating 4-1BB-based T cell engagers. Because instead of CD3-based T cell engager, which accounts for 60% of the bio-specifics out there and issues with systemic immunotoxicity, we decided that 4-1BB, because it's the best co-stimulator molecule as reported by Regeneron in terms of stimulating T cells and preventing exhaustion of active T cells. However, the first generation of 4-1BB antibody had issues with liver tox because indiscriminately by activate T cells. In the second generation, characterized by uliledlimab was a weak antibody, and it also had issues with antagonizing the endogenous 4-1BBL. So our 4-1BB antibody binds to the last extracellular domain 4-1BB, and it's inert unless it's connected to at T cell -- a tumor-associated antigen that can bring the molecules together to fully activate 4-1BB. So this tumor antigen dependency ensures that T cells are only activated in the tumor site and minimizes systemic toxicity and liver toxicity. So we decided that Claudin 18.2 was an ideal antigen for this bi-specific T-cell engager because it's a gastric cancer antigen that's exquisitely uniquely expressed in the stomach epithelial cells and nowhere else in the body normally. So we generated a more potent Claudin 18.2 antibody, than zolbetuximab, the first generation, allowing this antibody potentially to bind to a wider range of cancer cells with different levels of Claudin 18.2 expression. And connected is [indiscernible] 4-1BB single chain FV fragment. Next slide, please. So the next slide basically shows that after a series of in vitro and in vivo characterization, we were able to culminate in the preclinical animal work, we found that CD4B had -- compared to the other combinations, you see the red line here, almost completely eradicated tumors in the animal. And this is only after 6 doses, a very low dose of bispecific antibody treatment. Furthermore, rechallenging the animals with the second dose of tumor, the animals remain tumor-free, suggesting that the animals actually develop long-lasting immunological memory that resisted tumor growth. So this compound having gone through a GLP tox study, which confirmed our initial hypothesis that it has a wide therapeutic index and has gone now into the IND and Phase I clinical trials. Next slide, I'm going to switch gears to olamkicept, which Dr. Zang briefly described earlier. This is a unique IL-6 trans-signaling pathway inhibitor. As you know, [ Pen ] IL-6 inhibitors block both classical and now trans-signaling pathway. The classical pathway actually mediates protective immunity against infection. It also has a metabolic homeostatic active properties. By blocking IL-6 totally, you would have -- one would expect to have increased infection such -- and also GI perforation and metabolic disturbances. It turns out the majority of the inflammation that's mediated by IL-6 is through the trans-signaling pathway and on the right-hand side. This is due to an increase in IL-6 and soluble IL-6 receptor in the circulation after inflammation. Normally, there is physiological level of -- soluble GP130, the receptor that can counteract this increase -- this IL-6 receptor complex activity. However, during inflammation chronic, excessive complex formation overwhelm this physiological barrier, if you will. And therefore, olamkicept, the dimeric form of GP130 was discovered or was invented to augment this physiological level of GP130 to block the action of IL-6 and IL-6 receptor. And therefore, we believe by selectively blocking the trans-signaling pathway, olamkicept can be differentiated on safety while maintaining efficacy in autoimmune diseases. And the original developer, Ferring, took this molecule olamkicept through Phase I studies where they characterized the safety as well as PK and PD of this molecule. We subsequently in-licensed the molecule to develop and commercialize olamkicept for Greater China and South Korea. At the same time, a Phase II IIT study was initiated in Germany, where they -- where the investigators looked at safety as well as efficacy signals in the cohort of IBD patients with some encouraging results, and these results are published now in gastroenterology. Building on these findings, we decided to initiate a proof-of-concept Phase II study in moderate and active ulcerative colitis. The primary goal was to investigate the efficacy and safety in patients with active UC in Greater China and South Korea. And this was a randomized, multi-center, double-blind, placebo-controlled trial with 2 dose levels of olamkicept given IV every 2 weeks with each group consisting of 30 patients. And the key criteria are listed there. Basically, these patients have to be active, have active UC, with on therapy, but not well controlled of their disease. And finally, the vast majority of the patients were not on biologics, giving us a very pure cohort of patients. And this is quite unlike the situation found in western markets. The primary endpoint was clinical response, also safety measures of frequency and severity of AEs. Key secondary efficacy endpoints included clinical remission and mucosal healing. So we wanted to see the drug can, all the way, drive down -- completely shut down the disease activity. The next slide gives you a summary on the efficacy endpoints. Both primary and key secondary endpoints are met. In terms of clinical response, we saw a statistically increase in clinical response rate over the placebo in olamkicept 600 mg group from 34% to 58%. Furthermore, we saw a dramatic increase in clinical remission rate to 20%, with the difference of 20% compared to placebo that was highly significant. Finally, we also saw a highly significant increase in mucosal healing, read by a central review and reading group. And collectively, these data are quite comparable with the current drugs that have been approved in this indication. Next slide. I also want to report that the drug also did not disappoint in terms of safety profile. we observed a well-tolerated and favorable safety profile in both 300 and 600 groups. There were no new or unexpected safety signals observed in the context of the disease. And finally, by drawing up this table, we try to compare numerically in terms of the -- some of the IL-6 blocker related side effects. I want to know that these are not head-to-head comparisons. We compare the literature data of approved drugs, this IL-6 receptors, to look at -- although the caveats are we have -- in this -- in our trial, there was a small sample size and shorter treatment duration. Nevertheless, we saw that numerically, the numbers are quite compelling, showing a better safety profile. In terms of infection rate, we saw an equal overall infection with placebo in our study. And more importantly, the serious infection rate was 0 in 600 mg. Whereas the taselisib and sarilumab iL-6 receptor blockers, there was a clear difference. Related to this, it was -- there was no neutropenia in our trial, whereas there was a 3% to 6% in terms of neutropenia in IL-6 treatment groups in the literature. In terms of lipids, we saw nearly no change compared to the placebo or even a decrease in triglyceride levels. Whereas, clearly, you saw an increase in triglyceride total cholesterol as well as LDR levels in the IL-6 receptor antibody groups. Finally, in terms of liver enzyme, again, very negligible mild increase, transient increase in AST, but considerable increase in the other 2 groups. So we think our antibody -- sorry, our asset is well on its way to demonstrate its full potential in terms of safety profile. Next slide, basically, to summarize. The study hit both the primary endpoint and 2 key secondary efficacy endpoints for 600 mg 2 weeks. The remission rate was numerically comparable to the best-performing drugs for UC. This indeed was the first demonstration of IL-6 transitting pathway in the treatment of UC and potentially for IVD and other ALF immune diseases. It demonstrated excellent safety profile compared to the Pen IL-6 inhibitors. There were no drug-related side effects commonly associated with them such as GI perforation and infections and so on. I just want to say that the full data analysis would be released and Digestive Disease Week in the U.S. in May and [ Echo ] Meeting in July. I would conclude the segment by reporting that last week, I-Mab and Ferring signed a Memorandum of Understanding to explore the possible collaboration to advance the development and commercialization of olamkicept in major markets, U.S., Canada, Europe -- and European Union and Japan. I would now turn to Dr. Joan Shen, our CEO, to continue the presentation.

Thank you, Peter. Yes. Thank you for staying with us. In the next few minutes, I will give you an update of our plonmarlimab program and base status. Next. Plonmarlimab is [indiscernible] antibody discovered and developed by I-Mab ourselves. It has its very unique mechanism, and it targets the macrophages to inhibit macrophage-derived disease mediators such as [indiscernible], IL-1, IL-6 and, et cetera. It can effectively -- the antibody itself can effectively block the [indiscernible] pathway. It worked at upper streams of [ cytokine ] release cascade. And as a result, it can prevent effectively some of the inflammations observed in viral infections and other severe infection disease as well as CAR-T therapies associated with the cytokine-releasing syndromes and some other neurotoxicities. So therefore, we believe we have a very broad potential in the autoimmune disease space as well as cytokine releasing syndromes associated with multiple diseases. So I-Mab began clinical development in 2019 in U.S. with the first-in-human studies. We successfully conducted this study with maximum dose level at 10 milligram per kilo with the excellent safety profile and very good PK/PD correlations. With that data, we intended to continue the development, as I mentioned earlier, for the potentials in autoimmune disease space as well as CRS associated with CAR-T treatment. At the same time, and as you are all aware, since last January, COVID-19 pandemic begin starting in China. I-Mab immediate responded to the needs and to join the world against COVID-19. We look over our pipelines, we believe our GM-CSF antibody has its great potential. As the reports coming back from the COVID-19 patients studies, and you can tell, the cytokines is regulated in the COVID-19 patients, especially those very severe patient populations. In the same time, GM-CSF antibody can effectively down-regulate the cytokine release. All together, we believe this antibody can effectively suppress cytokine release associated with COVID-19, especially in the severe patients. It can be worked better than IL-6 and other cytokines comparing with our GM-CSF antibody, which act on the upper part of the cytokine-releasing cascade. So we immediately mobilized our company resources and assembled the team, both in U.S. and China, started these Phase II studies in last March. I believe ours is the first one among all the GM-CSF antibodies to initiate the Phase II trials against these COVID-19 patients in terms of CRS syndromes. So the overall in this slide showed you the basic study design of this study. So the primary goal is to investigate efficacy, safety and also the cytokine levels of this compound in severe patients. The study design is randomized, double-blind, placebo-controlled, multicenter study, seamless Phase II and III. By closely communicating with the agent. We come up with 2 parts of the study. the first part is 3 arms with each of the 8 patients is the 3 milligram per kilo 6 milligram per kilo in comparison with placebo, which is standard care at the time. As I mentioned earlier, our Phase I study had dosed patients up to 10 milligrams per kilo with very good safety profile. To be on a safe part, we introduced 3 milligrams and 6 milligrams. And then after we complete these 24 patients, we have independent DMC look at the data and recommended that this study is safe enough to proceed to the next part, which is larger population. And also because of the good safety profile of both arms, it was recommended that the 3-milligram per kilo patient arm being rolled over to 6 milligram per kilo to benefit patients to do better. So when we move to the Part 2, it becomes 2:1, which is 6 milligram per kilo patient arm to placebo. Again, it's the standard care at the time. So this part of the study is including 80 patients in the treatment arm and under 40 in the standard of care. On the right side, you can tell the key eligibility data is, we have confirmed the COVID-19 infection and also confirmed with the image about bilateral lung infection. And also, it has the oxygen saturation less than 93% as a requirement and also the patient uses oxygen supplement. The patient also needs [indiscernible] the primary endpoint is the proportion of subjects who are alive and free of mechanical ventilations in day 30. And the second endpoint -- secondary endpoint is a proportion of subjects who alive and 3 of mechanical ventilation and day 30 among subjects who are free of mechanical medications at baseline. And also all cost of mortality rates at base 30. So I mentioned that, it's because -- in the next slide, I'll show you, at the same time, our competitors have also launched these studies. These 3 are the major competitors. They had also advanced their Phase II programs to this point. As you can tell, our study is actually is very, very similar in the study design, including the patient population and also the primary endpoint. But there are slight differences. Our patient population is more severe in a way that include the patients for ventilating free and ventilation already started. So in that case, the patients are in a more severe status. And also, yes, the patient in the same time is solely in the United States. So at the time, the standard of care has significantly changed, so including remdesivir and dexamethasone as a baseline treatment. So that concomitant medications is introduced. Our competitors, some of them are actually conducting their studies out of U.S. So there are slight difference in the standard care. But overall, the primary endpoints are similar. And most of them have proven the drug works in this population in a certain degree. And I'm sure if you have this compound, you will hear that Humanigen have their primary endpoint mapped, and they are proceeding for UA. And [indiscernible], one of their cohort were positive and the others -- so this one, they are continuing to proceed. And the [ JF ] case studies in the patients who are older than 70 or 70 years old, actually proven to be efficacious and beneficial. So all of them giving us the confidence that the maximum actions worked in this population. So as to our I-Mab, we have currently have sufficient patient populations to conduct our Phase II interim analysis. This complementary results should be available in June, and that will include the patient both in ventilation-free and ventilations for the survival days at day 30 instead of 28 or 29. So that are some of the site differences. So regardless, the data coming out of that trial will be very, very valuable for us to pursue the next treatment, regiments, either in COVID-19 if the pandemic continued or to pursue other CRS associate such as the CAR-Ts treatment associated with CRS or other potential treatment related, for example, [ GBDT ] So all of those are the potential treatment beyond the current CRS for COVID-19. I think more important, I wanted to bring your attention, this really demonstrated our company's commitment. It's truly a testimony that we really joined the fight against COVID-19, and the testimony of our commitment and our employees like day and night work at the time. So I think I'm really proud of them who are really acting quickly to come up to this point and to deliver data, trying to deliver to the patients who are needed the most. So -- and stay tuned, in June, we will have more detail report on this study status. Well, in the next slide, I will give you a key deliverable milestones for our 2021 among all the clinical programs. So on the left side are the key regulatory finding or data readout. So felzartamab, our CD38, which has 2 registration trials. The third-line registration trial, we currently have completed enrollment. And then the top line results will be available in Q4. And in the same time, we will submit our company's first NDA. So -- and that is the second milestone. And the third is uliledlimab, our CD -- differentiated CD73, which will present the data in ASCO, as mentioned by [indiscernible] earlier. Olamkicept, again, the data presentation will be Q2 again and is expected soon. And then fifth is our CD47, lemzoparlimab. NHL data is expected the company results in the fourth quarter or the first quarter of next year. And lastly, is our lemzoparlimab assorted tumor data, which the top net results should be again also in the fourth quarter or earlier next year. So on entire execution on the right side, our first nonacting growth hormone will be -- already had the first-in-human -- I'm sorry, the first patient dosing achieved in the first quarter. And we are now acting -- actively enrolling more patients, which will expected be to complete the 165 patients enrollment in the first quarter of next year. And secondly is our nonacting IL-7, in the GBM trial, which we also achieved the first patient dosing last month. And we expect to have the patient enrolled next year. And then thirdly, [indiscernible], our combo treatment has already achieved in China for the PD-1 in combination with this our CD73. And the fourth is our Claudin 18.2 4-1BB. And that already, we have obtained IND approval in U.S. And then the first patient dosing can be expected any moment from now. On the fifth deliverables is our CD47 AML/MDS combo treatment in China. We already initial study had investigator meetings. And again, the first patient dosing could happen any moment in second quarter. The combo solid tumor treatment and also we'll be having our last patient dosing on the fourth quarter in United States. The combo NHL, the last patient dosing will be achieved in the fourth quarter as well. So -- and we -- as I mentioned, we have 2 registrational trials in our CD38, felzartamab. The second line of this trial will be able to complete the last patient dosing in our first -- in our fourth quarter as well. So those are all the major deliverable this year, and we are committed to accomplish that in time. So now I will hand it over to -- back to Dr. Zang for concluding our major presentation today. Thank you.

Okay. Just trying to fix some IT issue. All right. So Joan just explained to you the key milestones we're going to achieve this year. And I just want to add the 2021, it's going to be a great year for I-Mab. And we have a whole series of milestones -- key milestones to achieve. Many of them are critical catalysts. As you heard, we are scheduled to achieve 6 critical milestones on the left side for felzartamab, our CD38 monoclonal antibody, the most critical one being the R&D submission by the fourth quarter of this year. We also mentioned that for lemzoparlimab, our CD47 antibody, there are 2 critical milestones we're going to achieve by the end of this year. One is clinical readouts for non-Hodgkin's lymphoma by the end of this year and solid tumor clinical readouts by the end of this year. Both are combo studies. And we're very excited to look forward to this whole series of critical milestones to achieve. Now I want to say that at I-Mab, we say our innovative assets, the advantage of innovative assets must be met by good execution. We have a very good track record for clinical execution. And we hope to achieve the milestones we promised, and we continue to improve our capability to deliver results as we always do. Now I'd like to use last 2 slides to wrap up this presentation by the management team. Now on Slide 28, I'd like to say that I-Mab has evolved within 5 years from an early-stage discovery company to a clinical-stage company today, where we have 16 mostly clinical-stage assets in our pipeline, some of which we already discussed today. We're very excited about this pipeline because it's advancing, it's balanced. Many assets are globally competitive. Now going forward, our plan is to become and transform this company to an integrated global biopharma. But that's, I mean, in addition to global R&D, both in U.S. and China, to achieve clinical milestones and to focus more on discovery projects, we will move into commercialization. And there are 2 areas for us to focus on to become an integrated global biopharma. One area which is on the next slide, on 29, one area is to build our GMP manufacturing facility. Now we are in the process of building such a manufacturing facility in Hangzhou, China. Hangzhou is a city not too far from Shanghai. And as you can see, there's a picture there where we're going to complete our pilot plan by 2022 to make this facility operational by 2022 for pilot plant to supply all the clinical trial material to support our clinical trials, both in U.S. and China. And We have more ambition that is to -- in the process of building a commercial scale manufacturing facility as seen in the picture where we're going to build 6 lines of 4,000-liter reactors. And we plan to make this facility operational by the end of 2023 to accommodate our pre-NDA products, such as CD38, long-acting growth hormone and a few others. This is a very important step towards integrated global biopharma where we have our own manufacturing facility to control manufacturing slots, quality and also the cost. Most importantly, cost of goods to make our products more competitive in the China market. Now the other focus is around our capability to commercialize our projects. On the right side, Slide 29, you can see that we have already the commercialization strategy worked out. Now in the initial phase between 2022 and 2025, with the launch of our first product, felzartamab, CD38 for multiple myeloma, we will be focusing on hem oncology. In addition to CD38, to cover multiple myeloma, we will focus on CD47 to bring CD47 to the market to cover leukemia, AML, MDS. And in the same process, now we are in discussion with a few U.S.-based biotech companies and pharma companies to in-license a lymphoma product to cover lymphoma. And hopefully, we will close this deal to bring the product to China and to quickly bring this product to the market. If we were successful, within a very short time, we will rely on 3 key assets or key products in hematologic oncology with CD38 to cover multiple myeloma, with CD47 to cover leukemia, with an in-licensed product to cover lymphoma. With that, we hope to establish a leading position in hematologic oncology in China and to have a near full coverage of the major hematologic indications such as multiple myeloma, leukemia and lymphoma. More importantly, with the 3 key assets, and combination with either small molecules or other antibodies in our pipeline or with other companies, we may be able to achieve near-cure goal in this space, the hematologic malignancy in this particular space. And we're very excited about this. We are already in the process of building our commercialization capability with a medical regulatory market access teams in order to prepare for the first stage of commercialization between 2022 and 2025 to cover the major hematologic malignancies in China. Now this will be followed by the new products from our pipeline focusing on solid tumors, such as CD73 and a few other assets now in Phase II clinical trials by 2025. And after, we'll be able to bring those assets to the market. So with both manufacturing capability and commercialization capability, we hope that within the next 3 to 4 years, we will transition this company to an integrated global biopharma to deliver innovative medicines to patients and at the same time, create value for our shareholders. Now I'd like to stop here by introducing Jielun, who's our Chief Financial Officer. He's going to say a few words about the financial aspect of the company. And this is equally exciting, and we'll keep the company going in the next few years to achieve our goals. Jielun?

Thank you, Dr. Zang. I have one page to share with you before we turn the floor over to industry experts. Now on this financial summary page, I would like to point out, make 2 points quickly. First of all, last year, in 2020, we were able to achieve overall corporate profitability for the first time since the funding of I-Mab. We recorded or we recognized more than USD 72 million in net income or roughly RMB 471 million. That was driven primarily by the upfront and milestone payments we received from AbbVie in accordance with our global partnership, anchored on lemzoparlimab, which we announced in September 2020. Now this is a very strong testament to the potential value of lemzoparlimab highly -- at this highly competitive and globally differentiated asset. The second point I want to make here is that we are also very well-capitalized to pursue the tremendous opportunities ahead of us. At the end of 2020, we had more than USD 700 million in total cash and cash equivalent reserve or more than RMB 4.8 billion -- close to RMB 4.8 billion. That amount of cash is able -- will be sufficient to fund our operations through 2023, including the data readouts -- the key data readouts on our core clinical assets such as lemzoparlimab and uliledlimab and the commercialization efforts in China of our pre-NDA programs, including felzartamab and the active [indiscernible] alpha. Finally, to support our long-term growth, we are also considering potential options for further equity listings on Greater China stock exchanges, such as the star market in Shanghai and the main Board of the Hong Kong Stock Exchange and the Chapter 18A of the Hong Kong listing rules. We are very optimistic about the future of I-Mab, and we hope you share the same enthusiasm. With that, we conclude the management presentation portion of this virtual R&D Day. The next program will be -- I will be introducing one of our KOLs, Dr. Timothy Yap, MD and PHD. He will be presenting -- make a presentation on CD73 titled, Targeting Tumor Microenvironment by CD73 Pathway, New Hope for Overcoming Immune Resistance. Dr. Yap is an associate professor of Department of Investigational Cancer Therapeutics Phase I program and the Department of Thoracic and Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center. Now let's welcome Dr. Yap.

Good morning, everyone, and thank you all for being here. I'd like to thank the organizers for the very kind invitation to come and speak to you about a topic that's very close to my heart, and that's how we can target CD73 and how it's a new hope to overcome table resistance. These are my disclosures and disclaimers. So as you all know, PD-1 and PD-L1 antibodies have clearly been impacted immunotherapy agents with response rates of approximately 30%. However, not all patients will respond. And even in patients who do respond, drug resistance is nearly inevitable in many patients. And therefore, novel agents that enhance the response or overcome resistance to immunotherapy, certainly a high unmet need. Modulation of the immunosuppressive tumor microenvironment can actually improve the response to immunotherapy agents and, therefore, is a rational approach. As shown here, cD73-derived adenosine that can shape the inhibitor and leads to degeneration of a marked immunosuppressive environment. And high concentrations of adenosine-suppressed antitumor T cell activation survival and effective function through A2AR engagement. Adenosine can also negatively modulate differentiation and function of dendritic cells and further inhibit and K cell proliferation and cytolytic function. And as shown on this figure, CD73, the phosphorylates AMP to adenosine and over-expression in various solid timers has been associated with an adverse prognosis. And therefore, targeting this pathway actually leads to a novel way of actually inhibiting tumor-like environment. There are 2 pathways to generate adenosine. Once released into the extra cellular milieu, ATP and ADP are converted into AMP via CD39 as seen on the top row here and further into adenosine through CD33, which is the monoclonal pathway. As shown in the bottom row, extracellular NAD is hydrolyzed by CD38 generating adenosine diphosphate rivals or ADPR. And ADPR can be further hydrolized by CD2003A to produce AMP, subsequently converted to adenosine by CD73. And therefore, compared with CD39 and adenosine receptors, blocking CD73 really leads to a more complete innovation of adenosine-mediated in the implant phase. Now CD73 antagonism by either genetic knockout or neutralizing antibodies has been shown to enhance the antitumor efficacy by mean checkpoint inhibitors such as CTLA-4, and PD-1 antibodies are shown in these figures here. And this synergistic effect is dependent on the interferon gamma production. There are also data that have shown that monotherapy with anti-CD73, anti-CTLA-4 or anti-PD-1 monoclonal antibodies increase tumor infiltration with antigen-specific CD8-positive T cells compared with control treated mice. And when anti-CD73 monocle antibodies were combined with anti-PD-1 or anti-CTLA-4 monoclonal antibodies, tumor infiltrating antigen-specific CD8-positive T cells further increase compared with single-agent treatments. And also, there's increase accumulation of antigen-specific CD8-positive T cells following combinatorial treatments was indeed associated with increased expression of the Th1 immune genes, TVX21, also known as T-Bet and its target interferon gamma. Now in TGF-beta receptor 1 and P10 double conditional knockout head and neck cell cancer multi-models, CD73 expression was significantly increased on CD4 positive and CD8-positive T cells from spleen, draining lymph nodes and peripheral blood and tumor-bearing mice compared with normal mice as shown here. To further characterize the different subsets of CD4 positive and CD8-positive T cells based on CD73 expression, it was actually found that there was a relatively larger fraction of the CTLA-4 positive population among CD4 positive CD73 high subset versus the CD4, CD73 low subset. Whereas the CD4 positive CD73 negative subset had the smallest fraction of CTLA-4 expressing cells. Now likewise, similar results were obtained in CTLA-4 positive cells enriched in CD8-positive CD73 high subsets. Well, -- while PD-1-expressing cells followed a similar pattern with a CD4+ CD33 hi or CD8 CD73 hi having the highest proportion of PD-1. And so collectively, these results indicate that CD33 is indeed relevant to the exhausted phenotype of T cells in tumor-bearing mice. And based upon the relationship between CD33 and the exhausted phenotype of T cells, it was then tested if the blockade of CD73 actually has an effect on the effects and function and phenotype of CD4+ and CD8+ T cells. Now interestingly, a significant reduction of CD73 population on CD4+ and CD8+ T cells was observed after anti-CD73 antibody treatment. There was indeed a significant increase of interferon-gamma production in CD8+ and CD8+ T cells after CD73 antibody treatment, as expected. Remarkably, the expression of the CTLA-4 and PD-1 in CD73 antibody treatment group exhibited a significantly decreased level on CD4+ and CD8+ T cells as compared with isotype control groups, suggesting that the blockade of CD73 reversed exhausted phenotype of CD4+ and CD8+ T cells and, importantly, alleviated the suppression of T cells. This is an extremely important point. And certainly, as seen in this table here, through different cancers, you'll see that there was indeed a clinical significance and importance of CD73 with cancer prognosis across these different cancers, as listed here. Now there's also been evidence to show that increased CD73 activity is associated with resistance to anti-PD-1 therapy. For example, soluble CD73 expression and activity were retrospectively analyzed from the serum of a total of 546 patients with melanoma before starting treatment, so baseline samples, with anti-PD-1 agents nivolumab or pembrolizumab. The CD73 activity was then correlated with therapy response and survival of patients, and elevated pretreatment levels of CD73 activity was then associated with nonresponse to therapy with nivolumab or pembrolizumab. During treatment, the levels of soluble CD73 activity remain unchanged from baseline and stratified clinical responders from the nonresponders. And high levels of serum CD73 enzymatic activity were associated with reduced overall survivals as well as progression-free survival. Now there are now emerging clinical data from this field. For example, with the triplet of Arcus's AB680, which is a small-molecule inhibitor, in combination with PD-1 and chemotherapy in first-line pancreatic cancer, you'll see here a 41% overall response rate of approximately -- of 7 partial responses out of 17 patients in first-line pancreatic cancer. And also very recently at the ACR 2021 Annual Meeting, prolonged PFS was observed in EGFR mutant nonsmall cell lung cancer when AstraZeneca's CD73 antibody was combined with osimertinib, both supporting the finding from the data that have represented that nonsmall cell lung cancer and pancreatic cancer are among the potential cancer types when we think about targeting CD73 novel agents. And as you can see, this is a busy field and competitive field, but I-Mab excitingly will release the top line data from their Phase I combination dose escalation trial at ASCO 2021 in June this year. Now one might actually ask what the differentiation factor is. And when compared with MEDI9447, I-Mab's uliledlimab actually demonstrated a typical dose-dependent inhibition of soluble CD73 enzymatic activity without the hook effect, as you can see there in both graphs. And these data were recently presented at AACR this year. The second differentiation factor is as follows: that the epitope binding studies have shown that uliledlimab did not compete with the binding of MEDI9447 to CD73, indicating that these 2 antibodies really bind to a different epitope. Structural analysis using cryo-electron microscope further demonstrated that uliledlimab binds to the C terminal of CD73 dimer, whereas other CD73 antibodies, MEDI9447 and the BMS compound, bind to the N-terminal. So truly differentiated compounds. So to end, I'd just like to summarize my talk. CD73 as a novel immune checkpoint that's associated with adenosine metabolism which promotes tumor progression by generating an immune suppressive tumor microenvironment. Owing to its multifaceted capacity for tumor promotion, CD73 is an ideal therapeutic target for cancer treatment, especially in combination with conventional therapy and other amine checkpoint inhibitors. There are emerging clinical activities from agents targeting the CD73 pathway, which support further clinical investigation. Thank you very much.

Okay. Thank you very much, Dr. Yap. Okay. Thank you very much, Dr. Yap. Next up, I would like to welcome Dr. Roy Herbst to present his insights on next-generation immunotherapies. Dr. Herbst is the Ensign Professor of Medicine, Medical Oncology, Professor of Pharmacology and the Chief of Medical Oncology at Yale Cancer Center and the Smilow Cancer Hospital. He is also the Director of Translational Science at Associate Cancer Center. Without much further ado, let's welcome Dr. Herbst.

Thank you very much. It's a pleasure to be here. I just want to check that you can hear me. Just checking, do you hear me okay? Hello?

Yes, we do hear.

You do? The last thing I want is to talk for 20 minutes and no one hears me. So you hear and see my slide?

Yes, we can hear you.

Okay. Great. Well, it's really a pleasure to be here, and I enjoyed hearing Dr. Yap, my good friend.

Yes.

Dr. Yap, my good friend, and talking about CD73. So I'm going to try to pull things together and show you why it's important for treating cancer and some of the challenges we have. Now I'm going to give you a story of lung cancer. I only have 20 minutes. And this is what I focus mostly. I don't know, I do a lot of Phase I work, too. But it is amazing the progress we've made worldwide in lung cancer over the last 20 to 30 years. These are U.S. data, but I suspect they'd be similar around the world. Look at both in men, up top, and women on the bottom, the decline in mortality from lung cancer. Mortality rates have declined by 51% since 1990 for men and 26% since 2002 in women. And you can see in the inset over here that the incidence is going down by 2.6% per year, but their mortality by 4.3% per year in men. And in women, the incidence is going down 1.2% in women and the mortality 3.1%. Now much of this is still early detection targeted therapies, perhaps slightly better chemotherapy. So I don't think that they do much. But the immunotherapy is just hitting the field on these numbers. And lung cancer is almost 2 million people a year worldwide, #1 cause of cancer death worldwide. Well, I'm here at Yale. I'm sitting in my office now, and I've been here about 10 years. When I arrived here, I was very fortunate to join a team with Mario Sznol, Scott Gettinger, Harriet Kluger, who had been using MDX-1106. That's nivolumab. And we saw results like this. This patient is still alive now 11 years later with widely metastatic disease in her lung and her liver. Within months actually, it cleared on nivolumab. Actually, she's remained disease free for 11 years. I can tell you, having worked in this field for 25 years, you never see this with chemotherapy. You don't see this with targeted therapy because with targeted therapy, things relapse. But this patient had an amazing response and survival benefit. So I even asked, "Can we cure lung cancer?" And I would say the answer is yes. Vince DeVita is here at Yale, and we talk often about this. And what is cure to restore health to bring about recovery from disease? And Hippocrates always told us to cure sometimes, treat often and, of course, comfort always. But much like we've seen with Hodgkin's disease back in the '60s and '70s, I think we're seeing this in lung cancer. But what's the problem? It doesn't work for everyone. So the question is why and how can some of these new agents and targets we're hearing about play a role. And indeed, they will. Well, here's some data. This is from Scott Gettinger from that first trial. So the one I showed you is on this curve. These are patients with nivolumab with advanced lung cancer, and you can see overall survival. These are all second or more line patients, refractory disease. And you can see the actuarial 5-year survival is 16%. So 15%, 1 out of 6 patients, are still alive from that trial. The problem is, we didn't know which one of those 6 at the beginning. They can see Scott over there. And it's really -- it's about the tail of this curve. This is what we want. This tail is amazing. But how can we get more people over this? Because there's primary and acquired resistance. And that's what I'm going to show you some examples of today as I tie this into some of the pipeline from the I-Mab. Brain metastases, These are really a difficult area in lung cancer. These small brain metastases, you can see here with the red arrows, if we were to treat them with radiation, they'd probably be suppressed, but there could be other areas that are involved. So it's not just -- you never just find 1 or 2, but also the patient might have some cognitive impairment from this problem and they're never quite the same. But now we've shown actually in an investigator-initiated study, Dr. Kluger, Goldberg and Chiang, she's a neurosurgeon, 2 medical oncologists working in lung and in melanoma, that the brain responds often at a very similar rate as the systemic disease with immunotherapy. So immunotherapy probably will work in the brain. And then, of course, there are data, and, again, this is a very well-known study, KEYNOTE-024. This was the first study that used the PD-L1 biomarker and took immunotherapy with pembrolizumab versus dealer's choice, platinum doublet. There was crossover in this trial, about 60%. But this was PD-L1-high patients being treated. And why do I show this to you? Because these data are about to come out on publication. They were presented at ESMO last year. And what you can see is the 5-year overall survival is 32%, 31.9%. This is amazing actuarial 5-year survival. The control group is at 16.3% because 60% crossed over. But even though this is so good, and it really is good, you can see that almost everyone still progresses at 3 years. Only 22.8% of patients remain progression free. So what does that mean? That means almost 80% have already progressed, and you can see that goes down. So patients benefit a little bit more than -- even after they progress, they can still survive longer, but a lot of these patients are progressing early. We got to figure out why. And many of these tumors will be cold and noninflamed, as we've been talking about, and I'll show you some examples. Oh, and another thing to point out. The partial response, even in this PD-L1-high group, is only 41.6%, meaning even with the best drugs in the best setting with the highest PD-L1, more than half of patients don't respond. Tremendous opportunity for new combinations. We're doing some studies. Just finished our swag meeting last week. So we're asking, should you use the drug pembrolizumab alone? Should you combine it with chemotherapy? What should you do in a second-line treatment? All these use trials are ongoing with biomarkers, which will be informative. And the drugs are approved. Right now, there are 3 agents approved for single-agent use in the frontline setting: pembrolizumab, atezolizumab and cemiplimab. These 2, atezo and cemiplimab, for the high PD-L1; pembro actually for 1% or more, but we all sort of believe it works best in the high group. So we have these drugs out there. So is there room for improvement? Absolutely. So now with that as background, we're making progress. Patients are benefiting. I see it first hand. Many of you probably have, too. But there's the next hurdle, which is going to be huge. And that's, what are the biomarkers? And how can we better treat these tumors? Well, here at Yale with David Rimm and team, we've looked at some of the tumors and asked, what is it about PD-L1? Is it a good marker? I already showed you that PD-L1-high patients, about half of them respond. But half of them don't. Why? Because it's a heterogeneous marker. Here is one piece of lung tumor. And you can see 1 area that's stone-cold negative for PD-L1 with 2 different antibodies staining, and here is 1 area that's positive but to different extents. Where do you measure this PD-L1? In the tumor, the green is cytokeratin. So this is tumor. The blue is nuclei, it's a stroma. You measure it in the nucleus, in the stroma among the immune cells, or both. What do you call positive? 5%? 10%? 20%? What's your staining method? There are so many variables. PD-L1 is a good marker but not a great marker. It's probably necessary but not sufficient. And then, of course, the different antibodies behave differently. And you can see this is the so-called Blueprint project where they looked at 2 antibodies on the Dako system, 22C3 and 28.8, and 2 antibodies on the Ventana system, SP263 and SP142. And so looking at tumor cells. Three of them are about the same. One of them tails off, the SP142. It was designed more to measure the immune cells. In lung cancer, we focus mostly on the tumor cells. But in many other cancers, they look at the Combined Positive Score, looking at the immune cells. This is something that needs to be looked at more. But it's clearly both the microenvironment and the tumor. Both are quite important. And you can see most people are testing for PD-L1. Well, I want to show you a little experience that I had about 5 years ago now, wow it's a long time, that really sort of shows what we're trying to do. And this was a study we did with Genentech actually, Genentech Roche, Dan Chen, Ira Mellman and myself and investigators from around the country. And we're very fortunate because we included biopsies in the study. Not easy, but this was the first Phase I with a PD-L1 agent. Working with my colleague, Paul, across the hall here at Yale, we got biopsies on these patients. So here's a patient with multiple tumors in her lung. We biopsied these tumors pretreatment at 4 to 6 weeks. Why is that important? Because here's a patient that had a complete response. And when we stain for CD8 that gets the cytotoxic T cells, you can see very few T cells early on, but the T cells come rushing to the tumor. This is what you would call a hot tumor. This is the adaptive immune response. This is what you need to see to have good immune response with a checkpoint inhibition. And then we did an RNA chip where we looked at a number of markers to see if they were expressed or not. The green here is before. The yellow is after. And you can see granzyme A goes up, granzyme B goes up. Those are enzymes involved in activated T cells. Perforin. Perforin is an enzyme made by the T cells. It does just what it says, it perforates into the tumor -- into the tumor cell and bursts the cell. All these things are active immune response. So we actually buy this paper, and it's published in Nature if you want to see more data we actually were able to show. There are many supplemental figures there. Then the activated adaptive immune response, all these things occur which need to occur. However, the response rate in this trial, you guessed it, about 15%, 20%. Many patients did not respond. Why did they not respond? Well, we define that by getting the biopsies pre and post. Here you can see pre and post. You can see we had one group that we called immune inhibit pre, there were no CD8 cells; and post, there were none either. The tumor just laughed at this. I'll show you some reasons. There are probably mechanisms why the tumor could not have an immune response. Maybe there were issues with MHC I. Then there's the so-called nonfunctional immune response, where you'll have some T cells. You get maybe a few more post treatment. But if you look at that immune chip, it would be totally flat. No activation of those T cells. And then this is very interesting, what we call the excluded infiltrate. You can see that something happens. The T cells are sort of lining up, ready for battle. But they never touch the tumor. They never get into the tumor. And that's not going to work either. So these are 3 distinct patterns of nonresponse. Most patients who regress failed to show up-regulation of PD-L1 or evidence of activated T cells. And this is the so-called inflamed tumor hypothesis that we're about to talk about. So this is the immune desert. It's pretty bare. And this is what we call the immune excluded. Why do I show you this? Because this is what we have to tackle in lung cancer and almost all the other cancers where there's either primary or required resistance. Now just to show you, atezolizumab went on to Phase III. This was published last year in The New England Journal of medicine. And of course, in a Phase III trial in PD-L1, you can see the good results. Hazard ratio of 0.59. The biomarkers are now shown to be somewhat equivalent in the high, which is good. So most of the time now, we interchange the biomarkers. And then this is very interesting. We're even looking at tumor mutational burden. This is blood-based with Foundation Medicine. But if you look at tumor mutational burden greater than 16, mutations per megabase, you can see that, that seems to correlate with outcome. So PD-L1, tumor mutational burden, all reasonable biomarkers. However, many of these tumors are refractory. So we need to do more work here at Yale. We have a repeat biopsy program where any patient that's getting immunotherapy or targeted therapy who becomes recurrent, we actually do the biopsy in a protocol format, where we get consent for the initial biopsy. And when we do their rebiopsy procedure, we actually are able to get their tumor. We look at it with cytopathology to make sure we have a good sample. And we're doing frozen and paraffin. We're making PDX mice. So we're trying to understand why our patients are resistant to immunotherapy. Now I'll tell you that this slide is probably one of the most important of my talk because it really explains, in our group's opinion, the different types of resistance one might see. So I'll go through it rather slowly. These are 250 cases of lung cancer that we had in our archives here at Yale. And we did a very simple thing working with Lieping Chen and David Rimm and Vamsi Velcheti. We said, can we stain them for PD-L1? And can we stain them for TIL, for tumor-infiltrating lymphocytes? The tumor-infiltrating lymphocytes is the blue. The immune cells, the PD-L1, of course, we're measuring that on the tumor cells. What did we find? When we look at all of those samples, we found that only about 20 -- 17%, excuse me, of tumors had both PD-L1, that's the brown staining, the DAB staining, and had TIL. So these are tumors that had infiltrating TIL cells, they were hot, and had PD-L1. And it's no surprise that they seem to -- will respond to PD-L1 or PD-1 inhibitors. However, in lung cancer, again the most common cause of cancer death, you can see that here, there's 26% of tumors that are pretty high TIL. The immune system is active, but there's no PD-L1. And this is looking at a whole section. So this is not just a core biopsy. These tumors are going to need another checkpoint. This is why we need to look at other targets. No point hitting these tumors with a PD-L1/ PD-1 agent. It's not going to work. And then incredibly, 12% and 45% of lung tumors are immune cold. The TIL is negative. There are cold tumors, the immune microenvironment is bare. 45% are PD-L1 negative. So this is the biggest group, and this is the group that we want to inflame, and some of the agents we're going to talk about in a second, we'll do that, or 12% of tumors might have a little bit of PD-L1 even though they're TIL negative. And it's our belief that the immune system -- that the PD-L1 is being driven by oncogene, and it's not indicative of an adaptive immune response. So I would encourage everyone to think about it in this way, and we've written a few review articles on this that you can refer to. There's a new one actually in press now in Nature. If you have type 2, these are the tumors that have the TIL cells, that have the tumor with PD-L1, though, and B7-H1, by the way, is another name for PD-L1, then you have 3 different groups. You have those durable responders. I already showed you that patient. You might have primary resistance, the 50%, 60% that don't respond at all. And then you can have an acquired resistance, which occurs about half the time, and I'll show you that on the next slide. This we would call on-target resistance. You have a target. But look, the majority of patients in lung cancer have a target that's missing. And those are what we call type 1, 3 and 4. And for these, I would test. You need other therapies and other combinations. Well, we've done a lot of work, and we have 20 minutes. The references are shown below. And others have confirmed this, but Katie Politi, one of the leaders in our lung group, did a very nice study with a rebiopsy program working with Richard Lifton and with Scott Gettinger and our entire team and asked, "What happens when patients become refractory to immune therapy?" So we had a large series of 20, 30 patients We only had good tissue pre and post at about 15. But lo and behold then, one of those patients who had a tumor was treated with a PD-L1 and CTLA-4 combo had a complete response, and then this patient had recurrence. And we had biopsies at all stages of the operation. And when we looked at that -- and again, it's a little small here, you can go to the article if you want to see this more. But take my word for it that what we found is in that patient, when they became resistant, they lost Beta-2 microglobulin. Why is Beta-2 microglobulin important? Because that's part of the MHC I that allows the immune system to present neoantigen to the immune system. So you can see that these patients lost the ability to have an adaptive immune response. We're seeing this between 5% and 10% of the time. Kurt Schalper, as shown here on the right, led a team that actually asked, well, is it enough to have the tumor warm? Or is it the quality of the T cells in that tumor? CD3 stains for T cells. So you can see -- and CD3 would be red. So this is what you would call a cold tumor. There are no T cells in this tumor. You can then look at CD3, that's the red, and you can look for granzyme and Ki-67. I already told you granzyme was a necessary component of T cells to activate. Ki-67 is an indicator of cells dividing. You can see here are some cells that have high granzyme that have -- high granzyme and a high Ki-67. You can see a lot of the white, and you can see a lot of the green. That's the granzyme Ki-67. And here are cells that have a lot of CD3 but no granzyme and no Ki-67. And we asked from this cohort who survives the best. And interestingly, this green line, focus on number C here -- on letter C, these are the patients who do the best, which actually have a high CD3 with a low granzyme and Ki-67. And why is that? We've done some preclinical modeling now. These are the T cells that are exhausted. You heard a little bit about this just from Tim on the last talk. They need to be reinvigorated. This is where some of the other agents might come in. So we've shown this now in our tissue samples. We're doing some work. I talked about Type 3. Lieping Chen has done some screens, many of you are probably familiar with that, and pulled out a new molecule, a PD-L1 homolog, Siglec-15. So we're working at that at Yale. It's a homolog to PD-L1. And very interesting. Siglec-15 seems to be noninterferon regulated. So PD-L1 goes up with interferon. Siglec-15 goes down. So those tumors that don't have an active immune response, Siglec-15 seems to be higher. And we've done some work now with that preclinically to show that it is a T cell suppressor. And many of you are probably aware of Phase I data showing single-agent response to this agent. So an example of another agent that could work in patients who have no PD-L1. And now we're doing investigator-initiated trials, where we're looking at the drug alone or the drug plus pembrolizumab, exactly what you expect to happen in this space. And we have a Phase 1 team, and Phase 1 work is important. It's led by Pat LoRusso here. Here's Lieping. And it takes a lot of people to do this type of work at the academic center. But can we cure metastatic cancer with immunotherapy? I would say yes. We have survivors from these first trials. Treatments are well tolerated and retreatment is possible with reasonable response. The problem is we have a little way of knowing in advance who's going to respond and who's not. Do we need to personalize immunotherapy? Yes. We've spent 20 years personalizing targeted therapy. We need to do the same for immunotherapy. And that's going to require biomarkers and better combos and more science, innovative designs, collaborations, partnerships. So I'm going to propose that we need targeted immunotherapy. We need to identify the other targets of the microenvironment and then work to try to use them to get the tumor to be more responsive to the immune stimulation. And that's where this slide comes in. And you can see that if you think of a T cell, either activating and inhibitory receptors. And all of these are fair game now to target these with antibodies, either monoclonal or bispecific, to either block or activate the system. But it's really this area that has many of us intrigued. The microenvironment, the tumor that's cold, the tumor that doesn't have any T cells, how can you make that change? So you're hearing today, and many have come before me, so I decided to focus more on how these might work in a tumor as common as lung. You can see that there are other targets. CD73, you just heard from Tim the fact that adenosine is an immune suppressant. Block that, bring the T cells into the immune microenvironment. B7-H3, another checkpoint. Antibodies to block that. That would work in the Type 3. CD47, the fact that macrophages don't attack the tumor because they're inhibited. The don't eat-me signal. This is also important. All of these are targets that are viable for many tumors because of, again, the fact that most tumors don't have inhibition and other things going on that keep it from being just a simple PD-1/PD-L1 story. And then the bispecific antibodies, I think, are really going to be so important because of the cold tumors. I showed you the most common tumor. Half of them are cold. You've got to make it hot. And the way to do that is to engage T cells. And functional tumor engagers would be the PD-L1, CD47, the Claudin collaboration. Or immune cell activators, all of these different activators. Again, you've got to be careful when you hit an activator. But you got to activate and block -- take care of the block and then activate the tumor. So all these are possible with these bispecific antibodies. We're doing work here at Yale, just if I conclude. I think it's very important to get biopsies, to do sequencing. This is a trial we did with Bristol-Myers here, nivolumab, ipilimumab. Of course, it's already approved. It wasn't when we started the trial, but I would encourage some trials to have tumor tissue, blood and stool samples, even imaging, to really try to figure out -- this is imaging for PD-L1 -- figure out how to best target a tumor. I hope that I've given you a little bit of an introduction into the excitement I have in the next few years with some of these new agents, integrating biomarkers, integrating new agents to take the curve, as we show it here, with clearly a tail, no doubt, but many patients not benefiting and get over that hump and have an even bigger tail with some of these new agents. So hopefully, immunotherapy has transformed the treatment of lung cancer and many other tumors. Biomarkers and mechanistic understanding are critical to better determine mechanisms of sensitivity and resistance. And new combinations are needed to personalize immunotherapy. So in some days, someone can come into the store and say, I'll take a PD-L1 and CTLA-4 inhibitor and also anti-CD73 antibody, please. That's where we need to go. With that, I'll acknowledge my team, and thank you very much for having me here today.

Okay. Thank you very much. Thank you very much, Dr. Herbst. That was a great presentation. Thank you for all the insights. That concludes our second KOL presentation for tonight. Next up is our third and the last key opinion leader presentation. I would like to welcome Professor Schreiber to present additional insights on olamkicept, the product or the compound we talked about earlier tonight. Dr. Schreiber is the Director of the Department of Internal Medicine and the Head of the Institute of Clinical Molecular Biology, University of Kiel. He's a world-renowned gastrointestinal/GI expert. Now let's welcome Dr. -- let's welcome Professor Schreiber.

Ladies and gentlemen, my name Stefan Schreiber from Kiel University in Germany. I'd like to present new data on TJ301, olamkicept, which provides a new approach to anti-inflammation through the blockade of IL-6 trans-signaling. These are my potential conflicts of interest. In today's talk, I'd like to focus on ulcerative colitis, one of the 2 main forms of inflammatory bowel disease. As you can see, this is a rising problem, which first started in the Western world but now has also taken the newly industrialized countries. By 2027, I expect 1 million patients with ulcerative colitis alone in China. Ulcerative colitis is not a simple disease. As you can see from this population or representative study from Southern Norway, there's about 50% of patients that have a rather uncomplicated course. But the other 50% are chronically relapsing or develop severe noninflammatory complications, including cancer or the need to take the colon out. Because of the high unmet need, inflammatory bowel disease has been a battleground for pharmaceutical innovation. However, only a few developments have been successful. Let's have a look at those targeted therapies that are available today. The available targeted therapies comprise 5 different monoclonal antibodies that represent 3 different classes: blockade of alpha 4 beta 7 integrin, blockade of TNF and blockade of IL-12/23. In addition, there is tofacitinib, a pan-JAK inhibitor, which is oral. You see, all of these have one fundamental problem, and that is that induction rates are nowhere close to 50%, when our emission is counted more in the range of 20% to 30%. And the maintenance rates, and these are maintained patients among responders to induction, are again below 50%. So plenty of unmet need is still left. Therefore, we see many new agents being developed. These are more JAK inhibitors; however, the whole class is conflicted with potential severe side effects. More blockers of the IL-23 cytokine pathway. More anti-integrin molecules. However, one of the major developments, the development of etrolizumab by Genentech Roche has failed, and a new class, which is the S1P receptor stimulants, which come from the therapy of multiple sclerosis but are slow acting and probably modestly active substances. The blockade of IL-6 has been for long a major interest of immunologists. IL-6 is a master cytokine driving many aspects of acute and chronic inflammation, including metabolic and vascular changes. So blocking IL-6 is an important goal if you want to control inflammation. However, the traditional blockade of IL-6 via the antibodies against IL-6 or the IL-6 receptor, tocilizumab, is also affected with side effects that mainly come from that high level of immunosuppression which is coming with the therapeutic efficacy. The biology of IL-6-mediated immune activation can be divided in 2 parts. One is, IL-6 itself binds to the IL-6 receptor that's already assembled in 2 anchors that are called gp130. The second part is, during chronic activation, IL-6 receptor is produced in a soluble form, binds in the blood with IL-6. And then this complex, the IL-6 receptor and IL-6, can home into any pair of gp130 anchors that's empty on a cell of the body. So some cells have the already assembled IL-6 receptor and can be responsive to free IL-6. But once you have a chronic inflammatory state soluble IL-6/IL-6 receptor in the blood, almost every cell of the body can be activated. This latter part is called IL-6 trans-signaling. The drugs that are available either are blocking IL-6 by absorbing the cytokine or they bind to the IL-6 receptor and, therefore, interrupt the binding between IL-6 and the specific part of the receptor. The normal principle, however, is to emulate the gp130 anchor by creating a decoy protein here between 2 gp130 molecules and an Fc antibody fragment that can specifically absorb the IL-6/Il-6 receptor complex and, therefore, interrupt trans-signaling. As a fusion protein, TJ301 has a high affinity and little or no immunogenicity. Its efficacy has been widely proven in animal models, not just multiple models of inflammatory bowel disease but also a corona of other rheumatic and inflammatory diseases, including atherosclerosis, chronic lung inflammation and fibrosis and IL-6-driven cancer genesis. Most interestingly, there are no side effects. There's no immunosuppression in animal models. And this includes challenge models where animals inhale Mycobacterium tuberculosis. There's no inhibition of intestinal regeneration, no intestinal perforation. And finally, the compound is even protective in bacterial sepsis models. After a Phase I study in healthy volunteers has documented that TJ301 is well tolerated and doesn't have any immunosuppressive side effects, we set up this Phase IIa open-label study of TJ301 in inflammatory bowel disease patients. Patients were exposed to biweekly doses of 600-milligram TJ301 given over 12 weeks. The final endpoint of the therapy was at week 14. In a dense series of endoscopies starting as early as 4 and 24 hours after the first dose, we assessed the molecular mechanism of olamkicept with regards to trans-signaling inhibition in patients with active disease. The population you can recruit for such an early study represents very complex individuals with many failures in therapy before. In this group, olamkicept induced clinical response in up to 44% of patients. And also, clinical remission was seen in a subset of IBD patients. On this slide, you see 2 of the super responders we observed, one from Crohn's disease and one from ulcerative colitis, each screening and -- at week 14 after 12 weeks of drug exposure. TJ301 was given at a dose of 600 milligram in biweekly intervals. The pharmacokinetic parameters in patients were exactly what was before observed in healthy volunteers. We think that a future subcutaneous formulation of TJ301 has ideal pharmacokinetic parameters with short half-life times for an even and very steady exposure of patients. As expected, we did see only a very limited number of AEs and SAEs. The drug was very well tolerated and didn't give rise to any severe side effect that was attributed to study drug. However, the observed patient number was small and a more meaningful safety signal will be derived from future and larger randomized controlled trials. Here, we have an overview of the clinical parameters. We have the Mayo clinical score and the CDAI is split between patients who later went into remission and those who did not. The same with the CRP and the faecal calprotectin. Further down, you see the phospho-Stat3, the main signaling molecule that is engaged by IL-6 receptor gp130 signaling. You see the pharmacokinetics. But again, between patients who went through remission and who didn't, you see soluble IL-6 levels and soluble IL-6 receptor on those. We used Hyper-IL-6 to stimulate cells from peripheral blood and switch on trans-signaling. In this assay, we could document that the exposure of patients to olamkicept, TJ301, led to trans-signaling blockade in all of the patients, whether they later went into remission or not. We deepened the molecular medicine understanding of the mechanism of activity of TJ301, olamkicept, by investigating transcriptional changes in the peripheral blood. Four hours after exposure, you see multiplicity of genes being up or down-regulated. This signal deepens 24 hours after exposure, more than 715 genes been down-regulated and more than 146 up-regulated. Most importantly, we could use the peripheral blood transcriptomes to compare all patients with IBD who were exposed to a olamkicept with another cohort of patients with rheumatic arthritis who received tocilizumab, a commercially available antibody against interleukin-6 receptor sold as Ro-Actemra. The key difference in transcriptional profiles documents the uniqueness and specificity of the trans-signaling blockade carried out by olamkicept. We then investigated the causal gene expression by analyzing the transcriptome from biopsies taken during endoscopies. Two weeks after the first infusion, the gene expression pattern from patients who later reached remission starts to differentiate from patients who do not reach remission. We hope to be able to extend these findings in the future for development of a predictive assay of olamkicept's success. As expected, this difference in gene expression between patients who later reached remission and those who do not is also found on the level of STAT3 phosphorylation. STAT3 phosphorylation is a main signaling process after activation of the IL-6 gp130 receptor complex through IL-6 trans-signaling. We already have seen that TJ301, olamkicept, provides a specific transcriptomal signature in comparison to interleukin-6 receptor blockade by tocilizumab. But how about the most commonly used biologic drugs for the therapy of ulcerative colitis, infliximab and vedolizumab? We have compared transcriptomal signatures from 2 unrelated cohorts which we treated in our center. Olamkicept results in a unique and different transcriptomal regulatory signature differentiating from both infliximab and vedolizumab. Let me summarize. The molecular medicine approach shown here suggests clinical efficacy of the novel principle of 6 trans-signaling inhibition through olamkicept in patients with active IBD. Specific, early transcriptomal changes unique to IL-6 trans-signaling inhibition were detected. There is association of target engagement, namely mucosal STAT3 inhibition with clinical efficacy. Olamkicept is the first biologic in IBD where the mechanisms of response and nonresponse are understood before the clinical phase and can be used to optimize drug development. A Phase IIb trial has been concluded by I-Mab in the meantime. This is a multinational, placebo-controlled, double-blind, randomized controlled trial in moderately to severely active ulcerative colitis. Further details can be found under ClinicalTrials.gov. It examines a meaningful and large patient population. Clinical efficacy is examined by standard activity assessments, including central endoscopy reading. The results of these trials will be presented on the upcoming Digestive Disease Week and the annual meeting of the European Crohn's and Colitis Organization in May 2021 and July 2021, respectively. Let me take you to a speculative outlook to the next trends in the use of biologics for therapy of inflammatory bowel disease. This is the intravenous subcutaneous sequence therapy that, as I think, soon will become mainstay for all of the leading biologics in inflammatory bowel disease because it provides quick saturation with a new therapeutic compound but then constant exposure. You see in a schematic example the leading drug for the therapy of inflammatory bowel disease, infliximab. Infusions are given every 8 weeks, which lead to fairly high exposure concentrations and then quickly decline due to the half-life time of the drug before the next infusion is taken again another 8 weeks later. It becomes very clear that during maintenance phase, this is not ideal in that a shorter half-life time drug that will be given more frequently like a subcutaneous injection here provides a much more even and constant exposure of the patients. Already after 2.5 weeks, subcutaneous exposure appears to be superior to intravenous dosing. Therefore, new biologics will be using the IV subcutaneous sequence therapy, and this includes infliximab, where a subcu formulation just has been added; or secukinumab, vedolizumab, where also subcu formulations have been added; and all the new anti-IL-23 biologics that are developed in this paradigm. Olamkicept with a short half life time is particularly suitable for such a long-term subcutaneous maintenance dosing. Thank you very much.

Okay. Thank you very much, Professor Schreiber. Thanks for your time and very, very insightful talk. With that, we will conclude our R&D Day here. We hope you have found today's presentations fruitful and informative. At I-Mab, we continue to be fully committed to bring transformational medicines to patients around the world through drug innovation. And now we are rapidly progressing from a clinical-stage biotech company towards a fully integrated global biopharmaceutical company. Thank you again for your time and participation. We hope to see you soon. Thank you, everyone. Have a good day or good night.