Genentech’s Souped-Up Herceptin: The Odyssey Toward a More Powerful Breast Cancer Drug

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cancer therapy. “These are both exciting programs that have the potential to help thousands of cancer patients,” says Seattle Genetics CEO Clay Siegall. “I believe they represent only the beginning of what is possible with empowered antibody-based therapies.”

The FDA approval of Herceptin was pivotal, but T-DM1 began its journey inside Genentech as far back as late 1997, Sliwkowski says. Genentech in those days wasn’t really a cancer drug company. It was better known for its work in cardiovascular disease and with genetically engineered growth hormones. It had just gotten its first taste of success in cancer with rituximab (Rituxan), a hit drug for lymphoma.

Scientists at Genentech got fired up about another first-generation antibody for cancer, the original Herceptin, when the pivotal Phase III results arrived in late 1997 that proved the drug was likely good enough to win FDA approval. The thought of creating a more potent second-generation drug was floated internally, but didn’t get much traction right away, Sliwkowski says. That’s because the company was so preoccupied with getting its original Herceptin application filed with the FDA, passing muster at an expert advisory panel meeting, and lining up proper diagnostics to make sure the drug got to the right patients.

“We were a pretty lean and mean team, and didn’t have a lot of extra time to think about second generation drugs and all that kind of stuff,” Sliwkowski says.

Sliwkowski, who joined the company in 1991 and did a lot of work on the original Herceptin, started thinking more seriously about a more potent form of the drug the day after FDA approval in September 1998. “Not that the date means anything to me,” he joked.

There was enormous skepticism inside the company, and outside, at the time. Many researchers had tried to create this kind of “magic bullet,” virtually from the moment the Nobel Prize-winning team of Georges Kohler and Cesar Milstein created the first targeted antibodies in 1975. All subsequent efforts to make antibody drugs loaded with toxins had failed. Often, it was because nobody knew how to properly link a toxin to the antibody. The toxin would often break off in the bloodstream before it ever got to the tumor, making the drug less potent and possibly more toxic than it should have been than if it got to the target and was properly metabolized. “There was a lot of baggage,” Sliwkowski says.

Still, Genentech was in the mood to think big. It had proven its critics wrong about Herceptin. Scientists were skeptical about whether that treatment, like most antibodies before it, would provoke a human immune system reaction against the antibody itself that would render the product useless. Others wondered whether the target it was aimed at (the HER2 protein) was truly more abundant on cancer cells than healthy ones. Overcoming those doubts made a few people within Genentech think they could solve the problems again with antibody-drug conjugates, Sliwkowski says.

“The pendulum of interest in oncology within Genentech swung in a new direction. We were this oncology company now. We were serious.” Sliwkowski says.

They needed to be. The scientists at Genentech figured there were four major variables that needed to be resolved if an antibody-drug combination were ever to work.

First, they needed to aim the antibody at a truly valid target … Next Page »

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11 responses to “Genentech’s Souped-Up Herceptin: The Odyssey Toward a More Powerful Breast Cancer Drug”

  1. Jerry Jeff says:

    Sorry if I missed it in the article, but what is the toxin? In broad terms, at least.

  2. Jerry—I didn’t really get into this part, but the toxin is called DM1, which is a maytansanoid cell-killing agent.

    The National Cancer Institute has a nice little scientific description of this drug at the link below.

  3. I am a Herceptin patient had have been so for 8 years. My original diagnosis of breast cancer was in 1988. I recurred in 2002 and was given Taxol and Herceptin. I remain on Herceptin every three weeks. It has worked remarkable well for me, I remain cancer-free.
    However I have a delemma. I currently have COBRA insurance which will discontinue in April 20ll. I don’t turn 65 till Feb. 2012. There is a gap of nine months in which I will not be able to get Herceptin as I cannot afford the cost ($2,400 per treatment). I have been told that if I stop the Herceptin, my cancer in all probability will return, and once it does the Herceptin usually does not work. Can any body refer me to some one who can help me? I just need the help for that period when I have no insurance. I am 63, widowed and am on widow’s benefits and a little part time job. Thank you. This is a truely miracle drug for those of us it helps. I work out every day, walk 4.5 miles in 1 1/4 hours, do step aerobic, and my ejection fraction of my heart is 64%.

  4. Jdog says:

    Patrica, how is one supposed to verify that your needs are real?