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 MM-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 MM-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.”