Scientists have defied the daunting, impenetrable BLOOD-BRAIN BARRIER…
Drug molecules destined for the brain are often thwarted by tightly-packed cells that safeguard the brain from suspect microbes and chemicals.
Traditionally, antibodies are proteins used by the immune system to neutralize damaging foreign substances with sharpshooting specificity.
This new engineered antibody blocks an enzyme required for producing the small proteins that aggregate in brains and lead to the neurodegeneration and memory loss seen in Alzheimer’s patients.
These proteins are called amyloid-β peptides, and the enzyme is called β-secretase 1 (BACE1).
1. So his team tweaked the antibody, making it bind to a receptor at barrier. ScienceNOW explains:
It took advantage of the brain’s own mechanism for getting a necessary nutrient, iron, across the lining of endothelial cells that form the blood-brain barrier. Iron in the bloodstream is bound to a bulky molecule called transferrin. The endothelial cells have a receptor for transferrin that acts like a gatekeeper: When transferrin binds to a receptor on the blood side of the barrier, the endothelial cell transports it (and its iron cargo) to the other side and spits it out into the brain.
Antibodies that are attracted to the receptor get into the brain using a transport system that works like a ski lift – except these ‘high affinity’ antibodies hop on the lift and never get off, Watts says. Those molecules become trapped in blood vessels and never reach the brain.
So, the team engineered antibodies with ‘low affinity’ for binding to transferrin. These jump off the lift, slip past the blood-brain barrier, and according to Watts, they're widely distributed.
2. Next, the team made a ‘bispecific’ antibody that binds to (1) the transferrin receptor and (2) the popular Alzheimer’s target, BACE1. By clinging to the receptor, the antibody is transported into the brain, where it can act against BACE1.
3. They injected this intravenously into mice.
This two-armed bispecific antibody (pictured here in 3D) was effective at boosting uptake into the brain and then reducing the levels of amyloid peptides in the brains of mice.
Without the transferrin-binding arm, small amounts of the BACE1 antibody made it to the brain. About 10 times as much of the version with the transferrin-binding arm got in, Watts says.
Image: Genentech, Inc.