The Story of Mylotarg

George Ellestad, Ph.D.
Philip Hamann, Ph.D.
Janis Upeslacis, Ph.D.

I lost my father to bladder cancer several years ago. That was a learning experience for me - to have cancer strike so directly when I was working on it. I couldn't save him, but it gives you some feeling that maybe you are working in an area that is of benefit." - Philip Hamann, Ph.D.

The story of the breakthrough cancer drug Mylotarg® began on August 19, 1981 near Kerrville, Texas. Out of curiosity, a Lederle Labs (later became Wyeth) employee, who was traveling through the region, scooped up a small sample of soil known as caliche clay and brought it back to the laboratory. When the lab tested the soil sample, they found that it happened to contain tiny organisms that produced a powerful cancer-fighting substance called calicheamicin. The discovery was exciting because calicheamicin destroyed the DNA of cancer cells and proved to be more powerful than any anticancer drugs at the time.

Unfortunately, in addition to killing cancer cells, calicheamicin was 1,000 to 10,000 times more toxic to normal cells than traditional anticancer drugs. There seemed to be no safe way to administer it to patients without killing them. The researchers knew that if they could find a way to retain the anticancer power of the drug and reduce its affect on normal cells, they would help many patients.

"Our success rate is very small. I have gone through the calculations. A typical chemist - well, not that long ago - would make about 50 compounds a year. Then you calculate out how many compounds a chemist makes in a typical career, it should take at least two lifetimes to come up with a successful drug. I have the satisfaction of coming up with a successful drug in my career." - Janis Upeslacis, Ph.D.

Drs. George Ellestad and Janis Upeslacis, at Wyeth, along with colleagues, began working on the problem. They studied the basic structure of the substance for more than five years. During their research, they began to understand its basic molecular structure and learn why it was so effective in killing cancer cells. Another scientist, Dr. Philip Hamann, joined their efforts in 1987 and after reviewing what his colleagues had learned, got an interesting idea. Dr. Hamann knew that there were antibodies (proteins that are produced by the immune system that help fight disease) that specifically targeted cancer cells but left normal cells alone. Using a "linker," he thought the team could attach the toxic treatment to one of these antibodies, which would bring it directly to the tumor, bypassing most normal cells.

The challenge was actually getting the molecules to link. The team worked to find linker molecules to connect the toxic substance to the right antibody. Early in the process the team thought they found a way to link the molecules, but further testing showed that the linker they were using would not work in the human body. It was a serious setback for the researchers. Determined to find the proper way to link the antibody and cancer-fighting substance, they headed back to the lab.

Dr. Ellestad tells of a congratulatory e-mail he and the other scientists had received:

It was from an M.D. He said his wife died of acute myeloid leukemia 26 years ago. He said there hadn't been much progress in a number of years and it was very meaningful to him that, finally, there was something that seemed to work against this kind of cancer.. As a scientist, I always wanted to work on very exotic chemistry. But to have the exotic chemistry used where it actually helps somebody feels very gratifying. Clearly, this was the most interesting and satisfying project I have ever been involved with." - George Ellestad, Ph.D.

After six more months of searching, the team finally devised a way to link the antibody with the potent anti-tumor substance, resulting in the basis for a powerful weapon against relapsed acute myeloid leukemia (AML). On May 17, 2000 - nearly 19 years after the original soil sample was collected in Texas - the U.S. Food and Drug Administration approved Mylotarg for use in patients over 60 who suffer from relapsed AML, the most common form of leukemia in adults.

Mylotarg was the first approved drug in a new class of anticancer therapies called "antibody-targeted chemotherapy." Clinical trials demonstrated increased remission rates of about 30% for acute myeloid leukemia sufferers. Additionally, because the drug is targeted to cancer cells, incidence of many side effects associated with traditional chemotherapies, such as hair loss, nausea, oral and gastrointestinal tract sores, were significantly reduced.

These scientists showed for the first time that a powerful anticancer drug could be attached to an antibody and delivered directly to the cancer cells. This targeted approach to cancer therapy has been the foundation for many successful cancer treatments that followed, improving the lives of those who suffer from various forms of the disease.