From basic discovery to breakthrough drug

'Determination and persistence' carries a controversial theory to development of drug that prevents inflammation, reduces MS relapse
Dr. Elizabeth Wayner
Dr. Elizabeth Wayner developed a method to interfere with the development of inflammation in incurable autoimmune diseases like multiple sclerosis. Photo by Todd McNaught

There are few more satisfying experiences for scientists than to see their work benefit others. For Dr. Elizabeth Wayner, that gratification came last fall, when the U.S. Food and Drug Administration granted approval for a breakthrough drug to treat multiple sclerosis that is based on a discovery she made more than 15 years ago.

The drug, known as Tysabri®, was created with a method Wayner developed that uses an antibody to prevent the inflammation associated with multiple sclerosis (MS), a sometimes disabling autoimmune disease that strikes the central nervous system. Tysabri® also may prove beneficial for patients with other autoimmune diseases such lupus, Crohn's disease and rheumatoid arthritis, as well as melanoma, a serious form of skin cancer. The drug is being marketed by Biogen Idec Inc. and Elan Corp.

"I'm thrilled that my research can help prevent suffering," said Wayner, staff scientist and manager of the Antibody Development shared resource. An estimated 400,000 Americans are afflicted with MS, a disease with symptoms ranging from fatigue and numbness to an inability to walk.

The center holds patents for use of antibodies like Tysabri®, and Fred Hutchinson will receive a percentage of the royalties from the sale of the drug, a portion of which will be shared with Wayner. As with any other royalties generated from center inventions, the money will go directly back into the center's research and clinical programs — where it will support other potentially lifesaving discoveries, said Spencer Lemons, vice president for Industry Relations and Technology Transfer.

"The most rewarding thing for us is to see how our research can directly benefit people," he said. "It can take a long time to see the ancillary benefits of a basic research discovery like this one. Our goal is to make it possible for as many discoveries as we can to succeed commercially."

The drug's roots go back to 1988, when Wayner, then a postdoc in Dr. Bill Carter's Basic Sciences Division laboratory, proposed a controversial idea that could explain how immune cells cause the dangerous inflammation behind many incurable autoimmune diseases. Carter's lab studies what is known as the extracellular matrix — the glue that holds the body's cells together. "It's the reason we don't dissolve when we jump into a swimming pool," Wayner explained.

Carter's lab had been studying catcher's mitt-like proteins called integrins found on the surface of cells. Integrins enable cells to adhere to proteins in the extracellular matrix. This adhesion is critical for wound healing, blood clotting and the ability of cells to migrate to places where they are needed as well as to relay important signals to neighboring cells.

Prior to Wayner's joining the Carter lab, it had been known that skin cells or other cells that line the body's organs had these adhesive properties. But Wayner became curious about whether or not blood cells also could adhere to extracellular matrix proteins. In particular she became interested in the surface proteins called receptors that are produced by T cells, a class of white blood cells that help the body defend against infection.

"I had come from a lab that was studying T cells, and I wondered whether they had receptors that would allow them to bind to endothelial cells (cells that line blood vessels) and the extracellular matrix that supports these cells. This would allow them to adhere to and pass through the lining of blood vessels," she said.

The idea was somewhat heretical, Wayner said, because T cells are supposed to stay in circulation in the blood and were traditionally thought to be non-adherent. If T cells could bind to blood-vessel linings, that would give them the foothold needed to migrate out into and adhere to extracellular matrix components present in tissue — the exact definition of inflammation.

"People didn't believe me when I presented the work at meetings," she said. "But it turned out I was right."

Wayner quickly realized the potential value of her finding — for the first time, it might be possible to develop a way to specifically interfere with this process to prevent the inflammation that occurs in many types of diseases. In particular, inflammation is a hallmark of autoimmne diseases — a collection of disorders in which the body's own immune system attacks itself. In the case of MS, T cells inappropriately react against myelin, a protein that coats nervous tissue.

Wayner developed an antibody — a type of immune-system protein that binds exclusively to another protein — that was specific for the T cell-endothelial cell receptor, also known as the alpha 4/beta 1 integrin receptor. This antibody interferes with the T cell's ability to bind to blood-vessel linings.

A short time after she developed the antibody, Wayner left the center to work in the biotechnology industry. She first worked at a local company called Oncogen and at several other places, always discussing the merits of her new technology. In 1994, Wayner returned to the center as a staff scientist.

"Since the work was started here, I always felt that the center should benefit from it," she said.

Fred Hutchinson initially licensed the technology to Cytel, which subsequently sublicensed and eventually assigned the license to Elan in 2000. Later that year, Elan and Biogen entered into an exclusive collaboration to develop, manufacture and commercialize Tysabri®.

Tysabri® reduced the relapse rate in MS patients by more than 65 percent compared with patients who received a placebo. In contrast, the best selling MS drug, Avonex, reduces the relapse rate about half as often.

In patients already taking Avonex, the relapse rate was halved among patients who also were given Tysabri®. Based on these results, the drug manufacturers believe that Tysabri® could soon become the bestselling MS drug.

Wayner said she feels that her experience can be best summed up by the moral of the fable about the tortoise and the hare: Determination and persistence wins the race.

But mostly, she said, "I'm just very happy that this work can be used to benefit the public."

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