In the epic struggle to treat afflictions of the brain, antibodies may be the Trojan horse to sneak promising drugs past the super-selective blood-brain barrier.
Eric Shusta, assistant professor of chemical and biological engineering at the University of Wisconsin, spoke last week in front of the American Chemical Society.
He discussed his latest research in identifying antibodies that may work as stealthy delivery trucks carrying cargo of therapeutic agents that might otherwise never make it to the brain.
"They're really good at seeking out invaders, meaning they're good at specifically recognizing things to target," Shusta said. "In this case, it would be seeking out these nutrient transport systems."
Lining the blood vessels that lead to the brain are the endothelial cells that compose the blood-brain barrier, or BBB. These cells decide what substances will enter the brain, and most do not make the cut.
Among those rejected are 98 percent of medications that, in the petri dish, seem likely to help treat neurological disorders such as Parkinson's or Alzheimer's diseases, but are too large to undergo endocytosis, the process by which cells take in nutrients.
However, in the past decade, scientists have been exploring the possibility of using genetically engineered antibodies to deliver drugs to certain nutrient transport sites in the BBB. Antibodies show potential for this task because of their skills at hunting pathogens in the immune system.
Although using antibodies in this way is not a new idea, Shusta and his graduate student, Xin Xiang Wang, have developed a method for filtering through billions of antibodies to the handful that will actually cause endocytosis in the endothelial cells by creating an "in vitro immune system."
First, genetically engineered yeast is used to mass produce human antibodies isolated from a blood sample. Then the antibodies are dyed so they can be observed interacting with the BBB. When the right antibody does cause endocytosis, the dye can be seen entering the cell and can be visualized as it is preparing to enter the blood stream.
"That's what this whole research is about; the ability to look through a billion [antibodies] and find the needle in the haystack," Shusta said. "If we don't, this drug cargo could circulate a long time and never get enough material into the brain to do anything."
Using antibodies is not the only strategy for getting drugs into the brain. Another is using a catheter to deliver drugs directly into the brain.
Clive Svendsen, UW professor of anatomy and neurology, said he conducted such a clinical trial while working on his Ph. D. at the University of Cambridge. The use of catheters bypasses the BBB entirely, but antibodies would not require an invasive procedure on the brain.
"[Shusta's] method is far more elegant because it doesn't involve surgery," Svendsen said. "Any time you remove neurosurgery from [the] process, you're doing well."
Svendsen is now researching the possibility of genetically engineering stem cells to release drugs directly into the brain, avoiding the blood stream entirely. In the future, treatment of neurological disorders such as brain tumors may incorporate all of these techniques.
"There isn't any one therapy," Svendsen said. "You might try radiotherapy, you might try injecting drugs into the brain, you might try stem cells, but really they're really all attacking the tumor from different directions."
Given more research, antibodies may join that list once properly engineered and tested to carry pharmaceuticals.
"The caution here is that we're really excited about the things that we've found," Shusta said. "But we're still in the early stages."
