Antibody Mind Tricks: how to smuggle drugs into your brain

Scientists have designed a two-armed antibody that can cross the mostly impenetrable blood-brain barrier to deliver drugs against Alzheimer's (in mice, for now).

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.

A new antibody that can cross this blood-brain barrier could deliver drugs into the brain to fight diseases like Alzheimer’s, Parkinson’s, and schizophrenia.

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).

Until now, less than 0.1% of antibody-based drugs make it across the barrier, estimates study researcher Ryan Watts of Genentech. “We had to dose like crazy, frequently and at high levels,” he adds.

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.

The antibody treatment reduced levels of amyloid-β by up to half. "Before, the brain was considered off limits," says study coauthor, Genentech's Mark Dennis.

The research was published as a pair of papers in Science Translational Medicine yesterday.

Image: Genentech, Inc.

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