TRANSCRIPT
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Welcome to The Chain, the podcast exploring the lives, careers, research, and discoveries of protein engineers, scientists, and biotech professionals. We look at the impact their work is having on the field and where the industry is headed. Tune in to stay up to date on the newest advancements and to hear the stories that are impacting the world of biologics.
Rakesh Dixit:
Good morning. My name is Rakesh Dixit. I'm very pleased to welcome today's episodes of our Chain Protein Engineering podcast. To me, it's a great privilege to introduce Dr. Vibha Jawa. She's a distinguished leader in biopharmaceutical sciences and especially in the translational immunology. Dr. Jawa has made outstanding contributions in the field, especially on the emergency assessment and biologics development, with an extensive career spanning leadership role in both industry and scientific organizations. Her uh outstanding work has shaped how we understand immune responses to biologics and her thought leadership continues to influence drug development and regulatory science worldwide. Dr. Jawa, uh we are extremely honored to have you with us today and welcome to the podcast. So let me start with your first question. Um, if you want to tell about your career uh very quickly, in a few minutes, that will be helpful, and then I will get to the questions. Yeah.
Vibha Jawa:
Sure, yeah. So I started my career in uh in the United States of America uh almost 25 years ago. Um, and I was a postdoc at the University of Pennsylvania working on gene therapy uh research at that time. And so my first job was at a startup, uh, which was a UPEN um UPEN initiated startup by Dr. Katherine High. So I got an opportunity to work uh in a smaller setting and understand all the uh stages of drug development there, especially related to gene therapy of hemophilia, which was brand new technology and brand new disease indication uh for this modality. Then I um this this was in the Bay Area, so I kind of transitioned into a bigger biotech, Amgen, in LA, uh Thousand Oaks area, uh, right after. Um, and I spent considerable amount of my time learning about drug development now for proteins at Amgen. Um, so that's where my formative years of immunogenicity were uh really like I understood how the different components of drug development can uh introduce new risks to immunogenicity or biologics. Very recently, 10 years ago, I came back to uh East Coast and I joined Merck.
Vibha Jawa:
And Merck was looking for someone who could do their strategy for immunogenicity for vaccines and their biologics pipeline. So I spent four years there and then came to Bristol Meyer Squib right after and led this bioanalytical group, which does uh immunogenicity assays, PK assays, biomarkers, and more like CAR T cell therapy-based um immune responses. So um, four months ago, I just joined um Epvax, which is a small biotech uh who does uh customized evaluation of sequences during protein engineering for liabilities to immunogenicity. So the common factor is immunogenicity or immune response, but I have had uh the opportunity to work for both bigger and smaller biotechs.
Rakesh Dixit:
Thank you. Thank you very much, Vibha. Um, so from your career, uh, could you tell me what is the most rewarding project that you have worked on? Of course, you know, it's like having your children, every project is rewarding, but there are some special projects we all have where you feel like, wow, I've made a huge impact. Uh, could you elaborate on that, please?
Vibha Jawa:
Yeah, sure. And uh, and I want to go back to Amgen. I had joined as an early career senior scientist, and my manager thought that I was ready to do uh work on a project which was very close to licensing application, which I thought, oh great, like um I didn't feel that I was ready, but he thought I was. So, anyway, so we were uh working on this project, which was a pepti body, like a fusion protein. And uh interesting, or the thing that challenged me was that it was not meant for a huge population, it was for a very rare disease. And um Amgen already had some level of like failure with uh recombinant protein, which was meant for the same disease uh where they had neutralizing antibodies. So this fusion protein was designed so that it would have very low risk for these people, but still would be very useful because it was meant to treat uh spontaneous hemorrhages in uh little kids, and they would go to play, and then suddenly they would uh have a hammer, like sudden shock and their blood won't clot. So it was uh something to um hack with the uh blood clotting, with the platelet function.
Vibha Jawa:
And so I spent a lot of time on it, and uh FTA was closely watching us because we had already suffered from neutralizing antibodies to the recombinant protein, so they were very much on top of us. So that interaction with the agencies at every step, and how would you develop something which could uh make sure that you don't develop an immune response to this FC fusion protein, but still be efficacious? So that was so close to me because I was just breathing AMG531 all the time. So then it did get approved. Uh it got approved as a drug. It went through uh ODAC, which I was uh had a fortunate uh um had fortune to go attend. Um like this is the advisory committee for oncology, and there were all these uh physicians, and our um RD head was there. And so I was, uh you can imagine, like I was so overwhelmed. Like there are all these very knowledgeable people, but my manager and my head of department uh said that you have to go because you know this in and out. So if questions come, you can answer it. So, yes, the AMG Pi31 became N-plate, which is our approved drug now for multiple decades, and it has been helping all these rare disorders called uh uh immunothrombocytopenia idiopathic. So it's called ITP and it's treating that disease.
Rakesh Dixit:
Very nice. So just to just on the same topic, and that has been of interest to me because uh many years back I worked on a molecule with Amgen. I think you maybe remember, you may not. It's a CA BYTE program, uh, if carcinogenic embryonic antigen bite molecule um uh and that we had collaboration between AstraZeneca, medimune, and and amgen. And what was so interesting to me, that molecule, that byte molecule, almost 80%, 90% patients developed minogenicity. And people ask me what is so unique about that molecule caused so much immunogenicity. And so I would like to hear your thoughts that why these byte molecules and biospecific, of course, they are unnatural molecules, why they are a little bit more immunogenic than than other uh biologics molecules. And yeah, it will be interesting to hear your thoughts on that. Yeah.
Vibha Jawa:
Yeah, and and I think that uh that you just said that, right? Like when the body sees something which does not look like uh a natural protein that they're used to and we have been tolerized to it, then the first instinct is to react because so a bite or a bi-specific, uh, they do look very different. They are like what we call the Frankenstein molecules because they're just uh we are trying to engage the T cell on one side and engaging the tumor antigen on the cancer cell on the other side to bring them together. And so uh definitely I think uh what happened was that one, yes, they were a structure that the antigen-presenting cells or immune cells recognized as foreign, but then the other component was the engagement with the T cell. So T cell is your uh cell which is going to drive that T cell-dependent antibody response. But this is the same T cell which is also going to kill the cancer, right? So if you have a protein which gets taken up by antigen-presenting cell, and then you expose that to a T cell, which is already wrapped up to go kill, uh, it's going to take that sequence and also drive a T cell antibody response at the same time. So, so what we've found was that T cell engagers, PI-specific with a CD3 component or any other T cell activation, uh just meant for cancer killing, was also causing this bystander almost like a collateral effect of increasing the or enhancing the immunogenicity.
Vibha Jawa:
So, but you know, what we have found though, and this is something I spent a lot of time in MERC too, that we were starting to see the same phenomenon when we did checkpoint inhibitors, which on monotherapy would be fine. But the moment you added like a CTLA4 antibody, the immunogenicity would go up. And the reason is again, like, you know, Kitruda or Nivolumomap, they are very low immunogenic potential molecules. But the moment you give CTLA4 antibody, T cells are, they have lost their brakes, like they have lost their tolerance thresholds. So they will express whatever is being exogenously administered to the people. So they were, it's almost like an autoimmune condition where you can react to your own self. So what we are doing now though is we are asking, are we really seeing anything meaningful? So yes, you would make these uh uh extraordinary immune responses, the incidences go up, but are they really impacting the efficacy or the outcome of these subjects who are being given these drugs? So one thing that has happened in the minogenicity field is we have made very sensitive anti-drug antibody assays. So, yes, we will see an increase in incidence, but only a subset of that is really relevant. Like, you know, so it's more important to not worry about like, oh, I have 60% incidence. You have to ask off that how much is really uh changing the impact on exposure or efficacy or overall or both or both, you know.
Rakesh Dixit:
And I think our problem was with the CA byte program, which I remember, and that was that was an important program for us, uh, because that was the first byte molecule we're putting in solid cancers. And there the immunogenicity did impact the efficacy, uh, reduced the drug level so much, and that prevented the T cells getting into the tumor. So, so that was consequential. Yeah. Another question I get asked, Quin, and since you are here, so I will ask that question. One of the things people are concerned about pegylated, there's a lot of pegylated molecules are coming forward, uh pegylated biologics molecules as peptides or or fusion proteins and extending the half-life through PEG, and also many ADCs where actually you're using PEG to reduce the hydrophobicity of this molecule. What are your thoughts about pegylated molecules and immunogenicity? Yeah.
Vibha Jawa:
Yeah, and it's been there for a while. Like we have pre-existing immune responses to PEG already. And and the moment you now connect it to up protein, you're not only like at the conjugation sites, you're including introducing neoepitopes. PEG itself has some level of that immunogenic potential. So what we did find though, that you know, some most of the time it was there, we were asked to even detect those pre-existing PEG antibodies, but we were not seeing necessarily a change in that PEG-specific immune responses after dosing. So the the concept was you can run these assays, and there's a lot of pre-existing reactivity which would just stay. Uh, but more important was when you conjugate the PEG to the protein, are you changing the immunogenic potential of your protein itself? And that we were able to now, or we are doing it for the last uh decade or so more, uh, like you know, better in a better way is by engineering out those regions with like using the in-silico tools and understanding where those uh connections could make new antigens or neoepitopes. So there are ways to mitigate those kind of um risks where the PEC has to be used. But I would say that whenever we started looking, we would never find a very meaningful uh immune response that was really uh PEC specific, which was causing a lot of problems. So, and this was for ADCs. We have done ADCs recently, uh, and we have done at uh PEC fusion proteins. So it is there, you have to do it. Unfortunately, like you have to look at those changes in the immune responses to PEG alone or with the molecule, but in the end, we are not able to point that that caused the uh clearing effect. So it's more of an analytical assessment that agency will ask us to perform or provide a risk assessment that it's not necessarily uh problematic.
Rakesh Dixit:
No, that's great, great response.
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Rakesh Dixit:
Um, so a couple of more additional questions in the different topics. So, you know, since you have worked on multiple therapeutic modalities in your career, what would you say that that one therapeutic modality for the next decade, what it would be? The gene therapy, CAR T cells, you know, antibody oligonoclutide conjugates, and you know, just there, just so plethora of the molecules that we are seeing, newer and newer molecules, newer modalities for treatment of cancer, autoimmune diseases, where you think the field is is really moving uh from your perspective, since you have been in in biologics and drug overall drug development for for a large part of your career.
Vibha Jawa:
Yeah, and and you know, I um I am partial, of course, to gene therapies because that's how I started my career. And then when when I first saw the first gene therapy product, Lexterna, come out after all the derailments uh which happened with the field, it was very redeeming. But I would say that, you know, uh cell therapies, I've worked very closely at PMS on it. And I would say that it has so much potential. It's just the cost, which um like a cost manufacturing that makes uh people very uh worried that, you know, how would you offer it to masses? So with the new in vivo car T editing technologies, which we have seen come out of UPen and some of the startups like Capstan, I feel that combining, combining the uh like you know, the targets that have been validated by either biologics or by specifics or other modalities and combining them with um some of the in vivo editing uh vehicles uh will be the way to go because you really want to target, you want to get there, and you want to stay safe by just targeting the right cell and by removing that uh ex vivo uh manipulation of these cells or vectors, and just uh being able to target without any of the off-target uh effects uh would be the next generation.
Vibha Jawa:
But I would want to add that uh I'm seeing a lot of like AI-based molecules coming up, and they have already made a few which have been in clinic and they look very effective. Uh, the question is um uh like you know, how safe they are. So it comes back to like we have the technologies for all, like bi-specific, ADC, large molecule, sirna, ASOs, all of them are there. It's just more about are we targeting the right disease and even the stages of disease? Like if someone is in the last uh end of their line of treatments, waiting for a CAR T cell to do that job may not be the right way. Maybe a bi-specific is what would work or an ADC would work better till the uh engineered CAR T's are available. So it should be modality. Uh the modality should be chosen based on the stages of disease, and it should just not be one uh one kind of uh a modality that is going to be useful. So I feel we have to converge and decide who should get for a chronic disease, what kind of drug which is safe for a long time versus an acute uh cancer, uh, what can treat them right away? Would it be an in vivo um in vivo technology or would it be like something which is very precise, like a biospecific or bite?
Rakesh Dixit:
Yeah, no, no, that's a great question. And I think uh, you know, coming back to your immunogenicity expertise, you know, typically immunogenicity uh has been lesser of the safety problems, much more for the efficacy. But in some cases, we have seen with the ADA responses the activation of complement and infusion reaction, hypersensitivity reaction. Do you have any idea what we can do in these molecules that can reduce this safety uh also, um, you know, safety problems as well, um, which is not easily predictable from preclinical studies. Uh because as you know, I mean, the seeing immigrants in in the non-human primates, it doesn't have the same relevance for humans. Even the agency has accepted just because you're seeing ADA in monkeys doesn't mean that you're going to see ADA in humans. And then becomes, you know, the question, because I'm I'm a more of a safety assessment person, people ask me what does it mean? You know, do will I see more infusion reactions or hypersensitivity reaction? I said it's really hard to tell from animal studies. So are there tests EpiVax or other companies can run that can give us some insight on the safety side of emergency as well? Yeah.
Vibha Jawa:
Yeah, so uh this field has in fact uh exploded for peptides because uh the agency was very worried about the impurities of the peptides, and especially when the bio, the generics and the biosimilar started coming for all these the GLP1 peptides and others. So there is a very um strong recommendation from agency to look for impurities that can exactly uh cause the immediate innate phase immune responses, whether it's complement activation or it's the ERMIS, which are the immune response modulating impurities which work on the pattern associated uh pathogen um like pathways. So, so there is a and EpiVax has in fact done a lot of work on peptide-based impurities to evaluate these risks and also provide upfront these assays. So um, Dr. Daniela Wertelei from FDA published a lot of papers on what are the best assays to do up front to reduce that and to control the specifications uh during CMC for such um impurities and for such products. So, some of the work, and I want to go back to your comment on complement, right?
Vibha Jawa:
And we started noticing complement activation with AAV empty capsids and the CPG motifs that were present. And uh one way was to engineer them out and make re-engineered capsids that had less of that liability. And there are numerous uh papers and work which have shown success there, that you could reduce these liabilities upfront. And uh and there are ex vivo complement uh assays you could do. You don't have to do it in animals, you can do it ex vivo and uh, like you know, serum with the cells and show the uh reduction of the complement activation pathway and all the factors. But the other um, like the immune response modulating impurities, they have been well characterized now. So a lot of working groups have worked on innate assays using uh just whole blood-derived PPMCs, or they have gone into specialized antigen-presenting cells and shown that you could look at all the uh pathways, the TLRs of all kinds. So if it is an anti sense oligo or sirna, you can target the TLR9 pathway and understand are you seeing in your product something which is coming up? If you're looking more at uh like endotoxin or like other impurities, so TLR4 and five have that uh ability.
Vibha Jawa:
So um overall, yes, we have assays which are more human relevant and they have been used now with uh better acceptance criterion, better control. So we have controls that are targeted to that ligand. So if it is a not-like pathway, you have a not-like ligand, which we use to understand that pathway is activated. If it is TLR, there are specific TLR ligands. So the industry, the overall science and the evolution of these assays have made them more reliable. And we have also seen that effect in clinic where we have captured adverse events or captured the rash and hypersensitivity or complement activation and how that has moved on when you have reduced these liabilities up front.
Rakesh Dixit:
Very good. Since you have been in this field for a very long time, what advice would you give to young scientists, entrepreneurs who are new to this field, as well as biotech professionals starting their career? Let's assume they want to test, they want to try their career in immunogenicity assessment or other parts of the biologic development. What will be your advice to the young folks, you know, uh the relatively young folks? Yeah. Yeah.
Vibha Jawa:
Yeah, and and and I do mentor a lot of the early career scientists, uh, and especially I'm very interested in making sure high school students know that there's so much to do in STEM, right? Because I'm seeing a lot of kids are like, oh, I don't want to work in the lab. I mean, this is not my life and it's not cool, right? So uh, but I would say even with all the new machine learning and AI and like data sciences is coming up, we still need scientists who are grounded in biology. You really need the technology will keep on evolving, but the insight that will come from someone who is going to pursue a pure biological science, whether it's cell biology or biochemistry or chemistry or even like you know, immunology, which is so complex, it still needs to, someone has to guide the computer scientists or bioinformatics like professionals on what to even look for. There's so much of network which they won't understand. So even though even now I feel a little bit illiterate that I don't know coding, I don't know this Python, right? So, but when I talk to uh that bioinformatics or computational biologists, then I'm able to explain to them that this is what I'm looking for. So you need the grounded biological concepts for which you have to do the pure science. And then the other thing which I've always been telling everyone is to stay translational.
Vibha Jawa:
So even during my graduate school days, I was working in at All India Institute of Medical Sciences, and my thesis was to look at the rheumatoid arthritis patients, look at their synovial fluid and see what are the macrophages doing there. You could do all of that, as you said, ex vivo, right? You can work on a cell line, you can look at an animal, but what you see in the actual patient and from their blood or from their fluids is so enriching. And it just changes the way you would think of our research project. And I think the one thing which uh which I didn't do earlier in my career, but then I changed, was to also stay very collaborative because people, you know, you just mentioned that why would people go into an immunogenicity um area of uh career development? It can gets very siloed, and people will say, okay, go develop an assay and give it to us, we'll take care of it. Yeah. You know, you become like an internal CRO for people, and then everyone reacts, oh, I'm stagnating.
Vibha Jawa:
But no, there are opportunities. So one thing you could do is uh collaborate with your other functions. CMC needs immunogenicity. You just brought up that, you know, safety and quality want to know what immunogenicity is doing. So you have these opportunities to learn from other colleagues and functions, and then you suddenly understand that, oh, I have I have impacted all these functions. So, but unless you make that effort yourself to be like, you know, be fluent in these multidisciplinary um aspects of drug development, then yeah, you will still look like or you will feel that you are siloed. But actually, I learned everything from just like collaborating on different problems that immunogeneists has.
Rakesh Dixit:
Right. No, I totally 100% agree on that one. And I think this has been my experience. Of course, the AI is very potent. Uh, that's the future many ways, but AI also needs data. I mean, AI, AI cannot just extract things from air. And especially with the human biology, which is so complicated, so complex. It took millions of years to get that human biology all worked up. And there's no way AI can solve all this problem unless we have really good data coming from the labs. So, you know, similar to you, I always advise uh, you know, young chaps, you know, don't just look at the computer job that you can work from home. Somebody still have to do the experiments and generate the data so that we can give it to the AI machines learning so that we can get better data. Otherwise, it will be a lot of false uh alarms created by BI AI or or leading us to the wrong places. So, yeah, I totally agree with you that we need young scientists to still continue to work in the lab and and still try to help us to understand human biology, complexity of the human biology. But anyway, uh thank you so much, Vibha. I really appreciate your time. It was it was great. And and uh and thank you again.
Vibha Jawa:
Thank you, thank you, Dr. Dixit. And yeah, I would like to just say this to the younger scientists is that you know, uh what I have seen is that if you enable others, you kind of like you know, uh that's one thing which I understood from leadership. It doesn't have to be just like top-down to do that. You have to enable others, and suddenly everyone comes together and you also look good. So it doesn't you don't have to like just work in isolation.
Rakesh Dixit:
Absolutely. Thank you, thank you so much. Okay,