Researchers used to call it the “magic bullet,” a drug that would seek out cancer cells and destroy them while leaving healthy tissue alone. It’s taking much longer to find that bullet than scientists first hoped, but they’re getting closer.
For one, researchers have successfully engineered antibodies that target the workings behind cancer, as well as other diseases. These drugs home in on diseased cells much more specifically than chemotherapy and radiation do — but they still can cause side effects that interfere with treatment.
|John C. Williams|
Now, City of Hope researchers and colleagues have taken a step forward. They’ve developed a strategy to make these monoclonal antibodies even more effective while lessening their uncomfortable effects.
Some monoclonal antibodies, like Erbitux, work by blocking activity of a protein called epidermal growth factor receptor, or EGFR. This protein is key to tumor cells’ survival. But normal, noncancerous cells also use EGFR, making them vulnerable to the drugs’ effects.
The research team, which included John C. Williams, Ph.D., assistant professor in molecular medicine and director of the X-ray Crystallography Core at City of Hope, began looking at how to keep Erbitux from hurting healthy cells. If they succeed, that might mean fewer skin rashes and less debilitating stomach and intestinal upset for cancer patients. But the researchers also realized their efforts might have another bonus.
They might be able to concentrate the therapy directly on tumors, making it more effective, too.
Williams and the research team designed a molecule that would become active around tumors, but not healthy cells. The molecule is made up of two EGFR-blocking monoclonal antibodies, matuzumab and Erbitux, linked by a chemical chain. That chain can be broken by an enzyme that is very active in tumors.
When linked by the chain, the monoclonal antibodies resist their natural attraction to bind to EGFR. But when the cancer-related enzymes break the link between the antibodies, the antibodies become active once again and block the protein.
“We designed a product that is inactive around healthy tissue in its ‘masked’ state and is only activated at the tumor site into an ‘unmasked’ state by the action of enzymes overproduced by cancer cells,” said Williams. “The design has potential to improve the targeted release of therapeutic antibodies at disease sites, sparing healthy tissue and possibly lessening any side effects.”
The researchers are continuing their work with the matuzumab-Erbitux molecule, and they also hope to apply the same principle to other monoclonal antibodies, as well.
Monoclonal antibodies 101
Antibodies are immune system proteins produced by certain white blood cells. They circulate in the blood and attach to foreign molecules, such as those found on the surface of invading bacteria or viruses, directing the immune system to destroy the invaders.
Monoclonal antibodies are antibodies created in a lab. They can locate and bind to specific molecules such as those found on cancer cells.
City of Hope scientists pioneered the technology that has led to many monoclonal antibody-based therapies, including Erbitux, Herceptin, Rituxan and Avastin.