Sneaking Antibodies Into The Brain

One reason scientists have had a hard time developing treatments for neurodegenerative diseases such as Alzheimer’s is that it’s tough smuggling compounds into the brain. The brain’s security fence—known as the blood-brain barrier—is especially impenetrable to large molecules such as antibodies. To improve antibodies’ ability to pass through, a research team at biotech firm Genentech has targeted the transferrin receptor, a protein that dots the blood-brain barrier at high concentrations and normally helps transport iron into the brain. The researchers designed a bispecific antibody to take advantage of this machinery: One of its arms binds loosely to the transferrin receptor, and the other binds tightly to β-secretase, an enzyme often targeted by potential Alzheimer’s treatments. With the transferrin arm, “you don’t want to bind too tight,” says Ryan J. Watts, team leader and neuroscience director at Genentech. If the interaction is too strong, he adds, the receptor may transport the antibody across the blood-brain barrier but not let go. When the researchers administered the antibody to monkeys, they saw a 10- to 20-fold increase in brain uptake compared with a control antibody (Sci. Transl. Med. 2014, DOI: 10.1126/scitranslmed.3009835). In the past, the team has tested a similar antibody in mice, but this is the first time they applied the therapeutic strategy to primates.