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PEGylation: Changing the Landscape of Protein Drug Delivery
An Interview with Abe Abuchowski, PhD
The father of PEGylation and President and COO of Prolong Pharmaceuticals

An excerpt from a new Cambridge Healthtech Institute (CHI) Advances Report, Delivery Technologies for Therapeutic Proteins: Assessment and Outlook, by Tom Hollon, PhD. (see previous article for a report description)

CHI Advances Reports: Please begin by telling us about your position and background.

Abe Abuchowski: I am founder, president, and COO of Prolong Pharmaceuticals in Monmouth Junction, NJ. My professional life has been devoted to developing a protein drug delivery technology, starting at Rutgers University, where as a PhD student under Professor Frank F. Davis in the early 1970s, I found a way to chemically modify proteins with a polymer called polyethylene glycol (PEG). The idea was that PEG would cover the protein much like hair covers your head and disguise the protein from recognition by the body. This would enable the protein to circulate and exert pharmaceutical action for a long period of time, reducing the need for repeated injections. Disguising the protein would also minimize immune reactions against it. The first model protein that I PEGylated was bovine serum albumin. After that, the first model therapeutic protein was catalase. Using a strain of mice from the Argonne National Labs that did not produce catalase in the blood, I showed that I could treat their problem with PEGylated catalase injected once a week. This too was part of my PhD project.

After I received my PhD in 1975, I continued in the same lab until 1983. During that time I received a scholarship from the Leukemia Society of America to work on PEGylation of a protein that ultimately was approved to treat leukemia. I left Rutgers because it was clear that the time had come to move PEGylated proteins into the clinical stage. Since we could not get the pharmaceutical industry to bite on the technology, Frank and I decided to start our own company, Enzon.

CHI: Why did you choose PEG?

Dr. Abuchowski: PEG is very safe. The FDA had designated PEG as one of those compounds considered Generally Recognized as Safe (GRAS). PEG was used in food and cosmetics, and in injectable drugs it was used as a solubilizing agent for other pharmaceuticals. PEG is a unique polymer in that it does not have a tertiary structure. It’s like a hair, floating in the breeze.

CHI: What was Enzon’s first PEGylation success?

Dr. Abuchowski: The first was a drug called Adagen, which treated a rare disease in children called the "Bubble Boy" disease. These were kids born with no immune system because they lacked an enzyme called adenosine deaminase. Consequently they had to live inside germ-free plastic bubbles. But all kids who lived in these bubbles eventually died very young. We thought this genetic deficiency disorder would be ideal for showcasing our technology. We obtained adenosine deaminase in raw form and PEGylated it and convinced a group of scientists at Duke University to test it as a treatment. And lo and behold, it worked very well.

The FDA approved Adagen in 1990 as the first PEGylated therapeutic protein. And it was not just a biotechnology drug. It had this unique drug delivery system that had never been seen before. So at the time there was a huge question as to whether the FDA would stick its neck out and approve it. We used Adagen to prove to the FDA how great the technology was, for these kids would have to have this product injected once a CHI's Molecular Med Monthly Articles - Standard operating procedur... week for the rest of their lives. If it was safe in kids, it must be a pretty good drug delivery system. Because of the extraordinary results we got, in the end the FDA really had no choice but to approve it.

Not only did Adagen treat kids, it treated families. We had a mother with 2 kids with milder forms of the disease. She spent all of her time caring for them. She couldn’t work and was on welfare because her husband had left her. With Adagen, she was able to get her kids into school and return to a normal life. For her it was like a miracle.

CHI: After this, did pharmaceutical companies decide to take a risk on PEGylation?

Dr. Abuchowski: Nope. Adagen’s success was considered an anomaly. To prove it was not, we continued to work on our second drug, asparaginase. This was the drug I had worked on for the Leukemia Society. Asparaginase removes asparagine from the blood. Research at the time showed that some leukemic cells lose the ability to make asparagine and have to extract it from the blood. Destroying asparagine in the blood would starve and destroy those cells.

CHI: Was Oncaspar your breakthrough drug?

Dr. Abuchowski: The breakthrough was the third drug, PEG-interferon, which we did for Schering-Plough. But our success with asparaginase helped persuade them to give PEGylation a try. Schering [officials] originally approached us in 1989, looking for a second-generation version of their interferon and also for a longer acting version. They were curious as to whether we could turn their 3-times-a-week injectable into a once-a-week injectable. And we did, and they took it through the clinic and got it approved in 2001 as PEG-Intron. Within a year that product took 65% of the market for interferon. That told the industry that PEGylation was here to stay. Then other people jumped on the bandwagon. Roche brought out PEGASYS, another PEG-interferon. There are now 6 or 7 PEGylated products that together bring in more than $5 billion a year.

CHI: Is PEGylation a straightforward technology?

Dr. Abuchowski: People consider it a simple technology, but it really isn’t. They think of it from a conceptual perspective. You put PEG on and hide the product and everything’s fine, that’s the concept. The problems arise with how you put it on the protein. Each protein is different. Depending on how you add PEG, it may inactivate the protein. A lot of different chemistries have been developed to attach polyethylene glycol, and a lot of different PEGs have been developed. There are now long chains, branched chains, tree chains, and so on. All of these things have complicated the field. So the art of PEGylation—I call it an art more than a science—calls for knowing a little bit about protein chemistry, an awful lot about PEGylation, and also knowing about formulation and manufacturing and the regulatory process. Anyone can buy activated PEG from a supplier and PEGylate a protein. But does it have the physiological characteristics you are looking for? Does it have pharmaceutical activity? Does it have less toxicity? Can you make it to scale? Can you make it reproducibly and cost-efficiently? Not just anyone can do that.

CHI: What is Prolong’s pipeline?

Dr. Abuchowski: We’re working on a long-acting erythropoietin and developing our own long-acting versions of interferon and G-CSF [granulocyte-colony stimulating factor]. We’re also working on a long-acting PEG-hemoglobin for military applications to treat shock and hypovolemia. PEG-erythropoietin and PEG-hemoglobin are the furthest along and are scheduled to go into the clinic in the first quarter of 2008.

CHI: How is Prolong different from Enzon?

Dr. Abuchowski: Prolong is quite similar to the way Enzon used to be, but we are moving much faster because of the experience we gained at Enzon and because of the changed nature of the biotechnology industry. When Enzon was started there really was no biotechnology industry and so we had to do everything internally. We had to do our own manufacturing, our own product development, our own toxicity studies and clinical trials, our own submissions to the FDA, everything. Enzon became a fully integrated pharmaceutical company. Now the environment is much different. You don’t have to build a lot of your own infrastructure. You can do everything externally through clinical research organizations, or CROs, and it is much cheaper than doing it yourself. Because there is so much that Prolong does not have to do in-house, we can move much faster than we did at Enzon. Not that Enzon was slow. We still got 2 drugs approved in 10 years, which I think is better than just about any company out there.

CHI: How would you contrast PEGylation to other half-life extension technologies such as those that bind therapeutic proteins to human serum albumin?

CHI: So you expect Prolong’s PEGylated erythropoietin will be cheaper than Amgen’s Aranesp, an extended half-life erythropoietin made by adding glycosylations.

Dr. Abuchowski: Yes.

CHI: Most half-life engineering projects seek to extend therapeutic protein half-life as long as possible. An exception is insulin, from which other insulin products have been engineered or formulated for half-lives both shorter and longer. Are there other proteins that call for a range of half-lives? Dr. Abuchowski: Insulin is unique and is the only protein we will not PEGylate. It is not that we can’t. We won’t. And that is because the PEGylated version is deadlier than the native version. A long-acting PEGylated insulin in your bloodstream for a week could take you into hypoglycemia and kill you. I’m not saying that it is not possible to titrate it safely, but I am asking, what is the medical value?

CHI: Do you know if anyone is using PEGylated proteins in the tablets and medical devices being developed for oral, transdermal, nasal, and pulmonary delivery?

Dr. Abuchowski: I don’t know of anyone doing it right now. It’s too early. I think it probably can be done, but it adds another complication.

CHI: Can half-life extension help therapeutic proteins find new indications?

Dr. Abuchowski: Absolutely, because some proteins do not circulate long enough to be therapeutic in native form. Adenosine deaminase, for example, did not circulate long enough and could not be used as a therapeutic without PEGylation. A lot of cytokines may not be useful therapeutically because they don’t circulate long enough. Many of the obesity peptides being developed don’t circulate long enough; everybody is trying to PEGylate them. I venture to say that in the future more than half of all proteins introduced will be in PEGylated form. Almost every protein therapeutic that I know of that people are working on is being PEGylated.

CHI: What is the patent situation for PEG technology?

Dr. Abuchowski: The original patent on the concept has expired. Patents being generated currently relate to the chemistry of attaching PEG, the chemistry of the PEG itself, and specific product by process patents that relate to getting a superior product and the best yields.

CHI: So where do you see the field going from here?

Dr. Abuchowski: Believe it or not, I believe that even after 35 years this is just the beginning. The handful of products we have today is just the tip of the iceberg. Now everybody is trying to jump into it. There will even CHI's Molecular Med Monthly Articles - Standard operating procedur... be a whole generation of PEGylated biogenerics—a biogeneric PEGASYS, a biogeneric PEG-Intron, a biogeneric Neulasta. The reality is that there are simply so many proteins out there in search of a pharmaceutical application that I can spend the rest of my career developing new PEG proteins.

CHI: Any closing comments?