Crossing The Brain’s Berlin Wall
Designer antibody allows Alzheimer’s therapy to cross the blood-brain barrier
We have known about antibodies since 1890, and yet scientists are still discovering new uses for them today. From their innate function in the immune system, to possible therapies in neurological diseases, and recently even opening up the blood brain barrier, antibodies are at the forefront of modern medicine.
I had the opportunity to work with one very promising antibody that broke up beta amyloid (Aβ) plaques in APP transgenic mice (mice with Alzheimer’s disease). These plaques are thought to contribute to neuronal cell death, leading to the many symptoms associated with Alzheimer’s. Breaking up these plaques is an exciting step in the right direction, however we were left with cells full of fragmented plaques. The cells were still unable to take out the trash. According to some theories, this could be even more deadly than having the larger plaques.
The other downside was that this antibody could not cross the discriminating blood-brain barrier. The only way to administer it was straight into the brain. Not so hard in a mouse, but not ideal for people.
Recently though, I came across an article about a new Alzheimer’s antibody by Roche. This Swiss army-knife of an antibody not only seems to be effective in breaking up and clearing Aβ plaques from cells, but also crosses the blood-brain barrier.
The first trick up this antibody’s sleeve is its design. Roche scientists started with a monoclonal anti-Aβ (mAβ31), or an antibody that seeks out Aβ proteins to bind to, and tweaked it a little bit. At the bottom of the Fc region, they added another Fab fragment (a region of the antibody that binds antigens) that binds to the transferrin receptor (TfR). This receptor acts like a gate-keeper in the blood brain barrier. If a molecule has the right key, it can cross.
The double Fab structure (middle image) was able to cross into the brain but was quickly destroyed by lysosomes before it could bind Aβ. The single Fab structure (right image) though did not. Instead it was taken into the cell and was able to bind Aβ before being recycled to the cell surface.
So, theoretically, the journey inside the cell for sFab would look something like this: the antibody is injected and travels through the body. Eventually it gets shuttled up towards the brain where it binds to TfR, which allows it to enter the brain. From there, the other end of the antibody (the anti-Aβ region) seeks out and binds to the Aβ plaques in the brain. The whole complex (antibody and Aβ) then gets recycled out of the cell, possibly solving the problem of plaque clearance.
This is great news, not only for Alzheimer’s but potentially for Huntington’s, Parkinson’s, and a host of other diseases as well. Fingers crossed that this research continues to progress.
Jens Niewoehner et al. Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle. Neuron, Jan 2014. http://www.cell.com/neuron/abstract/S0896-6273%2813%2901035-0
