Hello, everybody, and thank you for joining us today for an in-depth exploration of the complex landscape of plaque psoriasis and the innovative use of anti-interleukin 17 A and F single domain antibodies, VHH antibodies, for intralesional treatment. I am Amir Reichman, the CEO of Scinai Immunotherapeutics, and together with me is a distinguished panel that will discuss together the significant unmet need in plaque psoriasis treatment, and will introduce us to the innovative approach with anti-interleukin 17 single domain antibody, the unique benefits of local administration, the key stages of development, the uniqueness of single domain antibodies as such, and of course, the clinical implications for the patients, so about a little bit about me, I'm the CEO of Scinai since 2021, located in Israel, here in the headquarters of Scinai in Jerusalem. I served in several global roles in the headquarters of GSK Vaccines in Belgium for many years, and prior to that, worked for Novartis in different sites in North America, including Cambridge, Massachusetts, and North Carolina. Worked also there in different global roles in the biologics, R&D, and the manufacturing operations. I earned my Master's degree in Biotechnology Engineering from the Ben-Gurion University in Israel, and my MBA in Finance and Healthcare Management from the Wharton School of the University of Pennsylvania, United States. Together with me here is Professor Matthias Dobbelstein. Matthias? Hi. Yeah, thanks very much for your kind introduction, and yeah, I'm Matthias Dobbelstein. I'm heading the Department of Molecular Oncology here in Göttingen, in Germany. I was trained as a medical doctor at Munich, and I then moved to Princeton University to do my postdoctoral stay in tumor virology. After that, I had group leader positions in Marburg, Germany, as well as Odense in Denmark, and I was then appointed full professor here in Göttingen, and I'm also a fellow of the Max Planck Institute of Natural Sciences here in Göttingen, and a couple of years ago, we started this exciting collaboration with my colleague Dirk Görlich, here in Göttingen, at the Max Planck Institute, about the development of VHH antibodies. And this also took us to this exciting collaboration with Scinai, and I'm looking forward to talking about this in more detail during this webinar. Thank you, Matthias, and Professor Michael Schön, please. Thank you very much, Amir, for having me. My name is Michael Schön. I'm a board-certified dermatologist and immunologist. I received my training at the universities of Ulm, Berlin, and Düsseldorf in Germany, and Harvard Medical School in Boston, and I served as a consultant at the University of Magdeburg, Würzburg, and now Göttingen. My current position is the Director of the Department of Dermatology, Venereology, and Allergology at the University Medical Center of Göttingen, and my primary research interests are chronic inflammation and immune processes governing those diseases. Quite relevant to the topic today. And thank you very much. It's a pleasure having you, too. Tami is our distinguished Chief Scientific Officer of Scinai. Tami, tell us about yourself a little bit. Thank you, Amir. I'm a chief scientist at Scinai for the last 20 years, an immunologist by training. My PhD was at the Weizmann Institute in Israel, and I'm responsible for the preclinical and for the clinical development, with a huge experience in vaccine development from phase I to phase III, and now in the immunotherapies. Thank you, Tami. So a little bit about Scinai, who's hosting this webinar today. Scinai Immunotherapeutics is a traded company on the Nasdaq under the symbol SCNI. Scinai is a biopharmaceutical company focused on developing inflammation and immunology, I&I, biological products, and on providing CDMO services through its Scinai Bioservices business unit. Scinai Immunotherapeutics has two business units, and the first one is an innovative R&D unit, discovering novel VHH antibodies under a research agreement and an exclusive license with the Max Planck Society in Germany, and developing those antibodies in its facility in Israel under an exclusive license from the Max Planck and University Medical Center Göttingen. The second business unit is a drug development service unit, a CDMO, providing services to early-stage biological drug development projects for customers in Israel, and now expanding its customer base to Europe and the United States. Our innovative R&D unit is developing, as I've mentioned, VHH antibodies for I&I, and they are derived from alpacas. We will discuss it soon. Those unique features that are coming with these VHH antibodies provide them advantages in manufacturing costs and efficiencies, faster drug discovery cycles, superior thermal stability, which translates to longer shelf life and the ability to withstand higher storage and transportation temperatures. Our pipeline is composed of antibodies that can treat various diseases, from COVID-19 to psoriasis, asthma, atopic dermatitis, and wet macular degeneration. Our next in-line project is a nanobody. VHH antibody for the treatment of psoriasis, which will be the topic of this roundtable discussion. So let's dive in now. After the introduction of the participants and the topics and the company that is hosting, let's dive to the discussion. Maybe the first question that we would like or the topic that we'd like to address is the disease, the psoriasis disease, and the unmet market need. Michael, let's start maybe with you. With so many solutions of biologics, monoclonal antibodies, and the new JAK inhibitors now, which fragment of the patient's population is still in need? Well, thanks, Amir. As you know, psoriasis is a chronic systemic disease, which means that it can basically recur throughout life, and a real cure is not yet possible for that disorder. So accordingly, the level of suffering or the burden of disease of those affected is often very high. Around 2%-3% of the worldwide population are affected, although of course there are some regional and ethnic differences. Worldwide, roughly 125 million people have psoriasis. So having that said, in most patients, psoriasis is a mild disease. However, around one-third have moderate to severe psoriasis, and for these, we have a number of systemic treatment options these days. As you have already mentioned, there are several biologics. There are roughly a dozen biologics approved for psoriasis, on top of that, small molecules. However, these molecules or these very successful treatments still leave some unmet needs with patients suffering from mild to moderate psoriasis, but they still may have a very high disease burden because they may have affection of highly visible or functionally important parts of the body or may not respond adequately to currently available treatments. So patients may have lesions on hard-to-treat areas, locations just like as the scalp, the genitals, the palms, and the soles of the hand and feet, and so on. In addition, there are some unfavorable adverse events of corticosteroids for local treatments in use, and all current biologics are basically for systemic treatment, and there is no real option for local treatment of recalcitrant lesions. That's basically why there is still an unmet medical need. Thank you. That's a very, you know, enlightening point. It sounds like there is still quite a lot of need in this segment. Let me think and maybe flip the discussion towards the next point, which is the role of cytokines in psoriasis pathogenesis. Again, Michael, this is still for you. What is the role of IL-17, interleukin-17, in the pathogenesis of plaque psoriasis? And follow-on question on that is, why is the IL-17 being considered a better target for treatment of psoriasis versus the, for example, TNF alpha, you know, Humira and the IL-23, which seems to be quite successful? Mm-hmm. Well, as you mentioned, I mean, there is quite a few cytokines that have been identified as players in the pathophysiological network of psoriasis. Among these, interleukin-17 can be considered a key cytokine because it influences quite a few or many immune cells and immunological functions. But this is, of course, important for many inflammatory diseases, especially for psoriasis in our case. Among other things, IL-17 is regulated by IL-23. This is one of the reasons why IL-23 inhibition is also an important therapeutic principle. However, there is also IL-23 independent reduction of IL-17, so that IL-17 inhibition is perhaps more specific in some respects. TNF inhibition is another principle, but it's even broader and therefore may be less specific than IL-17. Amazing. So what you're saying is, yes, indeed, there is a utility in the usage of both the TNF alpha blockers and the IL-23. However, there might be some level of IL-17 still escaping the route of IL-23 and therefore still generating the psoriatic response, and that's why IL-17 antibodies developed by different companies, for example, Cosentyx, that we know from Novartis. We have now Bimzelx from UCB, Taltz and Siliq, all are targeting this unique IL-17 or its receptor. And basically, you are saying it's much more specific. Is it... When you say more specific, does it mean that it is- we should perceive it as being safer than the more broader or, you know, targeting antibodies? Safety data from systemic application of all of these drugs indicate that they are all very safe compared to the older conventional systemic treatments, like Methotrexate, Cyclosporine, Acitretin, and so on, but having that said, there are certainly some differences because there are some side effects that may occur, such as a slightly increased risk of infection with all of these, and that also applies to IL-17, although overall, one has to state that treatment with anti-IL-17 therapeutics are very safe, very effective, and that's why they have such a broad place in the market so far. Interesting and just maybe last, a follow-on on this one. I know that there are two types of isoforms of the IL-17, the A and F. Could you maybe tell us a little bit about the, you know, the differences in the roles of these cytokines in the pathogenesis of psoriasis, and potentially the interesting, the opportunity with developing antibodies targeting also the F isoform? Yeah, that's an interesting and actually also a very specific question. Indeed, IL-17, in order to function, needs to dimerize. That means two parts of the molecule need to come together to interact with the receptor and then transmit the relevant signals to the immune cells. Now, there are several isoforms of IL-17 that can dimerize. In our case, two IL-17A molecules can dimerize, two IL-17F molecules can dimerize, or there may be heterodimers consisting of one IL-17A and one IL-17F. All these three different dimers interact with the same type of receptor and can transmit the signal. Now, the affinity to this receptor is much higher with IL-17A. On the other hand, in psoriasis, in particular, the concentration of IL-17F is much higher as compared to IL-17A. So having that said, it is very likely that both isoforms play important roles in the pathogenesis and the pathophysiology of psoriasis, so inhibiting both actually makes a lot of sense. And, drugs that target both of these isoforms tend to have a more pronounced effect as compared to those inhibiting only IL-17A. Thank you very much for this insightful answers. Let me move to the next topic, which is the comparison between a single domain VHH antibody and a monoclonal antibody, a human monoclonal antibody, and the question is to you, Professor Matthias Dobbelstein, what is a VHH single domain antibody, and how is it different than the monoclonal antibody? Yeah, thanks for this question, Amir. So, VHH antibodies are still antibodies, and they are still monoclonal antibodies, much like the monoclonal antibodies that are still being produced using technologies that were developed in the 1970s of the last century. However, we decided to take a different approach to make a more compact kind of antibodies, which we call, as others do, the VHH antibodies. So, what they really are is still proteins that bind to an antigen. That's what they have in common with just regular antibodies. And they are monoclonal, so there's just one kind of an amino acid sequence within that VHH antibody. That's what they have in common with regular antibodies. However, whereas regular monoclonal antibodies are typically composed of as many as four different chains, four different proteins that come together, the VHH antibody is just one peptide chain, and its overall size is about 10x lower, 10x smaller than what you find with a regular antibody. So what we feel is that in many cases, small is beautiful, so that this smaller antibody is more compact, it's more robust, it's more stable. Many of these VHH antibodies, you can actually boil to 95 degrees Celsius, then cool down, and they still retain their activity. So they're far more stable in many cases, they're more robust, and the technology that we use to make them allows us to choose from a very wide range of VHH antibodies, allowing us to select those that retain the utmost affinity. So what we get there is also very strong binders to the antigens. So that's how I would describe those VHH antibodies in the first place. Amazing. And so what are the advantages or, you know, and disadvantages of a VHH single domain antibody in comparison to a monoclonal human antibody or IgG antibody? Yeah, I mean, let me start with the advantages. So the advantages of VHH antibodies are yeah, just to summarize again, they're robust, they're stable, they're small, and since they have this simple composition, this just one peptide chain, you can also make them at a larger scale and with lower cost of goods to produce them. Moreover, you can also start being a little creative with these VHH antibodies, since you can quite easily fuse them to a different protein. So you can, for instance, make a bi- or even tri-specific VHH antibodies, and you can fuse them to, say, proteins that would alter the half-life, the biological half-life of the molecule. So yes, you can also be more creative with them as compared to regular antibodies. So that's what I would consider their main advantages. One disadvantage is, even though you can overcome it, if you simply inject such a small VHH antibody into the vein of a patient, it won't stay very long in the blood. It will be eliminated through the kidney because it goes through something that's called the glomerular filter, and that's something that would make these VHH antibodies more suitable for local administration to the skin, to the lung, wherever you want it. But as such, they are less suitable for systemic application. However, if you still wanna use it for a systemic application, what you need to do is to fuse them to something that will prolong the half-life. So that's also possible, and in that way, you can overcome that disadvantage. Mm. I got you. Okay, that's very interesting as well. So maybe I'm trying here to share, maybe the moderator can help me, allow me to share slides, 'cause I wanted to share your slide here about the discovery process of the NanoAbs or the single-domain antibodies. You prepared here a very nice slide that I'd like to share here with everybody. Hope you can see my screen. So- Yes. Yeah, so that's maybe just to summarize what you just described before. I'll take us to one slide before, and basically to demonstrate the differences between the conventional antibody, the IgG heavy chain only. Do you want anything just to highlight from what you said before, looking at this...? Oh, you can just, just compare the size. I mean, if you, if you look at the regular monoclonal antibody, that, what, what you see here, you have... I think you have your, your pointer just there. That's, what's derived from, from humans. You see these four chains, and then you just compare it, with a single domain antibody, and you can appreciate already that its, its, its composition is, is not only smaller, it's also simpler, and that's, why it's easier to work with it. Basically, not only that you are using the heavy chain only antibody, you are actually cleaving the variable heavy chain part right from here, but if you see it well. That's correct. Yeah, we are kind of cleaving it, or actually, what, what we really do is to just clone the coding region for only this VHH domain into an expression construct that allows us to make this in bacteria. I should add that this is something that would not be possible without the collaboration with our partners at the Max Planck Institute. You had our colleague on the previous slide, Görlich, who actually is heading the group, who is making these VHH antibodies. But yeah, you asked me about how they are made, and I think that's on the... That's, yeah, that's here on this slide. The animals that we need to identify such VHH antibodies in the first place are alpacas, or more generally, they are camelids, so camel-like animals, since they have this property that they can make such antibodies that only consist of the heavy chain, as we call it, but not the light chain. What we do with these animals is to just vaccinate them and draw blood on them. We treat them very well. What they get is the same as what most of us got for a COVID vaccination, for instance, that is a vaccination with the antigen. In this case, this was antigens derived from interleukin-17, and a few weeks later, you draw blood on these animals, and that's it. After that, you can send them back to their flock, and with the blood, what you do is you isolate what's called the B cells, the cells that encode antibodies, and from these B cells, you extract the DNA, and you amplify with a technology called polymerase chain reaction, you amplify those regions in the DNA that encode the this VHH domain, the antigen-binding domain of such single-chain antibodies. This then goes to bacteriophages, that's viruses that can infect bacteria, and those bacteriophages then make the single chain antibody and bind to the antigen, in our case, IL-17, and this allows us to select from a library of many as a hundred million different VHH antibodies. Ten to the power of eight, a hundred million antibodies to select the very best binders, and those we would then, you know, transfer to bacteria, express them, meaning that the bacteria would make the VHH antibody that we are desiring. We can sequence it, we can produce it, upscale it, and then test their ability to neutralize the antigen, in our case, to neutralize interleukin-17. That's basically how these VHH antibodies are made. Amazing. So let me maybe go back to the question I had before, and then these are, you know, the how we make them now is clear. So then last question for you, Matthias, is what is then the opportunity in using nanoAbs or VHH single domain antibodies for the treatment of psoriasis? Yeah, I think we can answer this jointly if you want, but my take of it is that due to the ease of production and due to the robustness of these nanobodies or these VHH antibodies, we have a chance to apply them locally, to apply them not in a systemic fashion, which would trigger toxicities that are almost inevitable, but rather apply them just where they are needed, and that's on the psoriatic lesion, and that's the major advantage of them in as compared to the systemically applied monoclonal antibodies. Thank you very much. And, Professor Schön, how do you see... What got you attracted with this, new potential innovative or novel use of, VHH single domain antibodies for the local treatment of psoriasis? In that case, we will have a chance of really individually targeting single lesions that are recalcitrant due to other treatments or difficult to treat, and still have a pathogenesis-oriented, therapeutic approach, rather than the very broad approach with all the side effects that, for example, topical corticosteroids would have. So that is an exciting and promising development. Okay. And, Tami, then you're our Chief Scientific Officer for Scinai, so, you know, tell us a little bit about the product you are in charge of developing. Describe a little bit about the target product profile of Scinai's anti-interleukin-17 single domain VHH antibody. Thank you, Amir, for this question. So eventually, we're planning to have these VHH antibodies as a pen for injection. When possible, it will be self-injection, and people will use it intralesionally, and will have the opportunity to have a biological drug, even though they have a mild disease and usually they are eligible to have only corticosteroid therapy and phototherapy. Maybe the other professor can tell more what are the limitations of these therapies, but we know that the most effective one is the biological, and this is what patients really want. We plan to apply this therapy for the mild to moderate patients suffering from lesions located in areas that generate high disease burden for them. It can be on the face, on the scalp. These people even cannot smear corticosteroid or have a phototherapy in these areas, and also the hand, the feet, and they are seeking for a better solution. We will be able to provide them a solution that doesn't need a daily therapy, unlike this, the phototherapy and the corticosteroids, because we showed in the preclinical studies at least, that we can give the therapy and see the effect for a prolonged time. Brilliant. So I, again, you know, I happen to have a slide here that can help. You know, for me, it's really astonishing to see the percentage of patients suffering from mild psoriasis. And so it goes back to what Professor Schön talked about before, about the classification of mild to moderate, et cetera. You know, we have this slide here that talks about the current psoriasis treatments. I go back to you, Michael Schön. You mentioned before briefly about the corticosteroids, and the phototherapy, and their potential limitations in treatment. Could you maybe expand on that, just to explain the need in this patient category? Certainly. Thinking of corticosteroids, they have a very broad immunosuppressing effect, immunosuppressive effect, and they're actually in the market for decades now. However, the flip side of that coin is that they have long-term side effects. They make the skin more vulnerable, they lead to skin atrophy, so you cannot just use them for any period of time. Similar limitations apply to phototherapy. It's sometimes just practical reasons for patients to not be able to use phototherapy, because they have to be applied three to four times a week, and you cannot do this indefinitely because phototherapy increases, for example, the risk of skin cancer and skin aging. There still is a need for alternatives, and a pathogenesis-oriented approach, such as the local modulation of key cytokines, such as IL-17, promises to be very advantageous to those patients. Interesting. And so, you know, many times, you know, we, I even have somebody that I know that just, you know, recently came back from a treatment of psoriasis, and she was given, you know, in addition to the phototherapy and corticosteroids, some systemic immunosuppressants. I think methotrexate was the one that is kind of all over the board was prescribed. She didn't really like it, but these are kind of, you know, generic drugs. What are the limitations in use of these, you know, immunosuppressant drugs? Methotrexate certainly is a classical systemic treatment for psoriasis and also associated disorders such as psoriatic arthritis, again, also for decades. However, it also has a long-term immunosuppressive effect. It can have adverse effects, for example, on liver functions, so you need to watch out for those. In general, however, methotrexate is a systemic treatment that is reasonably well-tolerated. Okay. And so what... Tell us a little bit about the decision-making of a physician. You are a dermatologist in practice, and you see patients, right? You see patients suffering from psoriasis in your clinic, and- Yes. So tell us a little bit about the line of thinking. Okay, here is a patient that, you know, already got corticosteroids, phototherapy, methotrexate. What makes you suggest to a patient, "Oh, you know what? You should so consider going to the second-line systemic immunomodulators- Mm ... such as, you know, Sotyktu, the JAK inhibitors, or even moving to the injectable biologics?" Could you maybe talk a little bit about- Mm ... the considerations and how you decide when to apply the, and recommend these, therapeutic, agents? Sure. So there's two major fields to be considered. One is the individual situation of the patient. So what is the nature of his or her disease? What is the area of body surface affected? What is the burden of disease? How chronic is the disease? How inflamed are the lesions, and so on? What comorbid diseases do we detect, such as cardiovascular diseases, gastrointestinal diseases? Is there arthritis? Are there any other medications that could interfere? So this is a patient individual basis for making this decision, and of course, you also have to make a shared decision with your patient. So what is most feasible for your patient? Would he or she rather take a pill? Would he or she rather have an injection every few weeks, or so on? The second area that is important for making the decision is the current approval status of the therapeutics, so is it a first-line treatment? What are the costs? That is also important in many countries, such as many European countries, and based on all these different factors, you come up with a decision that you make together with your patient and then find the most suitable treatment for him or her. Okay. Incredible. So that, this is very insightful. Thank you, everybody, for that. Let me maybe suggest that we move to the next topic. Tammy, this one is for you and for Professor Matthias Dobbelstein. The topic is drug development and drug development stages. So tell us a little bit about the various stages of drug development required to prove that a drug is effective and safe for use so that the clinical trials can commence. Whoever wants to go first, Tami or- Maybe I start because what I can describe is the more basic part of the development. You know, it's not enough to just select some VHH antibodies that happen to bind, in our case, IL-17, and we took great care that it would, first of all, bind not just to the IL-17A, but also to IL-17F, which were the two different kinds of interleukin-17 that Michael has been talking about before, so we selected a VHH antibody that binds both of them, and not only it binds there, but it neutralizes, so the first step was then to make sure that it really interferes with the activity of these interleukins and that it prevents them from binding to their receptor. So that was the first part. Then it was important to look at the stability of this VHH antibody. As mentioned before, you can actually boil it and still retain the activity, which makes it much easier later on to produce it, to store it. So that's something that we had to make sure. And thirdly, we had to make sure that it produces in large amounts, so that we could also make sure that ultimately we would be able to make kilogram amounts of this, and that also turned out to be possible. And I think that's now the point where I hand over to Tami who took care of the VHH antibodies from this point? Yeah, so talking generally about the drug development, we have the in vitro and then ex-vivo and in-vivo studies that show the efficacy and the safety and the potential of the drug to be a real drug. So Matthias mentioned the neutralization, the high affinity, the stability of the VHH antibody that was already shown in the work done in his own lab and at the Max Planck Institute by Professor Görlich. And then we received these VHH antibodies and presented the ex-vivo and the in-vivo studies. In the ex-vivo study, we used human skin samples that psoriasis was induced in them, and then just wanted to show that it really works, that the local administration is effective in treating the disease. We at that time, we had- Sorry, let me maybe jump into your words. Apologies. Maybe before delving into the specific activities done by Scinai, maybe. You know, I found on the very interesting, we have on our internet website kind of a Gantt that explains the horizon of, you know, of or the Gantt chart that high level describes the drug development. So before going into what we did in Scinai, maybe just walk through, you know, the different stages that are required for the development of a drug before it can go into the clinic. I would say clinic is already, yeah, clinical trials is stage number eight here on the graph. Okay, very well, so every drug begins with a bright idea of the inventor, and this is the molecular clone selection. In our case, it was the VHH antibodies that were identified and selected according to Scinai's request from our collaborator to find an antibody for IL-17A and IL-17F. Next, in a lab scale, you have to show that the molecule really works, that it is being able to produce, that you have a strain that is effective, and you have to develop all the analytical assays to confirm that what you produce is really what you initially planned to have, and then this is described also in the CMC section. You have to develop the upstream, the downstream, to upscale it, and make sure that it still have the same characteristics that were initially developed in the small scale. When you have the molecule, then you go to the preclinical evaluation, which I just mentioned, the in vitro, ex-vivo, and in-vivo studies. And then the last stage of the preclinical is the toxicology confirmation. You make sure that your drug doesn't cause any adverse event, doesn't damage any tissue still in an animal model that is relevant. And when everything is positive and done, you have to present your data to the regulator, and you get permission to go for a clinical trial. The regulator is usually very strict in their requirement. You have to show that it is both effective, that you're not just using people to something that is not going to be, of, advantage for them. And then, tech transfer when needed. In our case, we plan to have the manufacturing of the VHH antibodies in our own facility, and then you initiate the clinical trials, phase one, phase two, and phase three. I think it is an opportunity for us to tell that we met with the Paul-Ehrlich-Institut scientific advice earlier this year, and they allowed us to skip the healthy volunteers, stage, which is usually mandatory, and to go directly to patient and see already in the first trial that our drug is both safe and hopefully effective. Perfect. So, Tami, maybe now I'll jump into, you know, slides that describe what you just started to explain before about the specific attempts in the development of those unique single domain VHH antibodies developed between Max Planck and UMG in pursuing the drug development pathway for their development to become one day potentially a therapeutic drug. So what do we see here on this graph and slide, please? This is the ex-vivo study that we conducted also earlier this year. In this study, we take human skin samples and grow them in a dish. We then treat the skin, which is a psoriatic skin, with the current standard of cares, with betamethasone and with secukinumab, the monoclonal antibody against IL-17A, and also with two different doses of our own VHH antibodies, which were given once and also daily for three days. We then evaluated the IL-17A concentrations in the medium, which is mimicking the concentration in the blood. And we can see here that in untreated healthy skin have very low concentration of IL-17. In a psoriatic skin, we have a very high level of these cytokines, and then we can look at the different treatments. both betamethasone and secukinumab significantly reduce the content of IL-17 in the medium or in the blood, but when we treat it with our own VHH antibody, we see that the level of IL-17 was even lower than that of these standard therapies, and this was very encouraging for us. It was especially important for us to see that even one dose was sufficient to reduce the IL-17 levels. We know that the VHH antibody remains in the skin for a limited time, and we still see after three days that the IL-17 levels remain very low and significantly lower than those shown in the other treatments. In this study, we all- Sorry, sorry. We just apologize. It's so exciting, but, you know, we also have some time limitations here, and I really want to see maybe some explanation on the recent exciting in-vivo study that you managed. So, let me push forward to this area, please. When having these exciting ex-vivo studies, we move forward to the next, proof of concept study in, in animals. I'm saying animals, but actually, the study was done in SCID mice that were transplanted with human skin. Being a SCID mice mean that they do not have an immune system that can reject the human skin, and you can actually see the, piece of skin from a human transplanted on the back of these mice, and they having a appearance of the psoriasis, which is induced by injecting of a white blood cell into this, skin transplant. Next, we have the treatment session, and we have, for three weeks, treated the animals or the human skin engrafts with either a negative control, which is an irrelevant VHH antibodies, or with the standard of care, the secukinumab and the betamethasone, or with our own VHH antibodies. Here, we used quite a low dose that was given either every day or once a week or just once. The objective of the study was to make sure that we understand the mechanism of action of this VHH antibodies. At that time, we didn't know if we have to have a continuous exposure of the body, of the dermis to the VHH antibodies, or maybe it is sufficient to have it just once a week, and we still cause the blocking of the psoriatic cascade. We got a very clear replies to these questions. I think that the next slide shows how it really looks. In the bottom of the slide, we can see a negative control on the left side. We can see the scale. I think Matthias or Michael can tell exactly what we really see here and how it is related to psoriasis, but anyone that knows how psoriasis looks, that's the way it is. When looking at the samples treated with secukinumab and also with our VHH antibodies administered once a week, when we can see that the scale disappear, the skin looks healthy, clean, and like a normal one. We also look at the histopathological... No, go back to the previous one. We also looked at histopathological sections of these skins, and we see the IL-17 and IL-17A and IL-17F expression in these samples. In the red squares on the left with the vehicle, we see that there is IL-17A and IL-17F in the negative control in the vehicle sample, but not in those treated with the various treatment for the IL-17A. It is very nice to see that for the IL-17F, we do see the IL-17F in the samples treated with Cosentyx, which is specific only to the A, whereas in the sample treated with our VHH antibody, we can see that both IL-17A and IL-17F are not there. We then looked for different, psoriasis markers that, I will not go into the exact detail what, each and every one of them is, doing in the psoriasis, but generally, there are markers that are relevant to inflammation, to, keratinocytes, and we see that in all these, samples, there is no significant difference between the sample treated with the VHH antibodies, which is on the right side, and the, standard, therapies, the secukinumab and the betamethasone. So this is very encouraging. It is also important to tell that we treated the, human skin samples, for three times, and that's- Yeah. Sorry. We treated the animals for a limited time. We know that at the end of this time, the VHH antibody already disappears from the skin, and still we could see two weeks later that there is an effect, and the markers are very low, the skin looks much better, and we prove the concept that local administration of a biological drug can solve the burden caused by psoriasis. Okay. Thank you very much, Tami, for giving this review of that. Maybe tell us a little bit more now, you know, between the three of you, what do we see as potential future use of future plans for. Maybe start with you, Tami. What are the future plans for Scinai with regards to the development, further development of these nano-abs targeting interleukin-17AF for the treatment of mild to moderate psoriasis? In this study that I just presented, we look for the efficacy two weeks after the last administration. But having these nice results, we would like to push it further and see maybe we can see efficacy for a longer period of time. So now we are going to repeat this same study, and also evaluate a higher dose of the VHH antibodies, and follow the skin samples on these mice for two months. We will then know what is the duration of the effect and how far we can expect to see the healing of these therapies. Next, we'll have to do the toxicology, which is mandatory before going to clinical trial, and by the end of next year, we are going to be ready, and maybe even initiate the first in-human trial. This is going to be a really exciting milestone for our team. Absolutely. Maybe just on the next part before. So I have two last questions. One is for you, Professor Schön. You know, one of the things people ask me is: how do you know that patients will tolerate the pain that might be associated with the intradermal injection of VHH antibodies? What do you think Scinai needs to do to mitigate this risk? And is this risk massive, or do you think that there is a motivation from those patients suffering from these psoriatic lesions located in the specific areas, that will say, "Okay, if it's only a little bit of a pain, I... It's nothing"? You know, what do you think is going to be the patient thinking or, you know, sentiment towards such a solution? You're on mute again. Yeah, you're right, Amir. The question of acceptance by the patients is certainly a very important one, and I certainly agree that it will take a lot of research to minimize the local pain. But having that said, my assumption would be that very fine needles that reach only the uppermost layers of the dermis, which is the connective tissue within the skin, just underneath the epidermis, will go along with very little, if any, pain. So my expectation would be that if we could manage that, the acceptance will be very high among the patients, especially since you can come up with a means to specifically and treat individual lesions that are not otherwise accessible in these patients. So my expectation, with all due caution, of course, would be that the acceptance will be there. Okay. And maybe next and last one is for you, Matthias Dobbelstein. Tell us, you know, you are together with Professor Görlich, you are also responsible of development of the future pipeline that is covered in the research collaboration agreement between Max Planck, UMG, and Scinai. Tell us a little bit more about the, you know, future things that are upcoming the pike. Yeah. I mean, we are in the process, and we have actually developed VHH antibodies against additional cytokines that also act as mediators of inflammation. So the idea is always to dampen excessive inflammation that would otherwise cause disease. So those include VHH antibodies to cytokines called interleukin 4, interleukin 13, TSLP. Those are those are examples of of new targets that that we actually have developed VHH antibodies against. And the hope is that this will also broaden the the range of indications, the range of diseases that that can be treated in that way. One obvious target would be would be atopic dermatitis, if you if you talk about skin diseases. But something less obvious that seems very attractive to me, too, is to try and treat lung diseases with that. You know, what we have recently published, actually, is a VHH antibody to SARS-CoV-2, to the virus that causes COVID-19, and we would put this VHH antibody into an aerosol, into small droplets, and those droplets would then be inhaled by animals, and we achieve protection of hamsters against COVID-19 in that way. Now, the dream is that we would do the same thing with VHH antibodies targeting cytokines, targeting interleukins, and this would then be a way to treat diseases like asthma, for instance, because you, again, you dampen the inflammatory reaction that you would otherwise observe in the lung. So on top of treating skin diseases, I think treating lung diseases by inhaled VHH antibodies, that's another strong perspective that I see for the future developments. Exciting. So I think with that, we will adjourn for today, and I would like to thank everybody for coming, and participating, and contributing your amazing know-how, experience, and insights, so thank you, Matthias, thank you, Michael, thank you, Tami. For additional information, please do not hesitate to go to our website, which is www.scinai.com. There you can find lots of information. You can also contact us through IR-