Roche researchers develop antibody that crosses the blood-brain barrier more efficiently
New technology may spur development of therapies for diseases of the central nervous system
Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today two research publications from its Early Development unit gRED outlining how a new technology successfully facilitated transport of an anti-amyloidogenic antibody across the blood-brain barrier and release into the brain. This technology may increase the potential to utilize antibodies in the therapy of brain diseases such as Alzheimer’s disease.
The work is detailed in a pair of papers published in a recent issue of Science Translational Medicine.
In the first paper1, Jasi Atwal, senior research associate at Genentech, and colleagues tested an antibody to a protein called beta-secretase 1 (BACE1), which plays a role in amyloid production associated with Alzheimer's disease in the brain. An antibody approach to inhibiting BACE1 would generally not be considered, as antibodies are thought not to enter the brain due to the blood-brain barrier. As a result, scientists have typically focused on targeting BACE1 primarily with small molecules. A large molecule antibody drug is 300-400 times bigger than a small molecule. Therefore, although the anti-BACE1 antibody was effective at blocking BACE1 function in test tubes, it was only modestly successful in reducing the function of BACE1 in the brain even when given at high doses.
"The brain is the most protected organ in the human body," said Ryan Watts, associate director and head of the Neurodegeneration Labs at Genentech. "The blood-brain barrier serves as a fortress that excludes intruders, allowing only the molecules that the brain needs to function to be selectively transported into the brain."
The interdisciplinary team of scientists from the Neuroscience, Antibody Engineering, and Development Sciences Departments accomplished transport across the blood-brain barrier by designing an antibody that uses a physiological process called receptor-mediated transcytosis. Receptor-mediated transcytosis selectively transports particular proteins the brain needs across the blood-brain barrier. The scientists engineered an antibody that binds to the transferrin receptor, a protein carrier that transports the nutrient iron into the brain.
"The receptor-mediated transcytosis pathway was identified over 20 years ago as a potential way to get antibodies across the blood-brain barrier into the brain," Ryan said. "But everyone had the same problem: Once the antibodies got onto the transferrin receptor, they got stuck and wouldn't get off in the brain."
The second paper2 describes how Joy Yu, Yin Zhang and colleagues solved this problem. The team re-engineered the antibody to bind less tightly to transferrin receptor, thus helping the antibody to dissociate from the blood-brain barrier to enter the brain. A bispecific molecule was created using the two arms of the Y-shaped antibody to combine both the delivery and the therapeutic properties. One arm binds to the transferrin receptor to support transport of the antibody across the blood-brain barrier, albeit with low affinity - so the antibody is released from the receptor into the brain. The other arm is designed to bind with high affinity to the enzyme beta-secretase (BACE1) to target Alzheimer's disease.
Compared to monospecific anti-BACE1 antibody, the bispecific antibody enriched in the mouse brain and led to a greater reduction of amyloid-beta in the brain after a single systemic dose. Receptor-mediated transcytosis of this bispecific antibody through the blood-brain barrier may enhance its potency as an anti-BACE1 therapy for treating Alzheimer’s disease.
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