Research being carried out at the National Institute for Cellular Biology at Dublin City University is helping make the manufacture of the latest generation of life-saving medicines cheaper, more efficient and safer. The Science Foundation Ireland-funded research is focused on the use of Chinese Hamster Ovary (CHO) cells in the manufacture of biopharmaceuticals.
CHO cells have been used for years for testing new drugs for toxicity, but are now playing a role in the manufacture of new biologic or large molecule drugs. "We are utilising them as factories to make proteins," says Dr Niall Barron, programme leader in mammalian cell engineering at the institute. "Modern drugs are proteins."
He explains the difference between this latest generation of drugs and their forerunners by using cancer treatment as an example. “Most people are familiar with the terrible scenario of a cancer diagnosis. Oncologists have a range of drugs in their arsenal to tackle the cancers. These drugs have tended to be very poisonous and have quite awful side effects. These chemicals are essentially poisons and we have to take extreme care when we are handling them in the laboratory. The skill of the oncologist is to kill the tumour before they kill the patient.”
While the discovery of these small molecule drugs was a great step forward in cancer treatment, their non-specific nature presents difficulties. “They are relatively indiscriminate in what they kill,” Barron adds. “A tumour is effectively part of you – it is made up of your own cells which don’t die. The drugs kill the cancer cells and normal cells.”
Modern large molecule drugs are more discriminating, however. “The latest drugs take a lock-and-key approach. We look at cancer cells and normal cells and ask if there are any differences between them that we can use to target them. We look at the structures on the surface of the cells and ask if there are genes and proteins there that are key to targeting them.”
After that the search turns to finding the protein that will home in on that target. “By finding the key to a specific lock we can hopefully minimise the side effects from a treatment.”
Different
These modern antibody-based drugs are manufactured in an entirely different way to their forerunners, however. “Small molecule drugs like aspirin or Taxol can be synthesised reasonably cheaply in a lab and you can be sure that what you’ve got in the vial at the end of the process is the pure active ingredient you were looking for. The problem with large molecule drugs is that they can’t be synthesised in the lab – you have to ask a cell to make them for you.”
This requires a process quite similar to brewing, where alcohol and carbon dioxide are produced by yeast. Recombinant DNA technology, or genetic engineering as it is more widely known, now allows cells to be altered or reprogrammed to produce specific byproducts, such as protein-based drugs. This method is required due to the complexity involved. “The difference in scale between the two molecules is like a beach ball and a grain of sand,” Barron points out. “A good analogy would be to look at a bicycle and Gulfstream jet. A good engineer could probably have a go at building a bicycle from scratch at home, but a Gulfstream jet would be an impossible task. We ask the CHO cells to express the proteins we are looking for by sending it genetic information using MRNA.”
The CHO cells are placed in a reactor, similar to a brewing vat, where they grow and produce the proteins over time. At the end of the process the proteins, or antibodies, are harvested. “You eventually arrive at the point where you have a vial with a pure sterile version of the protein that can be injected into a patient.”
The work being carried out at the institute is hugely important due to a number of factors – principally cost and safety. “One of the big challenges with large molecule drugs is expense,” Barron explains. “This is partly related to the quantity involved. You tend to need a lot more of the drugs than you do with traditional small molecule medicines. Research and development costs are also very high. It costs about $2 billion to develop a new drug. For every one new drug which makes it through the 12-year development and clinical trial process, there are 100 failures.”
The early stages of antibody-based drug development are far more expensive than those for traditional medicines due to the differing processes. The large molecule drugs have to be produced in reactors instead of test tubes and that is very expensive. And the processes involving CHO cells are even more complex. “Systems which use bacteria or yeast are well understood and cheap, but CHO cells are much more complex. We are trying to better understand them to make the processes more efficient and hopefully get to the stage when we get to the era of personalised medicine that relatively small batches of medicines can be manufactured to order at an affordable cost.”
Attainment of that goal will also have implications for the development process, as the ability to make small quantities more efficiently and cheaply will allow for more drugs to go into testing. “The philosophy of the industry is to kill early and kill cheaply with early-stage drug candidates. Our work will support that.
“The other key aspect is safety”, Barron adds. “We have had a number of cases of people having terrible reactions to new drugs. We are dealing with very complicated systems which are highly complex and chaotic in nature. We are trying to get them to behave in a reliable and repeatable manner. We are working with industry to understand the cell lines better and improve them. We want to understand precisely how the cells will behave when they are dropped into a reactor from day one until the end of the process. The goal is to be absolutely sure of precisely what protein we will end up with at the end of the process.”
Economic implications
While this work is very important for drug development overall, Barron believes it also has significant implications for the economy. “The biopharma industry is unbelievably important to
Ireland
, with companies like
Wyeth
investing hundreds of millions in plants here. That’s why we are lucky enough to be supported by SFI [Science Foundation Ireland],
Enterprise Ireland
and the RU Horizon 2020 fund. We know when we are dealing with the site leaders of the plants here in Ireland that the internal competition they face within their companies for new investments is intense. Being able to point to a good academic infrastructure and research base which is valuable to the biopharma manufacturing process is an important consideration when those investment decisions are made.”
