ENG THU 2 Immunobiological development how to overcome the valley of death strategies and techno
moving forward with our program we invite as chair of the panel the vice director of Visa M for Innovation for the presentation online presentation we invite the tener scientist for the B generary for uh Max plant Institute for complex systems Ivon Geno who will give the presentation Next Generation virus production from clone tobr to profusion very highest virus yeld she’s a doctor in buat analysis by the Mediteranean University in Marc France and also postd doctorate in Von University in Germany where she acts as a professor and in the max Institute she leads the Upstream processing team with the production with mammal cells the vice president’s associate of strategy for investment and development of portfolio in innovation of global Health innovate technology hay urab who will make the presentation vaccines for a safer world the pitfalls in the the development of vaccines for neglected diseases he concluded his bachal in bi molecular biology he has a master in master of Entrepreneurship engineering has a doctorate in biomedic engineer for from Brown University he has an additional master degree with global policies in University of California San Diego and he acted in finance and Technology areas and strategic planning due diligence of startups and project management in the Silicon Valley he was accountant for synch genomics for technology that goes from neutral genomic and until bio com fuels he oversees all the activities of Investments and access such as exploratory activities to seek for technological seeds to apply to Global health and its Financial uh models that are innovators we invite to this stage the professor in Technology Innovation projects from uh Jas Foundation Paulo neg Figo he will make the presentation managing Innovation and human health biotechnology startups in Brazil evidence and LaRon learns he’s a doctor in science technology and Innovation who through uh by sucess University in the UK he’s a senior research at Oxford University and a founder and responsible for the research program in technology and innovation of foundation so I pass the floor to so good morning I’m here again with you I was here in the previous session and I would like to thank your the presence of the guests here I had the opportunity to talk a little bit with uh Ivon and ayato online and I would like to thank we have a speaker from sgv in this space that is being uh very good for a symposium this is a subject that has gained the visibility and attention in the uh regarding Innovation for uh to uh the government for the efficacy that is expected and we have given a very fair amount of dise of attention for this subject and also we have been working with implemental science and I would like to confirm with the speakers if their translation is okay if you are receiving the translation uh uh can are you able to understand because we speak English but I know you have interpretation so I can see that you can understand me the translation is okay right can you confirm please I think that Evon maybe the to the Bone so thank you for joining good evening for you I think it’s good afternoon for ION and as a just uh pass the word uh uh to Evon to start uh ion please if you can jump in and uh I will uh um take a close look on the the time so we can have more time to discussion with the audience here thanks so thank you I hope you can see my screen I have no no view on what it what it does right now can you see the screen Ricardo yeah we can see the screen okay thank thank you so I would like to start by thanking the organizers for giving me the opportunity here today to to give you uh my idea of how I see that we can overcome the valley of death um I will start um Sorry by um explaining that um well how how this goes for virus and and vaccine production so at the beginning you have a biologist um or a medical person who has an idea for a new vaccine he he’s producing this in a small scale typically with adherent cells in a in a tea flask and he’s happy to have 1 time 10 to six infectious variants per milliliter um then he tries first um first experiments in mice for that he needs to purify the the material and this is typically easily done in centrifugation and then comes the next step and this is what everybody um always refers to the Valley of Death you have the idea and now make it to a product um so what you will need you will need an easy scalable GMP um compliant process and you are targeting to much higher um V virus concentrations so for um getting into vaccine doses of 1 time 10 to the7 or 10 to the8 variants per dose or for gene therapy and virotherapy even higher you are aiming for producing in your bio Rector 1 time 10 to the 10 infectious doses typically for that you will need need a high producer cell line and doing this with your adherent cell line that you have in your lab will probably not be be okay because you need a qualified GMP ready cell line and if possible it should be a suspension cell line so the Technologies today um are are emerging and we have already heard it in the previous presentations this morning on what great Laboratories that are there at the cnpm um to be there so I would like to give you a flavor that um actually um I see it not as a valy of death but the Sea of opportunities that we have today with all the um technologies that are available so if you think of a producing a vaccine with adherent cells you grow the cells um to um typically to two million cells per male and then you infect them with virus if you do this with what we heard this morning with adherent Vero cells um and on micro carriers um there you do typically also medium exchange and um yeah if you do this with suspension cells your um starting material comes from Shake flask and here this is already good you can today grow these cells up to 10 million cells per M um with the new new pack bed bioreactors available you can with adherent cells easily also reach higher cell concentrations than that with microcarriers um disposable bioreactor available today are 4,000 lit ones and for example also orbital shaken um bio reactors to up to 2,500 lit scale but also microbioreactors are there and this can ease up your process development so these are small bio reactors of the size of 15 mL working volumes and you can um run 48 um bio reactors in parallel on top of that there is now um also automated equipment to do clonal selection this is not so much done in virus production yet but for monoclonal antibodies cell line development this is uh used a lot and I would like to demonstrate to you on what this can do and finally um what I want to show you here as well is that you can today also grow suspension cells with the respective cell retention devices easily up to more than 100 million cells per M why is this important if we look at the viruses that can be produced um so the ones that we work in our lab um mainly for example influenza modified vaccinia anchora yellow fever or zika also a vesicular stomatitis virus you see they all have different shapes different sizes they have a different genome they replicate differently but moreover if you look at the cell specific virus yield so how much the virus produces per cell you can already see that there is also quite a difference so in in respect of infectious particles for example yellow fever if you are happy you get 20 variants out of one cell line of one cell so and and at the end you need to match the cell line you’re using with the virus that you want to produce and not every cell is producing every virus so we are lucky with a long collaboration record with many many partners we have been now collecting several suspension cell lines in our group that you see here listed and um if you now take such a microbi ctor and you do parallel experiments you can do a quick screening of all the cell lines you have available and this is what you see here so we have tested for a yellow fever construct all the cell lines we had and the reference in adherent Vero cells is the red line here you see that already by screening without optimized condition we were doing better than the reference we continued by taking one high producer one middle producer and one low producer cell line and try to add viral sensitizers these are small compounds that you can add at time of infection and they have an impact on the virus yield but you need to screen them so we did a screening of eight different compounds together with the company Vera and here you can see that we were able to increase the yield even more so first of all 100 fold increase by just screening and then another more than threefold higher I said we I want to show you about the clonal selection so this was a cooperation with satorius where they did the Clone the the Clone generation and they gave us 10 different clones to compare you see here what the machine is doing so you really start from one clone and then you you get you expand them and then you can test it and we had the task to test these cells for influenza virus production we weren’t sure if this was really possible to to to um be able to to see which one was bad best so we first performed Shake flas exper experiments just to see on the grow so some of the Clones were just reaching maximal cell concentrations below 5 million cells per M but some were really outperforming reaching up to 15 million cells per M so really high growth when we then tested in the amember microbi reactor again for virus production here you see the Infectious virus Tighter and the ha virus tighter which is the important one for influenza for total irus yield you could see that the Clones were doing quite different and if you try to put this into numbers um and compare this so here we look again at the cell specific virus yield here in total virus particles you see that one clone was really outperforming all the other clones so it makes sense to to do something like that to um already give you a good starting material now trying to grow into high cell concent ations today there are several retention devices helping uh if you are growing cells in in suspension to retain them in the bioreactor OR to remove the medium and to give the med the cells fresh nutrients and fresh medium some of them are membrane based and some of them are non-membrane based all you have the retention device attached to the bioreactor in the outside here you can see how this looks like connected to an orbital shaken bio reactor in our lab this is a holiber membrane that is doing the cell retention and by using this membrane we were able to grow um Aven cells from the company probiogen up to more than 30 million cells per m in comparison without the cell retention device you see here the batch cultivation just um of 1 million cells per M so if you now look at the cell specific virus yield it is important that you’re able to produce the same amount of cells per viruses per cell as you can do without the cell retention device and we could even show that we were outperforming um and and getting better cell specific virus yields and you can see that we were reaching very high yields up to 1 time 10 to the 11 total virus particles we also um tried this for another virus this is for yellow fever and for zika virus this is also an Aven celline that we um um received from the company Vala and um here we were also trying different profusion strategies so feeding strategies during this cell retention and um with our best run we were able to grow these cells up to 160 million cells per M and this is the typical titter value that you get normally and here you see that we were obtaining 1 time 10 to the 10 infectious uh virus particles per per milliliter and again we were able to increase the cell specific yield so we think that um with this system out of one liter of harvest we were able to produce 10 million yellow fever Doss finally I want to present to you a work that we have done recently on a vesic vesicular somatis virus this is a virus that fuses the cells before um they lies and before the virus um gets out of the cells so get these big particles in your bioreactor meaning that running this with a cell retention device membrane based could give you some problems this is in collaboration with a a group in in Munich and they came to us and said yes we have the virus growing to 1 time 10 6 in adherent cells can you try to bring it to 1 * 10 10 we did a first screening and in this case the bhk21 cell were the ones that were performing best and we um optimized the whole process for this into a cell retention profusion run and finally used a new membrane which is a tendential flow death filtration membrane um and we’re able to um perform here also um grow the cells to 20 million cells per M and then finally almost produce 1 * 10^ 10 varant per Miller so with over the years with a lot of collaborations we have been able to grow different cells that are good for virus production to very high cell concentrations we have cultivated them in different bioreactor setups with different cell retention devices and we Tred different viruses and as you can see um from here we are able to obtain very high virus Titus by that and um so this is how we think that next generation virus production and vaccine production should should go for and I hope I have convinced you that all these new technologies really are giving you a new sea of opportunities and if I what I heard this morning in the Innovation Hub I think you’re you are very well prepared in Brazil to take this route on and to to make this happen by that I want to stop with my presentation and acknowledge all the cooperation partners and my team in mook thank [Applause] you so thanks a lot Ivon uh uh the session is structured in a way that we’ll go for like a technological Improvement perspective then we will start to discuss a little bit more uh management and business strategies so that’s why we do have different topics and it it was great to have your presentation in on that uh uh deals with uh the very first steps we need to have good technology to move forward and uh we need to have more and more uh a better uh system to to move forward so now I I I would ask you ay to jump in for a presentation please and uh ion please stay with us great can you can you hear me can you see this um slides yes perfectly yes yes great um I start uh everybody so this is my um so thank you very much I hope I’ll be there in person in in one of these uh um these U coming years so I’ll be talking about vaccines for um safe world and Pitfall so development for vaccines for NDS from from a funders perspective so uh if and I’ll be giving a little bit about introduction of what we do as a global Health Innovative technology fund or jit fund which I managed the entire portfolio and investment um process so so we are um and then um then I’ll be giving a little bit of the um one one of the investment that we have recently um made uh in terms of the vaccines in the NTD space so Gat fund we do have a vision of a world free of neglected infectious diseases that affect billions of people and we are trying to leverage Japanese Innovation collaboration with Innovations outside to resolve solve neglected infectious diseases um and uh free that from the burden from the people who are suffering from them in fact what we do is we do make investment in R&D and uh so that the product development would have this uh cycle which would stop uh the on set of different diseases and increase U the productivity of people in in those Nations who are suffering from these um just uh to start off with you know where we’re coming from our from our from our funer we do work we are quite unique in a sense that we’re getting funding from both in public and private sector from the public sector uh 50% coming from the Japanese government and 25% were funded by The Gates Foundation and the welcome trust so the foundation s providing us 25% and then the rest 25% coming from private sector and uh this particular model of public sector and private sector matching the fund is actually being replicated in places like Korea there’s right foundation Which models exactly the same and also you’re probably familiar with sepi Coalition for epidemics preparedness and Innovations which also work with this model public and private Partnerships so we have invested over the last 10 years over $300 million for product development in in the area of malaria TB and and neglected tropical diseases uh which I will talk a little bit more on but as you can see uh our interventions vary from drugs vaccines and Diagnostics and of course vaccines is our main topic of discussion today which covers about a quarter of our portfolio and we do cover everything from Discovery to clinical end and we have part uh partner with over close to 200 um Partners around the world and uh you can see uh how we have some presence um in bra Brazil as well with uh a work with fangos um in in one of the drug projects that we have um um I’ll skip this slides for now uh very quickly but just not not only do do we do R&D but we do actually connect with access and delivery which which kind is which is going to come to this U the thing about this um valley of death which uh our previous speaker has spoke um a little bit about um of course um ntds uh in vaccine space we do uh work um we have funded multiple projects and uh in the space of shagas disease Deni leishmaniasis and and leprosy these are the antd vaccines that we have funded um up until now ranging from preclinical or lead optimization stages up to um clinical phase one of or 2 A U for the case of leprosy and we we are actually seeing a lot more promising projects coming through and just referring back to uh our previous speaker Ivan with respect to the Valley of Death I think there are multiple valys of death I think uh it was very good start that we started this session with the translation R&D gap which was uh very well elaborated by the um Ivon but uh I think there’s also Al other types of valys of death uh with regards to approval policy of introduction challenges of course vaccines they have to be injected into um Health individuals and uh it does carry that um additional um usability um burden um etc for introducing these um interventions on the ground and also the uh the Val the the valley or the line that you see at the bottom the in efficient funding you know unless you have the funding for doing these interventions there’s always that uh uh you know you cannot Advance some of the r& DS that you you you would have so that there’s that inherent valy that that’s at the U that underlines um all the um factors as well the third um value being the access and delivery challenges with even if you have the um product that’s already registered how can you actually bring it to the to the ground and um that’s another Valley that I will um touch upon a little bit um just going through the first Valley of Death translation R&D um gap of course I’m not going to Bel the point that yvon has mentioned uh with regards to the um the complexity that that that that’s actually there coming from um translating from R&D space to actually moving into product development stages of course it’s very important for us to PRI prioritize an early vaccine development pipeline um identify the gaps and align the target product profiles which we really do emphasize uh for that investment um that we make to know where you’re exactly um targeting and if you don’t if you don’t know where you’re targeting obviously you’re not going to be able to make it make the product where you’re aiming for at the end so not only just start with the R&D but have the end goal in mind is a key to jumping over this valy of death and with regards to Second valy of death or or approval or the policy of introduction um challenges of course there are multiple regulatory um agencies around the world and each Regulatory Agencies around the world not only the FDA or EMA but also the you know who listed regulatory um authorities in how you’re actually going to be approving especially for ntds if they’re endemic if they are in endemic countries in different regions you have to know about their regulatory um cultures or regulatory procedure me in order for you to navigate that space um to successfully enter some of these products going in with regards to funding of course uh you know we’re only part of the puzzle uh we do make uh funding for NDS in in vaccines um but um someone like us just being able to fund product development but also looking at some Innovative financing mechanisms like uh such as the prvs or priority review vouchers or knowing Advanced commitments of the vaccine purchases by different entities is also another way of looking at ways to um tackle these insufficiencies of uh funding and of course access and delivery CH this is a whole talk in itself but you have to be able to understand even after you have the regulatory approvals how you’re going to be moving from that technology that you Cur that you have that’s been regulatory approved but then bringing into the different countries because you do have have uh not only if you have to consider the regulatory approvals but you have to think about usability and how they’re going to be procured um stockpiled and delivered onto the ground so there are multiple things to consider ahead of time now let me go back to a little bit of the Sciences in terms of what we um have invested in in this leishmaniasis U vaccine in the world currently there are three major pipeline of vaccines for L anasis um of which you can see uh three three of which you can see here the one that I’m going to talk a little bit on is the um what you see in the middle uh the centrine deficient lishman vaccines the laa 10at vaccine by janova biopharmaceutical in Japan in collaboration with Nagasaki University in Japan of course you you know very well about L anasis and its uh impact you you can see the um demo Geographic um expansion of how these are shown in the world and um this is if you have a vaccine tool even with a 50% blocking vaccines it’s modeled that we’ll be able to substantially uh decrease the amount of the um V uh that’s endemic in the world even with a 50% blocking you can actually go down uh with uh with that level of uh elimination and this most effective vaccination strategy so far as at least this is what our um grantees claim is it is possible by having this uh um live attenuated vaccines light attenuated lanin um where they would have the centry gene um taken out using crisper technology where they will be able to achieve this genetically um modified um tated parasites which which is not going to cause infection but you’ll be able to have a protection um so it’s it’s you know it’s it’s an all technology brought to life again U but using some of the gene editing technologies that are that are more Cutting Edge that weren’t available back in the days so to speak U it is a genetically modified alternative vaccines it’s it’s still it’s on the verge of getting into phase one but they they do have advantages over the other approaches and and let me show you a little bit about some of the initial animal um um um data um so to speak so Cent Gene you just removing sentr Gene for those of you who are participants in this panel you know about the um the crisper cast 9 technology basically editing the gene out and then you’re doing the inital growth for this well strain and the centrine deficient Gene and then uh you’re making sure that the um the whole with the whole genome sequencing you um you make sure that the centrine gene is taken out and you are immunizing these uh centrin deficient uh lanin parasites um onto um the animals and then you’re trying out with this sand flies uh basically you’re infecting them using this particular vector and what you see here uh this animal model product uh what you see on the on the top left um the immunized uh Mouse versus a non-immunized challenge Mouse you can see the um the weight loss uh being seen for the um hamsters for V visal anasis and then of course you can also see the um cutaneous l anasis in my by looking at some of the legions that are being affected with the comparison being shown uh on the bottom right in in in the graph there um so just as a summary of this uh particular um study that was done by um um professor sosar in Ohio State University in collaboration with Nagasaki University and Genova who is uh basically doing the manufacturing of this um centr deficient um parasite is that it is safe um and it has the has been shown the immunogenicity with high efficacy with as I said it’s a second generation of lman lonization U bringing up to speed basically combining all technology but combining with the new um Gene editing uh technology onto NTD space to create this particular parasite now being uh now it’s being planning to be tested in Phase One in the coming coming months so just concluding I I kind of rushed through this uh but just um coming back um to this uh of course we talked about the valley of of death uh the translational of Science valy of death as well as there’s a second Valley of Death about the regulatory valley of death which requires alignment of the regular policy financing Continuum but there is that portion of the financing value of death where that sustainable vaccine development will be key um for by using uh some sort of a collaboration of course we um as ourself jit fund um we’re just one piece of a puzzle uh which we would welcome any of the participant who’s um in in this uh in this room um to contact me if there’s any um interest um um in our work um as well as any potential synergies um um that we obviously observe for some of the programs that we see uh because we do make investments in not only vaccines but also in Diagnostics and Therapeutics we have seen some programs being able to be um um bunched up together to tackle the program together for instance the leishmaniasis vaccine that I mentioned at the end um that particular technology is been applied for lman in skin test um as a way of testing um um how the whether the patient has been subjected to this this this has has had L anasis before being able to use that as a diagnostic as well so we’re trying to look for innovative ways to combine Technologies together this last slide here um just I don’t know maybe it’s just a self-promotion in a sense if you’re interested in finding out a little bit more about um us uh please uh go to this QR code if you if you um sign up on the newsletter we’ll be able to send out the next request for proposal which is going to come out in in June this year so with that uh I’ll acknowledge uh Professor AE SAR for his his work um on some sub sides as well as my colleague Cecil who has helped me create these slides so with that uh I’ll pass over back to the chair and [Applause] has improved remarkably and uh thanks uh for your presentation I’m going to give give the floor now to Paula nras you can make your presentation from the pulpit from the lecturn and over there and we’ll move on to Q&A right afterwards uh good morning everyone it’s a great pleasure to be here with you I’d like to thank thank you at the jul FAS foundation and fire Cru for the chance to participate in the symposium this that we have a research problem and technological learning and Industrial re industrial knowledge I’ve been a leader at the Vagas Foundation involving the management of the process of innovation it’s a set of startups in Brazil in the area of biotechnology for human health I have I’ve had the privilege to uh to lead that study with a group of researchers that are highly talented involving bringing together for example thank you bringing together Professor Danielle oel from the University Federal University of Rio De Janeiro Marcela Cohen from the feral University of luminan Pedro gz a master’s student at the State University of campas and the assistant researcher at the jul Vagas Foundation Lana palini post do at the oswal Cruz Foundation and Bernardo cabal a professor of economics and biotechnology at the federal University of Baya that is we have an extremely varied and distinguished group with contributions that are very important to this study the motivations um for this study mostly involved um facts that even in the advanced economies Investments at risk high-risk Investments have not been uh geared to the science and health studies they’ve been geared the digital um Technologies and that there thereby avoiding risks in the Health Arena even accelerators have in a way they haven’t felt so attracted or drawn to the area of Health Sciences hence many Ventures and startup um initiatives have not gone too far due to lack of Investments um and certainly also in the literature on Innovation there is a scarce of studies involving the process of innovation and and biotech startups and how they may evolve till the stage of commercialization successful commercialization this scenario has been aggravated has been worsened in the context of developing economies which is the case of Brazil in which we have over 200 million and we have a demand an increasing demand for health Public Health Services and we have because of the universalization of the public health system in Brazil there is an increasing demand at and for therapies and biotechnological therapies and medications and certainly for pharmaceutical inputs at the same time the country has a very low supply of pharmaceutical inputs and biotechnological products which leads to high Imports large volumes of imports and that has been even um greater at at the time of covid a greater dependence of imports leading to a commercial trade deficit of over 7 billion RIS in Brazil and even though we’re the sixth largest pharmaceutical Market we only produce 5% of its inputs we produced 80% of them in the past but we have fallen down in the that in that production production there is an urgent need to better understand the the ecosystem biot technology for human health to try to see how we can strengthen it that’s why the objective of this study is to understand this process of accumulation of capabilities to produce and innovate and biotechnology for human health in the Brazilian ecosystem for health and biotechnology especially at the level of startups the analytical model of the study basically involves three large variants the central variant variable basically is the level of capacity technological capability which is a set of resources that will allow companies startup companies and and organizations and institutions to undertake production and also Innovation that’s a central variable and we would like to understand the sources for these capabilities and the results the outcomes the impacts that the accumulation or lack thereof of these capabilities have generated based basically our study has involved a set of 18 startup companies in two large four large areas inv vitro Diagnostics startup molecules and Gene therapies and tissue therapies and uh they have a time they’ve been in operation since 2008 some of them are younger 2021 for example the names have been codified because the startup companies their names would not be uh publicized we have an agreement with them we have a very interesting uh set of startups even though the sample is not too large but the study has been in-depth and they have offered Rich evidence wealthy evidence to illuminate public policies to shut light on public policies they are scattered around the southeast and south region in Brazil especially in the state of s Paulo and these the study started in 2021 and involved a series of steps going through recursive processes coming and going and so on and so forth so that we had a could obtain evidence in depth evidence and qualitative de uh also is this and the academic studies that review literature they obtain from the companies information and and the final they uh generate a paper that will be uh delivered to society so we seek to involve these startups since the beginning of the study so that they could help us with the design and the questions of the uh research so we made several workshop with them to feel the problems and the main issues and their pains and that this would could be embodied in the design of the city so they followed through all the study which gave us better connection with this important side of the demand in terms of business model the uh these startups are distributed among several different model business model the also the hybrid ones which involves uh product platform and uh platform and products and their Investments are basically uh that come from governmental bodies such as the development bank and if we opened the that part of the Investments we will find those that come from the state agencies for Innovations such as embra and F and we also have multi strapping Investments so going to the main uh variable which is the regarding uh technological uh capability we understand this is a storage of knowledge that the institutions accumulate to generate Innovative action so there a set of knowledge that distributes such as human resources skills uh business skills professionals and uh Technical and physical systems and so on and the case of the startups we prevails the human resource and the researchers and the uh professionals and the others are more well distributed in the ecosystem and the idea when we examine the technological capability is not if they have or not but the degree in which it exists so this is why we uh measure the level of technological capability in these startups so we avoid the conventional proy in literature and we identify this maturity model that is based mainly in the revealed capabilities that is the capability of the startups revealing their activities and what they’re able to do another distinction is where you differentiate the production and Innovation one thing is producing of vaccines with an existing technology ology and you’re user of this technology and the other thing is to develop the capability to adapt this vaccine and even more uh scale up and create a new vaccine so we identify these levels and up to which point these startups develop themselves in this the level the cap capabilities uh these are the results and from these startups to and for reach the levels two and three so they are able to adapt in Tech and existing Technologies uh and with a new degree that is for themselves are in the regional context but seven of them advance to the uh Advanced uh level next to the international Frontier but here we have gentlemen and ladies five startups that could reach world class level and two of them went to the commercialization phase it’s a great Merit considering the concept that we have the hardships that they face to operate in a country like Brazil to reach this level uh carrying out activities that are new to the world in a very difficult area so we have much to learn with these startups they generate interesting evidence to public policy generation and how we can support these technological capabilities and not allowed to uh these levels weaken themselves and get lost in the ecosystem so we should also look at these fives that could reach this level five this level five and some of them are hybrids and the type of Investments that they receive is are mainly for spap PK and faps faps and in terms of the Partnerships that they establish and they uh carry out many Partnerships that are local uh universities that are local in Brazil also with specialized consultants and private International research centers so the localization of these partners are Latin America followed by nor North America and this accesses from where they seek the knowledge to they can carry out these capabilities they use external sources for uh such as training abroad Partnerships some of them are basis in research and development some are not but they also carry out internal efforts for a knowledge creation so going to the results uh and the outcomes and the levels of these five startups we have uh uh outcomes in terms of patenting activities some in the US and also in Brazil and also results in terms of technological activities in the production and markets so in the end of the presentation we’re going to compare those that were able to achieve this commercialization stage against those that were not able to do so so in terms of Partnerships they all can uh make a Partnerships with a specialized consultants and also with local universities but there’s a difference those who could get to the commercial commercialization phase they have very important Partnerships with Pharmaceuticals and biotech institutions in addition to uh having these Partnerships with the local universities and specialized partner partner uh Consultants so there a clues that you can uh observe to get to the commercialization phase so the regions are Latin America and North America the efforts that they make are basically of uh International PhD International collaboration but also local and also internal efforts of knowledge generation so we can see a distinction in terms of efforts of learning uh that for those that could reach their commercialization uh against those that could not reach this level so regarding results obtained and this commercialization stage for uh P respectable patents in the US and Brazil and they could also reach um Market outcomes for these that have reached this level so these studies uh allowed us to uh issue some recommendations in terms of ensuring the needed funding for them to generate the Innovative activities the investment in Practical uh in learning pra practice to get to this level commercialization get to higher levels of technological capabilities also these in develop uh Partnerships with bi biotechs and pharmaceuticals is also very relevant in the process and the development of capabilities uh Beyond Technical and scientifical so Technical and scientific is essenti but it’s not enough so there you need to develop the skills a management skills marketing entrepreneurship skills so adjusting the business in itself that’s why it’s important this partnership with the management training for public policies we recommend we strongly recommend the simplification of access to funding which was a issue that was very much discussed by the startups the difficulty of finding Pathways of the lack of integration among the organization that operate the fundings and also consider the capacity of the Innovation uh of a a main activity in this process also to support uh startups to go through the com go up to the commercialization phase and also to uh expand the the commercial uh skills so I’m here thank you very much thank you I’m available to answer your questions thank you very much now or Paulo thank you very much your the study that you carried out is ex Ence and the previous organization who seek these spectrum of different initiatives and we have we’re having a tie time here we should end at noon but I will ask a little bit of patience so we have three minutes to have the opportunity to have one or two questions to uh the panel we have one here with and the questions that we received online we are trans committing directly to the speakers and some of them have are very specific that I think that they’re of uh much more of specific interest of one of the other so thank you very much congratulations for the three speakers and Paulo I have three questions for you one is the role of the meetings in these studies the the nule of te techological INF information and we show that 56% of the startups were in s Paulo and when you separate these five that reach the global level how do you is this divided uh in s Paulo and the other states and the other thing is the degree of investment that was done and if you have this number and I know that fesp role is very much is a key role compared to other states and the level of participation of the students especially of postto in these startups this is a great questions the nits uh nits are uh they belong to the federal University the public university especially in the Southeast region and in the south region of Brazil and they participate in these partnership with the startups and regarding the specific values we do not have this evidence but it’s is a important uh evidence to be seek in future studies and regarding the participation of students as yes in some cases we were able to find a participation of students but still very much reduced so this would be a suggestion for the public policies the invol M and the fostering of the researchers in this sense regarding these five startups the great majority are in the state of s Paulo for sure so and they reach the highest levels of the study uh so unfortunately we have to close our panel colleagues for uh being uh with us and we will direct to you uh any further question questions uh uh I received some specific questions that I instructed the team to direct to you all and I I’m pretty sure that we will have some followups from your presentations for all the three of you uh directly from from my team here at least thank you all for for being with [Applause] us we still have one session thank you very much thank you very much hi for your moderation thank you speakers and thank you um all well moving on forward to their program we invite as a chair of our prga panel the V Vice director of Boman Alberto bioty he’s a doctor in biotechnology by the federal University of patas he has a postdoctorate in the University of California in Los Angeles and uh Pastor Institute and uh we he acted as uh invited research and vaccine develop developer in GSK lab in Vienna Austria and we also invite prega Corporation senior research researcher Julian no Avis who will make the presentation platform of development of rapid and sensitive method for analy detection he’s a doctor in Pharmacology by the federal University of s Paulo he was a researcher of of the genomic uh Institute of for of arst and also script Research Institute at prega he worked with the development of several Technologies used in the Breakthrough of medicines the group leader in the Institute of leol noal Leonel Navaro who will give his presentation plant and micro uh extracellular vesicles as carriers of RNA based therap Therapeutics so we remind you all that this presentation has uh confidential classified data so it will be interrupted for those who are online for those who are present we ask you that do not use your smartphones either in video or photos or any kind of recording so he had has experience in the study of interactions pathogens and host and innate IM immunity epigenetics and sileny of RNA his research team was Pioneer in the role and the regulation of small RN intracellular rnas and their interactions with gas uh host and bacteria and identification and characterizations of bacteria suppressors and also the control transcriptional control of immunological for this metalization of DNA so he founded several companies and spin-offs developing techn disrupted Technologies to control infectious diseases of plants animals and humans so he’s currently uh director of researcher for natural scien in friend scientif so I pass the floor to maros Alberto medos excuse me I’d like to thank you and Julian for accept to talk in the in this event the International Symposium I I hope you enoy enjoying the your lecture go ahead please you all I would like to thank the opportunity of being able to talk to you all my name is julianis I am a senior researcher at SCA Corporation I’m going to talk about a set of solutions uh driven towards Theo Messengers and we talk about uh IM uh it says we think about the Elisa essay and we think you know that uh the time that is required to generate after uh the cleaning of the whs the wells and the regulators and obviously the time consumed with the proceedings are taken since you uh take several hours to have the results so thinking in a way of solute solving this process and to simplifying it we thought about the lumit platform so can I change this I’m not going to take the risk so in this limit concept these essays to simplify they consist in two primary antibodies that are combined with uh another uh substance and they in the presence of this analytes they unite and they conduce to the complation the activation of these analytes so in the substrate you have the bioluminous uh results one of the advantage you reduce consequently you reduce the time of incubation and Eliza can lead several hours to obtain results and this limit essay the time is reduced from uh to 120 minutes to hours one of the advantages is the high sensitivity for those researchers that work with cells there’s a possibility of reducing the number of cells um per study and the sa window is it’s better and uh also the development the possibility we we say we usually say that it’s a homogeneous essay because it doesn’t require the cleaning of the uh blades you add re agency do the reading of the results and it’s easily adaptable to the uh heart once I’ve said that we can Envision a series of applications possible applications for the Lum platform the detection direct and indirect detection of analytes at protein protein andaction studies development of competition essays and also uh the detection of antibodies when it comes to the direct detect detection of analytes the requirement main requirement is that there should be two primary antibodies and these antibodies should not be of different species the advantage as you maximize the number of antibodies that may be combined in order to select the pair that will be ideal for your essay when in a short span of time using this approach today we add many uh uh Solutions as you see on the screen interr and two and four F Alpha as well as hereditary factories like bgf or insulin but also there is a possibility of researchers generating their own in-house method through the use of essay kit which has all the necessary components to conjugate your antibod of Interest including fragments of the luminosas if the researcher does not have does not want to uh generate his or her own reagents the other option is to do the pairing of of the antibodies of Interest with secondary luminous antibodies these antibodies I can tell you they come in different flavors like uh anti uh Mouse anti- rabbit anti- goat antirat the difference in that’s adaptations you didn’t have to do the conjugation as I said before and this is an approach that’s used currently in intercellular events like phosph phosphorization and cellular degradation another possibility of this platform as I said before is that it allows for a study between of 1 to protein interactions with the use of anyti bodies that link to purification tags such says tack FL tag or GST this tool is used for example in screening of drugs like protex that induce the protein protic disruption of deregulated unregulated proteins in cancer cases another possibility also is the development of competition essays in which a tracer molecule be it a compound linked to luser fragment or an or an antibody for example it’s dislocated through the interest analy losing U luminescence for ex bioluminescence an example of the solution developed by prega was this SC in which you detect antibodies that link to the Arsenal detect receptor uh this methodology can also be used in essays for the uh the identification of metabolites the the last example I’d like to bring to your attention is the possibility of using this platform to detect platforms be it for the confirmation of um uh exp the exposure of individuals to certain pathogens or to try to visualize the potential of neutralization of these antibodies and human samples and we can use these tools also in the discovery of antibodies with Therapeutics and antiviral activities to exemp what I just said in the past in the recent past we’ve developed a limit biochemical essay that consists of the interaction my pointer is not working too well but I’ll try to explain it to you better step by step we have developed an essay essay some time ago it consists of the interaction between the RBD portion of the spike protein on SARS go 2 with the as soluble receptor the way how do how does a method work in the absence of an interference or an antibody or an organic molecule these two proteins find themselves in a solution they do protein to protein interaction and these protections have an fct tail derived from an antibody and that allows for the use of M secondary movements uh antibodies that will lead to the Reconstruction of analog M Ras and the generation of bioluminescence the absence of an inhibitor agent you have 100% luminesence And when you have an antibody or a molecule or something that interferes in that interaction the RBD will be sequestered and it will be kept from interacting with acid 2 and surely consequently limit antibodies won’t be able to get close to the luminesence the loss of bioluminesence in this case is a result of the presence of an antibody or a molecule that affects and that that interaction to demonstrate the concept and the prove the concept that this methodology Works we’ve did we’ve done a screening limited screening to uh antibodies available commercially available and we can assertain the fact that in the first part of the graph and the samples that that where where we didn’t have any bars these are antibodies with against Spike protein and Spar spark Co 2 and our method was a detect these antibodies with a neutralizing potential as as and and the control antibodies didn’t have any interference and the interaction between our ABS 2 it’s worth highlighting that the bars in the middle middle of the first graph are cut in half these are antibodies that were generated in the first outbreak of SARS Co in 2003 and they have and they they they’re able to interfere with up and up until a certain point we have tested also sequences generated with encyc predictions based on the on the interface the reg interface region between the S2 S2 and RBD receptors and we tested to see if we would be able to detect this interference we confirmed the remarks published at that time that three sequences that the authors called mini proteins were able to interfere with the rbds S2 in interaction they demonstrate the potential of this plat platform to you to be used in discoveries of antibodies with therapeutic potential in this case antiviral activity but it’s not only that you can do many studies molecular studies in this case we looked into the role of of the mutations present in RBD in the process of interaction with S2 various mutations were reported on and many variants and uh the concept is depending on the Affinity probably you will need uh more analetto to be able to interfere in the rbds 2 interaction to mutants that we have tested we noticed that three mutations caused a dislocation of the curve a displacement of the curve which suggests that these mutations conferred a certain increase a certain degree in increase in Affinity as S4 S2 VAV S2 in addition we looked into whether these mutations would have a role in the process of evasion of the immunological system of immune system that is if they would prevent the linkage of the antibody and and we had tested this small panel of antibodies we went back to that panel we generated rbds with FC portion so we could just replace them with the RBD that we have in the SC and we noticed that for two antibodies that led to complete neutralization two mutations were caused they caused the complete loss of ligation and it’s worth noting that one of these mutations n 5001 y has a double role it plays a double role it increases apparently increases Affinity with S2 but it also inhibits the linking of antibody that was previously able to neutralize the interaction between RBD and S2 and we looked into mutations of variant uh coming from sequences coming from variants um of SARS Co 2 from the United Kingdom South Africa and Brazil we noticed the same effect since these three variants have that mutation which reinforces the remark that this mutation can confer can lead to an escape of the immune system what when it comes to um human samples we did an analysis of samples that were positive confirmed for PCR and negative samples so as to observe the distribution of those samples in order to ascertain a off that could help us when we would test unknown samples when it came a time to test unknown samples as we can see in both cases thir samples of serum and plasma and we could notice that negative samples began to group together below 30% at a neutralization value of 30% as for positive samples in Grain we noticed that these samples most of them tend to group together come together between 80% and 100% % with this information we have defined a cut off line and 30% neutralization so as to distinguish between positive and negative samples and that led to a performance of u a sensitivity of roughly 80% in a specificity of approximately 100% in these cases with this Criterion uh the way we have def find it we analyzed we ran a temporal analysis of samples of patients that were infected by SARS covid and we’ve tested several samples throughout time and we noticed that the antibodies that were able to interfere in the RBD and S2 we be began the surface and the on the 12th day and these individuals that were affected the antibodies lasted up to six months so similarly we tested also our methodology with Pat on patients that were immunized through the with the Corona virus vaccine and we noticed that only those individuals that were immunized after the second dose there were there was a spike in the neutralization immunization the sample was able to completely eliminate the uh the bioluminescence signal in our methodology these results were published recently and recently we used this information the the Lessons Learned in the course of the pandemic to expand and try and develop new serological uh Solutions using the git platform and two neglected diseases that we are keen on developing our zika because of the historical background and dangi fever and because that is a problem a public health problem in Brazil and so many countries uh and the concept of U the essay the design of the essay is a bit different because in this case we used antigen antigens related to nuser nphase segments fragments and if there are antibodies present that recognize that antigen that antibody through during the linking process will complement noas generating a bioluminescent signal and preliminary results we can observe in the graph on the right side of the screen on the on the left side of the screen excuse me several antibodies allowed that we could we were able to detect several of them which makes us uh see that we have we can use that platform for other purposes different volumes of reactions can be used um showing the flexibility of this platform and miniaturizing and maximizing the use of the reagent but we also know that serological essays for the detection of antibodies against arbo viruses there’s a problem of cross uh contamination we use fonal antibodies dangi our kit was able to detect that’s the first graph to mitigate this problem we developed a blocking agent that was able to neutralize the presence of this antibody contaminant antibody but most importantly the presence of this blocking reagent didn’t interfere in the uh reaction and the identification of Z antibodies it’s still in progress and parallel to it using the data the same concept we’re developing a test to detect anti- dangi antibodies following the same principle using antibodies antigens and preliminary results we were able to detect and in this case the same problem surfaced when it comes to zika but we were able to develop a block Kang agent in this case that inhibits across re uh reaction but it doesn’t refere in the results but it’s also it’s still a pro project underway it’s currently underway and we’ll have more details to talk about it later on this topic uh just to wrap up my remarks today I presented to you uh the lumit platform the detection of the interaction between virus proteins and and and and and uh infected animals and their proteins it’s easier to to then host proteins they can this methodology can be used in addition to a virus neutralization platform the IM immunized animals or not this um stud molecular studies can can be can be done with through this platform to understand the role of mutations in the interaction between these two protein te and also they can expand it to other viruses of interest and most importantly this essay is it can be automated and miniaturized to wrap up I’d like to acknowledge all the uh scientists involved in the study we cannot we can’t do anything alone we depend all always rely on a network of collaborators and I would like to extend a warm thank you to all the participants of this panel and I’m I’m available for Q&A after leonel’s presentation we’ll run a coup of a series of questions after lol’s presentation Byron please you have a pointer pointer