Herceptin, one of the first monoclonal antibodies, opened the door to more precise, targeted therapies
Earlier this month, the prestigious Lasker Foundation, which honors mavericks in the world of medical research, recognized the three inventors of Herceptin. Honored were H. Michael Shepard and Axel Ullrich, who did their work on the targeted therapy while they were with the biotech giant Genentech, and Dennis Slamon, who did his own investigations while at the University of California, Los Angeles.
It cannot be overstated how the approval of Herceptin in 1998 transformed breast cancer treatment. Not only was it the first monoclonal antibody (mAb) approved for the treatment of breast cancer, it was only the second mAb ever to reach the market. It opened the door to a new era of drugs that took precise aim at proteins lurking on the surface of tumors. Unlike traditional chemo, targeted drugs did less harm to normal cells surrounding the tumor.
Today targeted therapy—along with the newer cancer immunotherapy drugs—are a standard way of attacking breast cancer. Yet the road to approval for Herceptin–the drug that kicked off this movement–was not a smooth one. The work was marked by disappointments, setbacks, delays, controversy and even protests from breast cancer patients desperate for a new direction in fighting their disease.
The story of Herceptin began in 1970 when cancer researcher Robert Weinberg identified the gene, known as HER-2, involved in multiple cancer pathways. Five years later, Ullrich identified the protein produced by the gene, but the unanswered question was figuring out the role the protein played in the onset or progression of cancer.
Ulrich’s chance meeting with Slamon in a Denver airport provided a vehicle to help answer the question. The two launched a two-year partnership that eventually found that cancers overexpressing HER-2 were more aggressive, grew faster and spread at rates higher than other breast cancers. In other words, having too many HER2 receptors didn’t just contribute to breast cancer, it potentially was the the driver behind one of the most aggressive and deadly forms. HER-2 overexpression occurs in about 25% of breast cancers.
Figuring out how to attack the overexpressing HER-2 gene became the next big challenge. Scientists at Genentech thought mAbs were the answer and built a mouse version of the antibody to test their theory. In mice, they found that the antibodies could bind to HER-2 receptors on breast cancer cells and help them from transmitting growth signals.
Unfortunately, this approach didn’t work in humans because their immune system didn’t recognize the mouse antibodies. So Genentech scientists, including Shephard, took the section of the mouse antibody that bound to HER-2 and grafted it onto a human antibody.
Today the development of therapeutic antibodies is standard, familiar and unremarkable. But in the 1980s, it was virgin territory. After plenty of urging from the scientists at the core of the discovery, Genentech eventually decided to move forward with the drug development project. It would be years, though, before they could build enough evidence to demonstrate the veracity of their breakthrough to the outside world.
Slamon relentlessly sought out patients and researchers to join his cause. Luckily, they responded. Women suffering from such tumors, and with little hope of beating their cancer, signed up for clinical trials. Meanwhile, scientists from Genentech worked to develop a recombinant monoclonal antibody known as trastuzumab. Clinical trials began around the country.
Large-scale trials would eventually show that the immunotherapy, in combination with chemotherapy, reduced the risk of tumor recurrence by 52% and decreased the death rate by 33%. The targeted therapy also carried fewer side effects—such as nausea, hair loss or fatigue—normally associated with traditional chemotherapy.
But even before then, as results from clinical trials began trickling out, women all over the United States demanded access to a treatment that had not yet gained FDA-approval, and limited access was granted. The patient reaction was unprecedented in the field of cancer. The drug had become a lightning rod for thousands of desperate women hoping for a cure, and the push for better treatments helped fuel a breast cancer activist movement that mirrored what was occurring among AIDS activists during the 1980s and 1990.
With October approaching, it’s hard to escape the pink ribbons reminding us of how much is left to do to conquer breast cancer. Herceptin is not a magic bullet, but it was arguably the earliest weapons in today’s war on cancer, and thus a reminder of what is possible.