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Dual-Action Antibodies

Fighting cancer more efficiently.
Two for the price of one: Antibody drugs work by binding to antigens such as extracellular proteins or receptors on a cell's surface, blocking their ability to function or targeting them for destruction by the immune system. Genentech's new antibodies can bind to two different antigens, potentially reducing the number of drugs required to treat diseases. The antibody colored yellow can bind only to a receptor on the surface of a cancer cell. The green-colored antibody can bind only to an extracellular protein that promotes tumor growth. The new antibody (red) can bind to both the surface receptor and the extracellular protein.

At Genentech’s sprawling headquarters south of San Francisco, senior scientist Germaine Fuh has been genetically redesigning two of the company’s most lucrative cancer drugs. One, Herceptin, is a monoclonal antibody that shuts down HER2, a growth accelerator in about 20 percent of breast tumors. The other, Avastin, is an antibody that blocks a protein that stimulates the formation of tumor-­feeding blood vessels. Last year the drugs had combined sales of $11 billion; a full course of Herceptin at wholesale costs about $43,000, while treating a breast cancer patient with a full course of Avastin costs about $55,000. Fuh’s goal: to show she can provide greater benefit for people fighting breast cancer by combining the action of the antibodies in one molecule. Last year, she and her coworkers showed that a modified version of the Herceptin antibody not only shut down the HER2 receptor in mice but also locked onto VEGF, Avastin’s target.

Designing such “dual-specific” antibodies could help solve a major problem with chemotherapy drugs: cancer cells can become resistant to them, mutating in ways that allow them to dodge the medication’s action. Doctors often mix various chemotherapy drugs in an effort to kill cancers before they can exploit this escape mechanism. Having a single drug that can hit the cancer from multiple directions would simplify treatment.

A single monoclonal antibody that could do the work of two is also attractive from a business perspective. It might cost half as much to manufacture as two separate antibodies, and the path to regulatory approval might also be shorter and less expensive, involving one set of clinical trials instead of multiple trials for two separate drugs in various dosage combinations. Genentech has started trials to determine whether Herceptin and Avastin together will fight breast cancer better than either used alone, but the cost of such studies is a big disincentive to doing them regularly.

Fuh’s research into whether one antibody drug could be redesigned to do the work of two began six years ago. An antibody, one of the immune system’s most robust weapons, is a Y-shaped protein about 10 nanometers long. At the tip of each branch is an active site, which grabs a specific molecule on an invading microbe or cancer cell. Swarms of antibodies disable the invader, marking it for destruction by white blood cells or other immune molecules.

Fuh notes that many mammalian antibodies have some ability to bind to a second antigen, but typically they do so weakly. Her goal was to exploit this ability while making both bonds tight and functional. Fuh’s team induced subtle mutations at the tips of Herceptin and screened 10 billion mutant clones for activity against VEGF. They netted several candidates–including one with active sites that could bind to both HER2 and VEGF strongly enough to limit tumor growth.

Genentech, now a wholly owned subsidiary of Swiss pharmaceutical giant Roche, is using this technique to develop another dual-specific drug, which may soon be ready for clinical trials. Fuh won’t disclose the details of what the drug is for and will only say, “Right now, we are very close.”

Meanwhile, her experiments have fueled interest in the overall potential of such drugs. “The two-for-one drug concept is important, especially for indications like cancer,” says Carlos Barbas III, a professor of molecular biology at the Scripps Research Institute in La Jolla, CA. Barbas is the founder of CovX, a company working on a different approach to making dual-specific antibodies (Pfizer acquired it in 2008). Despite the competition, he praises the accomplishment of the Genentech team as “a beautiful piece of antibody engineering.”

The implications of Fuh’s research are indeed far-reaching. If the concept proves successful, antibodies that stick to two targets might be used to treat infectious diseases as well as cancer–offering the promise of drugs that work better and cost less.

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