Seattle Genetics zeroes in on new era for cancer drugs

The problem remains one of the most tantalizing and elusive in all of cancer research.

For 30 years, researchers have been trying to develop a souped-up targeted drug for cancer. The idea is to take an antibody that can zero in directly on cancer cells, burrow inside and dump a nasty toxin that wipes them out. In theory, it could be done without seriously damaging healthy tissue.

Today, Seattle Genetics is taking a first step to see if it has figured out how.

The Bothell-based company has enrolled the first patient in a clinical trial of its next-generation technology for connecting antibodies to powerful drugs.

Over the next year, its trial of an "empowered antibody" will enroll about 40 patients, mainly with relapsed Hodgkin's disease. It will study a range of doses of its drug, SGN-35, measuring safety and the effect on tumors.

Cancer therapy has been revolutionized over the past decade by so-called "naked" antibody drugs that have become huge sellers, like Rituxan, Herceptin and Avastin. These drugs — with no attached toxic payload — are engineered to zero in on tumor cells and start killing them.

The drugs also hit selective healthy cells, but generally do not sledgehammer through them like chemotherapy does.

Partly because they extend patients' lives and have milder side effects, antibody drugs have gone mainstream.

In 2005, there were 17 on the market for a number of diseases, with $11.2 billion in worldwide sales, according to Dublin, Ireland-based Research and Markets. Another 80 antibody drugs were counted in biotech and pharmaceutical company pipelines.

Still, many antibodies are not considered strong enough to kill cancer on their own. And despite 30 years of effort, no one has had any commercial success with attaching an antibody to a potent drug.

Several empowered-antibody drugs — two with a radioactive payload — have reached the market since 2000 but haven't been popular because of nasty side effects and difficulty in use.

That hasn't discouraged Seattle Genetics.

Peter Senter, the company's 55-year-old vice president of chemistry, literally bounces in his seat when describing his company's approach.

"We've made it, it's in vials, and it's going to the clinic," he said. "This is an antibody-conjugate we like very much."

Here's how it works.

SGN-35 starts with the antibody, a Y-shaped protein engineered from human and mouse genes. The antibody seeks out and binds with a protein called CD-30, found on the surface of cells. It's an attractive target because it's on the vast majority of Hodgkin's disease cells, but seldom on healthy cells.

Seattle Genetics believes the next step is where its technology stands out.

In the past, Senter said, many empowered antibodies failed because the toxin snapped off within hours after injection and floated free in the bloodstream. That caused chemotherapy-like side effects and meant the toxin never arrived at the proper destination.

Seattle Genetics says it has developed a synthetic link that binds the toxin tightly to the antibody for about one week. That should give the antibody time to hunt down the tumors.

Then comes the real magical marriage of chemistry and biology, if the system works as intended. Once the antibody binds with its target on cancer cells, it is absorbed inside. There, and only there, specific enzymes act like molecular scissors to cut loose the toxin so that it can do its job, killing the cell.

The toxin used in SGN-35, originally found in ocean sponges, is far more toxic than standard chemotherapy so it can be lethal to cancer cells in the tiniest of doses.

Because of that potency, Seattle Genetics plans to use a one-tenth smaller dose of the drug than it would of a comparable "naked" antibody. If it can be effective at that dose, that could significantly lower the company's cost of raw materials.

Big questions still remain for the clinical trials. For instance, the toxin could snap off prematurely or cause other problems in the body after it kills the cancer cells. Patients may not stand up well to repeated doses. The body's immune system may recognize the antibody as foreign, and mount an inflammatory response that hurts the patient.

Edward Clark, a professor of immunology at the University of Washington, said antibodies often have difficulty squeezing through bulky tumors and navigating their slow, sludgy blood flow to reach the target cells.

To circumvent that problem, Clark co-founded another Seattle company, Trubion Pharmaceuticals, which is making smaller antibodies.

Despite all the past failures with empowered antibodies, Clark said he believes Seattle Genetics has chosen a viable cell target, and that its toxins have a better chance of success than radiation-linked antibodies, because they are easier to make, and use.

"It is not a harebrained idea," he said.

Pamela Trail, the company's chief scientific officer, was a research leader at Bayer Healthcare, and joined Seattle Genetics in May after getting a close look at its technology during partnership talks.

"I believe in this technology and the way we have put the pieces together," Trail said. "The reality is, we'll find out how well we did over the next year in the clinical trial."

Luke Timmerman: 206-515-5644 or ltimmerman@seattletimes.com