“What a great vehicle!” exclaims Dave Mead, Business Development Director at Novozymes Biopharma in Nottingham, UK. He is not talking about his favorite car but his favorite carrier – albumin. “Albumin is present in high volumes in the bloodstream and it has a naturally long half-life of 20 days,” he explains. “It doesn’t have an activity itself apart from being a carrier and that makes it effectively benign. It’s a great molecule to use as a carrier for transporting various proteins around the body.”
These properties make albumin a natural choice for a drug delivery system. In the mid-1990s, Novozymes Biopharma succeeded in developing a proprietary technology known as albufuse® for genetically fusing target proteins or peptides to albumin. A typical albumin fusion protein molecule is shown in Figure 2. The main benefit is that therapeutic proteins become much more effective with better uptake in the body.
Albuferon®* lasts a week
Human interferon is one example of an albufuse product. Interferon is administered as a drug to treat people suffering from a chronic hepatitis C viral infection. However, with a normal half-life of five hours, the interferon is soon lost from the body.
| Fig. 1. The benefits of half-life extension |
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- Significantly reduced frequency of administration – better compliance/ease of use
- Significantly reduced dose
- Significantly reduced side effects
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In this hypothetical case, the injected biotherapeutic is rapidly cleared from the circulation after administration, which means high dose rates and daily administration to maintain effective therapeutic levels. By extending the half-life of the biotherapeutic with albufuse® technology, the significantly reduced dose and reduced frequency of administration give reduced side effects for the same drug because it does not reach the toxicity level in the blood. |
One way to make it last longer is to use PEGylation, whereby a chemical is bolted on to the interferon. This extends the half-life to 35 hours. However, by fusing interferon to human albumin, the half-life becomes 160 hours or one week – a 32-fold improvement from five hours.
This solution has been chosen by Human Genome Sciences, Inc. in collaboration with Novartis to make a drug called Albuferon – a combination of albumin and interferon α-2b. Albuferon is used to treat people with hepatitis C infections. Human Genome Sciences has a license to use the albufuse technology from Novozymes.
Albuferon requires half the number of injections compared with PEGylated interferons, and phase 2 results demonstrated that Albuferon offers at least comparable efficacy, comparable safety, and the potential for improved health-related quality of life.
| Fig. 2. An albumin fusion protein molecule of human albumin with human interferon |
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Patient benefits
One advantage for patients is that less frequent injections are needed. Some biopharmaceuticals have to be administered by a nurse at home or at a clinic, so the number of visits can be dramatically reduced by improving the half-life.
Over the course of the treatment, a significantly reduced dose is required, making the treatment more cost-effective. This is becoming even more important with the increasing focus on healthcare costs and accessibility to medicine.
There is also a reduced risk of side effects. A lower dose rate means that the toxicity level of the protein may not be reached. Instead, the drug dose remains within the therapeutic range (see Fig. 1).
| Fig. 3. A variety of constructs can be designed and made |
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The DNA sequence for the protein of choice (shown in red) can be joined to albumin in a number of ways. |
Other licensees
Albuferon is just one of the drugs under development featuring albufuse technology. A number of major biotech and pharmaceutical companies such as GSK, Teva, CSL Behring, and Dyax are also using the technology under license.
The latest peptides to awaken great interest are antibody fragments. These antibody therapeutics are predicted to represent one of the most exciting and medically beneficial drug development areas of the next decade. However, development is being slowed by the high cost of commercial-scale manufacture using mammalian expression systems. Novozymes could provide a more cost-effective solution with a combination of its yeast expression technology and albufuse technology. Antibody–albumin fusions have been shown by Novozymes to significantly extend the in vivo residence time of the fragments and they can be made without the high costs associated with manufacturing monoclonal antibodies.
New possibilities
“You can rethink your whole approach and make completely new therapeutics,” comments Dave Mead, whose long research background started with Delta Biotechnology Ltd, which was acquired by Novozymes in 2006. “There are drugs that you could never produce before without this albufuse scaffold to support them. And the drugs can be patented, giving added value to our partners.”
The albufuse concept from Novozymes is suitable for many peptides and proteins. There are several binding points on the heart-shaped albumin molecule where proteins and peptides can be placed.
It is even possible to fuse two different proteins together with albumin in the same recombinant molecule to give two different functions at the same time (see Fig. 3). The new technology is therefore not just suitable for improving an existing product but also for making novel products such as bifunctional proteins.
The researchers at Novozymes have engineered about 100 different “constructs” and successfully expressed these fusions.
High yields with yeast
The fusion technique is based on fusing the DNA encoding for short-lived peptides or proteins to the DNA encoding for albumin. The recombinant DNA is engineered into the host cell Saccharomyces cerevisiae, known more commonly as baker’s yeast, which has been used for centuries in breadmaking, winemaking, and brewing. This microorganism is well understood and is generally recognized as safe (GRAS). The fusions are secreted with high yields in a fermentation tank and then purified to a high level of purity.
Another advantage of albumin fusion proteins is that they are produced in a system free of animal components.
License packages
Novozymes has 10 years’ experience of producing recombinant human albumin (rHA) using its proprietary yeast expression technology at its cGMP (current Good Manufacturing Practice) manufacturing plant in Nottingham in the UK. The company’s experts can help with license packages to develop drugs produced using this expression technology in combination with the albufuse technology.
“We’ve made many types of proteins over the years and they have all done remarkably well. We have a number of licenses already and we’ve performed technology transfer with a number of third parties across the globe,” says Dave Mead. “Our yeast expression system has been proven to produce pharmaceutical-grade products.
“At Novozymes, we can take our Biopharma customers a long way up the learning curve. We can give them access to our tremendous expertise, our patents, and our extensive series of yeast strains. We also offer contract manufacturing of pharmaceutical-grade biological drugs at our cGMP facility at Lund in Sweden. We are not a drug discovery company but we work with partners from initial protein expression through process development work to delivery of a commercial-scale bioprocess that is robust, reproducible, and cost-effective. This will help them get to the marketplace faster, which is where the pot of gold lies at the end of the day,”concludes Dave Mead.
* This registered trademark is the property of Human Genome Sciences, Inc.