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

Xconomy San Francisco — 

Scientists have been dreaming for decades about drugs that go after cancer cells like heat-seeking missiles. The idea is to destroy the enemy and spare other cells from the collateral damage that so many cancer drugs cause. Now after more than 10 years of sustained effort by one of largest teams ever assembled at Genentech, and some gut-wrenching ups and downs, that vision is on the verge of turning into reality.

This story began when Genentech, the South San Francisco biotech pioneer now owned by Roche, made history back in September 1998. That’s when it got the green light from the FDA to sell a genetically engineered antibody designed to seek out a mutated protein found on malignant cells in about one-fourth of women with breast cancer. The drug, trastuzumab (marketed as Herceptin), has been proven over the years to work even better than Genentech first imagined it would in women with early stages of cancer. The therapy is now one of the biggest selling biotech products in history, generating more than $5 billion in annual worldwide sales.

Yet from the moment of the FDA’s approval, a small group of scientists in-house were thinking even bigger. They suspected that their engineered antibody, even though it could hit a specific target on cells, would fail to land a real knockout punch against tumors. The scientists had shown that drugs of trastuzumab’s generation could interrupt signals cancer cells need to grow, and they later realized that the drugs could also sometimes provoke an immune system reaction against the tumor. But they weren’t a cure.

Mark Sliwkowski

Mark Sliwkowski

So scientists at Genentech, including Mark Sliwkowski, wondered if a targeted antibody would work even better if they could attach potent little toxins to it, making it into a “smart bomb” or an “empowered antibody.” Nobody has turned this concept into a commercial success after 30 years of trying, but Genentech and its partner in Waltham, MA, ImmunoGen (NASDAQ: IMGN), are betting they have finally been able to pull off this daunting scientific trick.

Evidence to support the claim arrived last December at the San Antonio Breast Cancer Symposium. A next-generation form of Herceptin, jointly developed by Genentech and ImmunoGen, called T-DM1, partially or completely shrank tumors in about one-third of 110 patients who were extremely sick, whose cancer was still worsening after they had endured an average of seven prior rounds of therapy. The most common severe adverse event was a depletion of blood platelet cells, which was found in 5.5 percent of patients, researchers said. The balance of safety and effectiveness was so convincing that Genentech plans to seek FDA approval before the end of this year to start selling T-DM1 in the U.S.

Important as it may be for breast cancer patients, the finding has re-energized the once moribund field of antibody-drug combinations, often called “antibody drug conjugates.” Genentech is so bullish on the concept that it now has 50 such drug candidates moving through its internal R&D pipeline, following the lead of T-DM1. This idea of “bombing” the tumor, once written off as a pipe dream by most people inside Genentech and academic research, has morphed into one of the company’s top strategies for fighting cancer, according to Sliwkowski, a longtime champion of the concept.

“We take this far more seriously than we did previously,” Sliwkowski says. “We are investing a lot of money and resources into this. That should answer your question.”

One of Genentech’s collaborators on antibody-drug conjugates, Seattle Genetics, says T-DM1 and another drug it is developing for Hodgkin’s disease called SGN-35, are at the forefront of a new wave of … Next Page »

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