A Two-Pronged Attack on Cancer

Last year marked a first for engineered antibodies--the European Commission approved a new cancer drug called Removab (catumaxomab), an antibody specially designed to grab both cancer cells and immune cells in such a way that the immune cell can kill the cancer cell. (The drug is undergoing testing for U.S. Food and Drug Administration approval.)

Double action: Researchers at Merrimack Pharmaceuticals have developed an antibody that binds to two receptors on the surface of cancer cells.

Now a handful of similarly complex molecules, dubbed "bispecific antibodies" for their ability to target two things at once, are in clinical trials. The two arms of these antibodies work together to treat cancer or other diseases, bringing together two types of cells. As with Removab, this means targeting two different types of receptors on the surface of a cell, or even using one arm to deliver drugs to specific cells targeted by the other.

Scientists say the two-front attack can make existing cancer therapeutics more powerful and help combat drug resistance, an issue for some targeted cancer therapies. "If you can wrap two treatments into one molecule, you have a potentially more active drug and can take it to the FDA more quickly," says Carlos Barbas, chair of the Skaggs Institute for Chemical Biology at the Scripps Research Institute in La Jolla, CA
While the concept of bispecific antibodies has been around for decades, the approach has only recently shown clinical success. The field has been driven forward by new ways of designing and making the antibodies, which take advantage of advances in protein engineering, as well as the success of single-target antibodies, such as herceptin, that are already on the market. "The European approval of the Trion antibody provides proof of principle that this technology works," said Tariq Ghayur, senior principle scientist at Abbott Laboratories, in Worcester, MA, at a conference in Boston organized by the Massachusetts Biotechnology Council on Wednesday. "I think in the next few years, we'll see lots of advances in this area."

Herceptin, an antibody used to treat some types of breast and other cancers, has been one of the earliest successful examples of targeted cancer treatment. Given primarily to women whose cancers overexpress a receptor called HER2, the antibody binds to the receptor, encouraging the immune system to attack the cell.
Newer bispecific antibodies also target HER2, but in a different way. Merrimack Pharmaceuticals, a startup in Cambridge, MA, has developed a candidate bispecific antibody called M-111. One arm binds to the HER2 receptor, and the other binds to a related receptor called HERB3. Binding both prevents the two receptors from coming together and activating a signaling pathway important for cell survival. The drug is now in early-stage clinical trials for cancers that overexpress HER2.

One of the problems with herceptin is that tumors can evolve resistance to the drug, an issue that bispecific antibodies may avoid. "Cancers often escape targeted treatments by either down-regulating the target or mutating it," says Barbas. "The chance of escaping a drug that can hit cancer at multiple sites is much lower because the cancer can't mutate two receptors at once."

While M-111 has the same target as Herceptin, it acts differently, using HER2 only as a marker for cancer cells rather than as the target for drug-induced activity. Ulrik Nielsen, chief scientific officer at Merrimack, says that because the antibody works through different mechanisms, M-111 could be delivered along with Herceptin. In fact, he says, it may prove effective in killing cancer cells that have become resistant to Herceptin.

Another bispecific antibody now in clinical testing by Pfizer takes a similar approach. It binds to two molecules that encourage the growth of the blood vessels that feed tumors: VEGF, a protein targeted by the popular drug Avastin, and ANG-2. If the tumor evolves resistance to one, the drug can still target the other.
Combining the action of two antibodies could also prove much cheaper for pharmaceutical companies and patients. Testing two experimental drugs separately and then in combination is prohibitively expensive. And the drugs already on the market are extremely costly. "Combinations of monofunctional drugs will be unaffordable--treatment with herceptin and avastin can cost upwards of $200,000," says Barbas, whose research led to the development of the Pfizer antibody now in clinical testing. "We need to wrap them into a single protein package that can be manufactured and delivered to patients with the cost of a single antibody."

By Emily Singer 
From Technology Review


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