FEATURE — Fall 2009
   

 

A holder of four degrees from Washington University, Morris Rosenberg speaks the language of both biology and chemical engineering, which he says has proven pivotal in engineering pharmaceutical manufacturing processes. (Photo: Wes Paz)

Stable Linking
Technology to Transform Cancer Treatment

As executive vice president of process sciences at Seattle Genetics, alumnus Morris Rosenberg is helping shepherd a revolutionary way to treat cancer, using the body’s own strategies to specifically target tumor cells.

by Steve Kohler

From his office at Seattle Genetics in suburban Bothell, Washington, Morris Z. Rosenberg looks ahead to 2012, when the company aims to release its first pharmaceutical product to treat cancer patients. Three more years may seem like a long time after nearly a decade devoted to the project, but Rosenberg, who is executive vice president of process sciences at Seattle Genetics, says the technology and the processes he is helping to devise reduce both development times and costs compared to traditional pharmaceutical processes.

They also represent a new and promising approach to cancer therapeutics. By using the body’s own strategies to specifically target tumor cells, the technique is designed to leave healthy cells unaffected and produce a lower frequency of side effects. That borders on being a revolution for those affected by cancer, the second leading cause of death in the United States, with more than 565,000 lives claimed annually.

Delivered systemically, conventional chemotherapy is highly toxic, often with unpleasant side effects. “Traditional, small-molecule drugs may go to the right place, but also to many of the wrong places,” says Rosenberg, BSChE ’83 (chemical engineering), AB ’83 (biology), MSChE ’86, DSChE ’89. Their design is foreign to the system, and many of the compounds that will work safely already have been discovered, so it is getting harder to find molecules that work for many patients. “To find a broadly effective drug like Lipitor, for example, you have to screen thousands of molecules, and for every success, hundreds of millions of dollars are spent on failures,” he says.

Seattle Genetics’ alternative approach is to take cues from the human body, using large-molecule antibodies for what Rosenberg calls “protein therapeutics.” The body naturally produces antibodies to fight foreign enemies, including cancer, so they don’t antagonize the immune system. In a helpful twist, antibodies all are similar in structure, with only a tiny portion, the so-called “highly variable tip,” significantly different. That tip is the guidance system that directs an antibody to its target and nowhere else.

Put simply, the approach Rosenberg works on is to link cytotoxic drugs to monoclonal antibodies that target tumor cells, creating antibody-drug conjugates (ADCs). “The antibody is the targeting agent that binds only to a specific antigen. The warhead is the cytotoxic drug that kills the cancer cell once it is delivered inside the cell,” he explains.

The sophisticated biochemistry behind producing ADCs requires discovering effective drugs, finding tumor-specific antigens that make targeting possible, and creating techniques for linking drugs securely to antibodies until it is time for them to be released at the disease site. All parts are necessary for the strategy to work. “This is all hard to do, which is one reason for what may seem like a slow pace,” Rosenberg says.

One of the challenges involved—making synthesized monoclonal antibodies tolerable—has been resolved. Rosenberg says that monoclonal antibodies were first found in the ’70s and commercialized in the ’80s, with the promise that they were a “magic bullet” for targeting disease. But only about 15 years ago did biochemists finally manage to boost their power and make them practical. The trick turned out to be eliminating the murine elements (they are hybridized in mice) so they would be tolerated by human immune systems. Now, Rosenberg says, monoclonal antibodies represent a hotbed of technological innovation and are a rapidly growing $25 billion-a-year portion of the pharmaceutical business.

What Seattle Genetics brings to the equation is an effective linking technology to bind drugs with monoclonal antibodies but release them once they are delivered to their targets. Early attempts to link drugs with antibodies were largely ineffective because the linker was not robust enough, and the payload was released before reaching the target. With Seattle Genetics’ more stable technology linker, Rosenberg says, “the majority of the drug is now released only once it is inside the cell’s lysosome storage compartment, where it goes on to disrupt cell division.” A cancer cell’s purpose is to divide, and when the process is inhibited, the cell commits suicide, a process called apoptosis. Seattle Genetics has outlicensed the technology to other pharmaceutical companies, greatly expanding the impact of this promising technique.

Rosenberg says his responsibility is to be “the ‘D’ of ‘R&D,’” charged with developing processes to manufacture antibodies and drugs, methods for linking the two, analyzing the effectiveness of the conjugate, and finally for scaling up the technology into an effective manufacturing process.

He credits his education in the once-uncommon combination of biology and engineering with putting him 10 years ahead of the game. “Until recently, 95 percent of the people I worked with were pure biologists, and I was a rare breed. Now, I’ve begun to see more people like me, people with skillsets including statistics and mathematical analysis who know how to engineer pharmaceutical manufacturing so that it can be scaled up. Speaking the languages of both biology and engineering has been a tremendous advantage in my profession.”

His career had its beginnings at Washington University when Rosenberg was an undergraduate with a developing interest in what he called “applied biology,” before the biotechnology industry had a name. His practical bent drew him toward the combination with chemical engineering, and he earned both master’s and doctoral degrees in engineering, working along the way with such iconic Washington University professors as Ursula Goodenough and Marilyn Krukowski in biology, Milorad Dudukovic in engineering, and Edward S. Macias in chemistry. “I didn’t have one professor I can single out but was fortunate to have many inspirational mentors and a rigorous academic program,” he says.

After a decade at Washington University, Rosenberg spent the next 15 years working in laboratories at prominent pharmaceutical companies including Monsanto, Biogen, Invitron, and, most recently, Eli Lilly. “Unlike many people who study science and then get into industry, I’ve been fortunate to apply much of what I learned during my academic career,” he says.

His practical background has been key to helping Seattle Genetics successfully develop six of its own drugs that now are in the pipeline and to begin moving from focusing only on cancers of the blood to exploring solid tumor therapies. The company is conducting clinical trials on its products, and despite a biotechnology industry economic downturn that Rosenberg calls “the worst I’ve seen in 20 years,” he remains confident about the prospects for helping those with cancer.

He stops short of calling the drugs he helps design and produce revolutionary, in the popular sense. “Cancer is patient-specific, and we know to no longer think in terms of a broadly applicable cure,” he says. “But we aspire to transform the disease from life-threatening and disabling into a manageable illness. In that sense, we do hope our work represents a breakthrough.”

Steve Kohler is a freelance writer based in Bonne Terre, Missouri.