A team at Oregon State University is researching antibody treatment for dogs with cancer. The treatment would rely on “nanobodies’' which come from alpacas and llamas. Christopher Cebra is a camelid expert and chair of the clinical sciences department in OSU’s veterinary college. Dan Mourich is a research associate and molecular biologist on the research team. And Carl Ruby is a research scientist and instructor at OSU. They join us with more about the treatment and how camelids — like alpacas and llamas — hold the key.
Note: The following transcript was created by a computer and edited by a volunteer.
Miller: From the Gert Boyle Studio at OPB, this is Think Out Loud, I’m Dave Miller. If dogs are man’s best friend then maybe alpacas and llamas could become dogs’ best friends. A team of researchers at Oregon State University has turned to these ungulates in the hopes of creating a new targeted medicine for canine cancer. Chris Cebra is a Camel Expert and the Chair of the Clinical Sciences Department at OSU’s Veterinary College. Dan Mourich is a Senior OSU Research Associate and the Molecular Biologist on this research team and Carl Ruby is a Research Scientist and Veterinary Science Instructor. Welcome to all three of you.
Chris Cebra/Dan Mourich/Carl Ruby:Thanks for having us… thank you
Miller: Chris Cebra, first. We’re gonna be talking here about a class of drugs, a kind of drug known as an immunotherapeutic. What does that mean?
Chris Cebra: So you know immunotherapeutics usually means you’re using an antibody as a treatment for a disease. And so antibodies are made usually to combat infections but they can attack other targets as well.
Miller: Like a tumor for example?
Cebra: Like a tumor. It’s sort of an infection of a different kind.
Miller: Dan Mourich, what is cancer treatment for dogs normally like right now?
Dan Mourich: Typically now the use of medicines that were previously used in humans that have sort of been passed over into the dog system. So typical things you think about is surgery, chemotherapy and radiation but the insertion of any type of immunotherapies are still waiting.
Miller: So, and maybe this is a dumb question, but is radiation or chemo or surgery in dogs…can it be just as terrible for a dog’s body as it can be…if also lifesaving, for a human body?
Mourich: Yes, that’s precisely it. That they do have all the side effects that humans realize when taking those types of therapeutics. As well, it impacts the quality of life for the dog and the owner and that’s why you see about 80% of individuals and dog owners choose to opt out of any type of current treatment for cancer.
Miller: Is part of that money as well?
Mourich: Yes. Yes there is a cost associated both monetarily and time and obviously emotionally.
Miller: So, Carl Ruby. Why has your team been looking into seeking out alpacas and llamas in particular? What is it about these animals that’s so enticing for medical research?
Carl Ruby: I think that Chris definitely can add to what I’m going to add here but they produce a unique antibody that is not found in other mammals. And this antibody allows for a lot of manipulation molecularly and structurally. That allows us to kind of create what could be modular therapeutic legos that we can build. We can keep at the very smallest level which allows us a lot of latitude for getting into certain tissues. It also allows us to add other elements to increase potency, to attack other targets. It’s it’s it’s it’s a platform that has been around for a while but it hasn’t been used in the veterinary setting. I think Chris can explain more about the uniqueness of alpacas and llamas with their antibody expression.
Miller: Yes, Christopher, as I mentioned, you are a camelid expert which I had to look up, meaning the group of animals [Camelidae] that includes camels, alpacas and llamas. What’s unique about their immune systems?
Chris Cebra: Well, I think Carl introduced the topic, so mammals make antibodies and they generally have the same structure they’re a ‘Y’ shaped molecule that has two regions at the tip where they bind to whatever their target is, a bacteria or in our case, cancer cell, and camelids, for whatever reason, make one that’s about 60% the size and has a less complicated binding region. So it’s a smaller molecule to begin with. And it really lends itself to some manipulations to become a better therapeutic.
Miller: What’s the significance from the research perspective or the clinical perspective of it being a smaller molecule. Why is that important?
Cebra: We often say bigger is better. But I think when you’re in a biological setting, smaller is often better in that if you have something like a tumor which is fairly dense tissue and doesn’t always have a great blood supply, a smaller molecule can work its way deeper into the tumor than a larger molecule would. It also can sometimes cross borders that the larger molecule can’t make it through.
Miller: Carl Ruby. Can you explain, hopefully in terms that I and our audience can understand, how you go about actually finding antibodies from a llama or an alpaca that’s going to target a piece of a canine tumor.
Ruby: One of the key elements is to understand what that target is, and a lot of times, in the case of tumors or other disease settings, it’s going to be a protein. So if we can figure out what protein that is, what we can do is go through and literally vaccinate the alpaca or llama as it may be with this protein for them to basically produce an immune response against it, start producing antibodies towards it, and then from there we go and we kind of take a little sampling of the blood, we take out the cells that produce these antibodies they’re known as ‘B’ cells. From there we can basically manipulate the molecular…the structures that they have for the antibodies themselves. And then using another system, we can then screen for those molecules that do bind to the protein of interest, the target that we want. And then from there it starts to become more of a production component where we then produce it, and in a number of different studies, either they’d be in yeast which, you know, a lot of us in Oregon are familiar with but also potentially bacteria or other mammalian cells and that’s kind of the the short, short and sweet version.
Miller: Dan Maurich, how far along is this team right now in the process that Carl Ruby was just outlining?
Maurich: We’ve taken a couple of different animals and hyper-immunized them as Carl explained and derived from them actively transcribed MRNA. And we’ve made libraries out of those so that we essentially have a catalog of all the different immune responses those animals that proceeded through, including the one to the immunizing protein of interest. And we’ve screened those against the target proteins of interest and have now drug candidates that do the effect, the blocking effect, that we’re hoping for to develop the drug. So we’re up to the stage now where we actually have lead candidates and we’re optimizing the production profile of those as Carl mentioned, in yeast, so that we can get them produced at scale, so that they could be commercialized and available for the clinic.
Miller: How adaptable might this be? I mean you had mentioned, Carl Ruby, that the hope here is that this could be sort of modular. So if and I understand that to be kind of adaptable for different kinds of targets, or tumors or diseases. So how would that work? Because if I understood the earlier part correctly, you found some important protein that is attached to a particular tumor and then you could find antibodies that go after that. Would you basically have to do that – that same technique for every different kind of cancer?
Carl Ruby: Right. So you get to an interesting point, and cancer is, obviously, a multitude of different types of diseases. So they all have different types of targets that create that malignant sort of phenotype that we see and being able to create, not just one target, because cancers have a way of basically hijacking what’s around them that will evolve to avoid any therapy. So a lot of times targeting multiple elements of what makes cancers become malignant and so dangerous, we can go through and we can do that, and then hypothetically if we understand your tumor, we can build that molecule that could be tailored to your specific cancer. Now this is kind of further out, but it is within the realm of the platform that we have and also the tools that we have available to us and also in the future. So you can modularize and tailorize whatever you need as far as the cancer you’re approaching.
Miller: What you’re describing sounds like versions of what we’ve heard in the past for human medicine, and I imagine that the more tailored something is, theoretically, the more expensive it would be. What is the market theory for how this could work – how this kind of new cancer therapeutic that’s really tailored, could actually be affordable enough for you know, pet lovers to take advantage of it?
Ruby: Right? And that’s one of the key elements, and Dan brought it up before is, you know, the use of yeast to produce this yeasts have this ability to exquisitely produce this type of molecule that we have. And if we can do that at scale and at cost, we believe that we can hit the price points, so to speak, that will allow the majority of pet parents to basically use these potential therapies in their pets when they are diagnosed with cancer. There of course are other therapies out there that could add to costs. But we think at the very base level we can produce a number of different therapies that are within reach for your everyday pet parent.
Miller: We heard at the beginning that the normal method for veterinary medicines is first, it’s approved and found to be effective in humans. And then after that it can go to animals. Is it possible in this case it could go the other way?
Ruby: Well, since we’re actually utilizing known targets that are in the human system, and that’s how we drive down the prices – the discovery portion of this has already been proven in the human clinic. So the target is known. So we can make the molecules much cheaper because we don’t have to go through that discovery process. But of course we’re making, now, tailor-made therapeutic reagents that target specifically the canine. Now it’s…in the future, if we discover new targets, yes, then they could be reversed engineered to target the human form. But we’re making at this point, specific drugs that target the canine Ortholog to the human clinical target that is effective.
Miller: Chris Cebra, let’s go back to these camelids – camels, alpacas and llamas. What are some other potential or actually current applications for their unique antibodies?
Cebra: Well, the sky is really the limit for that. These molecules were only discovered a little over 20 years ago so they’re relative newcomers to the world, and they offer a lot of unique attributes with the size and convenience of production and things that we’ve talked about. And so there’s been a huge amount of interest throughout the biomedical community at looking at them for everything from from COVID to Ebola virus to treatment of some autoimmune diseases. So lots of things that we have conventionally used regular antibodies or other immunotherapeutics for. People are now looking at these smaller camel-origin molecules to treat with. And I just… if I could, I wanted to reflect on something you’d asked about earlier, which is the human research space versus the veterinary, and I think there’s a lot of potential for synergy in that the human space generally has more people working in it. But the veterinary space offers some really good opportunities for advancement as well. And so we benefit from their advances. We would like to think they will benefit from our advances as well.
Miller: Are clinical trials easier to set up for animals than for humans?
Cebra: They generally are. Just the process for human clinical trials is fairly lengthy and one component of it is usually an animal trial prior to going into people. And so essentially you managed to skip that whole step, you go straight into an animal trial and therefore you get your results faster.
Miller: And Dan Mourich, just briefly, this grant- National Science Foundation Grant of $250,000, it’s real money but I imagine that going through all the steps to create a new medicine is going to cost a lot more than that. I imagine what it cost in the millions. Do you have other funding lined up?
Mourich: We have received funding from the university for the initial development of this platform so that we can utilize it for screening but of course you have through the National Science Foundation, this initial grant is going to help us launch into the stage where we can get a candidate and then of course, the next stages will be raising capital from private investors.
Miller: Dan Mourich, Chris Cebra and Carl Ruby, thanks very much.
Cebra, Mourich, Ruby [Together]: Thank you.
Miller: Dan Mourich is Senior OSU. Research Associate and a Molecular Biologist on this team. Chris Cebra is an expert on camelids, the Chair of the Clinical Sciences Department in OSU’s Veterinary College and Carl Ruby is a Research Scientist and Veterinary Science Instructor at Oregon State University.
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