‘I wanted to see where this could lead’, says Karperien, explaining the early history of Orthos Medical, the Twente spin-off that he founded five years ago together with Theo Verrips, professor at Utrecht University. ‘I was developing applications of tissue engineering at the time and Theo was working on a very interesting technology, based on llama antibodies. I wanted to know whether we could bring those technologies together.’
That turned out to be the case. Orthos Medical focuses on osteoarthritis, a joint disorder that affects about one and a half million Dutch people. What exactly causes it is unknown, but the condition always leads to the degeneration of cartilage located at the ends of the bones in a joint. The membrane in the joint capsule then starts producing inflammatory substances, the synovial fluid gradually loses its lubricating function and bone ends become more brittle and change shape. The result: stiffness and pain during movement, often in the knee, hip, or shoulder joint.
Patients can take daily painkillers to relieve the pain of a chronic condition like osteoarthritis. However, this means the medicine spreads throughout the entire body, which can have unpleasant side effects in the long term. By injecting antibodies directly into the joint, it may be possible to treat the pain in a very targeted and local manner.
‘The pain is caused by growth factors that are released and affect the nerve cells’, Karperien explains. ‘If we can get antibodies to bind to those growth factors, they are removed by macrophages, a sort of “clean-up” cells.’ This does not eliminate the cause of the disease, although Karperien hopes that alleviating the pain will help break the vicious cycle of inflammation and degeneration that so characterises osteoarthritis. But why does this require llama blood, what role does tissue engineering play in this and does it actually work?
Llama blood
Antibodies are proteins that protect us from diseases. They bind to invading organisms, such as viruses and bacteria, and are then cleaned up by the body. This prevents the pathogens from entering our cells. Llama blood contains antibodies that are very well suited for use in medication. ‘The antibodies’ molecular weight is much lower and they’re up to 10 times smaller than human antibodies’, says Karperien. ‘But they’re just as effective. Moreover, they’re very stable: they can withstand temperature changes very well and remain intact in organic solvents. We wouldn’t be able to do this with conventional antibodies.’
But that is not to say that every treatment requires antibodies from llama blood: Orthos Medical aims to replicate the antibodies found in llama blood using yeast cells. If you present yeast cells with the right DNA sequence that codes for the antibody in question, they will start enthusiastically producing these antibodies.
There is also a downside to the antibodies being so small: it means they can quickly leak out of the joint again. And of course, patients would rather not have to be injected daily with new antibodies in their joints. This problem can be avoided through the use of polymers that are also applied in tissue engineering, Karperien’s area of expertise. ‘We package the antibodies in biodegradable polymers, thus creating very stable structures that slowly release the antibodies. That way, the patient only has to see the doctor for a new injection once every few months.’
Rat gaits
It sounds good, but does it actually work? It does in rats, says Karperien. The researchers treated rats with osteoarthritis and then conducted a pain test. This involves the rat walking over a sensitive plate that measures how much pressure the animal exerts with each of its paws. A healthy rat has a balanced gait; a rat that’s in pain will limp slightly, or in other words, exert more pressure with one paw than the other. The initial results show that after administration of the antibodies, rats with osteoarthritis have a more balanced gait, i.e., suffer from less pain.
Just how many rats this applies to and exactly how much it has improved their gait, Karperien cannot yet say: the experiments are still ongoing. So he cannot yet refer to published results, which have been critically peer-reviewed by independent colleagues. Nevertheless, he is optimistic. ‘The results are promising. In the optimistic scenario, we will be testing it out on dog patients in early 2024. A clinical trial on humans is planned for late 2025, early 2026. That is, if everything goes well and there are no setbacks.’
Such setbacks are not inconceivable. For one thing, we would already be rid of quite a few nasty lifestyle diseases if people responded to experimental drugs in the same way that rats do. Unfortunately, that is not the case; humans and rats are very different. What’s more, it is possible that the human body will turn against the administered antibodies after a while, Karperien says. ‘What happens when you treat rheumatoid arthritis with antibodies is that the body starts to form its own antibodies against the injected antibodies. As a result, they become less effective and the doctor has to inject higher concentrations. This could conceivably happen here too.’
The reason why he is not too worried about this is because the llama blood antibodies he uses are so small. ‘They contain only the part of the protein that binds to the antigen, the growth factor NGF that causes pain’, Karperien explains. ‘That part is very similar to all the antibodies produced by the immune system itself. So our body is not very likely to recognise that structure as alien.’
Clashing interests
The professor spends over 20% of his time on research for his spin-off. In addition to Orthos Medical, he founded two other medical spin-offs, Hy2Care and LipoCoat. It is precisely that combination of research and entrepreneurship that makes his work so interesting, he thinks. ‘I consider simultaneously running a company and conducting scientific research as the best way to make a real impact. The university is a great place to do research, but there are too many examples of research dying a premature death on the lab table. If I really want to make an impact, I have to bring what I develop to the patients.’
When asked whether research and entrepreneurship can also clash sometimes, he doesn’t have to think long. ‘It’s always possible for situations of clashing interests to arise. In that case, our policy is for someone else in the faculty to make the decision. Let’s say the company produces some antigens that I’d be interested in testing out in research projects. I would have to buy those antigens from the company. Someone else would then have to take a very critical look at that. I wouldn’t be able to make any decisions in that process.’
He thinks the recent articles in the media about excessive corporate influence on university research are ‘somewhat tendentious’. ‘Yes, big companies like Shell and Philips sometimes sponsor chairs at universities. In all such cases, the university makes an overview of the activities undertaken by the professor in question. In doing so, the university always stipulates that the academic freedom of the professor in question may never be compromised. It’s not like Shell can lay down what’s going to happen in detail.’
According to the professor, that would not even be in the companies’ interest. ‘Those big companies turn to universities because they know that scientific research is needed for innovation, including the innovation of their products and business models. Research within the company itself often results in much less creativity than funding research at the university. So for them, it’s a way to have high-quality research conducted. And if it yields new ideas, then they’re first in line to incorporate it into their business. I think that’s something we should encourage.’
