Mastering Radiopharmaceutical Development: Preclinical Model Selection for Clinical Success

What if the next breakthrough in cancer treatment isn't a pill or infusion, but a precisely targeted radioactive payload that hunts down tumor cells like a guided missile? Today, are diving into the radiopharmaceutical revolution with Brian Miller, who is the director of scientific and technical operations at Crown Bioscience UK. From his early days studying colorectal cancer models to now leading preclinical development for one of oncology's hottest therapeutic classes, Brian is taking us inside the science that is transforming how we fight cancer. We hope you enjoy listening to this podcast with Brian hosted by Doctor. David Brulman from the Smart Biotech Scientist podcast. Welcome, Brian, to the Smart Biotech Scientist podcast. It's good to have you on today. It's great to be here, David. Brian, share something that you believe about early discovery research that most people disagree with? So I've found that research progress is rarely linear or predictable. Over my career, I've seen the undruggable become druggable. I've seen false starts in some areas and surprisingly rapid advances in others. And I think that's why I find I feel so dynamic and exciting and why I love being a part of it. To draw us into your story, tell us what sparked your interest working on cancer models and then what were some interesting stops along the way that got you to your current role? Yeah, it's quite interesting. My PhD was actually in cardiac disease, so that's where I started out, and it was when I did postdoctoral fellowships, first at the University of Toronto and the second at CR UK, that's really what took me towards oncology models, both in vitro and in vivo models. And my postdocs were focused on models of colorectal and pancreatic cancer, And I think what motivated me at that point is exactly the same as what motivates me now. I was passionate about contributing to the development of new therapies for cancer and identifying new therapeutic targets. And really, that's what motivates me to go to work every day to this day. Being part of Crown allows me to work across a large array of different cancer indications with a diverse range of clients, and it's really motivating when you're contributing to the development of new therapies, and it's fantastic when you've contributed to a research program that has led to a therapy going into the clinic. Tell us a bit more about your current work. How does that look like when you're developing these new therapies? So we're a preclinical contract research organisation, so we're oncology focused, but we do work with a large array of different clients working on various different therapeutic types. And we have a range of advanced preclinical models that are available to our clients to run the research programmes with. So we do work across most cancer indications and we do work across with most therapeutic types. So it's a very diverse area of work that we do conduct at Crown, which makes it really interesting for us. It's very varied, it's very interesting and it's absolutely fantastic to support this variety of client research projects. And when you say it's very diverse, so that includes the various diseases you're working on. I imagine also very diverse companies, which has have very diverse needs. What is the before we dive a bit further into the radiopharmaceuticals, what is the bane need companies have that come to you? What is the main problem they want to solve? So they typically come to us usually with a target in mind and usually with a therapeutic that they wish to test, and really one of our main roles is to guide them towards the most appropriate preclinical model to address the question that they're asking. And, you know, we do have a range of different models available. We've got an excellent array of in vitro models, particularly organoids. We're well known, I think, for an organoid platform. So certainly, if you get the in vitro phase, we do have an array of advanced in vitro models that can be very, very valuable. We're also very well known for our PDX library. We have PDX models that cover most cancer indications, and those are, you know, we have genomic data from them. If you have targets in mind, we can guide you towards the most appropriate PDX model for your work. In addition to that, we have an array of CDX and genetic models, humanised models. So really, think we're cancer focused, I think for most questions around development of cancer treatments, oncology therapies, we will have appropriate models for you to use in your research programme and we can help you filter those down and decide the most appropriate ones for you. When you say models, are these ANIMA models or are these two d cultures, three d cultures, or is it a combination of All various of that, actually. So yeah, I've got two d cell culture, three d cell lines, organoids. We've got various in vivo models, syginate models, CDx models, PDx models, humanized models. So it really is quite a wide array. Excellent. So let's dive into one specific area, the radiopharmaceuticals. A lot of our listeners, I imagine, are not familiar with that. So can you start with the basics? What are radiopharmaceuticals and how do they differ from, traditional cancer therapies? Yeah, so radiopharmaceuticals are diagnostic and therapeutic agents. So they consist of a targeting agent, so typically a small molecule or an antibody, and this will target the tumour. There's also a radionuclide and there's a linker that connects the two. And the radionuclide can act as either an imaging agent for diagnosis of cancer or as a therapeutic agent where the radionuclide will deliver a lethal dose of radiation to the tumour. Can you just elaborate a bit more because what I try to understand is how or give us an example how are they different from a traditional cancer? Is this the morphology? Is it the way or what is it exactly? What are the main differences? I'd say there's probably two real advantages of radiopharmaceuticals. First is safety because you're dealing with a therapeutic that can very specifically target a tumour. So one of the early stages that you do is you characterise the level of accumulation within the tumour and make sure you don't have accumulation in other organs of the body. So they can be, you know, have a greater safety profile than more traditional therapies. That's one advantage. The other thing that distinguishes them is the idea of theranostics. So you can use an agent that combines diagnostics with therapy. So you use the same scaffold, you can use one radionuclide, which will allow you to diagnose a tumour and potentially switch it to a second radionuclide, which will allow you to target the tumour and to kill the tumour. And because you are combining those, within the same strategy, this allows for firstly, really good stratification of patients, but also secondly, rapid progress from diagnosis through to therapy. Okay, I see. So it's faster and it's also a lot more things I'd say happening in parallel to get a much broader picture. Yeah, and I think safer. I think a lot of them are much safer than traditional chemotherapies. So the radiopharmaceutical field has gone from a niche therapy to now one of the hottest places in oncology. Tell us what is driving this rapid transformation in both the science and also the commercial interest? I mean, there's a lot I imagine happening on the scientific side, but then also the commercial interest investor side of things, right? I mean, that's what we find it as well. I think there seems to be growing interest in the area. It's quite a dynamic area right now. I think there's a lot of exciting things happening in it. And I think it does go back to some of those advantages that I just described, you know, theranostic approach, because that really does give these therapies, I think, quite a considerable advantage. And think the safety profile. I think the safety profile is another thing that I think a lot of companies we are working with are finding very valuable in the development of the therapies. And I think maybe the third aspect is just widening the range of cancer indications that radiopharmaceuticals are available for. So we are starting to see now more radiopharmaceuticals coming through that are starting to target a more diverse range of cancers. And the main purpose of all that is basically to make faster, actionable and more predictive decisions with all your models. I'm just curious, on top of your models, do you add a layer of machine learning, AI, advanced data driven approaches or how does that work in your field? In terms of model selection? Yeah, and then also in terms of interpretation of the data. So I would say that is certainly applicable to the selection of models because, I mean, absolutely crucially, you need to get your preclinical model right in order to have a successful research programme. And we do have large data sets associated with all of our models. So certainly, if you're looking for particular targets, particular gene profiles, then we can help you with that. We have these models very, very well characterised and it's certainly information that we're happy to share with you in order to guide you towards the most appropriate model for you. I'll say, you know, we're also very excited by the prospect of AI. I think that is something that is much more coming online and I think it is something we will be incorporating into workflows as well. Yeah, and you're making a very good point that you have to select the right clinical model because that's the foundation, isn't it? Exactly. Yes. Get the word wrong, you're not gonna have a successful program. Yes. And I imagine, yeah, you're you're gonna solve or answer the wrong question at the end of if you if you choose the wrong model. Besides that, what are other pitfalls when you're developing a new drug? What other choices or I'd say strategies have to be right? Yeah, I mean particularly in radiopharmaceutical field it is quite a, you know, can be quite a challenging area. So I think an early point is you need to get the targeted strategy for the tumour correct. I think that's a very important aspect. You need to be able to target that tumour and have a lot of specificity in that targeting as well. You also need to select an appropriate isotope and a correct labelling position and labelling strategy. Another important aspect is you need to make sure, you know, either you have or you're working with someone who has a reliable source of radionuclides. These materials do have to be labelled fresh before dosing, so you have to make sure that supply of radionuclides is reliable. And really, really crucial is to have a robust labelling strategy and to make sure that proper and thorough QC is done on the materials that are labelled. And nothing should be dosed unless it passes quite stringent QC tests. And as we discussed, make sure that the actual model you're selecting is the most appropriate one and is the one that's going to give you the best chance of success. And those are all areas that we can assist you with. We can take you through those areas, we can give you advice and we could help guide you in designing the most appropriate study design. And compared to, I'd say, conventional drug development, how does or what are the unique challenges that related to the radiopharmaceutical development? Because you mentioned now quite a lot of things that have to be right. You have to make sure how different is radiopharmaceutical development compared to conventional drug development and what are the unique challenges? I mean, obviously there's, you know, some commonalities, but I think the unique challenges would be that need to have it prepared fresh. Now, can't make it in bulk and store it. You'd have to have fresh material that can pretty much be dosed right away. And then also the complexity of some of the strategies and designing an appropriate labeling strategy. This is quite, you know, it's a specialised area, you really do need to work with people who, you know, have specialist understanding of it and can, you know, essentially advise on the most appropriate way to label it, the correct isotope to use, and also crucially the linker to use. Think those are all aspects of the design of a radiopharmaceutical that are going to be absolutely crucial in order for it to be successful. And how do you in your company manage all that and navigate these difficulties? What are some specific approaches you have to develop? So I think absolutely crucial, I think for this is the collaboration that we have established with Medicine's Discovery Catapult. So we've, you know, recently launched this strategic collaboration with MDC And what this does is it brings together the range of preclinical models and preclinical expertise from Crown Bioscience with the radiolabeling expertise and the experience with radiopharmaceuticals from MDC. It's a really, really strong partnership and I think we combine in real stress and real complementary experiences to deliver highly successful radiopharmaceutical studies for our clients. And what kind of clients do you usually work with? What kind of companies are they? Are they small companies, mid sized or even the big ones, the big pharma companies? Yeah, all three actually. We've got a diverse range of clients, you know, small, medium and large. And as we were alluding to before, there's a growing interest in the radiopharmaceutical field, so we are finding more and more people approaching us to discuss radiopharmaceuticals and discuss appropriate strategies for further studies. And that does range from quite small companies to larger ones. And I imagine their needs are quite diverse. I mean, can you just give us the highlights or a preview of what how much the needs differ between the small and the big pharma company? What are the typical needs they have and the difference between them? I I would say from what, you know, we've experienced, I would say one of the differences is in how mature the programme is. So we're finding that, you know, some people approach us with really a very, very early stage, so they won't have a strategy for labelling the test material yet. So in that case, we may have to do a lot of the optimisation, we may have to guide them on isotope selection and perform a lot of the validation work to make sure that we can label the material properly and that it's suitable for use. We find some, you know, other clients, their programme will be a little bit more mature, so they will have optimised the labelling already, they will come to us, you know, with a protocol, we may perform the labelling but it is from a protocol transfer rather than setting up from scratch. So I think those are two quite different, you know, requirements that we found with clients approaching us. Let me say this again. Since the interest is in radiopharmaceutical development is increasing, both on the scientific side and also the business side. I imagine that you're getting more and more demand for such a development. How do you make sure you can scale your preclinical and translational capabilities to meet the demands of all these companies coming to you? I think, we've got a lot of experience with it. So both ourselves and Medicine Scuff and Casapult have worked in our respective fields for many, many years and we are used to running a wide array of projects simultaneously. So scalability is something we are very experienced in. But you're absolutely right, you know, we are finding, you know, increasing demands for these types of studies. But it's having the same principle as we would use for other studies in terms of scalability of our in vivo models and from the MDC side, scalability of the radio labeling side of the project as well. And both parties have a lot of experience in delivering these studies and a lot of experience with scalability. Now I'd like to touch upon a different part of the technology. There's a lot of innovation happening. Many are saying that we're are entering into a new era for radiopharmaceutical innovation. What makes this moment or this season of time different? And how are you as a company positioned to help shape that evolution in this field as it scales? Yes, I would agree with that. I think we are entering a new era and it's certainly we are seeing increasing interest and increasing excitement about the potential of radiopharmaceuticals. And I think firstly, we are seeing increased interest in the theragnostic use of radiopharmaceuticals. So this idea that you're essentially using the same material as both a diagnostic agent and a treatment agent. And I think there's huge potential in that and that's something we are increasingly seeing coming through. And this has a lot of potential for patient stratification and rapid movement towards treatment of patients as well. I think secondly, we are also seeing radiopharmaceuticals developed for a wider range of cancers. So, you know, we do have therapies available for prostate cancer, neuroendocrine cancer, but we are, I think, seeing this expanding and this will further expand over the coming years, which I think is a really exciting prospect. And I think, really, I think particularly the value that Crown brings is what we touched on before in terms of the value of the models that Crown have. You know, in the radiopharmaceutical field, we can now offer our platforms of preclinical models to our clients to run radiopharmaceutical studies. And I think that gives lot of great opportunity to run studies with these very advanced preclinical models that we have available. What kind of limits do these models have? And where do you see development going? What kind of limitations are we able to overcome very shortly? So we don't suggest there's limitations as such. So as mentioned, we have a number of different platforms. So we can literally take a study from two dimensional cell lines to three-dimensional organoids, into CDX in vivo, into PDX in vivo. And I think that gives a very strong workflow in terms of maturing a study over time. And by the time run your study in, say, a PDX model, you're working with a model that is going to recapitulate the heterogeneity of human tumours and will give you some very clinically relevant information in your study, which I think can give a very powerful data set. Perhaps give us the definition once again of PDX and CDX. What does that mean? Yeah, so for CDX, that's cell line derived xenograft. So that will be xenograft models, which will be a human cell line implanted into a mouse to form a tumour, either subcutaneously or orthotopically. For PDX, that's patient derived xenografts. So we have set these models up from patient samples. They've never been in culture, they are grown in animals and then cryopreserved from the animal tumours. And so they will retain a lot of the features of the original tumour. So they give you a more physiologically, clinically relevant output than a CDX would, where it's gone to go on selection of cell culture. PDX haven't undergone that, so they retain more features of the original tumour. The power of using models is that you, as you highlighted before, you're faster, but the other purpose is also to have more predictive models to, I mean, get closer to your target, What if I shall are your strategies to achieve that? I think, I would say there's two, you know, main strategies that we use and it depends whether you're at the stage of, you know, in vitro, if you're doing in vitro studies or in vivo. In vitro, I think our organoid models are incredibly valuable for this. They form, you know, three d structures. They begin to form the features that you would see in an organ and I think that gives you a much more, you know, clinically relevant output from your in vitro study than you would get from, say, a traditional two d cell culture model. In in vivo, I think it's the value of the PDX models. As I say, they retain a lot of the features of the original tumour. Crucially, you don't have the uniformity that you would have, say, if you're growing a tumour from a cell line. By growing it from a tissue sample, your model is intrinsically heterogeneous, the way a tumour would be. So its response to your therapy will reflect much more of what you will see in a clinical context. I'm curious, Brian, because there's what I'm hearing is there's a lot going on in this space. There's a lot of innovation, a lot of changes, a lot of break breakthroughs. What breakthroughs are you most excited about? So I think for me, and I touched on this in previous answers, I think for me it's the diagnostics. I think that's something that I find very exciting and I think especially their applicability to how to treat cancers. So something like say PDAC, pancreatic ductal adenocarcinoma, very, very hard to treat. Know, current treatment options are not that effective. The five year survival rate is still so dreadful. And I think what we're going to see in the coming years is the development rate of pharmaceuticals with a third gnostic application towards these types of very hard to treat cancers, and that's certainly something that I'm quite excited about. I can see a lot of potential in it and I think you're actually starting to see, you know, more, you know, development in this space and I think it's something that we will see advance over the coming periods. And how do you balance in your role, on one hand, moving very fast, innovating very fast, but on the other hand, we are working in an industry where eventually everything will be regulated and we have to already very early have these considerations about how are we going to regulate things, how are we going to make sure that patient will finally get what we are developing? How do you balance these two worlds? Well, mean, what I would say is I think robust quality standards are always absolutely crucial. I mean, at cryo we're always, you know, very dedicated to delivering scientific studies of the highest possible quality. And in setting up our strategic collaboration with MDC, we have a partner who have similar values to us and are equally committed to the quality of their work. And really, by having these robust quality systems in place, this allows our teams to perform work rapidly to meet essential timelines while maintaining extremely high standards in the study. So I don't think there's any, you know, conflict between high quality and doing research rapidly because if you do a low quality study, that's what's going to set your timelines back. If you do things, you know, that isn't up to the necessary quality standards, then you're not going get the answer you want. It will set your research programme back. So I think it's crucial to work with partners who have, you know, very, very high standards of QC, very high standards of quality in everything they do, And that is really ingrained in the culture at Crown. I think our clients know the standards that we work to. And, you know, we are certainly good at delivering on timelines and delivering rapid research, but we'll do so with the highest possible quality standards as well. Let's make this now practical. What advice would you give a smart biotech scientist that's curious about radiopharmaceutical development? Where should they start or what should they do first? And then what are the things they, let me say this again. And what are the things that can wait until later? I mean, I would say my suggestion would be, to work with the right partners, because you need to develop a robust strategy for your study in terms of how you're going to target your tumour, how you're going to construct your therapeutic, what your preclinical models are going to be. But I think, you know, drawing on information from the best people in the industry is crucial. And I think that's a lot of the value that a CRO can bring. Certainly with Cryo, we've got a lot of experience with helping clients in the preclinical area. And we can certainly advise you on the development of your study. We can help you design your study, we can help you choose appropriate models. As part of the Reader Pharmaceutical collaboration, we can help you select isotopes and a labelling strategy for your test material as well. So I think partnering with the right people can really help guide you through those early stages and make sure you have the correct strategy in place to deliver a successful study. How do you make this partnership successful? Because entering into a partnership with the CRO or later on with the CDMO, sometimes people compare it with merit. It's very similar. You have to select very well your partner. What is your approach there? Because I'd say not every company fits every CRO. There are differences, and it doesn't always make sense for a company to go to one because it's the best or for whatever reason everybody recommends. Sometimes it makes sense to go to another, right? Yeah, think people choose CROs, you know, on different criteria. Certainly at Crown, like I say, we do work with a very wide array of clients with different needs and different interests, and we can always tailor a study to the individual client. So one of the things that we always try to do is we do like to see ourselves as an extension of that client's lab. We So do work in close collaboration in the design of the study and there's very open communication during the progress of the study as well. And I think the success is seen by the amount of repeat business that we get And we do form these close collaborations with our clients because we are really dedicated to helping them achieve the objectives of their studies. We've had the feedback time and again that they start to see us as part of their team. They almost see us as part of their research team and they collaborate very closely with us in terms of delivering, the study successfully. Now I would like to look forward into the future, since there's a lot of innovation going on. What is your picture? Where are we going to be in five years from now in this field? Yeah, mean, it's dynamic field at the moment. I think there is a lot of exciting progress that's already happening and I think there is more to come. We're certainly seeing, you know, rapid growth in the interest in radiopharmaceuticals. I expect this to continue in the coming years. And I think what excites me, I think, is the prospect of increasing the number of cancer indications that have radiopharmaceuticals as a viable option for diagnosis and or for therapy. It's particularly around, you know, how to treat cancers. I still think, you know, we all know there's a core cancers that we, you know, really the treatment options are not really there, they're not where they need to be. And I think radiopharmaceuticals does offer us the prospect of, you know, really driving forward the development of new treatments in this area. So I think what I would anticipate is that we will see, you know, quite a big impact of radiopharmaceuticals in this treatment of these very problematic cancers in the years to come. What is the most important takeaway from our conversation, Brian? I think probably the most important takeaway is just the level of excitement that there is in this area, you know, around radiopharmaceuticals and the potential that exists for radiopharmaceuticals in the coming years, particularly as pertains to oncology treatments. But of course, as we know, radiopharmaceuticals also have applications beyond as well into different disease areas as well. And, you know, as I've spoken about, you know, Crown is a really good partner for these types of studies and we can really support you in this field. We've got a fantastic library of different models, both in vitro and in vivo available for use in radiopharmaceuticals. And with our partnership with NDC, we are very well set. We have all the expertise in order to help you design and help you to deliver a highly successful radiopharmaceutical program. Where can people get ahold of you and further have a conversation about this year of work? Yeah, mean, people can contact me through LinkedIn and I'd be delighted to give them, you know, any more information that they need on, you know, radiopharmaceutical programs at Crown or indeed any other services that Crown offers. Fantastic. I will leave the links in the show notes, Smart Biotech Scientist. And Brian, thank you so much for coming on the show today. Thank you, David.