Interferons: A Family Business

When your father is Sidney Pestka, "the father of interferon," it's hard to grow up without learning something about the potent little protein that helps regulate the immune system. "I was surrounded by science my entire life," says his son Rob Pestka. "I worked in his laboratory.

Joan, Rob, and Sidney Pestka (l-r) have taken PBL from a basement start-up to a $30 million a year enterprise.

I published a paper together with him. " And so it seems only natural that one day Rob would become CEO of PBL Therapeutics.

PBL stands for Pestka Biomedical Laboratories, the name Sidney and Joan Pestka (and their lawyer) gave the company they founded in their basement in 1990. What started as a sideline business of making interferons for research is now a 25-person operation with $30 million a year in revenue. Despite its success, however, the reagent business is not the Pestkas' only focus. In fact, it generates capital to fund Sidney's dream of developing individual interferons that will treat the many forms of cancer.

Process Pioneer

Sidney began his interferon research in 1969 when he joined the Roche Institute of Molecular Biology. During the early years, the proteins came from living donors. "We obtained white blood cells from the New York Blood Center and the MD Anderson Cancer Center," he says, "and stimulated those cells to make interferon."

The 1972 discovery of recombinant DNA suggested that the mass manufacture of proteins was possible and opened the door to biotherapeutics. Then in 1975, Sidney altered the course of biological research by making interferon in vitro, becoming the first scientist to produce an active human protein in a test tube. He chose interferon because it was easily measured and showed great activity in small amounts.

"It is noteworthy," he says, "that the initial work was done because of the basic-science question: 'Can we synthesize an active humanprotein in the test tube?' It turned out that we could, which demonstrates that support of basic research is extremely important. Research that doesn't initially start out to diagnose or treat or prevent a disease can actually lead to major achievements."

Interferon at Work

In 1977, Sidney and his colleagues made history again by developing a method to purify proteins. The process -reverse-phase high performance liquid chromatography (HPLC)-is now a standard process in biotech, pharma, and academia.

"We had a big surprise when we purified interferon alpha," he recalls. "We thought we were looking for one interferon and instead we found about ten different proteins."

That discovery generated a substantial amount of excitement-both in research circles and among the public. Interferon was considered by many to be the "magic bullet" that would treat both viral diseases and cancer. But that dream proved to be elusive.

Too Much of a Good Thing

The body produces iterferon in response to a viral infection. Like all potent therapies, it comes with side effects. In fact, the headache, fever, and joint pain people experience when they have the flu are not a result of the virus but instead the result of interferon at work combating the virus. And, although interferon is currently approved to treat Hepatitis C and multiple sclerosis, its ability to treat cancers generally-which requires much greater doses-has been limited by its side effects.

Even though much of the industry abandoned the research, Sidney never lost faith that interferon could be used as an oncology treatment. He knew he needed to discover new and better interferons and to find a way to get more therapy into the tumor with less circulating in the body.

His original efforts were rewarded when, in 1986, FDA approved Roferon, the interferon Sidney had developed. With a sense of accomplishment, he left the institute that year and began teaching at the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, where he continued his research.

Then, in 1990, at the request of the university, he and his wife Joan founded Pestka Biomedical Laboratories in the basement of their home in North Caldwell, New Jersey. Their business model was simple: Supply interferons for research purposes. They started with one client and grew the company organically.

Biologic Logistics

Packaging and shipping interferons is not a typical home business. Joan describes the early months: "We had a freezer and a refrigerator in our basement, so we kept the products down there. To get the vials out to customers, Sid would bring home styrofoam boxes that the university was throwing out. I would run to the local ice cream store and pick up dry ice, then I would package everything on the ping pong table and bring it over to Federal Express."

As word of their business spread and demand for their product grew, they realized they would soon run out of the interferon supply they had licensed from Roche. So they hired a part-time technician and rented a small lab space in New Brunswick.

"She made up the materials for us in the lab, and I would go down there once or twice a week to ship them out," Joan says. "I would do the invoicing, the collection, and all the other paperwork. As we got more customers and people found out about what we were doing, we had to get more lab space and hire more people. At the end of our stay at the incubator, we had eleven different rooms, some labs, and some office space on several floors. At that point we knew we had to consolidate. So we leased and renovated some nice laboratory space in Piscataway where we are now."

Throughout that period, Sidney continued to carry out research and teach full time at the university while functioning as PBL's chief scientific officer, and Joan took on the roles of human resource director, bookkeeper, and general administrator. When the business began to grow beyond their ability to handle it, they asked their son Rob to run it for them.

Full Circle

Although Rob grew up with science and started out his college years as a molecular biology major, halfway through he switched to architecture and civil engineering. "I guess I had somewhat of a rebellious streak at that time," he says. "I finished my degree and actually worked in that field-architectural design, construction management, civil engineering-for about five years after graduation."

Then his parents asked him to join PBL. "At that time, I was getting a little disenchanted with the field I was in," Rob recalls. "It was a pretty bad time for the construction industry and for architects in general, and I was losing some interest as well. They offered me that job, and I saw it as an interesting opportunity."

Parents like to think they know what's best for their children, and in this case, they were right. Under Rob's leadership, the company flourished, growing from a $30,000 a year "hobby"-as Joan referred to it in the early years-to a $30 million a year enterprise. It now produces 150 products, including human and animal interferons, antibodies to interferons, assay kits, and reagents (www.interferonsource.com).

Once the company started making real money, the family saw it as an opportunity for Sidney to conduct research on his own terms. So they started PBL Therapeutics as a separate operating unit under the larger umbrella of PBL Biomedical Laboratories.

A Sure Thing

"He never wanted to just be a company selling a bunch of chemicals," Rob says of his father. "He's always had the goal of making an impact on humanity through scientific developments. He developed interferon, which has been quite successful against hepatitis and multiple sclerosis. But he always felt that interferon could be very powerful in the treatment of cancer. It just never came to pass. So when we had this company growing, we took some of the profits from the sales of biochemicals and invested them into developing some of our own technologies."

Growing Pains

With Sidney's history of scientific breakthroughs, it's no surprise that PBL has developed cutting edge therapies and methods for delivering them. First, Sidney's team discovered "ultra interferons"-proteins produced by diseased cells that, in the lab, demonstrate 20–30 times the therapeutic activity of marketed interferon. So far, PBL has about 50 different molecules that look promising in the test tube. But potency is only one issue.

In 2002, President George W. Bush presented Sidney Peskta, MD, with the National Medal of Technology for his pioneering efforts in biotechnology.

"How do we determine which one is going to have little or no side effects?" Sidney asks. "There is no surrogate marker that we could use, even in vitro or in cell cultures. So it is challenging." Also difficult is deciding which one has the most therapeutic potential and is, therefore, the best investment to start with. "Interferons are species specific," Sidney explains. "Human interferons work in human cells, but not very well in mice, for example. The closest animals that one can use for testing are the primates, and they are very expensive. Even in primates, they don't mimic exactly the effects as in humans. So this is the paradox, the difficulty that we now have."

But the Pestkas seem to thrive on challenges. One of their main goals is to secure $10 million in funding to support contract manufacturing and human clinical trials. They are now in the process of selecting which interferon to develop as their first product. And, in addition to seeking venture capital, the company also plans to license its proprietary delivery technologies to Big Pharma.

Stand and Deliver

Most current oncology products suffer from the same drawback: Drugs that are potent enough to kill cancer also have overwhelming side effects-if they are injected into the bloodstream and allowed to circulate throughout the body. The solution is a more targeted delivery system. Many companies are trying to find ways to sneak cancer drugs through the bloodstream, undelivered, until they reach the tumor.

PBL is no exception. The company has developed SuRe PD (sustained release protein delivery), which allows the ultra interferon to be injected directly into the tumor, thus bypassing a systemic reaction. The interferon is formulated into particles in a variety of states, and the active interferon is released at different times over a period of weeks. (See "A Sure Thing," page 86.)

"SuRe PD has applications to other proteins such as erythropoietin and human growth hormone," Rob says. Although he can't name any yet, Rob says, "We are in discussions with several companies interested in applying the technology to their proteins."

Also nearly ready to license out is another PBL breakthrough. "We've got a third technology-that's actually quite close to the clinic-that provides a better way to label monoclonal antibodies with radioisotopes," Rob says.

PBL's technology uses genetically engineered radiophosphates, which retain higher activity and selectivity for tumor antigens and appear less immunogenic than antibodies radiolabeled through conventional methods. Also, radioactive emissions are confined to the tumor site, minimizing the exposure of healthcare workers and patient family members.

With a $1.3 million grant from the National Cancer Institute, the company is conducting trials in vivo against human colon carcinoma xenografts to test its radioactive phosphate against standard-use radioactive iodine technology. If it proves successful, the application will give PBL yet another opportunity for licensing revenue.

Rewards and Challenges

In June 2002, President George W. Bush presented Sidney with the National Medal of Technology for "pioneering achievements that led to the development of the biotechnology industry and for basic scientific discoveries in chemistry, biochemistry, genetic engineering and molecular biology." Some people would be satisfied and call that a lifetime achievement. Not Sidney.

At a Glance

"I would love to have an approval date within two years of the time we start human trials," he says about his first interferon candidate. "If you ask anyone in the country, they would say that's unrealistic. I'm always over-optimistic. That's what keeps me going." As Joan says about him, "His philosophy has always been that everybody can work eight hours and sleep eight hours-it's what you do with the other eight hours that determines where your life is going."

But making interferons for research and making them for testing in humans are two different propositions.

To move forward, the Pestkas must raise enough capital to fund clinical studies. They must also either build or work with an FDA-approved GMP facility to manufacture the clinical trials material. Once the company begins to outsource its processes, one of the biggest challenges will be letting go.

"It's like a child," Joan explains. "When your children get older, you have to learn to let go of the apron strings and let them function on their own. I think it's the same when you have a business grow like PBL has."